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Over 12,000 home health agencies served buy symbicort online with free samples 5 million disabled and older Americans in 2018. Home health aides help their clients with the tasks of daily living, like eating and showering, as well as with clinical tasks, like taking blood pressure and leading physical therapy exercises. Medicare relies on home health care services because they help patients discharged from the hospital and skilled nursing facilities recover buy symbicort online with free samples but at a much lower cost.

Together, Medicare and Medicaid make up 76% of all home health spending.Home health care workers serve a particularly important role in rural areas. As rural areas lose buy symbicort online with free samples physicians and hospitals, home health agencies often replace primary care providers. The average age of residents living in rural counties is seven years older than in urban counties, and this gap is growing.

The need for home health agencies serving the elderly in rural areas will continue to grow over the coming decades.Rural home health agencies face unique challenges. Low concentrations of people are dispersed over large geographic areas buy symbicort online with free samples leading to long travel times for workers to drive to clients’ homes. Agencies in rural areas also have difficulties recruiting and maintaining a workforce.

Due to these difficulties, agencies may not be able to serve all rural beneficiaries, initiate care on time, or deliver all covered services.Congress has supported measures to buy symbicort online with free samples encourage home health agencies to work in rural areas since the 1980s by using rural add-on payments. A rural add-on is a percentage increase on top of per visit and episode-of-care payments. When a home health aide buy symbicort online with free samples works in a rural county, Medicare pays their home health agency a standard fee plus a rural add-on.

With a 5% add-on, Medicare would pay $67.78 for an aide home visit in a city and $71.17 for the same care in a rural area.Home health care workers serve a particularly important role in rural areas. As rural areas lose physicians and hospitals, home health agencies often replace primary care providers.Rural add-on payments have fluctuated based on Congressional budgets and political priorities. From 2003 to 2019, the amount Medicare buy symbicort online with free samples paid agencies changed eight times.

For instance, the add-on dropped from 10% to nothing in April 2003. Then, in April 2004, Congress set the rural add-on to 5%.The variation in payments created a natural buy symbicort online with free samples experiment for researchers. Tracy Mroz and colleagues assessed how rural add-ons affected the supply of home health agencies in rural areas.

They asked if the number of agencies in urban and rural counties varied depending on the presence and dollar amount of rural add-ons between 2002 and 2018. Though rural add-ons have been in place for over 30 buy symbicort online with free samples years, researchers had not previously investigated their effect on the availability of home healthcare.The researchers found that rural areas adjacent to urban areas were not affected by rural add-ons. They had similar supply to urban areas whether or not add-ons were in place.

In contrast, buy symbicort online with free samples isolated rural areas were affected substantially by add-ons. Without add-ons, the number of agencies in isolated rural areas lagged behind those in urban areas. When the add-ons were at least 5%, the availability of home health in isolated rural areas was comparable to urban areas.In 2020, Congress implemented a system of payment reform that reimburses home health agencies buy symbicort online with free samples in rural counties by population density and home health use.

Under the new system, counties with low population densities and low home health use will receive the greatest rural add-on payments. These payments aim to increase and maintain the availability of care in the most vulnerable rural home health markets. Time will tell if this approach gives sufficient incentive to ensure access to quality care in the nation’s buy symbicort online with free samples most isolated areas.Photo via Getty ImagesStart Preamble Correction In proposed rule document 2020-13792 beginning on page 39408 in the issue of Tuesday, June 30, 2020, make the following correction.

On page 39408, in the first column, in the DATES section, “August 31, 2020” should read “August 24, 2020”. End Preamble buy symbicort online with free samples [FR Doc. C1-2020-13792 Filed 7-17-20.

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Highlights and updates South Carolina exchange overviewSouth Carolina is among the states that have done the least to preserve the Affordable Care Act’s gains.South Carolina uses the federally run health insurance exchange, so residents enroll through HealthCare.gov.Open enrollment for 2021 health plans will begin symbicort thrush November 1, 2020, and will continue through December 15, 2020. Before open enrollment, South Carolina residents with qualifying events can still enroll or make changes to their coverage for 2020.(in previous years, Blue Cross Blue Shield of South Carolina’s BlueChoice affiliate has allowed people to purchase plans outside the exchange symbicort thrush until the end of December, so for a couple of weeks after open enrollment ends. It’s unclear whether they’ll continue to do this in future years.

Financial assistance is not available outside the exchange).Blue symbicort thrush Cross Blue Shield of South Carolina was the only insurer offering plans in the exchange in 2018, but Ambetter (Absolute Total Care) joined the exchange in Charleston County for 2019. And for 2020, Molina and Bright Health joined the exchange, bringing the total number of insurers to four. All four will continue to offer plans in the exchange for 2021, and average premiums are decreasing.Average rate decrease of about 1.5% for 2021Across the four insurers that offer individual market plans in the South Carolina exchange, the average approved rate change for 2021 is symbicort thrush a decrease of 1.48 percent.

The insurers will implement the following average pre-subsidy rate changes:Blue Cross Blue Shield of South Carolina. Average rate decrease of 1.85% (BCBSSC has the symbicort thrush vast majority of the state’s enrollment in ACA-compliant individual market plans, with roughly 197,000 members, according to SERFF filingBCSC-132369618. BCBSSC had symbicort thrush initially proposed a smaller rate decrease of just 0.1 percent)Ambetter/Absolute Total Care.

Average rate increase of 8.5% (Ambetter had 7,348 members in 2020, according to SERFF filingCECO-132377401)Bright. Average rate decrease of 0.05% (Bright symbicort thrush had initially proposed an average rate decrease of 2.04 percent. Bright has 5,754 policyholders—member count is likely higher—according to SERFF filing BRHP-132335829)Molina.

Average rate decrease of 3.6% (Molina has 5,168 members in 2020, according to SERFF filing MHSC-132366286)BlueChoice, which only offers plans outside the exchange, will reduce average premiums by symbicort thrush 1.62 percent for 2021 (on the heels of an average rate decrease of more than 7 percent in 2020). BlueChoice has 3,890 policyholders as of 2020. Average premiums for existing insurers decreased for 2020, Molina and Bright joined the exchange, and Centene/Ambetter expanded coverage areaTwo insurers offered plans symbicort thrush in South Carolina’s exchange in 2019.

Blue Cross Blue Shield of South Carolina, which offered plans statewide, and Ambetter (Absolute Total Care), which offered plans in Charleston County (according to Ambetter’s 2020 rate filing — SERFF tracking number CECO-131968188 — Ambetter/Absolute Total Care had 862 members in 2019. So BCBSSC had symbicort thrush the bulk of the market share).But as of 2020, residents in many areas of the state had more options available. Bright Health now offers plans in three counties, Molina offers symbicort thrush plans in 20 counties, and Ambetter expanded its coverage area to include a total of 12 counties.According to ratereview.healthcare.gov, the state’s existing exchange insurers implemented the following average rate changes for 2020:Blue Cross Blue Shield of South Carolina.

3.28% rate decrease (BCBSSC has the vast majority of the state’s enrollment in ACA-compliant individual market plans, and had initially proposed a slight rate increase)Ambetter/Absolute Total Care. 2.28% decrease (Ambetter had just 862 members in 2019, according to SERFF filing CECO-131968188)BlueChoice, which only offers plans outside the exchange, implemented an average rate decrease of 7.28 symbicort thrush percent for 2020. Overall, across the state’s entire individual market, there was an average rate decrease of about 4 percent for 2020.Here’s a look at how average premiums have changed in South Carolina’s exchange over the years:2015.

Average rate increase symbicort thrush of 0.93 percent. Assurant joined the South Carolina exchange for 2015, bringing the total number of carriers in the exchange to five. Assurant joined symbicort thrush the four companies that were already offering health insurance through the federally-run marketplace in South Carolina.

Blue Choice Health Plan, Blue Cross Blue Shield of South Carolina, Consumers’ Choice Health Plan and Coventry Health Care of the Carolinas. (this page has more symbicort thrush information about the participating carriers). There were a total of 52 plans available in the state, although not all of them were available in all areas.The South Carolina Department of Insurance found symbicort thrush that the weighted average rate increase in the exchange was just 0.93 percent for 2015, and 0.95 percent for the entire individual market.

In South Carolina, some people who had the benchmark plan (second lowest-cost silver plan) in 2014 and who switched to the new benchmark plan for 2015 experienced rate decreases for 2015, particularly in the western portion of the state. In the Greenville area, the benchmark plan as well as the lowest-cost symbicort thrush bronze and silver plans were all being offered by a different carrier in 2015 compared with 2014. And this was the case in much of the rest of the state as well.2016.

Average approved rate increase of 15.9 percent (but it ended up being lower after symbicort thrush Consumer’s Choice CO-OP exited the market, as their approved rate increase had been 22 percent). In early October 2015, South Carolina regulators released approved rate changes for 2016. The weighted average rate increase at that point was about 15.9 percent (slightly lower in the exchange, slightly higher symbicort thrush when off-exchange plans are included).In the exchange, the highest rate increases were for Coventry (Aetna) and Consumer’s Choice.

Since Consumers Choice ultimately ended up not offering plans for 2016, the overall weighted average rate increase ended up being lower than it would otherwise have been.Plans in the exchange ended up being available from Coventry/Aetna (in 15 counties), BlueChoice (statewide), BlueCross BlueShield of South Carolina (statewide), and UnitedHealthcare (in five counties. New to the exchange for symbicort thrush 2016). Time Insurance, which offered on-exchange plans in South Carolina in 2015, symbicort thrush initially requested the steepest rate hike (53 percent), but their parent company, Assurant, subsequently announced that they would exit the individual market nationwide.

Time products are no longer for sale in any state.2017. Average rate symbicort thrush increase of 27.8 percent. Coventry (Aetna), BlueChoice (a subsidiary of BCBSSC), and UnitedHealthcare all exited the South Carolina exchange at the end of 2016 (UnitedHealthcare exited the entire individual market in the state, as they did in several other states).

Coventry had symbicort thrush offered plans in 15 of the state’s 46 counties, and had 8,000 enrollees in 2016. United Healthcare had offered plans in just five counties in 2016. BlueChoice and Blue Cross symbicort thrush Blue Shield offered plans statewide in 2016.In South Carolina, the state guaranty fund had to pay $48 million in outstanding claims for Consumers Choice CO-OP members when the CO-OP ceased operations at the end of 2015 (details below).

This was symbicort thrush a larger outlay than the state had expected. Health insurance carriers contribute to the guarantee fund, and they were allowed to incorporate those fees into their premiums for 2016.2018. Average rate increase of symbicort thrush 31.33 percent.

Blue Cross Blue Shield of South Carolina was the only insurer offering plans in the exchange for 2018, as was the case in 2017. The average approved rate increase for 2018 was symbicort thrush 31.33 percent. But nearly three-quarters of the total average rate increase was due to the fact that the federal government stopped longer funding cost-sharing reductions (CSR) in the fall of 2017.The cost of CSR was added to on-exchange silver plans in South Carolina.

BCBSSC’s rate filing indicated that they are offering separate off-exchange-only silver plans that don’t have the cost symbicort thrush of CSR added to the premiums, and all of their non-silver plans (on and off-exchange) are also being sold without the cost of CSR added to the premiums.2019. Average rate increase of 5.26 percent. This was for Blue Cross Blue Shield of South Carolina, which had been the only symbicort thrush insurer in the exchange in 2018.

But Ambetter/Absolute Total Care also joined the exchange in symbicort thrush Charleston County as of 2019. BCBSSC had 203,000 enrollees in the individual market in 2018, and initially proposed an average rate increase of 9.3 percent. In their filing documents, the first two justifications for the higher rates were the impending elimination of the individual mandate penalty, and the fact that symbicort thrush short-term health plans and association health plans were being expanded, both of which were expected to “likely siphon better risks from the ACA market.”In SERFF, it notes that the filing for BCBSSC was “approved as amended.” So although the details of the amended filing (dated August 20) were redacted, presumably BCBSSC updated their filing with a 5.26 percent rate increase, instead of the filing they initially submitted.

At ACA Signups, Charles Gaba calculates that rates would have decreased by an average of 5.8 percent if the individual mandate hadn’t been eliminated and if short-term plans hadn’t been expanded. 2020 enrollment symbicort thrush. Slight decrease from 2019, down almost 8% since 2016214,030 people enrolled in plans through South Carolina’s exchange during the open enrollment period for 2020 coverage, which was just slightly lower than enrollment had been the year before.Here’s a look at how enrollment has changed over the years in South Carolina’s exchange:2014.

118,324 people symbicort thrush enrolled2015. 210,331 people enrolled2016. 231,849 people enrolled symbicort thrush (peak enrollment.

This fits the same trend that applies symbicort thrush to most state that use HealthCare.gov, with peak enrollment happening in 2016 and a gradual decline since then).2017. 230,211 people enrolled (South Carolina’s enrollment decline, at only 0.7 percent, was smaller than the average decline of about 5 percent across all states that use HealthCare.gov)2018. 215,983 people symbicort thrush enrolled2019.

214,956 people enrolled2020. 214,030 people enrolled South Carolina’s CSR approach protects most enrollees, makes non-silver plans particularly appealingAdding the cost of CSR to on-exchange silver plans while also making off-exchange silver plans available without the symbicort thrush cost of CSR added to the premiums is the approach that protects the greatest number of consumers. People who get premium subsidies receive larger subsidies than usual, and people who don’t get premium subsidies have multiple options for plans that don’t have the cost of CSR added to their premiums.With the cost of CSR added to premiums for silver plans, premium subsidies are larger than they would otherwise be, since the subsidies are based on the cost of the second-lowest-cost silver plan, and grow to keep pace with the increase in silver plan premiums.

Due to the larger premium subsidies, bronze plans became very inexpensive starting in 2018, and gold plans are also comparatively less expensive than they were in prior years.People who aren’t eligible for premium subsidies can purchase plans at other metal levels, or an off-exchange silver plan (people ineligible for a premium subsidy includes those impacted by the Medicaid coverage gap or the family glitch, as well as anyone earning above 400 percent of the poverty level).So although the bulk of the overall rate increase in South Carolina in 2018 was due to the elimination of federal funding for CSR, the symbicort thrush only people who had to bear that cost themselves were on-exchange silver plan enrollees who don’t get premium subsidies, and who chose to keep their silver plan for 2018 instead of switching to an off-exchange plan or switching to a plan at a different metal level.Despite the fact that the Trump Administration cut off funding for CSR, the benefits of CSR are still available to all eligible enrollees. If your income is between 100 percent and 250 percent of the poverty level and you select a silver plan in the South Carolina exchange, your coverage includes cost-sharing reductions that lower your out-of-pocket costs. The benefits are strongest for those with income below 200 percent of the poverty symbicort thrush level.With the elimination of federal funding for CSR, all that has changed is that the cost of CSR is now being added to premiums, rather than funded directly by the federal government.

And because the cost has been added to silver plan premiums in most states (including South Carolina), the added premiums are mostly covered by the federal government anyway, in the form of larger premium subsidies for all enrollees who qualify for premium subsidies.It’s symbicort thrush noteworthy that Blue Choice Health Plan — which only sells off-exchange plans, and thus doen’t have to add the cost of CSR to premiums, since CSR isn’t available outside the exchange — had an average rate increase of just 10 percent for 2018, while BCBSSC’s average rate increase was more than 31 percent. Judging from the rate filing that BCBSSC submitted, their average rate increase for 2018 would also have been around 10 percent if the federal government had continued to fund CSR.Consumers Choice CO-OP closed at the end of 2015On October 22, 2015 The South Carolina Department of Insurance announced that Consumers Choice – an ACA-created CO-OP – would wind down its operations by year-end, and would not participate in the 2016 open enrollment period that began November 1. Consumers Choice was the ninth CO-OP symbicort thrush to fail, and the fifth in October alone.The significant shortfall in risk corridors payments was blamed for the CO-OP’s demise, as was the case for all of the CO-OPs that failed since the beginning of October.

HHS announced on October 1 that carriers would get just 12.6 percent of the 2014 risk corridors payments that they were owed, leaving many smaller carriers well into the red. One of the other four CO-OPs that closed as a result of the risk corridor shortfall – Community Health Alliance symbicort thrush in Tennessee – was also run by Consumers Choice CEO Jerry Burgess.67,000 Consumers Choice members had to secure new coverage for 2016. The Department of Insurance put together a series of FAQs for impacted plan members.

One concern for patients with chronic conditions was the network coverage of the remaining health insurers symbicort thrush. None of them included the Medical University of South Carolina in their networks, despite the fact that MUSC is the only place where some patients are able to access specialists for their conditions. MUSC eventually accepted an offer from Blue Cross Blue Shield of South Carolina to cover specialty care for patients who had previously been insured with Consumers Choice, but the agreement had not yet symbicort thrush been finalized as of December 29 – just three days before the CO-OP members were to be transitioned to their new plans.No Medicaid expansionUS Rep.

James Clyburn (D – SC) views the ACA as the “Civil Rights Act of the 21st century” and has long called on South Carolina to embrace the law (including Medicaid expansion, which SC lawmakers have thus far resisted) and all that it can offer to the state and its symbicort thrush residents.In his article, Rep. Clyburn noted that SC ranks 43rd in the US in terms of overall health, and points out the myriad ways that the ACA can help to improve residents’ health.And on the 2016 presidential campaign trail, Ohio Governor John Kasich, a contender for the GOP nomination, called on South Carolina to accept federal funding to expand Medicaid.In large part because of the state’s failure to expand Medicaid, the uninsured rate in South Carolina is still higher than the national average. According to US Census data, the uninsured symbicort thrush rate was still 10.5 percent in 2018 in South Carolina.

That was down from 15.8 percent in 2013, but it was still significantly higher than the 8.9 percent national average as of 2018.And hospitals in South Carolina, particularly in rural areas of the state, are facing closure as a result of a lack of funding — a problem that hospital administrators believe could be addressed by accepting federal funding to expand Medicaid.Although South Carolina has made no progress so far in terms of expanding Medicaid eligibility, there is one small sliver of good news in the South Carolina Medicaid program. Starting in December symbicort thrush 2014, adults covered by Medicaid in South Carolina gained coverage for preventive dental coverage, fillings, and extractions with up to $750 in services available for each member per year. Grandmothered plansSouth Carolina was quick to accept President Obama’s policy cancellation compromise that allowed carriers to extend existing plans that had been scheduled to terminate at the end of 2013.

And when HHS extended that proposal in early 2014, South Carolina was once again among the majority of states that opted to allow symbicort thrush grandmothered plans to renew into 2015.These plans, described as grandmothered or transitional, are allowed to remain in force until the end of 2021, under the terms of the latest federal extension, issued in 2020. South Carolina has agreed to allow carriers to keep grandmothered plans in force until the end of 2021, at the carriers’ discretion.It has been left up to each carrier to determine whether they wanted to allow their pre-2014 plans to continue to be eligible for renewal. This gives many people — who had symbicort thrush individual coverage prior to 2014 — another alternative to compare with the options available in the exchange, but some critics contend that it keeps healthy people out of the new ACA-compliant insurance pools.OutreachThree federally funded groups launched training programs and outreach campaigns in 2013 to help consumers understand their options.

DECO Recovery Management, Cooperative Ministry, and the Beaufort County Black Chamber of Commerce all received grants to hire “navigators.” Navigators provide unbiased information about the options available through the marketplace and help consumers through the enrollment process, but cannot be directly or indirectly paid by insurance companies.South Carolina was among the states that received the least amount of federal funding symbicort thrush in the initial planning grants — the state got $1 million. This is a thousand times less than the $1 billion that California received (and several other states got hundreds of millions), but was predicated on the state’s refusal to promote the ACA – the money wouldn’t have been utilized by the South Carolina government.Prior to the 2016 open enrollment period, two navigator organizations in South Carolina received federal grant funding. The Beaufort County Black Chamber of Commerce symbicort thrush ($456,102) and the Palmetto Project ($1,123,916).Navigator funding was sharply reduced by the Trump Administration in 2017 and again in 2018.

Heading into the open enrollment period for 2019 coverage (in the fall of 2018), only one organization — DECO Recovery Management — received navigator funding in South Carolina, totaling $300,000. The same organizations also received $300,000 in 2019, prior to the start symbicort thrush of the open enrollment period for 2020 coverage.South Carolina health insurance exchange linksState Exchange Profile. South CarolinaThe Henry J.

Kaiser Family Foundation overview of South Carolina’s progress toward creating a state health insurance exchange.South Carolina Consumer Assistance ProgramAssists people insured by private health plans, Medicaid, or other plans in resolving problems pertaining symbicort thrush to their health coverage. Assists uninsured residents with access to care.(800) 768-3467 /consumers@doi.sc.govLouise Norris symbicort thrush is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org.

Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts.Key takeaways Medicaid expansion in West Virginia Federalpoverty levelcalculator 0.0% of Federal Poverty Level symbicort thrush West Virginia’s leaders opted to expand Medicaid under the Affordable Care Act (ACA) starting on January 1, 2014, providing coverage to low-income adults, most of whom have jobs but no option for employer-sponsored health insurance. The federal government paid the full cost for the expansion population for the first three years, but gradually reduced the funding split until reaching a 90/10 split in 2020, which will remain fixed in future years.Under the expanded eligibility guidelines, adults age 19-64 are eligible for Medicaid with a household income up to 138 percent of the poverty level. Medicaid expansion symbicort thrush significantly exceeded the 93,000 people that West Virginia had initially projected to enroll by 2020 under the expanded eligibility guidelines, but enrollment has declined after peaking in 2016.

