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Researchers at the University of Maryland School of Medicine (UMSOM) have conducted a study that has determined the role that a critical protein plays buy zithromax pills in the development of hair cells. These hair buy zithromax pills cells are vital for hearing. Some of these cells amplify sounds that come into the ear, and others transform sound waves into electrical signals that travel to the brain.

Ronna Hertzano, MD, PhD, Associate Professor in the Department of Otorhinolaryngology Head and Neck Surgery at UMSOM and Maggie Matern, PhD, a postdoctoral fellow at Stanford University, demonstrated that the protein, called GFI1, may be critical for determining whether an embryonic hair cell matures into a functional adult hair cell or becomes a different cell that functions more like a nerve cell or neuron.The study was published in the journal Development, and was conducted by physician-scientists and researchers at the UMSOM Department of Otorhinolaryngology Head and Neck Surgery and the UMSOM Institute for Genome buy zithromax pills Sciences (IGS), in collaboration with researchers at the Sackler School of Medicine at Tel Aviv University in Israel.Hearing relies on the proper functioning of specialized cells within the inner ear called hair cells. When the hair cells do not develop properly or are damaged by environmental stresses like loud noise, it results in a loss of hearing function.In the United States, the prevalence of hearing loss doubles with every 10-year increase in age, affecting about half of all adults in their 70s and about 80 percent of those who are over age 85. Researchers have been buy zithromax pills focusing on describing the developmental steps that lead to a functional hair cell, in order to potentially generate new hair cells when old ones are damaged.Hair cells in the inner earTo conduct her latest study, Dr.

Hertzano and her team utilized cutting-edge methods to study gene expression in the hair cells of genetically modified newborn mice that did not produce GFI1 buy zithromax pills. They demonstrated that, in the absence of this vital protein, embryonic hair cells failed to progress in their development to become fully functional adult cells. In fact, the genes expressed by buy zithromax pills these cells indicated that they were likely to develop into neuron-like cells."Our findings explain why GFI1 is critical to enable embryonic cells to progress into functioning adult hair cells," said Dr.

Hertzano. "These data also explain the importance buy zithromax pills of GFI1 in experimental protocols to regenerate hair cells from stem cells. These regenerative methods have the potential of being used for patients who have experienced buy zithromax pills hearing loss due to age or environmental factors like exposure to loud noise."Dr.

Hertzano first became interested in GFI1 while completing her M.D., Ph.D. At Tel buy zithromax pills Aviv University. As part of her dissertation, she discovered that the hearing loss resulting from mutations in another protein called POU4F3 appeared to largely result from a loss of GFI1 in the hair cells.

Since then, she has been conducting studies to discover the role of buy zithromax pills GFI1 and other proteins in hearing. Other research groups in the field are now testing these proteins to determine whether they can be used as a "cocktail" to regenerate lost hair buy zithromax pills cells and restore hearing."Hearing research has been going through a Renaissance period, not only from advances in genomics and methodology, but also thanks to its uniquely collaborative nature among researchers," said Dr. Herzano.The new study was funded by the National Institute on Deafness and Other Communication Disorders (NIDCD) which is part of the National Institutes of Health (NIH).

It was also funded by the Binational Scientific buy zithromax pills Foundation (BSF)."This is an exciting new finding that underscores the importance of basic research to lay the foundation for future clinical innovations," said E. Albert Reece, MD, PhD, MBA, Executive Vice President for Medical Affairs, UM Baltimore, and the John Z. And Akiko buy zithromax pills K.

Bowers Distinguished Professor and buy zithromax pills Dean, University of Maryland School of Medicine. "Identifying the complex pathways that lead to normal hearing could prove to be the key for reversing hearing loss in millions of Americans." Story Source. Materials provided by University of buy zithromax pills Maryland School of Medicine.

Note. Content may buy zithromax pills be edited for style and length.Researchers at Indiana University School of Medicine are learning more about how a person's genes play a role in the possibility they'll suffer from alcoholic cirrhosis with the discovery of a gene that could make the disease less likely.Alcoholic cirrhosis can happen after years of drinking too much alcohol. According to the researchers, discovering more about this illness couldn't come at a more important time."Based on buy zithromax pills U.S.

Data, alcohol-associated liver disease is on the rise in terms of the prevalence and incidents and it is happening more often in younger patients," said Suthat Liangpunsakul, MD, professor of medicine, dean's scholar in medical research for the Department of Medicine Division of Gastroenterology and Hepatology, and one of the principal investigators of the study. "There's a real public health buy zithromax pills problem involving the consumption of alcohol and people starting to drink at a younger age."The team describes their findings in a new paper published in Hepatology. The GenomALC Consortium was funded by the National Institutes on Alcohol Abuse and Alcoholism (NIAAA), part of the National Institute of Health (NIH).

This genome-wide association buy zithromax pills study began several years ago and is one of the largest studies related to alcoholic cirrhosis ever performed. DNA samples were taken from over 1,700 patients from sites in the United States, several countries in Europe and Australia and sent to IU School of Medicine buy zithromax pills where the team performed the DNA isolation for genome analysis. The patients were divided into two groups -- one made up of heavy drinkers that never had a history of alcohol-induced liver injury or liver disease and a second group of heavy drinkers who did have alcoholic cirrhosis."Our key finding is a gene called Fas Associated Factor Family Member 2, or FAF2," said Tae-Hwi Schwantes-An, PhD, assistant research professor of medical and molecular genetics and the lead author of the study.

"There's this convergence of findings now that are pointing to the genes involved in lipid droplet organization pathway, and that seems to be one of the biological reasonings of why certain people get liver disease and why certain people do not."The researchers are anticipating to study this gene more closely and looking at its relationship to other, previously-discovered genes that can make a person more likely to develop alcoholic cirrhosis."We know for buy zithromax pills a fact those genes are linked together in a biological process, so the logical next step is to study how the changes in these genes alter the function of that process, whether it's less efficient in one group of people, or maybe it's inhibited in some way," Schwantes-An said. "We don't know exactly what the biological underpinning of that is, but now we have a pretty well-defined target where we can look at these variants and see how they relate to alcoholic cirrhosis."As their research continues, the team hopes to eventually find a way to identify this genetic factor in patients with the goal of helping them prevent alcoholic cirrhosis in the future or developing targeted therapies that can help individuals in a more personalized way. Story Source buy zithromax pills.

Materials provided by buy zithromax pills Indiana University School of Medicine. Original written by Christina Griffiths. Note.