The total number of people enrolled under expanded Medicaid declined slightly by January 2017, to 174,026, and declined further, to 165,917, by March 2018. More than symbicort thrush 161,500 people enrolled under Medicaid expansion in West Virginia as of June 2019.CMS reporting shows that West Virginia’s overall Medicaid population (meaning individuals eligible and enrolled under pre-ACA eligibility requirements plus those eligible and enrolled under the ACA’s expansion criteria) the is up 47 percent between 2013 (pre-ACA) and June 202o. Given the 202o coronavirus outbreak and reporting lags, it is possible that the expansion population has grown since the June 2019 data cited in the previous paragraph.CHIP coverage for pregnant women as of 2019SB564 was signed into law in West Virginia in 2019.

The legislation called for CHIP symbicort thrush coverage in West Virginia to be expanded to include pregnant women. CHIP eligibility for kids in West Virginia already extended to households with income up to symbicort thrush 300 percent of the poverty level, and that’s the same level that now applies to pregnant women as well. The new CHIP coverage for pregnant women took effect on July 1, 2019 in West Virginia.Only five other states (Colorado, Missouri, New Jersey, Rhode Island, and Virginia) provide CHIP coverage to pregnant women, but there are numerous states with fairly high income limits for pregnant women to qualify for Medicaid (for example, Medicaid coverage is available to pregnant women in Iowa with household income as high as 375 percent of the poverty level.

In DC, it’s 318 percent)West Virginia has considered a Medicaid work requirement but has not yet created oneAs of late 2017, West Virginia’s Department of Health and Human Resources was considering the possibility of seeking a waiver from symbicort thrush the federal government in order to implement a work requirement for the state’s Medicaid expansion population. But nothing has happened yet on that front. Legislation (HB3136) to create a work requirement was considered in the 2019 legislative session, but it did not advance to a vote.Although work requirements were a non-starter with the Obama Administration, the Trump Administration has approved symbicort thrush them in several states.

But a judge has blocked the work requirements in Kentucky, New Hampshire, and Arkansas. Officials in Indiana have suspended their Medicaid work requirement pending the outcome of a similar lawsuit, and Arizona has also suspended implementation of a new work requirement.Consumer advocates in West Virginia have criticized the possibility of a work requirement, noting that such programs tend to just make it harder for people to maintain their health coverage, due to documentation requirements, despite the fact that the majority of Medicaid expansion enrollees are already in symbicort thrush a household where at least one person is working.The state has already entered into a $300 million contract with Optum to verify eligibility for various need-based programs, including SNAP and Medicaid. If a work requirement were to be added to Medicaid, it would increase the reporting and verification measures necessary in order to confirm ongoing eligibility for Medicaid.Medicaid expansion helping to combat opioid crisisThe opioid crisis has hit West Virginia particularly hard, and the state has the nation’s highest drug overdose death rate.

But 22,000 people covered under expanded Medicaid had received treatment for mental health and substance abuse disorders symbicort thrush by early 2017. Without Medicaid expansion, most of those people would have been uninsured and unable to access treatment.Previous and current governor support Medicaid expansionWest Virginia’s symbicort thrush former Governor, Earl Ray Tomblin, was instrumental in West Virginia’s acceptance of Medicaid expansion but was term-limited and could not seek re-election in 2016.Governor Jim Justice took office in January 2017. He campaigned and was elected as a Democrat, but in the summer of 2017, during his first year in office, he switched to the Republican party.

Justice reiterated his support for Medicaid expansion in the weeks leading symbicort thrush up to his party switch, stating in late June 2017 that it would be “beyond catastrophic” if the people who had gained coverage under Medicaid expansion were to lose it. But Justice also vetoed a supplemental appropriation for the state’s Medicaid program in 2019, saying that the Medicaid program already had enough funding.Substantial impact on uninsured rateExpansion of Medicaid has played a primary role in West Virginia’s sharp reduction in the uninsured rate.West Virginia had the sixth highest drop in uninsured rate during the first half of 2014, due primarily to Medicaid expansion (as of July 2014, 132,556 people in West Virginia Medicaid, while 25,856 had enrolled in subsidized private coverage through the exchange).According to US Census data, the state’s uninsured rate was 14 percent in 2013, and had fallen to 5.3 percent by 2016. It had increased symbicort thrush to 6.4 percent by 2018, however, mirroring the nationwide trend of increasing uninsured rates under the Trump administration.West Virginia’s uninsured rate had been similar to the U.S.

Average (14.5 percent) in 2013, but the state’s uninsured rate in 2018 was well below that national average at that point, which was 8.9 percent.However amid the Covid-10 pandemic, the uninsured rates have climbed across the nation. As of June 2020, West Virginia’s uninsured rate increased to 12 percent.Who is eligible for Medicaid in West symbicort thrush Virginia?. West Virginia Medicaid is available for these legally present residents, in addition to the aged, blind, and disabled.Infants aged 0 to 1 in households with income up to 158 percent of the federal poverty level (FPL)Children aged 1-5 in households with income up to 141 percent of FPLChildren aged 6-18 in households with income up to 133 percent of FPLPregnant women with income up to 185 percent of povertyAdults with incomes up to 133 percent of povertyPregnant women and children in households with up to 300 percent of FPL qualify for CHIP in West Virginia.How do I enroll in Medicaid in West Virginia?.

You can apply for West Virginia Medicaid through the federally-run exchange by visiting HealthCare.gov or calling 1-800-318-2596 24 hours a day.Or you can apply through the state at www.wvinroads.org and that site can also provide SNAP and cash assistance programs for eligible residents.Medicaid enrollment is year-round — there is no specific time frame during which applications must be completed.West Virginia Medicaid enrollment numbersAs of mid-July 2014, there were 132,556 new Medicaid enrollees symbicort thrush who were all newly-eligible under the expanded guidelines. Although most of the newly-eligible population enrolled during the first year, the number of newly-eligible enrollees had grown to 164,400 symbicort thrush by June 2015, and to 178,394 by August 2016. But enrollment in expanded Medicaid declined slightly by the beginning of 2017, to 174,026, and declined further, to 153,874 by December 2018.

It has since stabilized, and stands at 156,775 symbicort thrush as of November 2019.In 2013, the Kaiser Family Foundation estimated that about 143,000 people in West Virginia would be newly-eligible for Medicaid as of 2014. But the state’s estimate had been much lower, with a projected expansion enrollment of 93,000 by 2020.Opponents of Medicaid expansion predicted that states with a surge in Medicaid enrollment would find that Medicaid patients were unable to get appointments for primary care, but West Virginia doctors weren’t indicating that was a problem when enrollment initially spiked. Instead, some of their challenges include a significant population of newly-insured people who are requesting pain medication at office visits, and patients who have previously been on free drug samples and need to be switched to another drug that’s covered by Medicaid.And despite the unexpectedly large enrollment in Medicaid expansion — combined with the fact that the state began paying a portion of the Medicaid expansion costs starting in 2017 — West Virginia’s Medicaid budget had a surplus as of early 2019.Uncompensated care costs decline sharplyAccording to data compiled by symbicort thrush West Virginians for Affordable Health Care, hospitals in West Virginia saw a 40 percent decline in uncompensated care costs from 2013 to 2014, thanks in large part to Medicaid expansion that resulted in far fewer uninsured residents in the state.But although the hospitals acknowledge that their uncompensated care and charity care costs have declined significantly, some also note that Medicaid reimbursements are less than the cost of providing care, and that their losses on Medicaid volume are offsetting the improvements they’ve seen in uncompensated care.West Virginia’s Medicaid expansion historyWest Virginia had initially considered setting up a state-run exchange, but later opted for a partnership exchange, citing cost as one of the reasons for avoiding a fully state-run exchange.State leaders have said that given the choice between a state-run exchange and Medicaid expansion, the latter seemed like it would provide more bang for the buck (and judging by the state’s extremely successful Medicaid enrollment in 2014, it would appear they were correct).In May 2013, then-Governor Earl Ray Tomblin announced that West Virginia would proceed with Medicaid expansion.

Enrollment for newly-eligible residents began on October 1, 2013, with coverage effective January 1, 2014.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care symbicort thrush Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

Highlights and updates South Carolina exchange overviewSouth Carolina is buy symbicort online with free samples among the states that have done the least to preserve the Affordable Care Act’s gains.South Carolina uses the federally run health insurance exchange, so residents enroll through HealthCare.gov.Open enrollment for 2021 health plans will begin November 1, 2020, and will continue through December 15, 2020. Before open enrollment, South Carolina residents with qualifying events can still enroll or buy symbicort online with free samples make changes to their coverage for 2020.(in previous years, Blue Cross Blue Shield of South Carolina’s BlueChoice affiliate has allowed people to purchase plans outside the exchange until the end of December, so for a couple of weeks after open enrollment ends. It’s unclear whether they’ll continue to do this in future years.

Financial assistance is not available outside the exchange).Blue Cross Blue Shield of South Carolina was the only insurer offering plans in the exchange in 2018, buy symbicort online with free samples but Ambetter (Absolute Total Care) joined the exchange in Charleston County for 2019. And for 2020, Molina and Bright Health joined the exchange, bringing the total number of insurers to four. All four will continue to offer plans in the exchange for 2021, and average premiums are decreasing.Average rate buy symbicort online with free samples decrease of about 1.5% for 2021Across the four insurers that offer individual market plans in the South Carolina exchange, the average approved rate change for 2021 is a decrease of 1.48 percent.

The insurers will implement the following average pre-subsidy rate changes:Blue Cross Blue Shield of South Carolina. Average rate decrease of 1.85% buy symbicort online with free samples (BCBSSC has the vast majority of the state’s enrollment in ACA-compliant individual market plans, with roughly 197,000 members, according to SERFF filingBCSC-132369618. BCBSSC had initially proposed buy symbicort online with free samples a smaller rate decrease of just 0.1 percent)Ambetter/Absolute Total Care.

Average rate increase of 8.5% (Ambetter had 7,348 members in 2020, according to SERFF filingCECO-132377401)Bright. Average rate decrease of 0.05% buy symbicort online with free samples (Bright had initially proposed an average rate decrease of 2.04 percent. Bright has 5,754 policyholders—member count is likely higher—according to SERFF filing BRHP-132335829)Molina.

Average rate decrease of 3.6% (Molina has 5,168 members in 2020, according to SERFF filing MHSC-132366286)BlueChoice, which only offers plans outside the exchange, will buy symbicort online with free samples reduce average premiums by 1.62 percent for 2021 (on the heels of an average rate decrease of more than 7 percent in 2020). BlueChoice has 3,890 policyholders as of 2020. Average premiums for existing insurers decreased for 2020, Molina and Bright joined the exchange, and Centene/Ambetter expanded coverage areaTwo insurers offered plans in South buy symbicort online with free samples Carolina’s exchange in 2019.

Blue Cross Blue Shield of South Carolina, which offered plans statewide, and Ambetter (Absolute Total Care), which offered plans in Charleston County (according to Ambetter’s 2020 rate filing — SERFF tracking number CECO-131968188 — Ambetter/Absolute Total Care had 862 members in 2019. So BCBSSC had the buy symbicort online with free samples bulk of the market share).But as of 2020, residents in many areas of the state had more options available. Bright Health now offers plans in three counties, Molina offers plans in 20 counties, and Ambetter expanded its coverage area to include a total of 12 counties.According to ratereview.healthcare.gov, the state’s existing exchange insurers implemented the following average rate changes for 2020:Blue buy symbicort online with free samples Cross Blue Shield of South Carolina.

3.28% rate decrease (BCBSSC has the vast majority of the state’s enrollment in ACA-compliant individual market plans, and had initially proposed a slight rate increase)Ambetter/Absolute Total Care. 2.28% decrease (Ambetter had just 862 members in 2019, according to SERFF filing CECO-131968188)BlueChoice, which only offers plans buy symbicort online with free samples outside the exchange, implemented an average rate decrease of 7.28 percent for 2020. Overall, across the state’s entire individual market, there was an average rate decrease of about 4 percent for 2020.Here’s a look at how average premiums have changed in South Carolina’s exchange over the years:2015.

Average rate increase of 0.93 percent buy symbicort online with free samples. Assurant joined the South Carolina exchange for 2015, bringing the total number of carriers in the exchange to five. Assurant joined the four companies that were already offering health insurance through buy symbicort online with free samples the federally-run marketplace in South Carolina.

Blue Choice Health Plan, Blue Cross Blue Shield of South Carolina, Consumers’ Choice Health Plan and Coventry Health Care of the Carolinas. (this page has more information about the participating buy symbicort online with free samples carriers). There were a total of 52 buy symbicort online with free samples plans available in the state, although not all of them were available in all areas.The South Carolina Department of Insurance found that the weighted average rate increase in the exchange was just 0.93 percent for 2015, and 0.95 percent for the entire individual market.

In South Carolina, some people who had the benchmark plan (second lowest-cost silver plan) in 2014 and who switched to the new benchmark plan for 2015 experienced rate decreases for 2015, particularly in the western portion of the state. In the Greenville area, the benchmark plan as well as the lowest-cost bronze and silver plans were all being offered by a different carrier in 2015 compared with buy symbicort online with free samples 2014. And this was the case in much of the rest of the state as well.2016.

Average approved buy symbicort online with free samples rate increase of 15.9 percent (but it ended up being lower after Consumer’s Choice CO-OP exited the market, as their approved rate increase had been 22 percent). In early October 2015, South Carolina regulators released approved rate changes for 2016. The weighted average rate increase at that point was about 15.9 percent (slightly lower in the exchange, slightly higher when off-exchange plans are included).In the exchange, the highest rate buy symbicort online with free samples increases were for Coventry (Aetna) and Consumer’s Choice.

Since Consumers Choice ultimately ended up not offering plans for 2016, the overall weighted average rate increase ended up being lower than it would otherwise have been.Plans in the exchange ended up being available from Coventry/Aetna (in 15 counties), BlueChoice (statewide), BlueCross BlueShield of South Carolina (statewide), and UnitedHealthcare (in five counties. New to the exchange for buy symbicort online with free samples 2016). Time Insurance, which offered on-exchange plans in South Carolina buy symbicort online with free samples in 2015, initially requested the steepest rate hike (53 percent), but their parent company, Assurant, subsequently announced that they would exit the individual market nationwide.

Time products are no longer for sale in any state.2017. Average rate increase buy symbicort online with free samples of 27.8 percent. Coventry (Aetna), BlueChoice (a subsidiary of BCBSSC), and UnitedHealthcare all exited the South Carolina exchange at the end of 2016 (UnitedHealthcare exited the entire individual market in the state, as they did in several other states).

Coventry had offered plans in 15 of the state’s 46 counties, and had buy symbicort online with free samples 8,000 enrollees in 2016. United Healthcare had offered plans in just five counties in 2016. BlueChoice and Blue Cross Blue Shield offered plans statewide in 2016.In South Carolina, the state guaranty fund had to pay $48 million in outstanding claims for Consumers Choice CO-OP members when the CO-OP ceased operations at the end of buy symbicort online with free samples 2015 (details below).

This was a larger outlay than the state buy symbicort online with free samples had expected. Health insurance carriers contribute to the guarantee fund, and they were allowed to incorporate those fees into their premiums for 2016.2018. Average rate increase of buy symbicort online with free samples 31.33 percent.

Blue Cross Blue Shield of South Carolina was the only insurer offering plans in the exchange for 2018, as was the case in 2017. The average approved buy symbicort online with free samples rate increase for 2018 was 31.33 percent. But nearly three-quarters of the total average rate increase was due to the fact that the federal government stopped longer funding cost-sharing reductions (CSR) in the fall of 2017.The cost of CSR was added to on-exchange silver plans in South Carolina.

BCBSSC’s rate filing indicated that they are offering separate off-exchange-only silver plans that don’t have the cost of CSR added to the premiums, and all of their non-silver plans (on and off-exchange) are also being sold without the cost of CSR added to buy symbicort online with free samples the premiums.2019. Average rate increase of 5.26 percent. This was for Blue Cross Blue Shield of South Carolina, which had been the only insurer in the exchange in 2018 buy symbicort online with free samples.

But Ambetter/Absolute Total Care also joined the exchange in Charleston County as of buy symbicort online with free samples 2019. BCBSSC had 203,000 enrollees in the individual market in 2018, and initially proposed an average rate increase of 9.3 percent. In their filing documents, the first two justifications for the higher rates were the impending elimination of the individual mandate buy symbicort online with free samples penalty, and the fact that short-term health plans and association health plans were being expanded, both of which were expected to “likely siphon better risks from the ACA market.”In SERFF, it notes that the filing for BCBSSC was “approved as amended.” So although the details of the amended filing (dated August 20) were redacted, presumably BCBSSC updated their filing with a 5.26 percent rate increase, instead of the filing they initially submitted.

At ACA Signups, Charles Gaba calculates that rates would have decreased by an average of 5.8 percent if the individual mandate hadn’t been eliminated and if short-term plans hadn’t been expanded. 2020 enrollment buy symbicort online with free samples. Slight decrease from 2019, down almost 8% since 2016214,030 people enrolled in plans through South Carolina’s exchange during the open enrollment period for 2020 coverage, which was just slightly lower than enrollment had been the year before.Here’s a look at how enrollment has changed over the years in South Carolina’s exchange:2014.

118,324 people buy symbicort online with free samples enrolled2015. 210,331 people enrolled2016. 231,849 people buy symbicort online with free samples enrolled (peak enrollment.

This fits the same trend that applies to most state that use HealthCare.gov, with peak enrollment happening in 2016 buy symbicort online with free samples and a gradual decline since then).2017. 230,211 people enrolled (South Carolina’s enrollment decline, at only 0.7 percent, was smaller than the average decline of about 5 percent across all states that use HealthCare.gov)2018. 215,983 people buy symbicort online with free samples enrolled2019.

214,956 people enrolled2020. 214,030 people enrolled South Carolina’s CSR approach protects most enrollees, makes non-silver plans particularly appealingAdding the cost of CSR to on-exchange silver plans while also making off-exchange silver plans available without the cost of CSR added to the premiums is the approach that protects the buy symbicort online with free samples greatest number of consumers. People who get premium subsidies receive larger subsidies than usual, and people who don’t get premium subsidies have multiple options for plans that don’t have the cost of CSR added to their premiums.With the cost of CSR added to premiums for silver plans, premium subsidies are larger than they would otherwise be, since the subsidies are based on the cost of the second-lowest-cost silver plan, and grow to keep pace with the increase in silver plan premiums.

Due to the larger premium subsidies, bronze plans became very inexpensive starting in 2018, and gold plans are also comparatively less expensive than they were in prior years.People who aren’t eligible for premium subsidies can purchase plans at other metal levels, or an off-exchange silver plan (people ineligible for a premium subsidy includes those impacted by the Medicaid coverage gap or the family glitch, as well as anyone earning above 400 percent of the poverty level).So although the bulk of the overall rate increase in South Carolina in 2018 was due to the elimination of federal funding for CSR, the only people who had to bear that cost themselves were on-exchange silver plan enrollees who don’t get premium subsidies, and who chose to keep their silver plan for 2018 instead of switching to an off-exchange plan or switching to a plan at a different metal level.Despite the fact that the Trump Administration cut off funding for CSR, buy symbicort online with free samples the benefits of CSR are still available to all eligible enrollees. If your income is between 100 percent and 250 percent of the poverty level and you select a silver plan in the South Carolina exchange, your coverage includes cost-sharing reductions that lower your out-of-pocket costs. The benefits are strongest for those with income below 200 percent of the poverty level.With the buy symbicort online with free samples elimination of federal funding for CSR, all that has changed is that the cost of CSR is now being added to premiums, rather than funded directly by the federal government.

And because the cost has buy symbicort online with free samples been added to silver plan premiums in most states (including South Carolina), the added premiums are mostly covered by the federal government anyway, in the form of larger premium subsidies for all enrollees who qualify for premium subsidies.It’s noteworthy that Blue Choice Health Plan — which only sells off-exchange plans, and thus doen’t have to add the cost of CSR to premiums, since CSR isn’t available outside the exchange — had an average rate increase of just 10 percent for 2018, while BCBSSC’s average rate increase was more than 31 percent. Judging from the rate filing that BCBSSC submitted, their average rate increase for 2018 would also have been around 10 percent if the federal government had continued to fund CSR.Consumers Choice CO-OP closed at the end of 2015On October 22, 2015 The South Carolina Department of Insurance announced that Consumers Choice – an ACA-created CO-OP – would wind down its operations by year-end, and would not participate in the 2016 open enrollment period that began November 1. Consumers Choice was the ninth CO-OP to fail, and the fifth in October alone.The significant shortfall in risk corridors payments was blamed for the CO-OP’s demise, as was the case for all buy symbicort online with free samples of the CO-OPs that failed since the beginning of October.

HHS announced on October 1 that carriers would get just 12.6 percent of the 2014 risk corridors payments that they were owed, leaving many smaller carriers well into the red. One of the other four CO-OPs that closed buy symbicort online with free samples as a result of the risk corridor shortfall – Community Health Alliance in Tennessee – was also run by Consumers Choice CEO Jerry Burgess.67,000 Consumers Choice members had to secure new coverage for 2016. The Department of Insurance put together a series of FAQs for impacted plan members.

One concern for patients with chronic conditions was the network buy symbicort online with free samples coverage of the remaining health insurers. None of them included the Medical University of South Carolina in their networks, despite the fact that MUSC is the only place where some patients are able to access specialists for their conditions. MUSC eventually accepted an offer from Blue Cross Blue Shield of South Carolina to cover specialty care for patients who had previously been insured with Consumers Choice, but the agreement had not yet been finalized buy symbicort online with free samples as of December 29 – just three days before the CO-OP members were to be transitioned to their new plans.No Medicaid expansionUS Rep.

James Clyburn (D – SC) views the ACA as the “Civil Rights Act of the 21st century” and has long called on South Carolina to embrace the law (including Medicaid expansion, which SC lawmakers have thus far resisted) and all that it can offer to the state buy symbicort online with free samples and its residents.In his article, Rep. Clyburn noted that SC ranks 43rd in the US in terms of overall health, and points out the myriad ways that the ACA can help to improve residents’ health.And on the 2016 presidential campaign trail, Ohio Governor John Kasich, a contender for the GOP nomination, called on South Carolina to accept federal funding to expand Medicaid.In large part because of the state’s failure to expand Medicaid, the uninsured rate in South Carolina is still higher than the national average. According to US Census data, the uninsured rate was buy symbicort online with free samples still 10.5 percent in 2018 in South Carolina.

That was down from 15.8 percent in 2013, but it was still significantly higher than the 8.9 percent national average as of 2018.And hospitals in South Carolina, particularly in rural areas of the state, are facing closure as a result of a lack of funding — a problem that hospital administrators believe could be addressed by accepting federal funding to expand Medicaid.Although South Carolina has made no progress so far in terms of expanding Medicaid eligibility, there is one small sliver of good news in the South Carolina Medicaid program. Starting in December 2014, adults covered by Medicaid in South Carolina gained coverage for preventive dental coverage, fillings, and extractions with up to buy symbicort online with free samples $750 in services available for each member per year. Grandmothered plansSouth Carolina was quick to accept President Obama’s policy cancellation compromise that allowed carriers to extend existing plans that had been scheduled to terminate at the end of 2013.

And when HHS extended that proposal in early 2014, South Carolina was once again among the majority of states that opted to allow grandmothered plans to renew into 2015.These plans, described as grandmothered or transitional, are allowed to remain in force until the end of 2021, under buy symbicort online with free samples the terms of the latest federal extension, issued in 2020. South Carolina has agreed to allow carriers to keep grandmothered plans in force until the end of 2021, at the carriers’ discretion.It has been left up to each carrier to determine whether they wanted to allow their pre-2014 plans to continue to be eligible for renewal. This gives many people — who had individual coverage prior to 2014 — another alternative to compare with the options available in the exchange, but some critics contend that buy symbicort online with free samples it keeps healthy people out of the new ACA-compliant insurance pools.OutreachThree federally funded groups launched training programs and outreach campaigns in 2013 to help consumers understand their options.

DECO Recovery Management, Cooperative Ministry, and the Beaufort County Black Chamber of Commerce all received grants to hire “navigators.” Navigators provide unbiased information about the options available through the marketplace and help consumers through the buy symbicort online with free samples enrollment process, but cannot be directly or indirectly paid by insurance companies.South Carolina was among the states that received the least amount of federal funding in the initial planning grants — the state got $1 million. This is a thousand times less than the $1 billion that California received (and several other states got hundreds of millions), but was predicated on the state’s refusal to promote the ACA – the money wouldn’t have been utilized by the South Carolina government.Prior to the 2016 open enrollment period, two navigator organizations in South Carolina received federal grant funding. The Beaufort County Black Chamber of Commerce ($456,102) and the Palmetto Project ($1,123,916).Navigator funding buy symbicort online with free samples was sharply reduced by the Trump Administration in 2017 and again in 2018.

Heading into the open enrollment period for 2019 coverage (in the fall of 2018), only one organization — DECO Recovery Management — received navigator funding in South Carolina, totaling $300,000. The same organizations also received $300,000 in 2019, prior to the start of the open enrollment period for 2020 coverage.South Carolina buy symbicort online with free samples health insurance exchange linksState Exchange Profile. South CarolinaThe Henry J.

Kaiser Family Foundation overview of South Carolina’s progress toward creating a state health insurance exchange.South Carolina Consumer Assistance ProgramAssists people insured by private health plans, Medicaid, or other plans in resolving problems pertaining to buy symbicort online with free samples their health coverage. Assists uninsured residents with access to care.(800) 768-3467 buy symbicort online with free samples /consumers@doi.sc.govLouise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces about the Affordable Care Act for healthinsurance.org.

Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts.Key takeaways Medicaid expansion in West Virginia Federalpoverty levelcalculator 0.0% of Federal Poverty Level West Virginia’s leaders opted to expand Medicaid under the buy symbicort online with free samples Affordable Care Act (ACA) starting on January 1, 2014, providing coverage to low-income adults, most of whom have jobs but no option for employer-sponsored health insurance. The federal government paid the full cost for the expansion population for the first three years, but gradually reduced the funding split until reaching a 90/10 split in 2020, which will remain fixed in future years.Under the expanded eligibility guidelines, adults age 19-64 are eligible for Medicaid with a household income up to 138 percent of the poverty level. Medicaid expansion significantly exceeded the 93,000 people that West Virginia had initially projected to enroll by 2020 under the expanded eligibility buy symbicort online with free samples guidelines, but enrollment has declined after peaking in 2016.

The total number of people enrolled under expanded Medicaid declined slightly by January 2017, to 174,026, and declined further, to 165,917, by March 2018. More than 161,500 people enrolled under Medicaid expansion in West Virginia as of June 2019.CMS reporting shows that West Virginia’s overall Medicaid population (meaning individuals eligible and enrolled under pre-ACA eligibility requirements plus those eligible and enrolled under the ACA’s expansion criteria) the is up 47 percent between buy symbicort online with free samples 2013 (pre-ACA) and June 202o. Given the 202o coronavirus outbreak and reporting lags, it is possible that the expansion population has grown since the June 2019 data cited in the previous paragraph.CHIP coverage for pregnant women as of 2019SB564 was signed into law in West Virginia in 2019.

The legislation called for CHIP coverage in West Virginia to be expanded to include pregnant buy symbicort online with free samples women. CHIP eligibility for kids in West Virginia already extended to households with income up to 300 percent of the poverty level, and buy symbicort online with free samples that’s the same level that now applies to pregnant women as well. The new CHIP coverage for pregnant women took effect on July 1, 2019 in West Virginia.Only five other states (Colorado, Missouri, New Jersey, Rhode Island, and Virginia) provide CHIP coverage to pregnant women, but there are numerous states with fairly high income limits for pregnant women to qualify for Medicaid (for example, Medicaid coverage is available to pregnant women in Iowa with household income as high as 375 percent of the poverty level.

In DC, it’s 318 percent)West Virginia has considered a Medicaid work requirement but has not yet created oneAs of late 2017, West Virginia’s Department of Health and Human Resources was considering the possibility of seeking a waiver from the federal government in order to implement a work requirement buy symbicort online with free samples for the state’s Medicaid expansion population. But nothing has happened yet on that front. Legislation (HB3136) to create a work requirement was considered in the 2019 legislative session, but it did not advance to a vote.Although work requirements were a non-starter with the Obama Administration, buy symbicort online with free samples the Trump Administration has approved them in several states.

But a judge has blocked the work requirements in Kentucky, New Hampshire, and Arkansas. Officials in Indiana have suspended their Medicaid work requirement pending the outcome of a similar lawsuit, and Arizona has also suspended implementation of a new work requirement.Consumer advocates in West Virginia have criticized the possibility of a work requirement, noting that such programs tend to just make it harder for people to maintain their health coverage, due to documentation requirements, despite the fact that the majority of Medicaid expansion enrollees are already in a household where at least one person is working.The state has already entered into buy symbicort online with free samples a $300 million contract with Optum to verify eligibility for various need-based programs, including SNAP and Medicaid. If a work requirement were to be added to Medicaid, it would increase the reporting and verification measures necessary in order to confirm ongoing eligibility for Medicaid.Medicaid expansion helping to combat opioid crisisThe opioid crisis has hit West Virginia particularly hard, and the state has the nation’s highest drug overdose death rate.

But 22,000 people buy symbicort online with free samples covered under expanded Medicaid had received treatment for mental health and substance abuse disorders by early 2017. Without Medicaid expansion, most of those people buy symbicort online with free samples would have been uninsured and unable to access treatment.Previous and current governor support Medicaid expansionWest Virginia’s former Governor, Earl Ray Tomblin, was instrumental in West Virginia’s acceptance of Medicaid expansion but was term-limited and could not seek re-election in 2016.Governor Jim Justice took office in January 2017. He campaigned and was elected as a Democrat, but in the summer of 2017, during his first year in office, he switched to the Republican party.

Justice reiterated his support for Medicaid expansion in the weeks leading up to his party switch, stating in late June 2017 that it would be “beyond catastrophic” if the people who had gained coverage under Medicaid expansion were to lose it buy symbicort online with free samples. But Justice also vetoed a supplemental appropriation for the state’s Medicaid program in 2019, saying that the Medicaid program already had enough funding.Substantial impact on uninsured rateExpansion of Medicaid has played a primary role in West Virginia’s sharp reduction in the uninsured rate.West Virginia had the sixth highest drop in uninsured rate during the first half of 2014, due primarily to Medicaid expansion (as of July 2014, 132,556 people in West Virginia Medicaid, while 25,856 had enrolled in subsidized private coverage through the exchange).According to US Census data, the state’s uninsured rate was 14 percent in 2013, and had fallen to 5.3 percent by 2016. It had increased to 6.4 percent by 2018, however, mirroring the nationwide trend of increasing uninsured rates under the Trump administration.West Virginia’s uninsured rate had been similar buy symbicort online with free samples to the U.S.

Average (14.5 percent) in 2013, but the state’s uninsured rate in 2018 was well below that national average at that point, which was 8.9 percent.However amid the Covid-10 pandemic, the uninsured rates have climbed across the nation. As of June 2020, West Virginia’s buy symbicort online with free samples uninsured rate increased to 12 percent.Who is eligible for Medicaid in West Virginia?. West Virginia Medicaid is available for these legally present residents, in addition to the aged, blind, and disabled.Infants aged 0 to 1 in households with income up to 158 percent of the federal poverty level (FPL)Children aged 1-5 in households with income up to 141 percent of FPLChildren aged 6-18 in households with income up to 133 percent of FPLPregnant women with income up to 185 percent of povertyAdults with incomes up to 133 percent of povertyPregnant women and children in households with up to 300 percent of FPL qualify for CHIP in West Virginia.How do I enroll in Medicaid in West Virginia?.

You can apply for West Virginia Medicaid through the federally-run exchange by visiting HealthCare.gov or calling 1-800-318-2596 24 hours a day.Or you can apply through the state at www.wvinroads.org and that site can also provide SNAP and cash assistance programs for eligible residents.Medicaid enrollment is year-round — there is no specific time frame during which applications must be completed.West Virginia Medicaid enrollment numbersAs of mid-July 2014, there were 132,556 new Medicaid enrollees who buy symbicort online with free samples were all newly-eligible under the expanded guidelines. Although most of the newly-eligible population enrolled during the first year, the number of newly-eligible enrollees had grown to 164,400 by June 2015, and buy symbicort online with free samples to 178,394 by August 2016. But enrollment in expanded Medicaid declined slightly by the beginning of 2017, to 174,026, and declined further, to 153,874 by December 2018.

It has since stabilized, and stands at 156,775 as of November 2019.In 2013, the Kaiser Family Foundation estimated that about 143,000 people buy symbicort online with free samples in West Virginia would be newly-eligible for Medicaid as of 2014. But the state’s estimate had been much lower, with a projected expansion enrollment of 93,000 by 2020.Opponents of Medicaid expansion predicted that states with a surge in Medicaid enrollment would find that Medicaid patients were unable to get appointments for primary care, but West Virginia doctors weren’t indicating that was a problem when enrollment initially spiked. Instead, some of their challenges include a significant population of newly-insured people who are requesting pain medication at office visits, and patients who have previously been on free drug samples and need to be switched to another drug that’s covered by Medicaid.And despite the unexpectedly large enrollment in Medicaid expansion — combined with the fact that the state began paying a portion of the Medicaid expansion costs starting in 2017 — West Virginia’s Medicaid budget had a surplus as of early 2019.Uncompensated care costs decline sharplyAccording to data compiled by West Virginians for Affordable Health Care, hospitals in West Virginia saw a 40 percent decline in uncompensated care costs from 2013 to 2014, thanks in large part to Medicaid expansion that resulted in far fewer uninsured residents in the state.But although the hospitals acknowledge that their uncompensated care and charity care costs have declined significantly, some also note that Medicaid reimbursements are less than the cost of providing care, and that their losses on Medicaid volume are offsetting the improvements they’ve seen in uncompensated care.West Virginia’s Medicaid expansion historyWest Virginia had initially considered setting up a state-run exchange, but later opted for a partnership exchange, citing cost as one of the reasons for avoiding a fully state-run exchange.State leaders have said that given the choice between a state-run exchange and Medicaid expansion, the latter seemed like it would provide more bang for the buck (and judging by the state’s extremely successful Medicaid enrollment in 2014, it would appear they were correct).In May 2013, then-Governor Earl buy symbicort online with free samples Ray Tomblin announced that West Virginia would proceed with Medicaid expansion.

Enrollment for newly-eligible residents began on October 1, 2013, with coverage effective January 1, 2014.Louise Norris is an individual health insurance broker who has been writing about health insurance and health reform since 2006. She has written dozens of opinions and educational pieces buy symbicort online with free samples about the Affordable Care Act for healthinsurance.org. Her state health exchange updates are regularly cited by media who cover health reform and by other health insurance experts..

Common side effects

Symbicort for 2 year old

NONE

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition symbicort for 2 year old of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of symbicort for 2 year old sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach symbicort for 2 year old for countries with similarly structured healthcare systems and similar resources.

Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points symbicort for 2 year old in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders. For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may be challenging, especially for symbicort for 2 year old professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers.

Moreover, this enables DSD specialists to refer to the guideline when advising a referral. Transition from the symbicort for 2 year old prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed symbicort for 2 year old with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to symbicort for 2 year old the rapid changes in testing methods, for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper. Abstracts had to be written in English and were identified using a broad range of symbicort for 2 year old Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care).

Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, symbicort for 2 year old as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, symbicort for 2 year old after having obtained agreement on remaining points of discussion, revised into a final draft.

This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline. After receiving and incorporating their input, the final version was symbicort for 2 year old presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by symbicort for 2 year old ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), symbicort for 2 year old which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus. However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes symbicort for 2 year old are not always included in NIPT analysis and reports.

If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical symbicort for 2 year old aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team. After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and symbicort for 2 year old the limitations of this technique.

The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the symbicort for 2 year old type of information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about symbicort for 2 year old the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination symbicort for 2 year old of pregnancy, which, although considered controversial by some, is legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment and prognosis cannot be avoided symbicort for 2 year old completely. Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images.

In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact person before birth.After expert prenatal symbicort for 2 year old counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary symbicort for 2 year old (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array.

It was recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly symbicort for 2 year old common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS. NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases there is no tight time limit, and we propose completing the analysis well before the expected symbicort for 2 year old delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting.

A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition. Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers. A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline.

Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process. Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. * SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype. Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned.

Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences. If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing.

Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing. Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions. What do laboratories report?.

How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity. It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype.

This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD. In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium. We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time.

Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD. These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions.

One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved. A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication. Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing.

Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital. The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic.

In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors. Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation. We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2.

Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk. Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used.

€œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”. No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected. For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected.

Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis. For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant.

However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included. As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis. Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported.

Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram. *Reasons.

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009).

Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies. Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations.

Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene. Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene.

The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04. P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer. These can be activated by high levels of KLF5 (transcriptional activator).

Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21. P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20.

P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated. The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses. However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry.

There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer. We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant.

The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer. For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality. Thus, these should be interpreted with caution.

Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants. However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs.

It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data. This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit. In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS.

Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1. Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A.

This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes. The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women. This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans.

This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours. Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer.

It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes. It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations. Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk.

The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

IntroductionIn recent years, many studies have been published on new buy symbicort online with free samples diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD buy symbicort online with free samples consensus document by an international group of professionals and patient representatives.18 These initiatives have highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four buy symbicort online with free samples DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine buy symbicort online with free samples conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team buy symbicort online with free samples may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires buy symbicort online with free samples optimal communication between the specialists involved. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed with buy symbicort online with free samples all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, buy symbicort online with free samples for example, gene panels. All input provided by the group was synthesised by the chairperson (YvB), who also reviewed abstracts of papers on DSD published between 2010 and September 2017 for the guideline and up to October 2019 for this paper.

Abstracts had to be written in English and were identified using a broad buy symbicort online with free samples range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through buy symbicort online with free samples institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was discussed by the writing committee and, after having obtained agreement on remaining points of buy symbicort online with free samples discussion, revised into a final draft. This version was sent to a broad group of professionals from academic centres and DSD teams whose members had volunteered to review the draft guideline.

After receiving buy symbicort online with free samples and incorporating their input, the final version was presented to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but buy symbicort online with free samples may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism buy symbicort online with free samples or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant women in the Netherlands and to all pregnant women in Belgium, and later ultrasound findings. NIPT screens for CNVs in the fetus.

However, depending on legal restrictions and/or ethical considerations, the X and Y chromosomes are not always buy symbicort online with free samples included in NIPT analysis and reports. If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the buy symbicort online with free samples couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on the ultrasound findings and the limitations of buy symbicort online with free samples this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of buy symbicort online with free samples information genetic testing can and cannot provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist buy symbicort online with free samples should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as an apparently isolated condition, expecting parents may also consider termination of pregnancy, which, although considered controversial by some, is buy symbicort online with free samples legal in Belgium and the Netherlands. The psychologist of the DSD team can support parents during and after pregnancy and help them cope with feelings of uncertainty and eventual considerations of a termination of pregnancy, as well as with practical issues, for example, how to inform others. The stress of not knowing exactly what the child’s genitalia will look like and uncertainty about the diagnosis, treatment buy symbicort online with free samples and prognosis cannot be avoided completely.

Parents are informed that if the postnatal phenotype is different from what was prenatally expected, the advice given about diagnostic testing can be adjusted accordingly, for example, if a hypospadias is milder than was expected based on prenatal ultrasound images. In our experience, parents appreciate having already spoken to some members of the DSD team during pregnancy and having a contact buy symbicort online with free samples person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of buy symbicort online with free samples neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation of a suspected DSD in the prenatal situation is proposed in figure 1. When couples opt for invasive prenatal diagnosis, the genetic analysis usually involves an (SNP)-array. It was buy symbicort online with free samples recently estimated that >30% of individuals who have a DSD have additional structural anomalies, with cardiac and neurological anomalies and fetal growth restriction being particularly common.27 28 If additional anomalies are seen, the geneticist can consider specific gene defects that may underlie a known genetic syndrome or carry out NGS.

NGS-based techniques have also now made their appearance in prenatal diagnosis of congenital anomalies.29 30 Panels using these techniques can be specific for genes involved in DSD, or be larger panels covering multiple congenital anomalies, and are usually employed with trio-analysis to compare variants identified in the child with the parents’ genetics.29–31 Finding a genetic cause before delivery can help reduce parental stress in the neonatal period and speed up decisions regarding gender assignment. In such cases buy symbicort online with free samples there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

*SOX9. Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful.

NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 1 Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm. *SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing.First contact by a professional less experienced in DSDWhereas most current guidelines start from the point when an individual has been referred to the DSD team,1 15 the Dutch-Flemish guideline dedicates a chapter to healthcare professionals less experienced in DSD as they are often the first to suspect or identify such a condition.

Apart from the paper of Indyk,7 little guidance is available for these professionals about how to act in such a situation. The chapter in the Dutch-Flemish guideline summarises the various clinical presentations that a DSD can have and provides information on how to communicate with parents and/or patients about the findings of the physical examination, the first-line investigations and the need for prompt referral to a specialised centre for further evaluation. Clinical examples are offered to illustrate some of these recurring situations.

The medical issues in DSD can be very challenging, and the social and psychological impact is high. For neonates with ambiguous genitalia, sex assignment is an urgent and crucial issue, and it is mandatory that parents are informed that it is possible to postpone registration of their child’s sex. In cases where sex assignment has already taken place, the message that the development of the gonads or genitalia is still atypical is complicated and distressing for patients and parents or carers.

A list of contact details for DSD centres and patient organisations in the Netherlands and Flanders is attached to the Dutch-Flemish guideline. Publishing such a list, either in guidelines or online, can help healthcare professionals find the nearest centres for consultations and provide patients and patient organisations with an overview of the centres where expertise is available.Timing and place of genetic testing using NGS-based gene panelsThe diagnostic workup that is proposed for 46,XX and 46,XY DSD is shown in figures 2 and 3, respectively. Even with the rapidly expanding molecular possibilities, a (family) history and a physical examination remain the essential first steps in the diagnostic process.

Biochemical and hormonal screening aim at investigating serum electrolytes, renal function and the hypothalamic-pituitary-gonadal and hypothalamic-pituitary-adrenal axes. Ultrasound screening of kidneys and internal genitalia, as well as establishing genotypic sex, should be accomplished within 48 hours and complete the baseline diagnostic work-up of a child born with ambiguous genitalia.1 16 32 3346,XX disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm.

NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia. AMH, Anti-Müllerian Hormone." data-icon-position data-hide-link-title="0">Figure 2 46,XX disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. NGS, next-generation sequencing. CAH, Congenital adrenal hyperplasia.

AMH, Anti-Müllerian Hormone.46,XY disorders/differences of sex development (DSD) in the postnatal setting. A diagnostic algorithm. * SOX9.

Upstream anomalies and balanced translocations at promotor sites!. Conventional karyotyping can be useful. NGS, next-generation sequencing." data-icon-position data-hide-link-title="0">Figure 3 46,XY disorders/differences of sex development (DSD) in the postnatal setting.

A diagnostic algorithm. *SOX9. Upstream anomalies and balanced translocations at promotor sites!.