Content may be edited for style and length.Penn Medicine researchers have found that middle-aged individuals -- those born in the late 1960s and the 1970s -- may be in a perpetual state of H3N2 influenza virus susceptibility because their antibodies bind to H3N2 viruses but fail to prevent infections, according to a new study led by Scott Hensley, PhD, an associate professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania. The paper was published today in Nature Communications."We found that different aged individuals have different H3N2 flu virus antibody specificities," Hensley said. "Our studies show that early childhood infections can leave lifelong immunological imprints that affect how individuals respond to antigenically distinct viral strains later in life."Most humans are infected with influenza viruses by three to four years of age, and these initial childhood infections can elicit strong, long lasting memory immune responses.

H3N2 influenza viruses began circulating in humans in 1968 and have evolved substantially over the past 51 years. Therefore, an individual's birth year largely predicts which specific type of H3N2 virus they first encountered in childhood.Researchers completed a serological survey -- a blood test that measures antibody levels -- using serum samples collected in the summer months prior to the 2017-2018 season from 140 children (ages one to 17) and 212 adults (ages 18 to 90). They first measured the differences in antibody reactivity to various strains of H3N2, and then measured for neutralizing and non-neutralizing antibodies.

Neutralizing antibodies can prevent viral infections, whereas non-neutralizing antibodies can only help after an infection takes place. Samples from children aged three to ten years old had the highest levels of neutralizing antibodies against contemporary H3N2 viruses, while most middle-aged samples had antibodies that could bind to these viruses but these antibodies could not prevent viral infections.Hensley said his team's findings are consistent with a concept known as "original antigenic sin" (OAS), originally proposed by Tom Francis, Jr. In 1960.

"Most individuals born in the late 1960s and 1970s were immunologically imprinted with H3N2 viruses that are very different compared to contemporary H3N2 viruses. Upon infection with recent H3N2 viruses, these individuals tend to produce antibodies against regions that are conserved with older H3N2 strains and these types of antibodies typically do not prevent viral infections."According to the research team, it is possible that the presence of high levels of non-neutralizing antibodies in middle-aged adults has contributed to the continued persistence of H3N2 viruses in the human population. Their findings might also relate to the unusual age distribution of H3N2 infections during the 2017-2018 season, in which H3N2 activity in middle-aged and older adults peaked earlier compared to children and young adults.The researchers say that it will be important to continually complete large serological surveys in different aged individuals, including donors from populations with different vaccination rates.

A better understanding of immunity within the population and within individuals will likely lead to improved models that are better able to predict the evolutionary trajectories of different influenza virus strains."Large serological studies can shed light on why the effectiveness of flu vaccines varies in individuals with different immune histories, while also identifying barriers that need to be overcome in order to design better vaccines that are able to elicit protective responses in all age groups," said Sigrid Gouma, PhD, a postdoctoral researcher of Microbiology and first author on the paper.Other Penn authors include Madison Weirick and Megan E. Gumina. Additional authors include Angela Branche, David J.

Topham, Emily T. Martin, Arnold S. Monto, and Sarah Cobey.This work was supported by the National Institute of Allergy and Infectious Diseases (1R01AI113047, S.E.H..

1R01AI108686, S.E.H.. 1R01AI097150, A.S.M.. CEIRS HHSN272201400005C, S.E.H., S.C., E.T.M., A.S.M.

A.B., D.J.T.) and Center for Disease Control (U01IP000474, A.S.M.). Scott E. Hensley holds an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund.Males and females share the vast majority of their genomes.

Only a sprinkling of genes, located on the so-called X and Y sex chromosomes, differ between the sexes. Nevertheless, the activities of our genes -- their expression in cells and tissues -- generate profound distinctions between males and females.Not only do the sexes differ in outward appearance, their differentially expressed genes strongly affect the risk, incidence, prevalence, severity and age-of-onset of many diseases, including cancer, autoimmune disorders, cardiovascular disease and neurological afflictions.Researchers have observed sex-associated differences in gene expression across a range of tissues including liver, heart, and brain. Nevertheless, such tissue-specific sex differences remain poorly understood.

Most traits that display variance between males and females appear to result from differences in the expression of autosomal genes common to both sexes, rather than through expression of sex chromosome genes or sex hormones.A better understanding of these sex-associated disparities in the behavior of our genes could lead to improved diagnoses and treatments for a range of human illnesses.In a new paper in the PERSPECTIVES section of the journal Science, Melissa Wilson reviews current research into patterns of sex differences in gene expression across the genome, and highlights sampling biases in the human populations included in such studies."One of the most striking things about this comprehensive study of sex differences," Wilson said, "is that while aggregate differences span the genome and contribute to biases in human health, each individual gene varies tremendously between people."Wilson is a researcher in the Biodesign Center for Mechanisms in Evolution, the Center for Evolution and Medicine, and ASU's School of Life Sciences. advertisement A decade ago, an ambitious undertaking, known as the Genotype-Tissue Expression (GTEx) consortium began to investigate the effects DNA variation on gene expression across the range of human tissues. Recent findings, appearing in the Science issue under review, indicate that sex-linked disparities in gene expression are far more pervasive than once assumed, with more than a third of all genes displaying sex-biased expression in at least one tissue.

(The new research highlighted in Wilson's PERSPECTIVES piece describes gene regulatory differences between the sexes in every tissue under study.)Sex-linked differences in gene expression are shared across mammals, though their relative roles in disease susceptibility remain speculative. Natural selection likely guided the development of many of these attributes. For example, the rise of placental mammals some 90 million years ago may have led to differences in immune function between males and females.Such sex-based distinctions arising in the distant past have left their imprint on current mammals, including humans, expressed in higher rates of autoimmune disorders in females and increased cancer rates in males.Despite their critical importance for understanding disease prevalence and severity, sex differences in gene expression have only recently received serious attention in the research community.

Wilson and others suggest that much historical genetic research, using primarily white male subjects in mid-life, have yielded an incomplete picture.Such studies often fail to account for sex differences in the design and analysis of experiments, rendering a distorted view of sex-based disease variance, often leading to one-size-fits-all approaches to diagnosis and treatment. The authors therefore advise researchers to be more careful about generalizations based on existing databases of genetic information, including GTEx.A more holistic approach is emerging, as researchers investigate the full panoply of effects related to male and female gene expression across a broader range of human variation. Story Source.