Conventional karyotyping can be useful. NGS, next-generation sequencing.Very recently, a European position paper has been published focusing on the genetic workup of DSD.16 It highlights the limitations and drawbacks of NGS-based tests, which include the chance of missing subtle structural variants such as CNVs and mosaicism and the fact that NGS cannot detect methylation defects or other epigenetic changes.16 28 31 Targeted DNA analysis is preferred in cases where hormonal investigations suggest a block in steroidogenesis (eg, 11-β-hydroxylase deficiency, 21-hydroxylase deficiency), or in the context of a specific clinical constellation such as the often coincidental finding of Müllerian structures in a boy with normal external genitalia or cryptorchidism, that is, persistent Müllerian duct syndrome.33 34 Alternative tests should also be considered depending on the available information. Sometimes, a simple mouth swab for FISH analysis can detect mosaic XY/X in a male with hypospadias or asymmetric gonadal development or in a female with little or no Turner syndrome stigmata and a normal male molecular karyotyping profile or peripheral blood karyotype.

Such targeted testing avoids incidental findings and is cheaper and faster than analysis of a large NGS-based panel, although the cost difference is rapidly declining.However, due to the genetic and phenotypic heterogeneity of DSD conditions, the most cost-effective next steps in the majority of cases are whole exome sequencing followed by panel analysis of genes involved in genital development and function or trio-analysis of a large gene panel (such as a Mendeliome).16 35–38 Pretest genetic counselling involves discussing what kind of information will be reported to patients or parents and the chance of detecting VUS, and the small risk of incidental findings when analysing a DSD panel should be mentioned. Laboratories also differ in what class of variants they report.39 In our experience, the fear of incidental findings is a major reason why some parents refrain from genetic testing.Timing of the DSD gene panel analysis is also important. While some patients or parents prefer that all diagnostic procedures be performed as soon as possible, others need time to reflect on the complex information related to more extensive genetic testing and on its possible consequences.

If parents or patients do not consent to panel-based genetic testing, analysis of specific genes, such as WT1, should be considered when appropriate in view of the clinical consequences if a mutation is present (eg, clinical surveillance of renal function and screening for Wilms’ tumour in the case of WT1 mutations). Genes that are more frequently involved in DSD (eg, SRY, NR5A1) and that match the specific clinical and hormonal features in a given patient could also be considered for sequencing. Targeted gene analysis may also be preferred in centres located in countries that do not have the resources or technical requirements to perform NGS panel-based genetic testing.

Alternatively, participation by these centres in international collaborative networks may allow them to outsource the molecular genetic workup abroad.Gene panels differ between centres and are regularly updated based on scientific progress. A comparison of DSD gene panels used in recent studies can be found at https://www.nature.com/articles/s41574-018-0010-8%23Sec46.15 The panels currently used at the coauthors’ institutions can be found on their respective websites. Given the pace of change, it is important to regularly consider repeating analysis in patients with an unexplained DSD, for example, when they transition into adult care or when they move from one centre to another.

This also applies to patients in whom a clinical diagnosis has never been genetically confirmed. Confusion may arise when the diagnosis cannot be confirmed or when a mutation is identified in a different gene, for example, NR5A1 in someone with a clinical diagnosis of CAIS that has other consequences for relatives. Hence, new genetic counselling should always accompany new diagnostic endeavours.Class 3 variants and histopathological examinationsThe rapidly evolving diagnostic possibilities raise new questions.

What do laboratories report?. How should we deal with the frequent findings of mainly unique VUS or class 3 variants (ACMG recommendation) in the many different DSD-related genes in the diagnostic setting?. Reporting VUS can be a source of uncertainty for parents, but not reporting these variants precludes further investigations to determine their possible pathogenicity.

It can also be difficult to prove variant pathogenicity, both on gene-level and variant-level.39 Moreover, given the gonad-specific expression of some genes and the variable phenotypic spectrum and reduced penetrance, segregation analysis is not always informative. A class 3 variant that does not fit the clinical presentation may be unrelated to the observed phenotype, but it could also represent a newly emerging phenotype. This was recently demonstrated by the identification of the NR5A1 mutation, R92W, in individuals with 46,XX testicular and ovotesticular DSD.40 This gene had previously been associated with 46,XY DSD.

In diagnostic laboratories, there is usually no capacity or expertise to conduct large-scale functional studies to determine pathogenicity of these unique class 3 VUS in the different genes involved in DSD. Functional validation of variants identified in novel genes may be more attractive in a research context. However, for individual families with VUS in well-established DSD genes such as AR or HSD17B3, functional analysis may provide a confirmed diagnosis that implies for relatives the option of undergoing their own DNA analysis and estimating the genetic risk of their own future offspring.

This makes genetic follow-up important in these cases and demonstrates the usefulness of international databases and networks and the centralisation of functional studies of genetic variants in order to reduce costs and maximise expertise.The same is true for histopathological description, germ-cell tumour risk assessment in specific forms of DSD and classification of gonadal samples. Germ-cell tumour risk is related to the type of DSD (among other factors), but it is impossible to make risk estimates in individual cases.41–44 Gonadectomy may be indicated in cases with high-risk dysgenetic abdominal gonads that cannot be brought into a stable superficial (ie, inguinal, labioscrotal) position that allows clinical or radiological surveillance, or to avoid virilisation due to 5-alpha reductase deficiency in a 46,XY girl with a stable female gender identity.45 Pathological examination of DSD gonads requires specific expertise. For example, the differentiation between benign germ cell abnormalities, such as delayed maturation and (pre)malignant development of germ cells, is crucial for clinical management but can be very troublesome.46 Centralised pathological examination of gonadal biopsy and gonadectomy samples in one centre, or a restricted number of centres, on a national scale can help to overcome the problem of non-uniform classification and has proven feasible in the Netherlands and Belgium.

We therefore believe that uniform assessment and classification of gonadal differentiation patterns should also be addressed in guidelines on DSD management.International databases of gonadal tissues are crucial for learning more about the risk of malignancy in different forms of DSD, but they are only reliable if uniform criteria for histological classification are strictly applied.46 These criteria could be incorporated in many existing networks such as the I-DSD consortium, the Disorders of Sex Development Translational Research Network, the European Reference Network on Urogenital Diseases (eUROGEN), the EndoERN and COST actions.15–17 47Communication at the transition from paediatric to adult carePaediatric and adult teams need to collaborate closely to facilitate a well-organised transition from paediatric to adult specialist care.15 48–50 Both teams need to exchange information optimally and should consider transition as a longitudinal process rather than a fixed moment in time. Age-appropriate information is key at all ages, and an overview of topics to be discussed at each stage is described by Cools et al.15 Table 1 shows an example of how transition can be organised.View this table:Table 1 Example of transition table as used in the DSD clinic of the Erasmus Medical CenterPsychological support and the continued provision of information remains important for individuals with a DSD at all ages.15 22 In addition to the information given by the DSD team members, families and patients can benefit from resources such as support groups and information available on the internet.47 Information available online should be checked for accuracy and completeness when referring patients and parents to internet sites.Recommendations for future actionsMost guidelines and articles on the diagnosis and management of DSD are aimed at specialists and are only published in specialist journals or on websites for endocrinologists, urologists or geneticists. Yet there is a need for guidelines directed towards first-line and second-line healthcare workers that summarise the recommendations about the first crucial steps in the management of DSD.

These should be published in widely available general medical journals and online, along with a national list of DSD centres. Furthermore, DSD (expert) centres should provide continuous education to all those who may be involved in the identification of individuals with a DSD in order to enable these healthcare professionals to recognise atypical genitalia, to promptly refer individuals who have a DSD and to inform the patient and parents about this and subsequent diagnostic procedures.As DSD continues to be a rare condition, it will take time to evaluate the effects of having such a guideline on the preparedness of first-line and second-line healthcare workers to recognise DSD conditions. One way to evaluate this might be the development and use of questionnaires asking patients, carers and families and referring physicians how satisfied they were with the initial medical consultation and referral and what could be improved.

A helpful addition to existing international databases that collect information on genetic variations would be a list of centres that offer suitable functional studies for certain genes, ideally covering the most frequently mutated genes (at minimum).Patient organisations can also play an important role in informing patients about newly available diagnostic or therapeutic strategies and options, and their influence and specific role has now been recognised and discussed in several publications.17 47 However, it should be kept in mind that these organisations do not represent all patients, as a substantial number of patients and parents are not member of such an organisation.Professionals have to provide optimal medical care based on well-established evidence, or at least on broad consensus. Yet not everything can be regulated by recommendations and guidelines. Options, ideas and wishes should be openly discussed between professionals, patients and families within their confidential relationship.

This will enable highly individualised holistic care tailored to the patient’s needs and expectations. Once they are well-informed of all available options, parents and/or patients can choose what they consider the optimal care for their children or themselves.15 16ConclusionThe Dutch-Flemish guideline uniquely addresses some topics that are under-represented in the literature, thus adding some key aspects to those addressed in recent consensus papers and guidelines.15–17 33 47As more children with a DSD are now being identified prenatally, and the literature on prenatal diagnosis of DSD remains scarce,20 21 we propose a prenatal diagnostic algorithm and emphasise the importance of having a prenatal specialist involved in or collaborating with DSD (expert) centres.We also stress that good communication between all involved parties is essential. Professionals should be well informed about protocols and communication.

Collaboration between centres is necessary to optimise aspects of care such as uniform interpretation of gonadal pathology and functional testing of class 3 variants found by genetic testing. Guidelines can provide a framework within which individualised patient care should be discussed with all stakeholders.AcknowledgmentsThe authors would like to thank the colleagues of the DSD teams for their input in and critical reading of the Dutch-Flemish guideline. Amsterdam University Center (AMC and VU), Maastricht University Medical Center, Erasmus Medical Center Rotterdam, Radboud University Medical Center Nijmegen, University Medical Center Groningen, University Medical Center Utrecht, Ghent University Hospital.

The authors would like to thank Kate McIntyre for editing the revised manuscript and Tom de Vries Lentsch for providing the figures as a PDF. Three of the authors of this publication are members of the European Reference Network for rare endocrine diseases—Project ID 739543.IntroductionEndometrial cancer is the most common gynaecological malignancy in the developed world.1 Its incidence has risen over the last two decades as a consequence of the ageing population, fewer hysterectomies for benign disease and the obesity epidemic. In the USA, it is estimated that women have a 1 in 35 lifetime risk of endometrial cancer, and in contrast to cancers of most other sites, cancer-specific mortality has risen by approximately 2% every year since 2008 related to the rapidly rising incidence.2Endometrial cancer has traditionally been classified into type I and type II based on morphology.3 The more common subtype, type I, is mostly comprised of endometrioid tumours and is oestrogen-driven, arises from a hyperplastic endometrium, presents at an early stage and has an excellent 5 year survival rate.4 By contrast, type II includes non-endometrioid tumours, specifically serous, carcinosarcoma and clear cell subtypes, which are biologically aggressive tumours with a poor prognosis that are often diagnosed at an advanced stage.5 Recent efforts have focused on a molecular classification system for more accurate categorisation of endometrial tumours into four groups with distinct prognostic profiles.6 7The majority of endometrial cancers arise through the interplay of familial, genetic and lifestyle factors.

Two inherited cancer predisposition syndromes, Lynch syndrome and the much rarer Cowden syndrome, substantially increase the lifetime risk of endometrial cancer, but these only account for around 3–5% of cases.8–10 Having first or second degree relative(s) with endometrial or colorectal cancer increases endometrial cancer risk, although a large European twin study failed to demonstrate a strong heritable link.11 The authors failed to show that there was greater concordance in monozygotic than dizygotic twins, but the study was based on relatively small numbers of endometrial cancers. Lu and colleagues reported an association between common single nucleotide polymorphisms (SNPs) and endometrial cancer risk, revealing the potential role of SNPs in explaining part of the risk in both the familial and general populations.12 Thus far, many SNPs have been reported to modify susceptibility to endometrial cancer. However, much of this work predated genome wide association studies and is of variable quality.

Understanding genetic predisposition to endometrial cancer could facilitate personalised risk assessment with a view to targeted prevention and screening interventions.13 This emerged as the most important unanswered research question in endometrial cancer according to patients, carers and healthcare professionals in our recently completed James Lind Womb Cancer Alliance Priority Setting Partnership.14 It would be particularly useful for non-endometrioid endometrial cancers, for which advancing age is so far the only predictor.15We therefore conducted a comprehensive systematic review of the literature to provide an overview of the relationship between SNPs and endometrial cancer risk. We compiled a list of the most robust endometrial cancer-associated SNPs. We assessed the applicability of this panel of SNPs with a theoretical polygenic risk score (PRS) calculation.

We also critically appraised the meta-analyses investigating the most frequently reported SNPs in MDM2. Finally, we described all SNPs reported within genes and pathways that are likely involved in endometrial carcinogenesis and metastasis.MethodsOur systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) collaboration 2009 recommendations. The registered protocol is available through PROSPERO (CRD42018091907).16Search strategyWe searched Embase, MEDLINE and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases via the Healthcare Databases Advanced Search (HDAS) platform, from 2007 to 2018, to identify studies reporting associations between polymorphisms and endometrial cancer risk.

Key words including MeSH (Medical Subject Heading) terms and free-text words were searched in both titles and abstracts. The following terms were used. €œendomet*”,“uter*”, “womb”, “cancer(s)”, “neoplasm(s)”, “endometrium tumour”, “carcinoma”, “adenosarcoma”, “clear cell carcinoma”, “carcinosarcoma”, “SNP”, “single nucleotide polymorphism”, “GWAS”, and “genome-wide association study/ies”.

No other restrictions were applied. The search was repeated with time restrictions between 2018 and June 2019 to capture any recent publications.Eligibility criteriaStudies were selected for full-text evaluation if they were primary articles investigating a relationship between endometrial cancer and SNPs. Study outcome was either the increased or decreased risk of endometrial cancer relative to controls reported as an odds ratio (OR) with corresponding 95% confidence intervals (95% CIs).Study selectionThree independent reviewers screened all articles uploaded to a screening spreadsheet developed by Helena VonVille.17 Disagreements were resolved by discussion.

Chronbach’s α score was calculated between reviewers and indicated high consistency at 0.92. Case–control, prospective and retrospective studies, genome-wide association studies (GWAS), and both discovery and validation studies were selected for full-text evaluation. Non-English articles, editorials, conference abstracts and proceedings, letters and correspondence, case reports and review articles were excluded.Candidate-gene studies with at least 100 women and GWAS with at least 1000 women in the case arm were selected to ensure reliability of the results, as explained by Spencer et al.18 To construct a panel of up to 30 SNPs with the strongest evidence of association, those with the strongest p values were selected.

For the purpose of an SNP panel, articles utilising broad European or multi-ethnic cohorts were selected. Where overlapping populations were identified, the most comprehensive study was included.Data extraction and synthesisFor each study, the following data were extracted. SNP ID, nearby gene(s)/chromosome location, OR (95% CI), p value, minor or effect allele frequency (MAF/EAF), EA (effect allele) and OA (other allele), adjustment, ethnicity and ancestry, number of cases and controls, endometrial cancer type, and study type including discovery or validation study and meta-analysis.

For risk estimates, a preference towards most adjusted results was applied. For candidate-gene studies, a standard p value of<0.05 was applied and for GWAS a p value of <5×10-8, indicating genome-wide significance, was accepted as statistically significant. However, due to the limited number of SNPs with p values reaching genome-wide significance, this threshold was then lowered to <1×10-5, allowing for marginally significant SNPs to be included.

As shown by Mavaddat et al, for breast cancer, SNPs that fall below genome-wide significance may still be useful for generating a PRS and improving the models.19We estimated the potential value of a PRS based on the most significant SNPs by comparing the predicted risk for a woman with a risk score in the top 1% of the distribution to the mean predicted risk. Per-allele ORs and MAFs were taken from the publications and standard errors (SEs) for the lnORs were derived from published 95% CIs. The PRS was assumed to have a Normal distribution, with mean 2∑βipI and SE, σ, equal to √2∑βi2pI(1−pi), according to the binomial distribution, where the summation is over all SNPs in the risk score.

Hence the relative risk (RR) comparing the top 1% of the distribution to the mean is given by exp(Z0.01σ), where Z is the inverse of the standard normal cumulative distribution.ResultsThe flow chart of study selection is illustrated in figure 1. In total, 453 text articles were evaluated and, of those, 149 articles met our inclusion criteria. One study was excluded from table 1, for having an Asian-only population, as this would make it harder to compare with the rest of the results which were all either multi-ethnic or Caucasian cohorts, as stated in our inclusion criteria for the SNP panel.20 Any SNPs without 95% CIs were also excluded from any downstream analysis.

Additionally, SNPs in linkage disequilibrium (r2 >0.2) with each other were examined, and of those in linkage disequilibrium, the SNP with strongest association was reported. Per allele ORs were used unless stated otherwise.View this table:Table 1 List of top SNPs most likely to contribute to endometrial cancer risk identified through systematic review of recent literature21–25Study selection flow diagram. *Reasons.

Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study. Adapted from.

Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses. The PRISMA Statement.

PLoS Med 6(6). E1000097. Doi:10.1371/journal.pmed1000097." data-icon-position data-hide-link-title="0">Figure 1 Study selection flow diagram.

*Reasons. Irrelevant articles, articles focusing on other conditions, non-GWAS/candidate-gene study related articles, technical and duplicate articles. GWAS, genome-wide association study.

Adapted from. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

The PRISMA Statement. PLoS Med 6(6). E1000097.

Doi:10.1371/journal.pmed1000097.Top SNPs associated with endometrial cancer riskFollowing careful interpretation of the data, 24 independent SNPs with the lowest p values that showed the strongest association with endometrial cancer were obtained (table 1).21–25 These SNPs are located in or around genes coding for transcription factors, cell growth and apoptosis regulators, and enzymes involved in the steroidogenesis pathway. All the SNPs presented here were reported on the basis of a GWAS or in one case, an exome-wide association study, and hence no SNPs from candidate-gene studies made it to the list. This is partly due to the nature of larger GWAS providing more comprehensive and powered results as opposed to candidate gene studies.

Additionally, a vast majority of SNPs reported by candidate-gene studies were later refuted by large-scale GWAS such as in the case of TERT and MDM2 variants.26 27 The exception to this is the CYP19 gene, where candidate-gene studies reported an association between variants in this gene with endometrial cancer in both Asian and broad European populations, and this association was more recently confirmed by large-scale GWAS.21 28–30 Moreover, a recent article authored by O’Mara and colleagues reviewed the GWAS that identified most of the currently known SNPs associated with endometrial cancer.31Most of the studies represented in table 1 are GWAS and the majority of these involved broad European populations. Those having a multi-ethnic cohort also consisted primarily of broad European populations. Only four of the variants in table 1 are located in coding regions of a gene, or in regulatory flanking regions around the gene.

Thus, most of these variants would not be expected to cause any functional effects on the gene or the resulting protein. An eQTL search using GTEx Portal showed that some of the SNPs are significantly associated (p<0.05) with modified transcription levels of the respective genes in various tissues such as prostate (rs11263761), thyroid (rs9668337), pituitary (rs2747716), breast mammary (rs882380) and testicular (rs2498794) tissue, as summarised in table 2.View this table:Table 2 List of eQTL hits for the selected panel of SNPsThe only variant for which there was an indication of a specific association with non-endometrioid endometrial cancer was rs148261157 near the BCL11A gene. The A allele of this SNP had a moderately higher association in the non-endometrioid arm (OR 1.64, 95% CI 1.32 to 2.04.

P=9.6×10-6) compared with the endometrioid arm (OR 1.25, 95% CI 1.14 to 1.38. P=4.7×10-6).21Oestrogen receptors α and β encoded by ESR1 and ESR2, respectively, have been extensively studied due to the assumed role of oestrogens in the development of endometrial cancer. O’Mara et al reported a lead SNP (rs79575945) in the ESR1 region that was associated with endometrial cancer (p=1.86×10-5).24 However, this SNP did not reach genome-wide significance in a more recent larger GWAS.21 No statistically significant associations have been reported between endometrial cancer and SNPs in the ESR2 gene region.AKT is an oncogene linked to endometrial carcinogenesis.

It is involved in the PI3K/AKT/mTOR pro-proliferative signalling pathway to inactivate apoptosis and allow cell survival. The A allele of rs2494737 and G allele of rs2498796 were reported to be associated with increased and decreased risk of endometrial cancer in 2016, respectively.22 30 However, this association was not replicated in a larger GWAS in 2018.21 Nevertheless, given the previous strong indications, and biological basis that could explain endometrial carcinogenesis, we decided to include an AKT1 variant (rs2498794) in our results.PTEN is a multi-functional tumour suppressor gene that regulates the AKT/PKB signalling pathway and is commonly mutated in many cancers including endometrial cancer.32 Loss-of-function germline mutations in PTEN are responsible for Cowden syndrome, which exerts a lifetime risk of endometrial cancer of up to 28%.9 Lacey and colleagues studied SNPs in the PTEN gene region. However, none showed significant differences in frequency between 447 endometrial cancer cases and 439 controls of European ancestry.33KRAS mutations are known to be present in endometrial cancer.

These can be activated by high levels of KLF5 (transcriptional activator). Three SNPs have been identified in or around KLF5 that are associated with endometrial cancer. The G allele of rs11841589 (OR 1.15, 95% CI 1.11 to 1.21.

P=4.83×10-11), the A allele of rs9600103 (OR 1.23, 95% CI 1.16 to 1.30. P=3.76×10-12) and C allele of rs7981863 (OR 1.16, 95% CI 1.12 to 1.20. P=2.70×10-17) have all been found to be associated with an increased likelihood of endometrial cancer in large European cohorts.21 30 34 It is worth noting that these SNPs are not independent, and hence they quite possibly tag the same causal variant.The MYC family of proto-oncogenes encode transcription factors that regulate cell proliferation, which can contribute to cancer development if dysregulated.

The recent GWAS by O’Mara et al reported three SNPs within the MYC region that reached genome-wide significance with conditional p values reaching at least 5×10–8.35To test the utility of these SNPs as predictive markers, we devised a theoretical PRS calculation using the log ORs and EAFs per SNP from the published data. The results were very encouraging with an RR of 3.16 for the top 1% versus the mean, using all the top SNPs presented in table 1 and 2.09 when using only the SNPs that reached genome-wide significance (including AKT1).Controversy surrounding MDM2 variant SNP309MDM2 negatively regulates tumour suppressor gene TP53, and as such, has been extensively studied in relation to its potential role in predisposition to endometrial cancer. Our search identified six original studies of the association between MDM2 SNP rs2279744 (also referred to as SNP309) and endometrial cancer, all of which found a statistically significant increased risk per copy of the G allele.

Two more original studies were identified through our full-text evaluation. However, these were not included here as they did not meet our inclusion criteria—one due to small sample size, the other due to studying rs2279744 status dependent on another SNP.36 37 Even so, the two studies were described in multiple meta-analyses that are listed in table 3. Different permutations of these eight original studies appear in at least eight published meta-analyses.

However, even the largest meta-analysis contained <2000 cases (table 3)38View this table:Table 3 Characteristics of studies that examined MDM2 SNP rs2279744In comparison, a GWAS including nearly 13 000 cases found no evidence of an association with OR and corresponding 95% CI of 1.00 (0.97 to 1.03) and a p value of 0.93 (personal communication).21 Nevertheless, we cannot completely rule out a role for MDM2 variants in endometrial cancer predisposition as the candidate-gene studies reported larger effects in Asians, whereas the GWAS primarily contained participants of European ancestry. There is also some suggestion that the SNP309 variant is in linkage disequilibrium with another variant, SNP285, which confers an opposite effect.It is worth noting that the SNP285C/SNP309G haplotype frequency was observed in up to 8% of Europeans, thus requiring correction for the confounding effect of SNP285C in European studies.39 However, aside from one study conducted by Knappskog et al, no other study including the meta-analyses corrected for the confounding effect of SNP285.40 Among the studies presented in table 3, Knappskog et al (2012) reported that after correcting for SNP285, the OR for association of this haplotype with endometrial cancer was much lower, though still significant. Unfortunately, the meta-analyses which synthesised Knappskog et al (2012), as part of their analysis, did not correct for SNP285C in the European-based studies they included.38 41 42 It is also concerning that two meta-analyses using the same primary articles failed to report the same result, in two instances.38 42–44DiscussionThis article represents the most comprehensive systematic review to date, regarding critical appraisal of the available evidence of common low-penetrance variants implicated in predisposition to endometrial cancer.

We have identified the most robust SNPs in the context of endometrial cancer risk. Of those, only 19 were significant at genome-wide level and a further five were considered marginally significant. The largest GWAS conducted in this field was the discovery- and meta-GWAS by O’Mara et al, which utilised 12 096 cases and 108 979 controls.21 Despite the inclusion of all published GWAS and around 5000 newly genotyped cases, the total number did not reach anywhere near what is currently available for other common cancers such as breast cancer.

For instance, BCAC (Breast Cancer Association Consortium) stands at well over 200 000 individuals with more than half being cases, and resulted in identification of ~170 SNPs in relation to breast cancer.19 45 A total of 313 SNPs including imputations were then used to derive a PRS for breast cancer.19 Therefore, further efforts should be directed to recruit more patients, with deep phenotypic clinical data to allow for relevant adjustments and subgroup analyses to be conducted for better precision.A recent pre-print study by Zhang and colleagues examined the polygenicity and potential for SNP-based risk prediction for 14 common cancers, including endometrial cancer, using available summary-level data from European-ancestry datasets.46 They estimated that there are just over 1000 independent endometrial cancer susceptibility SNPs, and that a PRS comprising all such SNPs would have an area under the receiver-operator curve of 0.64, similar to that predicted for ovarian cancer, but lower than that for the other cancers in the study. The modelling in the paper suggests that an endometrial cancer GWAS double the size of the current largest study would be able to identify susceptibility SNPs together explaining 40% of the genetic variance, but that in order to explain 75% of the genetic variance it would be necessary to have a GWAS comprising close to 150 000 cases and controls, far in excess of what is currently feasible.We found that the literature consists mainly of candidate-gene studies with small sample sizes, meta-analyses reporting conflicting results despite using the same set of primary articles, and multiple reports of significant SNPs that have not been validated by any larger GWAS. The candidate-gene studies were indeed the most useful and cheaper technique available until the mid to late 2000s.

However, a lack of reproducibility (particularly due to population stratification and reporting bias), uncertainty of reported associations, and considerably high false discovery rates make these studies much less appropriate in the post-GWAS era. Unlike the candidate-gene approach, GWAS do not require prior knowledge, selection of genes or SNPs, and provide vast amounts of data. Furthermore, both the genotyping process and data analysis phases have become cheaper, the latter particularly due to faster and open-access pre-phasing and imputation tools being made available.It is clear from table 1 that some SNPs were reported with wide 95% CI, which can be directly attributed to small sample sizes particularly when restricting the cases to non-endometrioid histology only, low EAF or poor imputation quality.

Thus, these should be interpreted with caution. Additionally, most of the SNPs reported by candidate-gene studies were not detected by the largest GWAS to date conducted by O’Mara et al.21 However, this does not necessarily mean that the possibility of those SNPs being relevant should be completely dismissed. Moreover, meta-analyses were attempted for other variants.

However, these showed no statistically significant association and many presented with high heterogeneity between the respective studies (data not shown). Furthermore, as many studies utilised the same set of cases and/or controls, conducting a meta-analysis was not possible for a good number of SNPs. It is therefore unequivocal that the literature is crowded with numerous small candidate-gene studies and conflicting data.

This makes it particularly hard to detect novel SNPs and conduct meaningful meta-analyses.We found convincing evidence for 19 variants that indicated the strongest association with endometrial cancer, as shown in table 1. The associations between endometrial cancer and variants in or around HNF1B, CYP19A1, SOX4, MYC, KLF and EIF2AK found in earlier GWAS were then replicated in the latest and largest GWAS. These SNPs showed promising potential in a theoretical PRS we devised based on published data.

Using all 24 or genome-wide significant SNPs only, women with a PRS in the top 1% of the distribution would be predicted to have a risk of endometrial cancer 3.16 and 2.09 times higher than the mean risk, respectively.However, the importance of these variants and relevance of the proximate genes in a functional or biological context is challenging to evaluate. Long distance promoter regulation by enhancers may disguise the genuine target gene. In addition, enhancers often do not loop to the nearest gene, further complicating the relevance of nearby gene(s) to a GWAS hit.

In order to elucidate biologically relevant candidate target genes in endometrial cancer, O’Mara et al looked into promoter-associated chromatin looping using a modern HiChIP approach.47 The authors utilised normal and tumoural endometrial cell lines for this analysis which showed significant enrichment for endometrial cancer heritability, with 103 candidate target genes identified across the 13 risk loci identified by the largest ECAC GWAS. Notable genes identified here were CDKN2A and WT1, and their antisense counterparts. The former was reported to be nearby of rs1679014 and the latter of rs10835920, as shown in table 1.

Moreover, of the 36 candidate target genes, 17 were found to be downregulated while 19 were upregulated in endometrial tumours.The authors also investigated overlap between the 13 endometrial cancer risk loci and top eQTL variants for each target gene.47 In whole blood, of the two particular lead SNPs, rs8822380 at 17q21.32 was a top eQTL for SNX11 and HOXB2, whereas rs937213 at 15q15.1 was a top eQTL for SRP14. In endometrial tumour, rs7579014 at 2p16.1 was found to be a top eQTL for BCL11A. This is particularly interesting because BCL11A was the only nearby/candidate gene that had a GWAS association reported in both endometrioid and non-endometrioid subtypes.

The study looked at protein–protein interactions between endometrial cancer drivers and candidate target gene products. Significant interactions were observed with TP53 (most significant), AKT, PTEN, ESR1 and KRAS, among others. Finally, when 103 target candidate genes and 387 proteins were combined together, 462 pathways were found to be significantly enriched.

Many of these are related to gene regulation, cancer, obesity, insulinaemia and oestrogen exposure. This study clearly showed a potential biological relevance for some of the SNPs reported by ECAC GWAS in 2018.Most of the larger included studies used cohorts primarily composed of women of broad European descent. Hence, there are negligible data available for other ethnicities, particularly African women.

This is compounded by the lack of reference genotype data available for comparative analysis, making it harder for research to be conducted in ethnicities other than Europeans. This poses a problem for developing risk prediction models that are equally valuable and predictive across populations. Thus, our results also are of limited applicability to non-European populations.Furthermore, considering that non-endometrioid cases comprise a small proportion (~20%) of all endometrial cancer cases, much larger cohort sizes are needed to detect any genuine signals for non-endometrioid tumours.

Most of the evaluated studies looked at either overall/mixed endometrial cancer subtypes or endometrioid histology, and those that looked at variant associations with non-endometrioid histology were unlikely to have enough power to detect any signal with statistical significance. This is particularly concerning because non-endometrioid subtypes are biologically aggressive tumours with a much poorer prognosis that contribute disproportionately to mortality from endometrial cancer. It is particularly important that attempts to improve early detection and prevention of endometrial cancer focus primarily on improving outcomes from these subtypes.

It is also worth noting that, despite the current shift towards a molecular classification of endometrial cancer, most studies used the overarching classical Bokhman’s classification system, type I versus type II, or no histological classification system at all. Therefore, it is important to create and follow a standardised and comprehensive classification system for reporting tumour subtypes for future studies.This study compiled and presented available information for an extensively studied, yet unproven in large datasets, SNP309 variant in MDM2. Currently, there is no convincing evidence for an association between this variant and endometrial cancer risk.

Additionally, of all the studies, only one accounted for the opposing effect of a nearby variant SNP285 in their analyses. Thus, we conclude that until confirmed by a sufficiently large GWAS, this variant should not be considered significant in influencing the risk of endometrial cancer and therefore not included in a PRS. This is also true for the majority of the SNPs reported in candidate-gene studies, as the numbers fall far short of being able to detect genuine signals.This systematic review presents the most up-to-date evidence for endometrial cancer susceptibility variants, emphasising the need for further large-scale studies to identify more variants of importance, and validation of these associations.

Until data from larger and more diverse cohorts are available, the top 24 SNPs presented here are the most robust common genetic variants that affect endometrial cancer risk. The multiplicative effects of these SNPs could be used in a PRS to allow personalised risk prediction models to be developed for targeted screening and prevention interventions for women at greatest risk of endometrial cancer..

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Latest Sleep symbicort 6gm News By Dennis ThompsonHealthDay ReporterTHURSDAY, Aug. 27, 2020A frequent need to nap could be a red flag for future heart problems and a higher risk of early death, a new analysis concludes.Long naps lasting more than an hour are associated with a 34% elevated risk of heart disease and a symbicort 6gm 30% greater risk of death, according to the combined results of 20 previous studies.Overall, naps of any length were associated with a 19% increased risk of premature death, a Chinese research team found. The study results were released Wednesday for presentation at the virtual annual meeting of the European Society of Cardiology."If you want to take a siesta, our study indicates it's safest to keep it under an hour," lead researcher Zhe Pan of Guangzhou Medical University said in a society news release. "For those of us not in the habit of a daytime slumber, there is no convincing evidence to start."For their study, the researchers analyzed data from 20 studies symbicort 6gm involving more than 313,000 participants.

About two in five people in the studies said they nap.The investigators found that the connection was more pronounced in people aged 65 and older. These older folks had a 27% higher risk of death associated with napping and a 36% greater risk of heart disease symbicort 6gm. Women also had a stronger association between napping and poor health, with a 22% greater risk of death symbicort 6gm and a 31% greater risk of heart problems.Interestingly, long naps were linked with an increased risk of death in people who sleep more than six hours a night. That would seem to rule out poor sleep as an explanation for the increased risk of death and heart health issues.Adults who get less than seven hours of sleep each night are more likely to say they've had a heart attack, according to the U.S.

Centers for symbicort 6gm Disease Control and Prevention. Poor sleep also has been linked to high blood pressure, type 2 diabetes and obesity, all of which increase the risk of heart disease, heart attack and stroke.Pan speculated that long naps might affect the body because they are associated with higher levels of inflammation.But heart health experts said that just because you're sleeping through the night doesn't mean you've gotten a good night's sleep -- something for which this study doesn't account.Regarding how well you're resting at night, napping "might be a sign that there's something else going on," said Dr. Nieca Goldberg, a cardiologist and director of the NYU Langone Center symbicort 6gm for Women's Health, in New York City."What kind of sleep were these individuals getting?. " Goldberg said of the study participants symbicort 6gm.

"Were they waking up at night?. Did they symbicort 6gm have sleep apnea?. "Dr. Matthew Tomey, a cardiologist with Mount Sinai Morningside in New York City, agreed that these folks might be suffering from poor sleep."Some people take naps as a symbicort 6gm matter of habit, or they take a power nap," Tomey said.

"For others, they're taking potentially longer naps during the daytime because of too little or too poor quality sleep at night."People should take a nap when they feel like it, but if they regularly need naps that could be a sign of trouble, Tomey said."If they notice that they feel excessively sleepy during the daytime, needing multiple or long naps, that's a wake-up call to pay attention to the quality and quantity of their nighttime sleep," he added.People who frequently nap should talk with their doctor about their sleep issues, since they might be suffering from sleep apnea or some other issue that disrupts quality sleep, Tomey and Goldberg said.Good sleep habits, according to the CDC, include:Sticking to a regular sleep schedule.Getting enough natural light during the day, to positively influence brain chemicals related to sleep.Exercising regularly, but not within a few hours of bedtime.Avoiding artificial light near bedtime.Keeping your bedroom cool, dark and quiet.Copyright © 2020 HealthDay. All rights symbicort 6gm reserved. SLIDESHOW symbicort 6gm Sleep Disorders. Foods That Help Sleep or Keep You Awake See Slideshow References SOURCES.

Nieca Goldberg, MD, cardiologist and director, symbicort 6gm NYU Langone Center for Women's Health, New York City. Matthew Tomey, MD, cardiologist, Mount Sinai Morningside, New York City. European Society of Cardiology, annual meeting.Latest Heart News By Serena McNiffHealthDay ReporterWEDNESDAY, symbicort 6gm Aug. 26, 2020 (HealthDay News)Most strokes strike when an artery in the brain suddenly becomes blocked, but new research shows a rarer cause of strokes is becoming more common.It's called cerebral venous thrombosis (CVT), and it happens when a vein in the brain is clogged.

While CVT is estimated to cause less than 1% of all strokes, scientists discovered it is now more prevalent and affecting a symbicort 6gm different demographic than previously thought.Study author Dr. Fadar Otite and his colleagues pored over years of hospital records from New York and Florida to find out how symbicort 6gm many cases of CVT occurred in these states between 2006 and 2016. Otite is an assistant professor of neurology at SUNY Upstate Medical University in Syracuse, N.Y.Based on the data they analyzed, the researchers estimated that the number of CVT cases in the United States rose from around 14 cases per million in 2006 to 20 cases per million in 2014."We still find that the incidence of CVT is less than 1% of all strokes, even across our study period, but the incidence increased by 70% over time," Otite said. "In 2006, the proportion symbicort 6gm of all strokes that were CVT was 0.47%.

At the end of our study, which was in 2016, that proportion increased to 0.80%."CVT causes blood clots to form in the veins of the brain. These veins drain blood that has already been used by brain cells, sending it back to the heart to be replenished symbicort 6gm with oxygen. If a clot forms in one of these veins, it may leak into the symbicort 6gm surrounding brain tissue and could cause a stroke, the researchers explained.While CVT is still most common in young women -- about two-thirds of all CVT hospitalizations included in the study were in females -- the researchers found that the number of cases among this demographic did not increase over the 10-year study period. Instead, they saw increases in CVT among men and older women."Part of the message is that we agree that CVT is still more common in women, but because of the diverse clinical presentation of CVT, when other symptoms that may be attributable to CVT are present in other demographics, we should take them with more seriousness," Otite said.Another major finding was that CVT incidence in Black people was significantly higher than in other races.

But why that is the case symbicort 6gm remains unknown. "We have no clear explanation, because this is truly the first study to ever relate the incidence of CVT between races," he added.Several factors may put one at a higher risk of developing CVT, including pregnancy and taking hormonal birth control pills, which may be why it is more common in younger women, the researchers noted.And many of the risk factors for CVT -- like blood clotting disorders or medications that cause clotting, severe dehydration, infections of the ear, face or neck, head trauma, obesity and cancer -- are somewhat different from the triggers typically associated with stroke.It is important for clinicians to be aware of this rise in CVT incidence because the condition can easily be confused as something else, Otite said. Patients with CVT may symbicort 6gm have unspecific complaints such as headaches, blurry vision or seizures.Around 3% of patients in a prior study who had CVT and went to the hospital were diagnosed with something else and sent home, according to Otite. "So, it's important to recognize this from the start, because by the next time the clinical condition may be worse," he said.CVT can be treated with medication to thin the blood and help prevent further clotting, which may not be prescribed if the condition isn't properly diagnosed, he added.Dr.

Jose Biller, chair of symbicort 6gm the neurology department at Loyola University Medical Center in Hines, Ill., said the takeaway from this study is that more attention should be paid to CVT."I think that there should be an increased awareness of cerebral venous thrombosis because, by and large, when people think about stroke, they don't think about it," Biller said. "There should be an increasing level of awareness because this is a condition that has a specific treatment."The study was published symbicort 6gm online Aug. 26 in the journal Neurology.Copyright © 2020 HealthDay. All rights symbicort 6gm reserved.

SLIDESHOW Stroke Causes, Symptoms, and Recovery See Slideshow References SOURCES. Fadar Oliver Otite, MD, symbicort 6gm assistant professor, neurology, State University of New York (SUNY) Upstate Medical University, Syracuse, N.Y.. Jose Biller, MD, symbicort 6gm chair, department of neurology, Loyola University Medical Center, Hines, Ill.. Neurology, Aug.

26, 2020, onlineLatest Hearing symbicort 6gm News WEDNESDAY, Aug. 26, 2020 (HealthDay News)Even if they appear unresponsive, dying people may still be able to hear.That's the takeaway from a Canadian analysis of hospice patients in Vancouver.Researchers compared electroencephalography (EEG) data -- a measure of electrical activity in the brain -- collected when patients were conscious and when they became unresponsive at the end of life. Those patients were compared to a healthy control group.The study looked at brain response to various patterns of common and rare sounds that changed frequency, and found that responses of some of the dying patients were similar to those of healthy people -- even symbicort 6gm hours before death."In the last hours before an expected natural death, many people enter a period of unresponsiveness," said lead author Elizabeth Blundon, a doctoral student in psychology at the University of British Columbia at the time of the study."Our data shows that a dying brain can respond to sound, even in an unconscious state, up to the last hours of life," she said in a university news release.Co-author Lawrence Ward, a professor of psychology, said researchers were able to identify specific mental processes in both groups of participants."We had to look very carefully at the individual control participants' data, to see if each one of them showed a particular type of brain response before we felt confident that the unresponsive patient's brain reacted similarly," he said in the release.The findings were recently published in the journal Scientific Reports."This research gives credence to the fact that hospice nurses and physicians noticed that the sounds of loved ones helped comfort people when they were dying," said study co-author Dr. Romayne Gallagher, a now-retired palliative care physician at St.

John Hospice in Vancouver."And to me, it adds significant meaning to the last days and hours of life and shows that being symbicort 6gm present, in person or by phone, is meaningful," she said. "It is a comfort to be able to say goodbye and express love."While the evidence of brain activity supports the idea that dying people might hear, it's not known if they're aware of what they're hearing, Blundon noted."Their brains responded to the auditory stimuli, but we can't possibly know if they're remembering, identifying voices, or understanding language," she said symbicort 6gm. "There are all these other questions that have yet to be answered. This first glimpse supports the idea that we have to keep talking to people when they are dying symbicort 6gm because something is happening in their brain."-- Robert PreidtCopyright © 2020 HealthDay.

All rights reserved. QUESTION What is symbicort 6gm hearing loss?. See Answer References SOURCE symbicort 6gm. University of British Columbia, news release, July 8, 2020Latest Pregnancy News THURSDAY, Aug.

27, 2020 (HealthDay News)A new case study adds to growing evidence that the new coronavirus can be transmitted from a pregnant woman to her fetus."It's very important to bring to the forefront this finding that mothers and infants can be affected by COVID-19, transmission can occur symbicort 6gm during pregnancy, and pregnant mothers need to protect themselves," said Dr. Amanda Evans, senior author of the report."We don't know whether there are any long-term effects of COVID-19 infection in babies," she added. Evans is an assistant symbicort 6gm professor of pediatrics specializing in infectious diseases at UT Southwestern (UTSW) Medical Center in Dallas.The case involved a woman who was 34 weeks pregnant. She visited the emergency department at Parkland Memorial Hospital in Dallas with signs of premature labor and was admitted when she tested positive for SARS-CoV-2, the virus that causes COVID-19.Though the patient didn't have the typical respiratory symptoms associated with COVID-19, she did have a fever and diarrhea, suggesting possible viral infection.

Before going to the hospital, she didn't know she had the coronavirus.After a few days symbicort 6gm in the hospital, the woman gave birth in early May to a 7-pound, 3-ounce girl who initially appeared healthy. After 24 hours, however, symbicort 6gm the baby developed a fever and signs of respiratory distress, including an abnormally high breathing rate and lower blood-oxygen levels. Tests showed that she had COVID-19.Study first author Dr. Julide Sisman, an associate professor symbicort 6gm of pediatrics who cared for the newborn, said, "At that time, the knowledge we had was that transmission doesn't occur in utero, so we really weren't expecting that at all."Further investigation showed the baby was infected while in the womb.