Materials provided by Arizona State University. Original written by Richard Harth. Note.

Content may be edited for style and length..

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Kluge said the tightening up of how to get zithromax without prescription restrictions by governments is “absolutely necessary” as the disease continues to surge, http://sw.keimfarben.de/get-zithromax-online/ with “exponential increases” in cases and deaths. €œThe evolving epidemiological situation in Europe raises great concern. Daily numbers of cases are up, hospital admissions are up, COVID-19 is now the fifth leading cause of death and the bar of 1,000 deaths per day has now been reached,” he reported.

Cases reach how to get zithromax without prescription record highs Dr. Kluge said overall, Europe has recorded more than seven million cases of COVID-19, with the jump from six million taking just 10 days. This past weekend, daily case totals surpassed 120,000 for the first time, and on both Saturday and Sunday, reaching new records.

However, he how to get zithromax without prescription stressed that the region has not returned to the early days of the pandemic. €œAlthough we record two to three times more cases per day compared to the April peak, we still observe five times fewer deaths. The doubling time in hospital admissions is still two to three times longer,” he said, adding “in the meantime, the virus has not changed.

It has not become more nor less dangerous.” Potential how to get zithromax without prescription worsening a reality Dr. Kluge explained that one reason for the higher case rates is increased COVID-19 testing, including among younger people. This population also partly accounts for the decreased mortality rates.

“These figures say that the epidemiological curve rebound is so far higher, how to get zithromax without prescription but the slope is lower and less fatal for now. But it has the realistic potential to worsen drastically if the disease spreads back into older age cohorts after more indoor social contacts across generations,” he warned. Looking ahead, Dr.

Kluge admitted how to get zithromax without prescription that projections are “not optimistic”. Reliable epidemiological models indicate that prolonged relaxing of policies could result in mortality levels four to five times higher than in April, with results visible by January 2021. He stressed the importance of maintaining simple measures already in place, as the modelling shows how wearing masks, coupled with strict control of social gathering, may save up to 281,000 lives across the region by February.

This assumes a 95 per cent rate for mask use, up from the current rate, which is less than 60 per cent. Restrictions ‘absolutely necessary’ “Under proportionately more stringent scenarios, the model is reliably much how to get zithromax without prescription more optimistic, still with slightly higher levels of morbidity and mortality than in the first wave, but with a lower slope – as if we should rather expect a higher and longer swell instead of a sharp peak, giving us more reaction time,” said Dr. Kluge.

“These projections do nothing but confirm what we always said. The pandemic won’t reverse its course on its own, but we will.” The WHO bureau chief underlined the importance of targeted national responses to contain COVID-19 how to get zithromax without prescription spread. €œMeasures are tightening up in many countries in Europe, and this is good because they are absolutely necessary,” he said.

€œThey are appropriate and necessary responses to what the data is telling us. Transmission and sources of contamination occur in homes and indoor public places, and within communities poorly complying with self-protection measures.”According to new estimates from UNICEF, 40 per cent of the world’s how to get zithromax without prescription population – or 3 billion people – do not have a handwashing facility with water and soap at home. The number is much higher in least developed countries, where nearly three-quarters go without.

Kelly Ann Naylor, Associate Director of Water, Sanitation and Hygiene at UNICEF, said that it was “unacceptable” that the most vulnerable communities are unable to use the simplest of methods to protect themselves and their loved ones. €œThe pandemic has highlighted the critical role how to get zithromax without prescription of hand hygiene in disease prevention. It has also stressed a pre-existing problem for many.

Handwashing with soap remains out of reach for millions of children where they’re born, live and learn.” “We must take immediate action to make handwashing with soap accessible to everyone, everywhere – now and in the future,” she urged. The situation is also how to get zithromax without prescription alarming at schools. 43 per cent globally (70 per cent in least developed countries) lack a handwashing facility with water and soap, affecting hundreds of millions of school-age children, according to the estimates.

► See also. Everything you need to know about washing your hands to protect against coronavirus ‘Hand Hygiene for All’Against this backdrop, UNICEF, along with the UN World Health Organization launched the how to get zithromax without prescription “Hand Hygiene for All” initiative to support the development of national roadmaps to accelerate and sustain progress towards making hand hygiene a mainstay in public health interventions. This means rapidly improving access to handwashing facilities, water, soap and hand sanitizer in all settings, as well as promoting behavioural change interventions for optimal hand hygiene practices, said UNICEF.

The initiative brings together international, national, and local partners, to ensure affordable products and services are available and sustainable, especially in vulnerable and disadvantaged communities. The estimates were released on Thursday, coinciding with Global Handwashing Day, which serves as a platform to raise awareness on the importance of handwashing with soap..

Dr http://sw.keimfarben.de/get-zithromax-online/ buy zithromax pills. Hans Henri P. Kluge said the tightening up of restrictions by governments is “absolutely necessary” as the disease continues to surge, with “exponential increases” in cases and deaths. €œThe evolving buy zithromax pills epidemiological situation in Europe raises great concern.

Daily numbers of cases are up, hospital admissions are up, COVID-19 is now the fifth leading cause of death and the bar of 1,000 deaths per day has now been reached,” he reported. Cases reach record highs Dr. Kluge said overall, Europe has recorded more than seven million cases of COVID-19, with the jump from six million taking just 10 buy zithromax pills days. This past weekend, daily case totals surpassed 120,000 for the first time, and on both Saturday and Sunday, reaching new records.

However, he stressed that the region has not returned to the early days of the pandemic. €œAlthough we record two to three times more cases per day compared to the April peak, we still observe five buy zithromax pills times fewer deaths. The doubling time in hospital admissions is still two to three times longer,” he said, adding “in the meantime, the virus has not changed. It has not become more nor less dangerous.” Potential worsening a reality Dr.

Kluge explained that one reason buy zithromax pills for the higher case rates is increased COVID-19 testing, including among younger people. This population also partly accounts for the decreased mortality rates. “These figures say that the epidemiological curve rebound is so far higher, but the slope is lower and less fatal for now. But it has the realistic buy zithromax pills potential to worsen drastically if the disease spreads back into older age cohorts after more indoor social contacts across generations,” he warned.

Looking ahead, Dr. Kluge admitted that projections are “not optimistic”. Reliable epidemiological models indicate that prolonged relaxing of policies could result in mortality levels four to five times higher than in April, with results visible by January 2021. He stressed the importance of maintaining simple measures http://sw.keimfarben.de/get-zithromax-online/ already in place, as the modelling shows how wearing masks, coupled buy zithromax pills with strict control of social gathering, may save up to 281,000 lives across the region by February.