Both mother and baby fully recovered, according to the case study published online recently in The Pediatric Infectious Disease Journal.More than 20 million people worldwide have been infected with the new coronavirus, but data on how it affects pregnant women have been limited, the authors noted in a UTSW news release."The fact that this can occur, even if rare, illustrates how important it is to limit exposure for mothers and newborns," said Dr. Wilmer Moreno, an assistant professor of obstetrics symbicort 6gm and gynecology at UTSW. "Anything, like telemedicine visits, that can eliminate the need for mom to be around other people will be very helpful."-- Robert PreidtCopyright © 2020 HealthDay. All rights reserved.

SLIDESHOW Conception. The Amazing Journey from Egg to Embryo See Slideshow References SOURCE. UT Southwestern Medical Center, news release, Aug. 24, 2020.

Latest Sleep News By Dennis ThompsonHealthDay ReporterTHURSDAY, buy symbicort online with free samples Aug. 27, 2020A frequent need to nap could be a red flag for future heart problems and a higher risk of early death, a new analysis concludes.Long naps lasting more than an hour are associated with a 34% elevated buy symbicort online with free samples risk of heart disease and a 30% greater risk of death, according to the combined results of 20 previous studies.Overall, naps of any length were associated with a 19% increased risk of premature death, a Chinese research team found. The study results were released Wednesday for presentation at the virtual annual meeting of the European Society of Cardiology."If you want to take a siesta, our study indicates it's safest to keep it under an hour," lead researcher Zhe Pan of Guangzhou Medical University said in a society news release. "For those of us not in the habit buy symbicort online with free samples of a daytime slumber, there is no convincing evidence to start."For their study, the researchers analyzed data from 20 studies involving more than 313,000 participants. About two in five people in the studies said they nap.The investigators found that the connection was more pronounced in people aged 65 and older.

These older folks had a 27% higher risk of buy symbicort online with free samples death associated with napping and a 36% greater risk of heart disease. Women also had a stronger association between napping and poor health, with a 22% greater risk of death and a 31% greater risk of heart problems.Interestingly, long naps were linked with an increased risk of death in people who sleep more buy symbicort online with free samples than six hours a night. That would seem to rule out poor sleep as an explanation for the increased risk of death and heart health issues.Adults who get less than seven hours of sleep each night are more likely to say they've had a heart attack, according to the U.S. Centers for Disease Control buy symbicort online with free samples and Prevention. Poor sleep also has been linked to high blood pressure, type 2 diabetes and obesity, all of which increase the risk of heart disease, heart attack and stroke.Pan speculated that long naps might affect the body because they are associated with higher levels of inflammation.But heart health experts said that just because you're sleeping through the night doesn't mean you've gotten a good night's sleep -- something for which this study doesn't account.Regarding how well you're resting at night, napping "might be a sign that there's something else going on," said Dr.

Nieca Goldberg, a cardiologist and director of the NYU Langone Center for Women's Health, in New York City."What kind buy symbicort online with free samples of sleep were these individuals getting?. " Goldberg buy symbicort online with free samples said of the study participants. "Were they waking up at night?. Did they have sleep apnea? buy symbicort online with free samples. "Dr.

Matthew Tomey, a cardiologist with Mount Sinai Morningside in New York City, agreed that these folks might be suffering from poor sleep."Some people take naps as a matter of habit, or they buy symbicort online with free samples take a power nap," Tomey said. "For others, they're taking potentially longer naps during the daytime because of too little or too poor quality sleep at night."People should take a nap when they feel like it, but if they regularly need naps that could be a sign of trouble, Tomey said."If they notice that they feel excessively sleepy during the daytime, needing multiple or long naps, that's a wake-up call to pay attention to the quality and quantity of their nighttime sleep," he added.People who frequently nap should talk with their doctor about their sleep issues, since they might be suffering from sleep apnea or some other issue that disrupts quality sleep, Tomey and Goldberg said.Good sleep habits, according to the CDC, include:Sticking to a regular sleep schedule.Getting enough natural light during the day, to positively influence brain chemicals related to sleep.Exercising regularly, but not within a few hours of bedtime.Avoiding artificial light near bedtime.Keeping your bedroom cool, dark and quiet.Copyright © 2020 HealthDay. All rights reserved buy symbicort online with free samples. SLIDESHOW buy symbicort online with free samples Sleep Disorders. Foods That Help Sleep or Keep You Awake See Slideshow References SOURCES.

Nieca Goldberg, MD, cardiologist and director, NYU Langone Center for Women's Health, New York City buy symbicort online with free samples. Matthew Tomey, MD, cardiologist, Mount Sinai Morningside, New York City. European Society of Cardiology, annual meeting.Latest Heart News By Serena McNiffHealthDay buy symbicort online with free samples ReporterWEDNESDAY, Aug. 26, 2020 (HealthDay News)Most strokes strike when an artery in the brain suddenly becomes blocked, but new research shows a rarer cause of strokes is becoming more common.It's called cerebral venous thrombosis (CVT), and it happens when a vein in the brain is clogged. While CVT buy symbicort online with free samples is estimated to cause less than 1% of all strokes, scientists discovered it is now more prevalent and affecting a different demographic than previously thought.Study author Dr.

Fadar Otite and his colleagues pored over years of hospital records from New York and Florida buy symbicort online with free samples to find out how many cases of CVT occurred in these states between 2006 and 2016. Otite is an assistant professor of neurology at SUNY Upstate Medical University in Syracuse, N.Y.Based on the data they analyzed, the researchers estimated that the number of CVT cases in the United States rose from around 14 cases per million in 2006 to 20 cases per million in 2014."We still find that the incidence of CVT is less than 1% of all strokes, even across our study period, but the incidence increased by 70% over time," Otite said. "In 2006, the proportion of all strokes buy symbicort online with free samples that were CVT was 0.47%. At the end of our study, which was in 2016, that proportion increased to 0.80%."CVT causes blood clots to form in the veins of the brain. These veins drain blood that has already been used buy symbicort online with free samples by brain cells, sending it back to the heart to be replenished with oxygen.

If a clot forms in one of these veins, it may leak into the surrounding brain tissue buy symbicort online with free samples and could cause a stroke, the researchers explained.While CVT is still most common in young women -- about two-thirds of all CVT hospitalizations included in the study were in females -- the researchers found that the number of cases among this demographic did not increase over the 10-year study period. Instead, they saw increases in CVT among men and older women."Part of the message is that we agree that CVT is still more common in women, but because of the diverse clinical presentation of CVT, when other symptoms that may be attributable to CVT are present in other demographics, we should take them with more seriousness," Otite said.Another major finding was that CVT incidence in Black people was significantly higher than in other races. But why that is the buy symbicort online with free samples case remains unknown. "We have no clear explanation, because this is truly the first study to ever relate the incidence of CVT between races," he added.Several factors may put one at a higher risk of developing CVT, including pregnancy and taking hormonal birth control pills, which may be why it is more common in younger women, the researchers noted.And many of the risk factors for CVT -- like blood clotting disorders or medications that cause clotting, severe dehydration, infections of the ear, face or neck, head trauma, obesity and cancer -- are somewhat different from the triggers typically associated with stroke.It is important for clinicians to be aware of this rise in CVT incidence because the condition can easily be confused as something else, Otite said. Patients with CVT may have unspecific complaints such as headaches, blurry vision or seizures.Around 3% of patients in a buy symbicort online with free samples prior study who had CVT and went to the hospital were diagnosed with something else and sent home, according to Otite.

"So, it's important to recognize this from the start, because by the next time the clinical condition may be worse," he said.CVT can be treated with medication to thin the blood and help prevent further clotting, which may not be prescribed if the condition isn't properly diagnosed, he added.Dr. Jose Biller, chair of the buy symbicort online with free samples neurology department at Loyola University Medical Center in Hines, Ill., said the takeaway from this study is that more attention should be paid to CVT."I think that there should be an increased awareness of cerebral venous thrombosis because, by and large, when people think about stroke, they don't think about it," Biller said. "There should be an increasing level of awareness because this is a buy symbicort online with free samples condition that has a specific treatment."The study was published online Aug. 26 in the journal Neurology.Copyright © 2020 HealthDay. All rights buy symbicort online with free samples reserved.

SLIDESHOW Stroke Causes, Symptoms, and Recovery See Slideshow References SOURCES. Fadar Oliver Otite, MD, assistant professor, neurology, State University of New buy symbicort online with free samples York (SUNY) Upstate Medical University, Syracuse, N.Y.. Jose Biller, MD, chair, department of neurology, Loyola University Medical buy symbicort online with free samples Center, Hines, Ill.. Neurology, Aug. 26, 2020, onlineLatest Hearing News buy symbicort online with free samples WEDNESDAY, Aug.

26, 2020 (HealthDay News)Even if they appear unresponsive, dying people may still be able to hear.That's the takeaway from a Canadian analysis of hospice patients in Vancouver.Researchers compared electroencephalography (EEG) data -- a measure of electrical activity in the brain -- collected when patients were conscious and when they became unresponsive at the end of life. Those patients were compared to a healthy control group.The study looked at brain response to various patterns of common and rare sounds that changed frequency, and found that responses of some buy symbicort online with free samples of the dying patients were similar to those of healthy people -- even hours before death."In the last hours before an expected natural death, many people enter a period of unresponsiveness," said lead author Elizabeth Blundon, a doctoral student in psychology at the University of British Columbia at the time of the study."Our data shows that a dying brain can respond to sound, even in an unconscious state, up to the last hours of life," she said in a university news release.Co-author Lawrence Ward, a professor of psychology, said researchers were able to identify specific mental processes in both groups of participants."We had to look very carefully at the individual control participants' data, to see if each one of them showed a particular type of brain response before we felt confident that the unresponsive patient's brain reacted similarly," he said in the release.The findings were recently published in the journal Scientific Reports."This research gives credence to the fact that hospice nurses and physicians noticed that the sounds of loved ones helped comfort people when they were dying," said study co-author Dr. Romayne Gallagher, a now-retired palliative care physician at St. John Hospice in Vancouver."And to me, it adds significant meaning to the last days and hours of life buy symbicort online with free samples and shows that being present, in person or by phone, is meaningful," she said. "It is a comfort to be able to say goodbye and express love."While the evidence of brain activity supports the idea that dying people might hear, it's not known if buy symbicort online with free samples they're aware of what they're hearing, Blundon noted."Their brains responded to the auditory stimuli, but we can't possibly know if they're remembering, identifying voices, or understanding language," she said.

"There are all these other questions that have yet to be answered. This first glimpse supports the buy symbicort online with free samples idea that we have to keep talking to people when they are dying because something is happening in their brain."-- Robert PreidtCopyright © 2020 HealthDay. All rights reserved. QUESTION What is hearing loss? buy symbicort online with free samples. See Answer References SOURCE buy symbicort online with free samples.

University of British Columbia, news release, July 8, 2020Latest Pregnancy News THURSDAY, Aug. 27, 2020 (HealthDay News)A new case study adds to growing evidence that the new coronavirus can be transmitted from a pregnant woman to her fetus."It's very important to bring to the forefront this finding that buy symbicort online with free samples mothers and infants can be affected by COVID-19, transmission can occur during pregnancy, and pregnant mothers need to protect themselves," said Dr. Amanda Evans, senior author of the report."We don't know whether there are any long-term effects of COVID-19 infection in babies," she added. Evans is an assistant professor of pediatrics specializing in infectious diseases at UT Southwestern (UTSW) Medical Center in Dallas.The case involved a woman who was buy symbicort online with free samples 34 weeks pregnant. She visited the emergency department at Parkland Memorial Hospital in Dallas with signs of premature labor and was admitted when she tested positive for SARS-CoV-2, the virus that causes COVID-19.Though the patient didn't have the typical respiratory symptoms associated with COVID-19, she did have a fever and diarrhea, suggesting possible viral infection.

Before going to the hospital, she didn't know she had the coronavirus.After a few days in the hospital, the woman gave birth in early buy symbicort online with free samples May to a 7-pound, 3-ounce girl who initially appeared healthy. After 24 hours, however, the baby developed a fever and signs buy symbicort online with free samples of respiratory distress, including an abnormally high breathing rate and lower blood-oxygen levels. Tests showed that she had COVID-19.Study first author Dr. Julide Sisman, an associate professor of pediatrics who cared for the newborn, said, "At that time, the knowledge we had was that transmission doesn't occur in utero, so we really weren't expecting that at all."Further investigation showed the baby was infected while in the womb. Both mother and baby fully recovered, according to the case study published online recently in The Pediatric Infectious Disease Journal.More than 20 million people worldwide have been infected with the new coronavirus, but data on how it affects pregnant women have been limited, the authors noted in a UTSW news release."The fact that this can occur, even if rare, illustrates how important it is to limit exposure for mothers and newborns," said Dr.

Wilmer Moreno, an assistant professor of obstetrics and gynecology at UTSW. "Anything, like telemedicine visits, that can eliminate the need for mom to be around other people will be very helpful."-- Robert PreidtCopyright © 2020 HealthDay. All rights reserved. SLIDESHOW Conception. The Amazing Journey from Egg to Embryo See Slideshow References SOURCE.

UT Southwestern Medical Center, news release, Aug. 24, 2020.

Symbicort for copd

NONE

Astronomers have pinned down our universe's expansion rate, the mean density of its main constituents, symbicort for copd and other key numbers to a precision of 1 or 2 percent. They have also worked out new laws of physics governing space—general relativity and quantum mechanics—that turn out to be much more outlandish than the classical laws people understood before. These laws in turn predicted cosmic oddities such as black holes, neutron stars and gravitational waves. The story of how we gained this knowledge is symbicort for copd full of accidental discoveries, stunning surprises and dogged scientists pursuing goals others thought unreachable. Our first hint of the true nature of stars came in 1860, when Gustav Kirchhoff recognized that the dark lines in the spectrum of light coming from the sun were caused by different elements absorbing specific wavelengths.

Astronomers analyzed similar features in the light of other bright stars and discovered that they were made of the same materials found on Earth—not of some mysterious “fifth essence” as the ancients had believed. But it took longer to understand what fuel made symbicort for copd the stars shine. Lord Kelvin (William Thomson) calculated that if stars derived their power just from gravity, slowly deflating as their radiation leaked out, then the sun's age was 20 million to 40 million years—far less time than Charles Darwin or the geologists of the time inferred had elapsed on Earth. In his last paper on the subject, in 1908, Kelvin inserted an escape clause stating that he would stick by his estimate “unless there were some other energy source laid up in the storehouse of creation.” That source, it turned out, is nuclear fusion—the process by which atomic nuclei join to create a larger nucleus and release energy. In 1925 astrophysicist Cecilia Payne-Gaposchkin used the light spectra of stars to calculate their chemical abundances and found that, unlike Earth, they were made mainly of hydrogen and symbicort for copd helium.

She revealed her conclusions in what astronomer Otto Struve described as “the most brilliant Ph.D. Thesis ever written in astronomy.” A decade later physicist Hans Bethe showed that the fusion of hydrogen nuclei into helium was the main power source in ordinary stars. What is the symbicort for copd source of the sun's power?. The answer—fusion—came in 1938. Credit.

SOHO (ESA and NASA) At the same time stars were becoming less symbicort for copd mysterious, so, too, was the nature of fuzzy “nebulae” becoming clearer. In a “great debate” held before the National Academy of Sciences in Washington, D.C., on April 26, 1920, Harlow Shapley maintained that our Milky Way was preeminent and that all the nebulae were part of it. In contrast, Heber Curtis argued that some of the fuzzy objects in the sky were separate galaxies—“island universes”—fully the equal of our Milky Way. The conflict was settled not that night but just a few years later, in 1924, when Edwin Hubble symbicort for copd measured the distances to many nebulae and proved they were beyond the reaches of the Milky Way. His evidence came from Cepheids, variable stars in the nebulae that reveal their true brightness, and thus their distance, by their pulsation period—a relation discovered by Henrietta Swan Leavitt.

Soon after Hubble realized that the universe was bigger than many had thought, he found that it was still growing. In 1929 he discovered that spectral features in the starlight from distant galaxies appeared redder—that is, they had symbicort for copd longer wavelengths—than the same features in nearby stars. If this effect was interpreted as a Doppler shift—the natural spreading of waves as they recede—it would imply that other galaxies were moving away from one another and from us. Indeed, the farther away they were, the faster their recession seemed to be. This was the first clue symbicort for copd that our cosmos was not static but was expanding all the time.

The universe also appeared to contain much that we could not see. In 1933 Fritz Zwicky estimated the mass of all the stars in the Coma cluster of galaxies and found that they make up only about 1 percent of the mass necessary to keep the cluster from flying apart. The discrepancy symbicort for copd was dubbed “the missing mass problem,” but many scientists at the time doubted Zwicky's suggestion that hidden matter might be to blame. The question remained divisive until the 1970s, when work by Vera Rubin and W. Kent Ford (observing stars) and by Morton Roberts and Robert Whitehurst (making radio observations) showed that the outer parts of galactic disks would also fly apart unless they were subject to a stronger gravitational pull than stars and gas alone could provide.

Finally, most astronomers were compelled to accept that some symbicort for copd kind of “dark matter” must be present. €œWe have peered into a new world,” Rubin wrote, “and have seen that it is more mysterious and more complex than we had imagined.” Scientists now believe that dark matter outnumbers visible matter by about a factor of five, yet we are hardly closer than we were in the 1930s to figuring out what it is. Gravity, the force that revealed all that dark matter, has proved to be nearly as baffling. A pivotal moment came in 1915 when Albert symbicort for copd Einstein published his general theory of relativity, which transcended Isaac Newton's mechanics and revealed that gravity is actually the deformation of the fabric of space and time. This new theory was slow to take hold.

Even after it was shown to be correct by observations of a 1919 solar eclipse, many dismissed the theory as an interesting quirk—after all, Newton's laws were still good enough for calculating most things. €œThe discoveries, while very important, did not, however, affect anything on this earth,” symbicort for copd astronomer W.J.S. Lockyer told the New York Times after the eclipse. For almost half a century after it was proposed, general relativity was sidelined from the mainstream of physics. Then, beginning in the 1960s, symbicort for copd astronomers started discovering new and extreme phenomena that only Einstein's ideas could explain.

One example lurks in the Crab Nebula, one of the best-known objects in the sky, which is composed of the expanding debris from a supernova witnessed by Chinese astronomers in a.d. 1054. Since it appeared, the nebula symbicort for copd has kept on shining blue and bright—but how?. Its light source was a longtime puzzle, but the answer came in 1968, when the dim star at its center was revealed to be anything but normal. It was actually an ultracompact neutron star, heavier than the sun but only a few miles in radius and spinning at 30 revolutions per second.

€œThis was a totally unexpected, totally new kind of object behaving in a way that astronomers had never expected, never dreamt of,” said Jocelyn Bell Burnell, symbicort for copd one of the discoverers of the phenomenon. The star's excessive spin sends out a wind of fast electrons that generate the blue light. The gravitational force at the surface of such an incredibly dense object falls way outside of Newton's purview—a rocket would need to be fired at half the speed of light to escape its pull. Here the relativistic effects predicted by Einstein must be taken into symbicort for copd account. Thousands of such spinning neutron stars—called pulsars—have been discovered.

All are believed to be remnants of the cores of stars that exploded as supernovae, offering an ideal laboratory for studying the laws of nature under extreme conditions. The most exotic result of Einstein's theory was the concept of black holes—objects that have collapsed so far that symbicort for copd not even light can escape their gravitational pull. For decades these were only conjecture, and Einstein wrote in 1939 that they “do not exist in physical reality.” But in 1963 astronomers discovered quasars. Mysterious, hyperluminous beacons in the centers of some galaxies. More than symbicort for copd a decade passed before a consensus emerged that this intense brightness was generated by gas swirling into huge black holes lurking in the galaxies' cores.

It was the strongest evidence yet that these bizarre predictions of general relativity actually exist. When did the universe begin?. Did it even have a beginning? symbicort for copd. Astronomers had long debated these questions when, in the middle of the 20th century, two competing theories proposed very different answers. The “hot big bang” model said the cosmos began extremely small, hot and dense and then cooled and spread out over time.

The “steady state” hypothesis held that the universe symbicort for copd had essentially existed in the same form forever. The contest was settled by a serendipitous discovery. In 1965 radio astronomers Arno Penzias and Robert Wilson were trying to calibrate a new antenna at Bell Labs in New Jersey. They had a problem symbicort for copd. No matter what they did to reduce background interference, they measured a consistent level of noise in every direction.

They even evicted a family of pigeons that had been nesting in the antenna in the hope that they were the source of the problem. But the symbicort for copd signal persisted. They had discovered that intergalactic space is not completely cold. Instead it is warmed to nearly three kelvins (just above absolute zero) by weak microwaves. Penzias and Wilson had symbicort for copd accidentally uncovered the “afterglow of creation”—the cooled and diluted relic of an era when everything in the universe was squeezed until it was hot and dense.

The finding tipped the balance firmly in favor of the big bang picture of cosmology. According to the model, during the earliest, hottest epochs of time, the universe was opaque, rather like the inside of a star, and light was repeatedly scattered by electrons. When the temperature fell to symbicort for copd 3,000 kelvins, however, the electrons slowed down enough to be captured by protons and created neutral atoms. Thereafter light could travel freely. The Bell Labs signal was this ancient light, first released about 300,000 years after the birth of the universe and still pervading the cosmos—what we call the cosmic microwave background.

It took a symbicort for copd while for the magnitude of the discovery to sink in for the scientists who made it. €œWe were very pleased to have a possible explanation [for the antenna noise], but I don't think either of us really took the cosmology very seriously at first,” Wilson says. €œWalter Sullivan wrote a first-page article in the New York Times about it, and I began to think at that point that, you know, maybe I better start taking this cosmology seriously.” Measurements of this radiation have since enabled scientists to understand how galaxies emerged. Precise observations of the microwaves reveal that they are not symbicort for copd completely uniform over the sky. Some patches are slightly hotter, others slightly cooler.