This assumes a 95 per cent rate for mask use, up from the current rate, which is less than 60 per cent. Restrictions ‘absolutely necessary’ “Under proportionately more stringent scenarios, the model is reliably much more optimistic, still with slightly higher levels of morbidity and mortality than in the first wave, but with a lower slope – as if we should rather expect a higher and longer swell instead of a sharp peak, giving us more reaction time,” said Dr. Kluge. “These projections do nothing but confirm what we always said.

The pandemic won’t reverse its course on its own, but we will.” The WHO bureau chief underlined the importance of targeted national responses to contain COVID-19 spread. €œMeasures are tightening up in many countries in Europe, and this is good because they are absolutely necessary,” he said. €œThey are appropriate and necessary responses to what the data is telling us. Transmission and sources of contamination occur in homes and indoor public places, and within communities poorly complying with self-protection measures.”According to new estimates from UNICEF, 40 per cent of the world’s population – or 3 billion people – do not have a handwashing facility with water and soap at home.

The number is much higher in least developed countries, where nearly three-quarters go without. Kelly Ann Naylor, Associate Director of Water, Sanitation and Hygiene at UNICEF, said that it was “unacceptable” that the most vulnerable communities are unable to use the simplest of methods to protect themselves and their loved ones. €œThe pandemic has highlighted the critical role of hand hygiene in disease prevention. It has also stressed a pre-existing problem for many.

Handwashing with soap remains out of reach for millions of children where they’re born, live and learn.” “We must take immediate action to make handwashing with soap accessible to everyone, everywhere – now and in the future,” she urged. The situation is also alarming at schools. 43 per cent globally (70 per cent in least developed countries) lack a handwashing facility with water and soap, affecting hundreds of millions of school-age children, according to the estimates. ► See also.

Everything you need to know about washing your hands to protect against coronavirus ‘Hand Hygiene for All’Against this backdrop, UNICEF, along with the UN World Health Organization launched the “Hand Hygiene for All” initiative to support the development of national roadmaps to accelerate and sustain progress towards making hand hygiene a mainstay in public health interventions. This means rapidly improving access to handwashing facilities, water, soap and hand sanitizer in all settings, as well as promoting behavioural change interventions for optimal hand hygiene practices, said UNICEF.

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IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have zithromax z pak price without insurance 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 http://sw.keimfarben.de/get-zithromax-online/ 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 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance 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 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 zithromax z pak price without insurance 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 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed 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 zithromax z pak price without insurance 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, 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 Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary zithromax z pak price without insurance 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 zithromax z pak price without insurance 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, after having obtained agreement on remaining points of discussion, revised into a final draft zithromax z pak price without insurance.

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 presented to zithromax z pak price without insurance 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 zithromax z pak price without insurance 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 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance and/or ethical considerations, the X and Y chromosomes 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 zithromax z pak price without insurance 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 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 this technique zithromax z pak price without insurance. The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the type of zithromax z pak price without insurance 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 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance occurs as an apparently isolated condition, expecting parents may also consider termination 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, zithromax z pak price without insurance treatment 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 person before birth.After expert prenatal counselling, a significant number of pregnant couples zithromax z pak price without insurance 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 zithromax z pak price without insurance 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 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 zithromax z pak price without insurance 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 zithromax z pak price without insurance 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 diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex click site 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 buy zithromax pills 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 buy zithromax pills 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 buy zithromax pills 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 conditions (EndoERN), in which DSD is buy zithromax pills 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 buy zithromax pills why this may warrant referral to a specialised team 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 buy zithromax pills 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 with all members responsible for updating the buy zithromax pills 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 buy zithromax pills guidelines with sufficient evidence due to 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 buy zithromax pills to be written in English and were identified using a broad 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 institutional access buy zithromax pills. 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 buy zithromax pills writing committee and, 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, buy zithromax pills 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 may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can buy zithromax pills 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, buy zithromax pills 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), 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 included in NIPT analysis and reports buy zithromax pills.

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 buy zithromax pills 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 the limitations of buy zithromax pills this technique.

The procedure(s) that can be followed, including the risks associated with an amniocentesis. And the buy zithromax pills 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 the diagnostic possibilities given the limited time span in which test results need to be available to buy zithromax pills allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy buy zithromax pills 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 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, buy zithromax pills treatment 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 person before birth.After buy zithromax pills 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 buy zithromax pills 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 (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 buy zithromax pills 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 there is no tight time limit, and we propose completing the analysis well before the expected delivery.Disorders/differences buy zithromax pills 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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Still, across the board, mental health experts say certain behaviors shouldn’t be ignored.Signals that may indicate someone is in need of help can include both verbal signs and behavioral cues. Verbal signs zithromax for pneumonia may be talking about wanting to die or kill oneself. Declarations of feeling trapped or having nothing to live for. Talking about great guilt zithromax for pneumonia or unbearable pain.

Insistence of being a burden to others. Speaking of zithromax for pneumonia revenge. Lack of communication or noticeable withdrawal.Behavioral cues that may signal an individual is in trouble can include acting anxious, agitated or restless. Increased use of zithromax for pneumonia alcohol or drugs.

Sleeping too zithromax for pneumonia little or too much. Suggestive actions, such as online searches or obtaining a gun. Giving away possessions zithromax for pneumonia or making visits to say goodbye. Reckless conduct or extreme mood swings.Suicide can become a threat after a loss.

It could be the death of a loved one, including a pet, or the loss of a job or relationship.Although the age of onset is usually mid-teens, mental health conditions can also begin to develop in younger zithromax for pneumonia children. Because they’re still learning how to identify and talk about thoughts and emotions, their most obvious symptoms in children and teens are behavioral. Symptoms may include changes in school performance, excessive worry or anxiety, fighting to avoid bed zithromax for pneumonia or school, hyperactive behavior, frequent nightmares, disobedience or temper tantrums. In addition to the symptoms mentioned, teens might isolate, use substances, and have drastic personality changes.To help address mental health and the wellbeing of middle and high school youth, the ROCK Center for Youth Development was recently awarded a grant from the Midland Area Community Foundation.

The grant will be used to implement the University of Michigan’s Peer zithromax for pneumonia to Peer Depression Awareness Program in Midland county high and middle schools.“Middle and high school age is when students first experience depression and anxiety symptoms, so it is important that they are able to recognize it and feel comfortable seeking help early,” explains Dollard, co-chair of a coalition for youth suicide prevention and a board member of the ROCK. €œThe Peer to Peer program includes training for school personal about mental health concerns and suicide prevention, selecting youth who will be trained and mentored as they launch a school-wide awareness campaign and establishing mental health resources for successful and timely referral when a youth is identified as needing care. The program is built on the premise that teens are more likely to zithromax for pneumonia listen to their friends than a well-meaning adult. If we can help youth to know what to do when one of their friends is zithromax for pneumonia struggling, we can potentially save lives.”MidMichigan Health offers a variety of behavioral health programs, including psychiatric inpatient care, outpatient care and office-based care.

Those interested in learning more may visit www.midmichigan.org/mentalhealth.Those concerned about the imminent danger of another taking their life should call 911 immediately. Those needing assistance or have questions are recommended to call the National Suicide Prevention Lifeline zithromax for pneumonia at 1 (800) 273-TALK (8255). In addition, people in crisis can also text HOME to 741741 to connect with a crisis counselor.Tammy Terrell, M.S.N., R.N., system vice president and chief nursing officer, MidMichigan Health, was recognized for her excellent patient care, teamwork and the positive example she sets for other employees in a recent ceremony in which she was named this year’s recipient of the Bernard E. Lorimer Award.Tammy Terrell, M.S.N., R.N., system vice president and chief nursing officer, MidMichigan Health, was recognized for her excellent patient care, teamwork and the positive example she sets for other employees in a recent ceremony in which she was named this year’s recipient zithromax for pneumonia of the Bernard E.

Lorimer Award.Her co-workers, who nominated her for the award, said Terrell is a dedicated and loyal employee who has led the health system through extraordinary challenges this year. Her leadership through the COVID-19 crisis zithromax for pneumonia was calm and steady. In addition, she remained unruffled as MidMichigan Medical Center – Midland experienced a historical flood, spending both days and nights onsite to ensure patients and employees were safe.“The Lorimer Award is like being selected into our Hall of Fame,” said Greg Rogers, president, MidMichigan Medical Center – Midland, and executive vice president and chief operating officer, MidMichigan Health. €œIt’s a zithromax for pneumonia lifetime award for an employee’s commitment to our Medical Center.

Tammy is very deserving of this award. She is zithromax for pneumonia selfless, kind, wise, intelligent and thoughtful. She is the perfect example of what makes MidMichigan Health excellent.”Terrell has been with MidMichigan Health for 38 years, beginning her career in 1982 as a staff nurse in the Emergency Department (ED) for 14 years and later was the nurse manager for the ED and Perioperative Services Departments zithromax for pneumonia at MidMichigan Medical Center – Gratiot. Then, in February 2006, she was promoted to director of nursing for the Medical Center in Alma.

Seven years later she moved over to the zithromax for pneumonia director of nursing administration for MidMichigan Medical Center – Midland. In August 2018, Terrell then became the system director of emergency services in Midland and shortly after was promoted to system vice president and chief nursing officer for MidMichigan Health.The Lorimer Award was first given in 1978 and recognizes one employee each year who possesses the characteristics that Bernard E. Lorimer exemplified during his career as president of the Medical Center zithromax for pneumonia in Midland. Those qualities include compassion and concern for people, loyalty and dedication to the Medical Center through extended length of service, cooperation, a positive attitude and a willingness to help others.Previous Bernard E.

Lorimer Award recipients include zithromax for pneumonia. Carolyn Fraser, Mary Buffa-Tacey, Pete McKnight, Fran Mayhew, Marilyn Haeussler, Lloyd Hoag, Rea Mason, Jan Albar, Harriet Robbins, Barb Dinger, Pauline Fischer, JoAnne Johnston, Sandy Ebright, Becky Dunn, Dave Chapman, Deb Badour, Jan Penney, Dennis Bauer, Karen Calkins, Jan Morrone, Pam Gifford, Carol Campbell, Mary Jane Howe, Norm Adams, Jeanie Hepinstall, Randy Wyse, Bob Valenta, Sally Vajda, Donna Herringshaw, Kathy Squires, Mary Ann Kovacevich, Sue Haley, Andrea Frederick, Peggy Lark, Tonia VanWieren, Rich Weiler, Teresa Wakeman, Susan Janke, Kathleen Ludwig, Sasha Savage, M.D., Cheryl Meyette and Jodi Herman.Terrell attended the University of Phoenix where she received her Bachelor of Science degree in nursing in 2007. She completed her Master of Science degree zithromax for pneumonia in nursing at Walden University in June 2013. Terrell is married and resides with her husband of 37 years on their family farm in Gratiot County.

She is the mother of four children and has five zithromax for pneumonia grandchildren. Her favorite pastime is being at the lake and spending time with family.Those interested in more information on MidMichigan Health may visit www.midmichigan.org..

€œYou are not alone.” These four words is a message to each and every one buy zithromax pills who has ever been depressed, anxious, had suicidal thoughts or suffer from mental illness. During Suicide Prevention Month, MidMichigan Health professionals remind you that it is okay to talk about suicide and that seeking help is crucial and never a sign of weakness.“According to the buy zithromax pills National Alliance on Mental Illness, suicide is now the tenth most common cause of death in the United States and the second leading cause of death in those 10 to 34 years old,” said Kathy Dollard, Psy.D., L.P., director of behavioral health at MidMichigan Health. €œPaying attention to warning signs and certain behaviors in individuals can be key to getting them the support and help that they need.”The warning signs before suicide aren’t always clear, nor are they universal. Suicide is often complex and usually not from a single cause buy zithromax pills.

Still, across the board, mental health experts say certain behaviors shouldn’t be ignored.Signals that may indicate someone is in need of help can include both verbal signs and behavioral cues. Verbal signs may be talking about wanting to die or buy zithromax pills kill oneself. Declarations of feeling trapped or having nothing to live for. Talking about great guilt or buy zithromax pills unbearable pain.

Insistence of being a burden to others. Speaking of buy zithromax pills revenge. Lack of communication or noticeable withdrawal.Behavioral cues that may signal an individual is in trouble can include acting anxious, agitated or restless. Increased use buy zithromax pills of alcohol or drugs.