The amplitude of these fluctuations is only one part in 100,000, but they are the seeds of today's cosmic structure. Any region of the expanding universe symbicort for copd that started off slightly denser than average expanded less because it was subjected to extra gravity. Its growth lagged further and further, the contrast between its density and that of its surroundings becoming greater and greater. Eventually these clumps were dense enough that gas was pulled in and compressed into stars, forming galaxies. The crucial point is symbicort for copd this.

Computer models that simulate this process are fed the initial fluctuations measured in the cosmic microwave background, which represent the universe when it was 300,000 years old. The output after 13.8 billion years of virtual time have elapsed is a cosmos where galaxies resemble those we see, clustered as they are in the actual universe. This is a real triumph symbicort for copd. We understand, at least in outline, 99.998 percent of cosmic history. It is not only the big cosmic picture that we have come to understand.

A series of discoveries has symbicort for copd also revealed the history of the elemental building blocks that make up stars, planets and even our own bodies. Starting in the 1950s, progress in atomic physics led to accurate modeling of stars' surface layers. Simultaneously, detailed knowledge of the nuclei not just of hydrogen and helium atoms but also of the rest of the elements allowed scientists to calculate which nuclear reactions dominate at different stages in a star's life. Astronomers came to understand how nuclear fusion creates an onion-skin structure in massive stars as atoms successively fuse to build heavier and heavier elements, ending with iron in the innermost, hottest layer. Inside the Crab Nebula is a neutron star symbicort for copd.

Classical physics fails, and relativity applies. Credit. NASA, ESA and Hubble Heritage Team (STSCI and AURA) Astronomers also learned how stars die when they exhaust their hydrogen fuel and blow off symbicort for copd their outer gaseous layers. Lighter stars then settle down to a quiet demise as dense, dim objects called white dwarfs, but heavier stars shed more of their mass, either in winds during their lives or in an explosive death via supernova. This expelled mass turns out to be crucial to our own existence.

It mixes into the symbicort for copd interstellar medium and recondenses into new stars orbited by planets such as Earth. The concept was conceived by Fred Hoyle, who developed it during the 1950s along with two other British astronomers, Margaret Burbidge and Geoffrey Burbidge, and American nuclear physicist William Fowler. In their classic 1957 paper in Reviews of Modern Physics (known by the initials of its authors as BBFH), they analyzed the networks of the nuclear reactions involved and discovered how most atoms in the periodic table came to exist. They calculated why oxygen and carbon, for instance, are common, whereas gold and uranium symbicort for copd are rare. Our galaxy, it turns out, is a huge ecological system where gas is being recycled through successive generations of stars.

Each of us contains atoms forged in dozens of different stars spread across the Milky Way that lived and died more than 4.5 billion years ago. Scientists long symbicort for copd assumed this process was seeding planets—and possibly even life—around stars other than our own sun. But we did not know for sure whether planets existed outside our solar system until the 1990s, when astronomers developed clever methods for identifying worlds that are too dim for us to see directly. One technique looks for tiny periodic changes in a star's movement caused by the gravitational pull of a planet orbiting it. In 1995 Michel Mayor and Didier Queloz used this strategy to detect 51 symbicort for copd Pegasi b, the first known exoplanet orbiting a sunlike star.

The technique can reveal a planet's mass, the length of its “year” and the shape of its orbit. So far more than 800 exoplanets have been found this way. A second technique symbicort for copd works better for smaller planets. A star dims slightly when a planet transits in front of it. An Earth-like planet passing a sunlike star can cause a dimming of about one part in 10,000 once per orbit.

The Kepler spacecraft launched in 2009 found more than symbicort for copd 2,000 planets this way, many no bigger than Earth. A big surprise to come from astronomers' success in planet hunting was the variety of different planets out there—many much larger and closer to their stars than the bodies in our solar system—suggesting that our cosmic neighborhood may be somewhat special. By this point scientists understood where almost all the elements that form planets, stars and galaxies originated. The final piece in this puzzle, symbicort for copd however, arrived very recently and from a seemingly unrelated inquiry. General relativity had predicted a phenomenon called gravitational waves—ripples in spacetime produced by the movement of massive objects.

Despite decades of searching for them, however, no waves were seen—until September 2015. That was when the Laser Interferometer Gravitational-wave Observatory symbicort for copd (LIGO) detected the first evidence of gravitational waves in the form of a “chirp”—a minute shaking of spacetime that speeds up and then dies away. In this case, it was caused by two black holes in a binary system that had started out orbiting each other but gradually spiraled together and eventually converged into a single massive hole. The crash occurred more than a billion light-years away. LIGO's detectors consist of mirrors four kilometers apart whose separation is measured by laser beams symbicort for copd that reflect light back and forth between them.

A passing gravitational wave causes the space between the two mirrors to jitter by an amount millions of times as small as the diameter of a single atom—LIGO is indeed an amazing feat of precision engineering and perseverance. Since that first find, more than a dozen similar events have been detected, opening up a new field that probes the dynamics of space itself. One event was of special astrophysical interest because symbicort for copd it signaled the merger of two pulsars. Unlike black hole mergers, this kind of collision, a splat between two ultradense stars, yields a pulse of optical light, x-rays and gamma rays. The discovery filled a gap in the classic work of BBFH.

The authors had explained the genesis of many of the elements in space but were flummoxed by the forging of symbicort for copd gold. In the 1970s David N. Schramm and his colleagues had speculated that the exotic nuclear processes involved in hypothetical mergers of pulsar stars might do the job—a theory that has since been validated. Despite the incredible progress in astronomy over the past 175 years, we have perhaps more symbicort for copd questions now than we did back then. Take dark matter.

I am on record as having said more than 20 years ago that we would know dark matter's nature long before today. Although that prediction has proved wrong, I have not given up hope symbicort for copd. Dark energy, however, is a different story. Dark energy entered the picture in 1998, when researchers measuring the distances and speeds of supernovae found that the expansion of the universe was actually accelerating. Gravitational attraction pulling galaxies toward one another seemed to be overwhelmed by a mysterious new force latent symbicort for copd in empty space that pushes galaxies apart—a force that came to be known as dark energy.

The mystery of dark energy has lingered—we still do not know what causes it or why it has the particular strength it does—and we probably will not understand it until we have a model for the graininess of space on a scale a billion billion times smaller than an atomic nucleus. Theorists working on string theory or loop quantum gravity are tackling this challenge, but the phenomenon seems so far from being accessible by any experiment that I am not expecting answers anytime soon. The upside, however, is that a theory that could account for the energy in the vacuum of space might also yield insights into the very beginning of our universe, when everything symbicort for copd was so compressed and dense that quantum fluctuations could shake the entire cosmos. Which brings us to another major question facing us now. How did it all begin?.

What exactly set off the big bang that started our symbicort for copd universe?. Did space undergo a period of extremely rapid early expansion called inflation, as many theorists believe?. And there is something else. Some models, symbicort for copd such as eternal inflation, suggest that “our” big bang could be just one island of spacetime in a vast archipelago—one big bang among many. If this hypothesis is true, different big bangs may cool down differently, leading to unique laws of physics in each case—a “multiverse” rather than a universe.

Some physicists hate the multiverse concept because it means that we will never have neat explanations for the fundamental numbers that govern our physical laws, which may in this grander perspective be just environmental accidents. But our preferences are irrelevant symbicort for copd to nature. About 10 years ago I was on a panel at Stanford University where we were asked by someone in the audience how much we would bet on the multiverse concept. I said that on a scale of betting my goldfish, my dog or my life, I was nearly at the dog level. Andrei Linde, who had spent 25 symbicort for copd years promoting eternal inflation, said he would almost bet his life.

Later, on being told this, physicist Steven Weinberg said he would happily bet my dog and Linde's life. Linde, my dog and I will all be dead before the question is settled. But none of this should be dismissed as metaphysics symbicort for copd. It is speculative science—exciting science. And it may be true.

And what will happen to this universe—or multiverse—of symbicort for copd ours?. Long-range forecasts are seldom reliable, but the best and most conservative bet is that we have almost an eternity ahead with an ever colder and ever emptier cosmos. Galaxies will accelerate away and disappear. All that will be left from our vantage point will symbicort for copd be the remnants of the Milky Way, Andromeda and smaller neighbors. Protons may decay, dark matter particles may be annihilated, there may be occasional flashes when black holes evaporate—and then silence.

This possible future is based on the assumption that the dark energy stays constant. If it decays, symbicort for copd however, there could be a “big crunch” with the universe contracting in on itself. Or if dark energy strengthens, there would be a “big rip” when galaxies, stars and even atoms are torn apart. Other questions closer to home tantalize us. Could there be life on any of these new planets we are discovering? symbicort for copd.

Here we are still in the realm of speculation. But unless the origin of life on Earth involved a rare fluke, I expect evidence of a biosphere on an exoplanet within 20 years. I will symbicort for copd not hold my breath for the discovery of aliens, but I think the search for extraterrestrial intelligence is a worthwhile gamble. Success in the search would carry the momentous message that concepts of logic and physics are not limited to the hardware in human skulls. Until now, progress in cosmology and astrophysics has owed 95 percent to advancing instruments and technology and less than 5 percent to armchair theory.

I expect that symbicort for copd balance to persist. What Hubble wrote in the 1930s remains a good maxim today. €œNot until the empirical resources are exhausted, need we pass on to the dreamy realms of speculation.” There have been many particularly exhilarating eras in the past 175 years—the 1920s and 1930s, when we realized the universe was not limited to the Milky Way, and the 1960s and 1970s, when we discovered objects that defy classical physics, such as neutron stars and quasars, and clues about the beginning of time from the cosmic microwave background. Since then, the pace of advancement has crescendoed symbicort for copd rather than slackened. When the history of science gets written, this amazing progress will be acclaimed as one of its greatest triumphs—up there with plate tectonics, the genome and the Standard Model of particle physics.

And some major fields in astronomy are just getting going. Exoplanet research is only 25 years old, and serious work in astrobiology is really only starting. Some exoplanets may have life—they may even harbor aliens who know all the answers already. I find that encouraging. Credit.

Not only does it extend beyond the buy symbicort online with free samples Milky Way to untold numbers of other galaxies—this would come as a surprise to astronomers of the 19th and early 20th century to whom our galaxy was “the universe”—but it is expanding faster every day. Now we can confidently trace cosmic history back 13.8 billion years to a moment only a billionth of a second after the big bang. Astronomers have pinned down our universe's expansion rate, the mean density of its main constituents, and other key numbers to a precision of 1 or 2 percent. They have also buy symbicort online with free samples worked out new laws of physics governing space—general relativity and quantum mechanics—that turn out to be much more outlandish than the classical laws people understood before.

These laws in turn predicted cosmic oddities such as black holes, neutron stars and gravitational waves. The story of how we gained this knowledge is full of accidental discoveries, stunning surprises and dogged scientists pursuing goals others thought unreachable. Our first hint of the true nature of stars came in 1860, when Gustav Kirchhoff recognized that the dark lines in the spectrum of light coming from the sun were caused by different elements absorbing specific wavelengths buy symbicort online with free samples. Astronomers analyzed similar features in the light of other bright stars and discovered that they were made of the same materials found on Earth—not of some mysterious “fifth essence” as the ancients had believed.

But it took longer to understand what fuel made the stars shine. Lord Kelvin (William Thomson) calculated that if stars derived their power just from gravity, slowly deflating as their radiation leaked out, then buy symbicort online with free samples the sun's age was 20 million to 40 million years—far less time than Charles Darwin or the geologists of the time inferred had elapsed on Earth. In his last paper on the subject, in 1908, Kelvin inserted an escape clause stating that he would stick by his estimate “unless there were some other energy source laid up in the storehouse of creation.” That source, it turned out, is nuclear fusion—the process by which atomic nuclei join to create a larger nucleus and release energy. In 1925 astrophysicist Cecilia Payne-Gaposchkin used the light spectra of stars to calculate their chemical abundances and found that, unlike Earth, they were made mainly of hydrogen and helium.

She revealed her conclusions in what buy symbicort online with free samples astronomer Otto Struve described as “the most brilliant Ph.D. Thesis ever written in astronomy.” A decade later physicist Hans Bethe showed that the fusion of hydrogen nuclei into helium was the main power source in ordinary stars. What is the source of the sun's power?. The answer—fusion—came in 1938 buy symbicort online with free samples.

Credit. SOHO (ESA and NASA) At the same time stars were becoming less mysterious, so, too, was the nature of fuzzy “nebulae” becoming clearer. In a “great debate” held before the National Academy of Sciences in Washington, D.C., on April 26, 1920, Harlow Shapley maintained that our Milky Way was preeminent and that all the nebulae were part buy symbicort online with free samples of it. In contrast, Heber Curtis argued that some of the fuzzy objects in the sky were separate galaxies—“island universes”—fully the equal of our Milky Way.

The conflict was settled not that night but just a few years later, in 1924, when Edwin Hubble measured the distances to many nebulae and proved they were beyond the reaches of the Milky Way. His evidence came from Cepheids, variable stars in the nebulae that reveal their true brightness, and thus buy symbicort online with free samples their distance, by their pulsation period—a relation discovered by Henrietta Swan Leavitt. Soon after Hubble realized that the universe was bigger than many had thought, he found that it was still growing. In 1929 he discovered that spectral features in the starlight from distant galaxies appeared redder—that is, they had longer wavelengths—than the same features in nearby stars.

If this effect was buy symbicort online with free samples interpreted as a Doppler shift—the natural spreading of waves as they recede—it would imply that other galaxies were moving away from one another and from us. Indeed, the farther away they were, the faster their recession seemed to be. This was the first clue that our cosmos was not static but was expanding all the time. The universe also appeared to contain much buy symbicort online with free samples that we could not see.

In 1933 Fritz Zwicky estimated the mass of all the stars in the Coma cluster of galaxies and found that they make up only about 1 percent of the mass necessary to keep the cluster from flying apart. The discrepancy was dubbed “the missing mass problem,” but many scientists at the time doubted Zwicky's suggestion that hidden matter might be to blame. The question remained divisive buy symbicort online with free samples until the 1970s, when work by Vera Rubin and W. Kent Ford (observing stars) and by Morton Roberts and Robert Whitehurst (making radio observations) showed that the outer parts of galactic disks would also fly apart unless they were subject to a stronger gravitational pull than stars and gas alone could provide.

Finally, most astronomers were compelled to accept that some kind of “dark matter” must be present. €œWe have peered into a new world,” Rubin wrote, “and have seen that it buy symbicort online with free samples is more mysterious and more complex than we had imagined.” Scientists now believe that dark matter outnumbers visible matter by about a factor of five, yet we are hardly closer than we were in the 1930s to figuring out what it is. Gravity, the force that revealed all that dark matter, has proved to be nearly as baffling. A pivotal moment came in 1915 when Albert Einstein published his general theory of relativity, which transcended Isaac Newton's mechanics and revealed that gravity is actually the deformation of the fabric of space and time.

This new theory buy symbicort online with free samples was slow to take hold. Even after it was shown to be correct by observations of a 1919 solar eclipse, many dismissed the theory as an interesting quirk—after all, Newton's laws were still good enough for calculating most things. €œThe discoveries, while very important, did not, however, affect anything on this earth,” astronomer W.J.S. Lockyer told buy symbicort online with free samples the New York Times after the eclipse.

For almost half a century after it was proposed, general relativity was sidelined from the mainstream of physics. Then, beginning in the 1960s, astronomers started discovering new and extreme phenomena that only Einstein's ideas could explain. One example lurks in the Crab Nebula, one of the best-known objects in the sky, which buy symbicort online with free samples is composed of the expanding debris from a supernova witnessed by Chinese astronomers in a.d. 1054.

Since it appeared, the nebula has kept on shining blue and bright—but how?. Its light source was a longtime puzzle, but the answer came in 1968, when buy symbicort online with free samples the dim star at its center was revealed to be anything but normal. It was actually an ultracompact neutron star, heavier than the sun but only a few miles in radius and spinning at 30 revolutions per second. €œThis was a totally unexpected, totally new kind of object behaving in a way that astronomers had never expected, never dreamt of,” said Jocelyn Bell Burnell, one of the discoverers of the phenomenon.

The star's excessive spin sends out a wind of fast electrons that generate the buy symbicort online with free samples blue light. The gravitational force at the surface of such an incredibly dense object falls way outside of Newton's purview—a rocket would need to be fired at half the speed of light to escape its pull. Here the relativistic effects predicted by Einstein must be taken into account. Thousands of such spinning buy symbicort online with free samples neutron stars—called pulsars—have been discovered.

All are believed to be remnants of the cores of stars that exploded as supernovae, offering an ideal laboratory for studying the laws of nature under extreme conditions. The most exotic result of Einstein's theory was the concept of black holes—objects that have collapsed so far that not even light can escape their gravitational pull. For decades these were only conjecture, and Einstein wrote in 1939 that they “do not exist in physical reality.” But in 1963 astronomers discovered buy symbicort online with free samples quasars. Mysterious, hyperluminous beacons in the centers of some galaxies.

More than a decade passed before a consensus emerged that this intense brightness was generated by gas swirling into huge black holes lurking in the galaxies' cores. It was the strongest evidence yet that these bizarre predictions of general relativity actually buy symbicort online with free samples exist. When did the universe begin?. Did it even have a beginning?.

Astronomers buy symbicort online with free samples had long debated these questions when, in the middle of the 20th century, two competing theories proposed very different answers. The “hot big bang” model said the cosmos began extremely small, hot and dense and then cooled and spread out over time. The “steady state” hypothesis held that the universe had essentially existed in the same form forever. The contest buy symbicort online with free samples was settled by a serendipitous discovery.

In 1965 radio astronomers Arno Penzias and Robert Wilson were trying to calibrate a new antenna at Bell Labs in New Jersey. They had a problem. No matter what they did buy symbicort online with free samples to reduce background interference, they measured a consistent level of noise in every direction. They even evicted a family of pigeons that had been nesting in the antenna in the hope that they were the source of the problem.

But the signal persisted. They had discovered that intergalactic space is buy symbicort online with free samples not completely cold. Instead it is warmed to nearly three kelvins (just above absolute zero) by weak microwaves. Penzias and Wilson had accidentally uncovered the “afterglow of creation”—the cooled and diluted relic of an era when everything in the universe was squeezed until it was hot and dense.

The finding tipped the balance firmly in favor of the big buy symbicort online with free samples bang picture of cosmology. According to the model, during the earliest, hottest epochs of time, the universe was opaque, rather like the inside of a star, and light was repeatedly scattered by electrons. When the temperature fell to 3,000 kelvins, however, the electrons slowed down enough to be captured by protons and created neutral atoms. Thereafter light buy symbicort online with free samples could travel freely.

The Bell Labs signal was this ancient light, first released about 300,000 years after the birth of the universe and still pervading the cosmos—what we call the cosmic microwave background. It took a while for the magnitude of the discovery to sink in for the scientists who made it. €œWe were very pleased to have a buy symbicort online with free samples possible explanation [for the antenna noise], but I don't think either of us really took the cosmology very seriously at first,” Wilson says. €œWalter Sullivan wrote a first-page article in the New York Times about it, and I began to think at that point that, you know, maybe I better start taking this cosmology seriously.” Measurements of this radiation have since enabled scientists to understand how galaxies emerged.

Precise observations of the microwaves reveal that they are not completely uniform over the sky. Some patches are slightly hotter, others slightly cooler buy symbicort online with free samples. The amplitude of these fluctuations is only one part in 100,000, but they are the seeds of today's cosmic structure. Any region of the expanding universe that started off slightly denser than average expanded less because it was subjected to extra gravity.

Its growth lagged further and buy symbicort online with free samples further, the contrast between its density and that of its surroundings becoming greater and greater. Eventually these clumps were dense enough that gas was pulled in and compressed into stars, forming galaxies. The crucial point is this. Computer models that simulate this process are fed the initial fluctuations measured in buy symbicort online with free samples the cosmic microwave background, which represent the universe when it was 300,000 years old.

The output after 13.8 billion years of virtual time have elapsed is a cosmos where galaxies resemble those we see, clustered as they are in the actual universe. This is a real triumph. We understand, buy symbicort online with free samples at least in outline, 99.998 percent of cosmic history. It is not only the big cosmic picture that we have come to understand.

A series of discoveries has also revealed the history of the elemental building blocks that make up stars, planets and even our own bodies. Starting in the 1950s, progress in atomic physics led to accurate modeling of stars' surface layers. Simultaneously, detailed knowledge of the nuclei not just of hydrogen and helium atoms but also of the rest of the buy symbicort online with free samples elements allowed scientists to calculate which nuclear reactions dominate at different stages in a star's life. Astronomers came to understand how nuclear fusion creates an onion-skin structure in massive stars as atoms successively fuse to build heavier and heavier elements, ending with iron in the innermost, hottest layer.

Inside the Crab Nebula is a neutron star. Classical physics fails, and relativity applies buy symbicort online with free samples. Credit. NASA, ESA and Hubble Heritage Team (STSCI and AURA) Astronomers also learned how stars die when they exhaust their hydrogen fuel and blow off their outer gaseous layers.

Lighter stars then settle down to a quiet demise as dense, dim objects buy symbicort online with free samples called white dwarfs, but heavier stars shed more of their mass, either in winds during their lives or in an explosive death via supernova. This expelled mass turns out to be crucial to our own existence. It mixes into the interstellar medium and recondenses into new stars orbited by planets such as Earth. The concept was conceived by Fred Hoyle, who developed it during the 1950s along with two other buy symbicort online with free samples British astronomers, Margaret Burbidge and Geoffrey Burbidge, and American nuclear physicist William Fowler.