Sleeping too buy zithromax pills little or too much. Suggestive actions, such as online searches or obtaining a gun. Giving away possessions or buy zithromax pills making visits to say goodbye. Reckless conduct or extreme mood swings.Suicide can become a threat after a loss.

It could be the death of a loved one, including a pet, or the loss of a job or relationship.Although the age of onset is usually mid-teens, mental health conditions can also begin to develop buy zithromax pills in younger children. Because they’re still learning how to identify and talk about thoughts and emotions, their most obvious symptoms in children and teens are behavioral. Symptoms may include changes in school performance, excessive worry or anxiety, fighting to avoid bed or school, hyperactive behavior, frequent nightmares, disobedience or buy zithromax pills temper tantrums. In addition to the symptoms mentioned, teens might isolate, use substances, and have drastic personality changes.To help address mental health and the wellbeing of middle and high school youth, the ROCK Center for Youth Development was recently awarded a grant from the Midland Area Community Foundation.

The grant will be used to implement the University of Michigan’s Peer to Peer Depression Awareness Program in Midland county high and middle buy zithromax pills schools.“Middle and high school age is when students first experience depression and anxiety symptoms, so it is important that they are able to recognize it and feel comfortable seeking help early,” explains Dollard, co-chair of a coalition for youth suicide prevention and a board member of the ROCK. €œThe Peer to Peer program includes training for school personal about mental health concerns and suicide prevention, selecting youth who will be trained and mentored as they launch a school-wide awareness campaign and establishing mental health resources for successful and timely referral when a youth is identified as needing care. The program is built on buy zithromax pills the premise that teens are more likely to listen to their friends than a well-meaning adult. If we can help youth to know what to do when one of their friends is struggling, we can potentially save lives.”MidMichigan Health offers a variety of behavioral health programs, including psychiatric inpatient care, outpatient care and office-based buy zithromax pills care.

Those interested in learning more may visit www.midmichigan.org/mentalhealth.Those concerned about the imminent danger of another taking their life should call 911 immediately. Those needing assistance or have questions buy zithromax pills are recommended to call the National Suicide Prevention Lifeline at 1 (800) 273-TALK (8255). In addition, people in crisis can also text HOME to 741741 to connect with a crisis counselor.Tammy Terrell, M.S.N., R.N., system vice president and chief nursing officer, MidMichigan Health, was recognized for her excellent patient care, teamwork and the positive example she sets for other employees in a recent ceremony in which she was named this year’s recipient of the Bernard E. Lorimer Award.Tammy Terrell, M.S.N., R.N., system vice president and chief nursing officer, MidMichigan Health, was recognized for her excellent patient care, teamwork and the positive example she sets for other employees in a recent ceremony in buy zithromax pills which she was named this year’s recipient of the Bernard E.

Lorimer Award.Her co-workers, who nominated her for the award, said Terrell is a dedicated and loyal employee who has led the health system through extraordinary challenges this year. Her leadership buy zithromax pills through the COVID-19 crisis was calm and steady. In addition, she remained unruffled as MidMichigan Medical Center – Midland experienced a historical flood, spending both days and nights onsite to ensure patients and employees were safe.“The Lorimer Award is like being selected into our Hall of Fame,” said Greg Rogers, president, MidMichigan Medical Center – Midland, and executive vice president and chief operating officer, MidMichigan Health. €œIt’s a lifetime award for an buy zithromax pills employee’s commitment to our Medical Center.

Tammy is very deserving of this award. She is selfless, kind, buy zithromax pills wise, intelligent and thoughtful. She is the perfect example of what makes MidMichigan Health excellent.”Terrell has been with buy zithromax pills MidMichigan Health for 38 years, beginning her career in 1982 as a staff nurse in the Emergency Department (ED) for 14 years and later was the nurse manager for the ED and Perioperative Services Departments at MidMichigan Medical Center – Gratiot. Then, in February 2006, she was promoted to director of nursing for the Medical Center in Alma.

Seven years later she moved over to the director of nursing administration buy zithromax pills for MidMichigan Medical Center – Midland. In August 2018, Terrell then became the system director of emergency services in Midland and shortly after was promoted to system vice president and chief nursing officer for MidMichigan Health.The Lorimer Award was first given in 1978 and recognizes one employee each year who possesses the characteristics that Bernard E. Lorimer exemplified during his career as president of buy zithromax pills the Medical Center in Midland. Those qualities include compassion and concern for people, loyalty and dedication to the Medical Center through extended length of service, cooperation, a positive attitude and a willingness to help others.Previous Bernard E.

Lorimer Award buy zithromax pills recipients include. Carolyn Fraser, Mary Buffa-Tacey, Pete McKnight, Fran Mayhew, Marilyn Haeussler, Lloyd Hoag, Rea Mason, Jan Albar, Harriet Robbins, Barb Dinger, Pauline Fischer, JoAnne Johnston, Sandy Ebright, Becky Dunn, Dave Chapman, Deb Badour, Jan Penney, Dennis Bauer, Karen Calkins, Jan Morrone, Pam Gifford, Carol Campbell, Mary Jane Howe, Norm Adams, Jeanie Hepinstall, Randy Wyse, Bob Valenta, Sally Vajda, Donna Herringshaw, Kathy Squires, Mary Ann Kovacevich, Sue Haley, Andrea Frederick, Peggy Lark, Tonia VanWieren, Rich Weiler, Teresa Wakeman, Susan Janke, Kathleen Ludwig, Sasha Savage, M.D., Cheryl Meyette and Jodi Herman.Terrell attended the University of Phoenix where she received her Bachelor of Science degree in nursing in 2007. She completed her Master of Science degree in nursing buy zithromax pills at Walden University in June 2013. Terrell is married and resides with her husband of 37 years on their family farm in Gratiot County.

She is the mother of four children and has five grandchildren buy zithromax pills. Her favorite pastime is being at the lake and spending time with family.Those interested in more information on MidMichigan Health may visit www.midmichigan.org..

Can you drink on zithromax

NONE

This story also ran on Fortune. This story can be republished can you drink on zithromax for free (details). Donella Pogue has trouble finding dentists in her rural area willing to accommodate her 21-year-old son, Justin, who is 6 feet, 8 inches tall, is on the autism spectrum http://sw.keimfarben.de/get-zithromax-online/ and has difficulty sitting still when touched.And this summer, he had a cavity and his face swelled. Pogue, of Bristol, New York, reached out to the Eastman Institute for Oral can you drink on zithromax Health in Rochester, which offers teledentistry.Dr. Adela Planerova looked into his mouth from 28 miles away as Pogue pointed her laptop’s camera into her son’s mouth. Planerova determined they did not can you drink on zithromax need to make an emergency one-hour drive to her clinic. Instead, the dentist prescribed antibiotics and anti-inflammatory drugs, and weeks later he had surgery.Teledentistry allows dental professionals like Planerova to remotely review records and diagnose patients over video.

Some smile about its promise, seeing it as a way can you drink on zithromax to become more efficient, to reach the one-third of U.S. Adults who federal figures from 2017 estimate hadn’t seen a dentist in the previous year and to practice more safely during the pandemic.But others see it as lesser-quality care that’s cheaper for dental professionals to provide, allowing them to make more money. At the same time, widespread adoption is hindered by issues such as spotty internet and insurance companies unwilling can you drink on zithromax to reimburse for teledentistry procedures. Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. Dr can you drink on zithromax.

Christina Carter, an orthodontist in Morristown, New Jersey, said teledentistry has its place but shouldn’t replace time in the dental chair.“It cannot be used for a full diagnosis because we need other tools, like X-rays,” she said. €œWe have all tried to see things on our phone or even on a Zoom call, and can you drink on zithromax there is still just a different feel.”Still, as the pandemic curbs in-person visits and reduces dentists’ revenue, more dentists are seeking guidance from Dr. Nathan Suter, a leading teledentistry advocate who owns the consulting company Access Teledentistry. Since March, he said, he’s done webinars for about 9,000 dental professionals, up from fewer than 1,000 in the three years before the pandemic.Teledentistry providers trace the can you drink on zithromax practice to 1994, when the Army launched a pilot program in which health care providers used an intra-oral camera to take photos of a patient’s mouth at a fort in Georgia and then sent them over the internet to a dental clinic at a fort 120 miles away.Over the next two decades, dentists in upstate New York and the San Francisco Bay Area led teledentistry pilot programs for underserved children, some of whom were in preschool and already had cavities. The number of children who completed the prescribed dental treatment rose significantly.Supporters say teledentistry can you drink on zithromax can help reach the 43% of rural Americans who lack access to dental care.

Medicaid and the Children’s Health Insurance Program will pay for many dental procedures for those enrolled in those programs, but only 38% of dentists participate in those programs, according to the American Dental Association. One reason can you drink on zithromax. Medicaid typically reimburses at a significantly lower rate than those of private insurance plans.Teledentistry could help dentists treat more patients and make more money a number of ways. If dentists remotely review data captured can you drink on zithromax by hygienists, they can see more patients. Because video appointments save them time, dentists then have room for the people “who need the more expensive services” while also focusing on preventive care, said Kirill Zaydenman, vice president of innovation for DentaQuest, an administrator of dental insurance and oral health care provider.Donella Pogue says that teledentistry was the best option for her 21-year-old son, Justin, when he had a cavity this summer that caused his face to swell.

Justin has special needs and was able to see the dentist from the comfort can you drink on zithromax of home. (Donella Pogue)But dentists have not widely adopted teledentistry — mainly because they’ve had difficulty getting insurers to pay for it, said Dr. Dorota Kopycka-Kedzierawski, a Rochester can you drink on zithromax dentist. That’s partly because of insurers’ concerns about fraud. Dr.

Paul Glassman, who started the Virtual Dental Home project to reach underserved preschool children in the Bay Area, considers those fears “completely incorrect.”“If you want to bill for something you didn’t do,” he said, “you can do that just as easily in an in-person environment as you can using teledentistry.”Since March, as the pandemic descended, most, if not all, private dental plans have been reimbursing for teledentistry, said Tom Meyers, vice president of public policy for America’s Health Insurance Plans, a trade organization. And all state Medicaid programs now reimburse for teledentistry in some form, Glassman said, though policies differ by state and some practices may not be covered in some places.But teledentistry isn’t reimbursable under Medicare. (Most dentistry isn’t.) Another obstacle to widespread adoption. Some dentists and lawmakers connect teledentistry to companies offering at-home teeth aligners with little or no in-person contact with a dentist. Glassman has promoted teledentistry throughout the United States and reviewed proposed legislation or regulations in states such as Idaho, Massachusetts and Texas.

He said he hears concerns from dentists about the lack of an in-person exam during which X-rays are taken. Such concerns are reflected in some legislation.SmileDirectClub, an at-home teeth-aligner company, has argued in statehouse testimony that in-person care is not always needed. The company opposed a 2019 bill in Texas that aimed to improve access to dentistry in rural areas because it included a number of restrictions on teledentistry, including one that would have required an in-person dentist’s examination if a teledentistry provider treated that patient for more than 12 months.SmileDirect’s attorney argued at a hearing the rule “could interrupt the course of a patient’s treatment.”The measure failed.Proponents argue teledentistry isn’t just about making more money. Pogue, the New York woman, said it was the best option for her son with special needs.“He is really afraid of dentistry, so when he goes to see someone, he is really tense and really jumpy, so that’s another reason the teledentistry was nice was because he was in my bedroom doing it, so he was really comfortable,” said Pogue, 53, whose son is covered by Medicaid.A few weeks later, Justin did have to have surgery, which went “perfect,” his mom said.Some dentists say teledentistry faces particular stumbling blocks in rural areas. Dr.

Mack Taylor, 36, a dentist who grew up in the small town of Dexter, Missouri, now practices in a health center just down the road. Twenty years ago, he said, Dexter had eight dentists. Now there are only three.Technology is a major obstacle for local residents, many of whom lack reliable internet service. Taylor recently applied for a U.S. Department of Agriculture grant that would give him $26,500 to buy equipment so that, for example, a hygienist can take photos inside the mouths of nursing home residents and send them to Taylor to review.“It’s not like medicine where you can discuss someone’s ailments and have a good idea what’s going on,” Taylor said.

€œMaybe all you can tell me is ‘I have a broken tooth,’ but I can’t physically see what’s going on and prescribe the right treatment.” Related Topics COVID-19 Dental Health Telemedicine.