In their classic 1957 paper in Reviews of Modern Physics (known by the initials of its authors as BBFH), they analyzed the networks of the nuclear reactions involved and discovered how most atoms in the periodic table came to exist. They calculated why oxygen and carbon, for instance, are common, whereas gold and uranium are rare. Our galaxy, it turns out, is a huge ecological buy symbicort online with free samples system where gas is being recycled through successive generations of stars. Each of us contains atoms forged in dozens of different stars spread across the Milky Way that lived and died more than 4.5 billion years ago.

Scientists long assumed this process was seeding planets—and possibly even life—around stars other than our own sun. But we did not know for sure whether planets existed outside our solar system until the 1990s, when astronomers developed clever methods for identifying worlds that are too dim for us buy symbicort online with free samples to see directly. One technique looks for tiny periodic changes in a star's movement caused by the gravitational pull of a planet orbiting it. In 1995 Michel Mayor and Didier Queloz used this strategy to detect 51 Pegasi b, the first known exoplanet orbiting a sunlike star.

The technique buy symbicort online with free samples can reveal a planet's mass, the length of its “year” and the shape of its orbit. So far more than 800 exoplanets have been found this way. A second technique works better for smaller planets. A star dims slightly when a planet transits in front of buy symbicort online with free samples it.

An Earth-like planet passing a sunlike star can cause a dimming of about one part in 10,000 once per orbit. The Kepler spacecraft launched in 2009 found more than 2,000 planets this way, many no bigger than Earth. A big surprise to come from astronomers' success in planet hunting was the variety of different planets out there—many much larger and closer to their stars than the bodies in our solar system—suggesting that our cosmic neighborhood may buy symbicort online with free samples be somewhat special. By this point scientists understood where almost all the elements that form planets, stars and galaxies originated.

The final piece in this puzzle, however, arrived very recently and from a seemingly unrelated inquiry. General relativity had predicted a phenomenon called gravitational waves—ripples in spacetime produced buy symbicort online with free samples by the movement of massive objects. Despite decades of searching for them, however, no waves were seen—until September 2015. That was when the Laser Interferometer Gravitational-wave Observatory (LIGO) detected the first evidence of gravitational waves in the form of a “chirp”—a minute shaking of spacetime that speeds up and then dies away.

In this case, it was caused by two black holes in a binary system that had started out orbiting each other but gradually spiraled together buy symbicort online with free samples and eventually converged into a single massive hole. The crash occurred more than a billion light-years away. LIGO's detectors consist of mirrors four kilometers apart whose separation is measured by laser beams that reflect light back and forth between them. A passing gravitational wave causes the space between the two mirrors to jitter buy symbicort online with free samples by an amount millions of times as small as the diameter of a single atom—LIGO is indeed an amazing feat of precision engineering and perseverance.

Since that first find, more than a dozen similar events have been detected, opening up a new field that probes the dynamics of space itself. One event was of special astrophysical interest because it signaled the merger of two pulsars. Unlike black hole mergers, this buy symbicort online with free samples kind of collision, a splat between two ultradense stars, yields a pulse of optical light, x-rays and gamma rays. The discovery filled a gap in the classic work of BBFH.

The authors had explained the genesis of many of the elements in space but were flummoxed by the forging of gold. In the buy symbicort online with free samples 1970s David N. Schramm and his colleagues had speculated that the exotic nuclear processes involved in hypothetical mergers of pulsar stars might do the job—a theory that has since been validated. Despite the incredible progress in astronomy over the past 175 years, we have perhaps more questions now than we did back then.

Take dark buy symbicort online with free samples matter. I am on record as having said more than 20 years ago that we would know dark matter's nature long before today. Although that prediction has proved wrong, I have not given up hope. Dark energy, however, is a buy symbicort online with free samples different story.

Dark energy entered the picture in 1998, when researchers measuring the distances and speeds of supernovae found that the expansion of the universe was actually accelerating. Gravitational attraction pulling galaxies toward one another seemed to be overwhelmed by a mysterious new force latent in empty space that pushes galaxies apart—a force that came to be known as dark energy. The mystery of dark energy has lingered—we still do not know what causes it or why it has the particular strength it does—and we probably will not understand it until we have a model for the graininess of space on a scale a billion billion times buy symbicort online with free samples smaller than an atomic nucleus. Theorists working on string theory or loop quantum gravity are tackling this challenge, but the phenomenon seems so far from being accessible by any experiment that I am not expecting answers anytime soon.

The upside, however, is that a theory that could account for the energy in the vacuum of space might also yield insights into the very beginning of our universe, when everything was so compressed and dense that quantum fluctuations could shake the entire cosmos. Which brings buy symbicort online with free samples us to another major question facing us now. How did it all begin?. What exactly set off the big bang that started our universe?.

Did space undergo a period of extremely rapid early expansion called buy symbicort online with free samples inflation, as many theorists believe?. And there is something else. Some models, such as eternal inflation, suggest that “our” big bang could be just one island of spacetime in a vast archipelago—one big bang among many. If this hypothesis is true, different big bangs may buy symbicort online with free samples cool down differently, leading to unique laws of physics in each case—a “multiverse” rather than a universe.

Some physicists hate the multiverse concept because it means that we will never have neat explanations for the fundamental numbers that govern our physical laws, which may in this grander perspective be just environmental accidents. But our preferences are irrelevant to nature. About 10 years ago I was on a panel at Stanford University where we were asked by buy symbicort online with free samples someone in the audience how much we would bet on the multiverse concept. I said that on a scale of betting my goldfish, my dog or my life, I was nearly at the dog level.

Andrei Linde, who had spent 25 years promoting eternal inflation, said he would almost bet his life. Later, on being told this, physicist Steven Weinberg said he would happily bet my dog and buy symbicort online with free samples Linde's life. Linde, my dog and I will all be dead before the question is settled. But none of this should be dismissed as metaphysics.

It is speculative science—exciting buy symbicort online with free samples science. And it may be true. And what will happen to this universe—or multiverse—of ours?. Long-range forecasts are seldom reliable, buy symbicort online with free samples but the best and most conservative bet is that we have almost an eternity ahead with an ever colder and ever emptier cosmos.

Galaxies will accelerate away and disappear. All that will be left from our vantage point will be the remnants of the Milky Way, Andromeda and smaller neighbors. Protons may decay, dark matter particles may be annihilated, there may buy symbicort online with free samples be occasional flashes when black holes evaporate—and then silence. This possible future is based on the assumption that the dark energy stays constant.

If it decays, however, there could be a “big crunch” with the universe contracting in on itself. Or if dark energy strengthens, there would be a “big rip” when galaxies, buy symbicort online with free samples stars and even atoms are torn apart. Other questions closer to home tantalize us. Could there be life on any of these new planets we are discovering?.

Here we are still buy symbicort online with free samples in the realm of speculation. But unless the origin of life on Earth involved a rare fluke, I expect evidence of a biosphere on an exoplanet within 20 years. I will not hold my breath for the discovery of aliens, but I think the search for extraterrestrial intelligence is a worthwhile gamble. Success in the search would carry the momentous message that concepts of buy symbicort online with free samples logic and physics are not limited to the hardware in human skulls.

Until now, progress in cosmology and astrophysics has owed 95 percent to advancing instruments and technology and less than 5 percent to armchair theory. I expect that balance to persist. What Hubble wrote in the 1930s remains a good maxim buy symbicort online with free samples today. €œNot until the empirical resources are exhausted, need we pass on to the dreamy realms of speculation.” There have been many particularly exhilarating eras in the past 175 years—the 1920s and 1930s, when we realized the universe was not limited to the Milky Way, and the 1960s and 1970s, when we discovered objects that defy classical physics, such as neutron stars and quasars, and clues about the beginning of time from the cosmic microwave background.

Since then, the pace of advancement has crescendoed rather than slackened. When the history of science gets written, this amazing progress will be acclaimed as one of its greatest triumphs—up there with plate tectonics, the genome and the Standard Model buy symbicort online with free samples of particle physics. And some major fields in astronomy are just getting going. Exoplanet research is only 25 years old, and serious work in astrobiology is really only starting.

Some exoplanets may have life—they may even harbor aliens who know all the answers already.

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Influenza affects millions of people each year, and because of the buy symbicort inhaler uk COVID-19 pandemic, many physicians and health experts are concerned that this year’s flu season will hit with full force. In the Lone Star State, it’s important for Texans to be proactive about their health by getting the yearly flu vaccination. One of the worst things that could happen would be having many people sick with the flu while many are ill with coronavirus.Flu vaccination is buy symbicort inhaler uk the best way to reduce the risk of getting and spreading the flu. This year, it also will help keep hospitalizations down as physicians, nurses, and other medical staff continue to care for COVID-19 patients.

Traditionally, Texas buy symbicort inhaler uk falls behind on flu vaccination. According to the Centers for Disease Control and Prevention (CDC), only 43.3% of Texas adults got a flu shot in 2018-2019, compared to the national average of 45.3%.Although influenza viruses circulate throughout the year, flu season usually starts in the fall and winter, and peaks between December and February.Like COVID-19, the flu is contagious. Both have some similar symptoms, including fever, chills, cough, buy symbicort inhaler uk fatigue, body aches, vomiting, and diarrhea. People with the flu may not experience symptoms until one to four days after catching the virus.

The CDC outlines key similarities and differences between influenza and COVID-19 here.While most people recover from the flu, many can experience complications, especially older adults, people with pre-existing buy symbicort inhaler uk medical conditions, young children, and pregnant women. If left untreated, infected patients can develop pneumonia, inflammation of the heart, brain, or muscle tissues, organ failure, sepsis, or they could even die. In Texas, buy symbicort inhaler uk more than 21,000 people died from the flu in the past two years. To put that into perspective, that is the population of Katy!.

Everyone 6 months or older is encouraged to get the flu vaccine each year – especially adults aged 65 and older, pregnant women, young children, and people who have chronic illnesses such as diabetes, asthma, and buy symbicort inhaler uk heart disease. The CDC is urging the public to get the flu vaccine while maintaining social distancing, wearing a mask in public, and practicing good hygiene.People who receive the flu shot may experience some mild side effects like aches and a mild fever, but they can’t get the flu from the shot. Those who get the flu after being vaccinated might have buy symbicort inhaler uk been exposed to the virus beforehand. The flu vaccination can help lessen flu symptoms and severity, helping reduce the amount of time spent away from work and school.In a time when community health is front and center, getting a flu shot is more important than ever.

The Texas Medical Association’s Be Wise Immunize℠ program recently created a downloadable poster below in English and Spanish with key buy symbicort inhaler uk takeaways about the flu vaccination. You can print the poster, or save it and share it on social media. Be Wise – Immunize is funded in 2020 by the TMA Foundation, thanks to major support from H-E-B and Permian Basin Youth Chavarim.Be Wise – Immunize is a service mark of the Texas Medical Association..

Influenza affects millions of people each year, and buy symbicort online with free samples because of the COVID-19 pandemic, many physicians and health experts are concerned that this year’s flu season will hit with full force. In the Lone Star State, it’s important for Texans to be proactive about their health by getting the yearly flu vaccination. One of the worst things that could happen would be having many people sick with the flu while many are ill with coronavirus.Flu vaccination is the best way to reduce the risk buy symbicort online with free samples of getting and spreading the flu.

This year, it also will help keep hospitalizations down as physicians, nurses, and other medical staff continue to care for COVID-19 patients. Traditionally, Texas falls buy symbicort online with free samples behind on flu vaccination. According to the Centers for Disease Control and Prevention (CDC), only 43.3% of Texas adults got a flu shot in 2018-2019, compared to the national average of 45.3%.Although influenza viruses circulate throughout the year, flu season usually starts in the fall and winter, and peaks between December and February.Like COVID-19, the flu is contagious.

Both have some buy symbicort online with free samples similar symptoms, including fever, chills, cough, fatigue, body aches, vomiting, and diarrhea. People with the flu may not experience symptoms until one to four days after catching the virus. The CDC outlines buy symbicort online with free samples key similarities and differences between influenza and COVID-19 here.While most people recover from the flu, many can experience complications, especially older adults, people with pre-existing medical conditions, young children, and pregnant women.

If left untreated, infected patients can develop pneumonia, inflammation of the heart, brain, or muscle tissues, organ failure, sepsis, or they could even die. In Texas, more than 21,000 people died from the buy symbicort online with free samples flu in the past two years. To put that into perspective, that is the population of Katy!.

Everyone 6 months or older is encouraged to get the flu vaccine each year – especially adults buy symbicort online with free samples aged 65 and older, pregnant women, young children, and people who have chronic illnesses such as diabetes, asthma, and heart disease. The CDC is urging the public to get the flu vaccine while maintaining social distancing, wearing a mask in public, and practicing good hygiene.People who receive the flu shot may experience some mild side effects like aches and a mild fever, but they can’t get the flu from the shot. Those who get the flu after being vaccinated might have been exposed buy symbicort online with free samples to the virus beforehand.

The flu vaccination can help lessen flu symptoms and severity, helping reduce the amount of time spent away from work and school.In a time when community health is front and center, getting a flu shot is more important than ever. The Texas Medical Association’s Be Wise Immunize℠ program recently created a downloadable poster below in English buy symbicort online with free samples and Spanish with key takeaways about the flu vaccination. You can print the poster, or save it and share it on social media.

Be Wise – Immunize is funded in 2020 by the TMA Foundation, thanks to major support from H-E-B and Permian Basin Youth Chavarim.Be Wise – Immunize is a service mark of the Texas Medical Association..

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Daily reporting and analysis The most comprehensive industry coverage from a powerhouse team of reporters Subscriber-only newsletters Daily newsletters to brief you on the most important industry news of the day STAT+ Conversations Weekly opportunities to engage with our reporters and leading industry experts in live video conversations Exclusive industry events Premium access to subscriber-only networking events around the country The best reporters in the industry The most trusted and well-connected newsroom in the health care industry And much more Exclusive interviews with industry leaders, profiles, and premium tools, like our CRISPR Trackr.A new report that aims to prioritize groups to receive Covid-19 vaccine focuses on who is at risk, rather than using job categories or ethnic groups to determine who should be at the front of the line.It was widely expected that health care workers would be the first priority grouping, and some — though not all — are. There were also many voices arguing for people of color to be given priority access, because the pandemic has exacted a disproportionately heavy toll on Black and Latinx people, both in terms of overall numbers of infections and deaths.But in the end the panel of experts that wrote the priority setting framework for the National Academies of Sciences, Engineering, and Medicine chose instead to focus on the factors that create the risk for some people of color — systemic racism that leads to higher levels of poor health and socioeconomic factors such as working in jobs that cannot be done from home or living in crowded settings. The report, a draft, was issued Tuesday.advertisement “This virus has no sense symbicort online in canada of skin color. But it can exploit vulnerabilities,” said Bill Foege, a former director of the Centers for Disease Control, who is co-chair of the committee. The committee was set up by the National Academies at the request of Francis Collins, director of the National Institutes of Health, and Robert Redfield, director of the symbicort online in canada Centers for Disease Control and Prevention.Foege said he expects pushback.

A virtual public meeting on the recommendations will be held Wednesday afternoon, and written comments can be submitted until Friday. The committee’s final report will be submitted later in September.advertisement When Covid-19 vaccines are symbicort online in canada approved for use, initial supplies will be tight — potentially in the tens of millions of doses. Most of the vaccines under development will require two doses per person. A priming dose followed by a booster either three or four weeks later.A phased approach outlined in the draft National Academy report. The National Academies of Sciences, Engineering and MedicineThe resulting recommendations put health workers in high risk settings and first responders to the very front of the vaccination line, in what the committee called the “jumpstart phase.” Closely behind are adults of any age who have medical conditions that put them at significantly higher risk of having severe disease, primarily heart or kidney failure or a symbicort online in canada body mass index of 40 and over.

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Remaining Americans who were not vaccinated in the first three groups would be offered vaccine during a fourth and final phase.The report is meant to serve as a guide for more detailed prioritization plans on the order in which Americans will be offered vaccine. That more granular work is already being conducted by the Advisory Committee on Immunization Practices, an expert panel that crafts vaccination guidance for the CDC, and by state, local, and tribal health authorities, who must identify the actual people in their regions who fall into the symbicort online in canada priority groups. The ACIP’s recommendations will go to the CDC. It remains unclear, however, whether the CDC, Operation Warp Speed — the task force set up to fast-track development of symbicort online in canada Covid-19 vaccines, drugs, and diagnostics — or the White House will make the final determinations on who will be vaccinated first.The draft report, produced in just a little over a month, earned some early praise.“I think they did a really good job,” said Eric Toner of the Johns Hopkins Center for Global Security, calling the report credible and based on sound reasoning.Toner and colleagues published their own report on the issue recently, recommending two tiers. Health workers and others essential to the Covid-19 response in the first tier and other health workers in the second.In that report, people at greatest risk and their caregivers, and workers most essential to maintaining core societal functions would also be designated to be in the first tier.

The task of determining who should be at the front of the vaccines line is not an easy one, and must be made without crucial pieces of information. It’s not yet known how many vaccines will prove to be successful, when they will be approved for use, and in what quantities. Critically, some vaccines may prove to be more effective in key groups — the elderly, for instance — than others. Knowing that in advance could influence the recommendations, but people working on the priority groups cannot wait for that information to become available.Initial discussions suggest, depending on how some of the target groups are defined, large numbers of Americans would qualify as members of priority groups, a reality that will likely require additional tough decisions to be made.The CDC estimates that there are between 17 million and 20 million health care workers in the country, and roughly 100 million people with medical conditions that put them at increased risk of severe illness if they contract Covid-19. There are roughly 53 million Americans aged 65 and older, and 100 million people in jobs designated as essential services.

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There were also many voices arguing for people of color to be given priority access, because the pandemic has exacted a disproportionately heavy toll on Black and Latinx people, both in terms of overall numbers of infections and deaths.But in the end the panel of experts that wrote the priority setting framework for the National Academies of Sciences, Engineering, and Medicine chose instead to focus on the factors that create the risk for some people of color — systemic racism that leads to higher levels of poor health and socioeconomic factors such as working in jobs that cannot be done from home or living in crowded settings. The report, a draft, was issued Tuesday.advertisement “This virus has no sense of skin buy symbicort online with free samples color. But it can exploit vulnerabilities,” said Bill Foege, a former director of the Centers for Disease Control, who is co-chair of the committee.

The committee was set up by the National Academies at the request of Francis Collins, director of the National Institutes of Health, and buy symbicort online with free samples Robert Redfield, director of the Centers for Disease Control and Prevention.Foege said he expects pushback. A virtual public meeting on the recommendations will be held Wednesday afternoon, and written comments can be submitted until Friday. The committee’s buy symbicort online with free samples final report will be submitted later in September.advertisement When Covid-19 vaccines are approved for use, initial supplies will be tight — potentially in the tens of millions of doses.

Most of the vaccines under development will require two doses per person. A priming dose followed by a booster either three or four weeks later.A phased approach outlined in the draft National Academy report. The National Academies of Sciences, Engineering and MedicineThe resulting recommendations put health workers in high risk settings and first responders to the very front of the vaccination line, in what the committee called the “jumpstart phase.” Closely behind are adults of any age who have medical conditions that put buy symbicort online with free samples them at significantly higher risk of having severe disease, primarily heart or kidney failure or a body mass index of 40 and over.

Also in this group are older adults living in long-term care homes or other crowded settings.The report suggests that a second phase of vaccinations should involve critical risk workers — people in industries essential to the functioning of society — as well as teachers and school staff. People of all ages with an buy symbicort online with free samples underlying health problem that moderately increases the risk of severe Covid-19. All older adults not vaccinated in the first phase.

People in homeless shelters and group homes, and prisons. And staff working in these facilities.Young adults, children, and workers in buy symbicort online with free samples essential industries not vaccinated previously would make up the third priority group. Remaining Americans who were not vaccinated in the first three groups would be offered vaccine during a fourth and final phase.The report is meant to serve as a guide for more detailed prioritization plans on the order in which Americans will be offered vaccine.

That more granular work is already being conducted by the Advisory Committee on Immunization Practices, an expert panel that crafts vaccination guidance for the CDC, and by state, buy symbicort online with free samples local, and tribal health authorities, who must identify the actual people in their regions who fall into the priority groups. The ACIP’s recommendations will go to the CDC. It remains unclear, however, whether the CDC, Operation Warp Speed — the task force set up to fast-track development of Covid-19 vaccines, drugs, and diagnostics — or the White House will make the final determinations on who will be vaccinated first.The draft report, produced in just buy symbicort online with free samples a little over a month, earned some early praise.“I think they did a really good job,” said Eric Toner of the Johns Hopkins Center for Global Security, calling the report credible and based on sound reasoning.Toner and colleagues published their own report on the issue recently, recommending two tiers.

Health workers and others essential to the Covid-19 response in the first tier and other health workers in the second.In that report, people at greatest risk and their caregivers, and workers most essential to maintaining core societal functions would also be designated to be in the first tier. The task of determining who should be at the front of the vaccines line is not an easy one, and must be made without crucial pieces of information. It’s not buy symbicort online with free samples yet known how many vaccines will prove to be successful, when they will be approved for use, and in what quantities.

Critically, some vaccines may prove to be more effective in key groups — the elderly, for instance — than others. Knowing that in advance could influence the recommendations, but people working on the priority groups cannot wait for that information to become available.Initial discussions suggest, depending on how some of the target groups are defined, large numbers of Americans would qualify as members of priority groups, a reality that will likely require additional tough decisions to be made.The CDC estimates that there are between 17 million and 20 million health care workers in the country, and roughly 100 million people with medical conditions that put them at increased risk of severe illness if they contract Covid-19. There are roughly 53 million Americans aged 65 and older, and 100 million people in jobs designated as essential services.

There is some overlap among these groups — health workers, for instance, are also essential workers..