This story also ran on Fortune. This story will zithromax treat chlamydia can be republished for free (details). Donella Pogue has trouble finding dentists in her rural area willing to buy zithromax pills accommodate her 21-year-old son, Justin, who is 6 feet, 8 inches tall, is on the autism spectrum and has difficulty sitting still when touched.And this summer, he had a cavity and his face swelled. Pogue, of buy zithromax pills Bristol, New York, reached out to the Eastman Institute for Oral Health in Rochester, which offers teledentistry.Dr. Adela Planerova looked into his mouth from 28 miles away as Pogue pointed her laptop’s camera into her son’s mouth. Planerova determined they did not need to make an emergency one-hour drive to her clinic buy zithromax pills. Instead, the dentist prescribed antibiotics and anti-inflammatory drugs, and weeks later he had surgery.Teledentistry allows dental professionals like Planerova to remotely review records and diagnose patients over video.

Some smile about its promise, seeing it as a way to become more efficient, to reach the buy zithromax pills one-third of U.S. Adults who federal figures from 2017 estimate hadn’t seen a dentist in the previous year and to practice more safely during the pandemic.But others see it as lesser-quality care that’s cheaper for dental professionals to provide, allowing them to make more money. At the same time, widespread adoption is hindered by issues such as spotty internet and insurance companies unwilling to reimburse for buy zithromax pills teledentistry procedures. Don't Miss A Story Subscribe to KHN’s free Weekly Edition newsletter. Dr buy zithromax pills.

Christina Carter, an orthodontist in Morristown, New Jersey, said teledentistry has its place but shouldn’t replace time in the dental chair.“It cannot be used for a full diagnosis because we need other tools, like X-rays,” she said. €œWe have all tried to see things on our phone or even on a Zoom call, and there is still just a different feel.”Still, as the pandemic curbs in-person buy zithromax pills visits and reduces dentists’ revenue, more dentists are seeking guidance from Dr. Nathan Suter, a leading teledentistry advocate who owns the consulting company Access Teledentistry. Since March, he said, he’s done webinars for about 9,000 dental professionals, up from fewer than 1,000 in the three years before the pandemic.Teledentistry providers trace the practice to 1994, when the Army launched a pilot program in which health care providers used an intra-oral camera to take photos of a patient’s mouth at a fort in Georgia and then sent them over the internet to a dental clinic at a fort 120 miles away.Over the buy zithromax pills next two decades, dentists in upstate New York and the San Francisco Bay Area led teledentistry pilot programs for underserved children, some of whom were in preschool and already had cavities. The number of children who completed the prescribed dental treatment rose significantly.Supporters say teledentistry can help reach buy zithromax pills the 43% of rural Americans who lack access to dental care.

Medicaid and the Children’s Health Insurance Program will pay for many dental procedures for those enrolled in those programs, but only 38% of dentists participate in those programs, according to the American Dental Association. One reason buy zithromax pills. Medicaid typically reimburses at a significantly lower rate than those of private insurance plans.Teledentistry could help dentists treat more patients and make more money a number of ways. If dentists remotely review data captured by hygienists, they buy zithromax pills can see more patients. Because video appointments save them time, dentists then have room for the people “who need the more expensive services” while also focusing on preventive care, said Kirill Zaydenman, vice president of innovation for DentaQuest, an administrator of dental insurance and oral health care provider.Donella Pogue says that teledentistry was the best option for her 21-year-old son, Justin, when he had a cavity this summer that caused his face to swell.

Justin has special needs and was able to see the buy zithromax pills dentist from the comfort of home. (Donella Pogue)But dentists have not widely adopted teledentistry — mainly because they’ve had difficulty getting insurers to pay for it, said Dr. Dorota Kopycka-Kedzierawski, a buy zithromax pills Rochester dentist. That’s partly because of insurers’ concerns about fraud. Dr.

Paul Glassman, who started the Virtual Dental Home project to reach underserved preschool children in the Bay Area, considers those fears “completely incorrect.”“If you want to bill for something you didn’t do,” he said, “you can do that just as easily in an in-person environment as you can using teledentistry.”Since March, as the pandemic descended, most, if not all, private dental plans have been reimbursing for teledentistry, said Tom Meyers, vice president of public policy for America’s Health Insurance Plans, a trade organization. And all state Medicaid programs now reimburse for teledentistry in some form, Glassman said, though policies differ by state and some practices may not be covered in some places.But teledentistry isn’t reimbursable under Medicare. (Most dentistry isn’t.) Another obstacle to widespread adoption. Some dentists and lawmakers connect teledentistry to companies offering at-home teeth aligners with little or no in-person contact with a dentist. Glassman has promoted teledentistry throughout the United States and reviewed proposed legislation or regulations in states such as Idaho, Massachusetts and Texas.

He said he hears concerns from dentists about the lack of an in-person exam during which X-rays are taken. Such concerns are reflected in some legislation.SmileDirectClub, an at-home teeth-aligner company, has argued in statehouse testimony that in-person care is not always needed. The company opposed a 2019 bill in Texas that aimed to improve access to dentistry in rural areas because it included a number of restrictions on teledentistry, including one that would have required an in-person dentist’s examination if a teledentistry provider treated that patient for more than 12 months.SmileDirect’s attorney argued at a hearing the rule “could interrupt the course of a patient’s treatment.”The measure failed.Proponents argue teledentistry isn’t just about making more money. Pogue, the New York woman, said it was the best option for her son with special needs.“He is really afraid of dentistry, so when he goes to see someone, he is really tense and really jumpy, so that’s another reason the teledentistry was nice was because he was in my bedroom doing it, so he was really comfortable,” said Pogue, 53, whose son is covered by Medicaid.A few weeks later, Justin did have to have surgery, which went “perfect,” his mom said.Some dentists say teledentistry faces particular stumbling blocks in rural areas. Dr.

Mack Taylor, 36, a dentist who grew up in the small town of Dexter, Missouri, now practices in a health center just down the road. Twenty years ago, he said, Dexter had eight dentists. Now there are only three.Technology is a major obstacle for local residents, many of whom lack reliable internet service. Taylor recently applied for a U.S. Department of Agriculture grant that would give him $26,500 to buy equipment so that, for example, a hygienist can take photos inside the mouths of nursing home residents and send them to Taylor to review.“It’s not like medicine where you can discuss someone’s ailments and have a good idea what’s going on,” Taylor said.

€œMaybe all you can tell me is ‘I have a broken tooth,’ but I can’t physically see what’s going on and prescribe the right treatment.” Related Topics COVID-19 Dental Health Telemedicine.

Zithromax and wine

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Extension of timeline http://sw.keimfarben.de/get-zithromax-online/ for publication of final zithromax and wine rule. This notice announces an extension of the timeline for publication of a Medicare final rule in accordance with the Social Security Act, which allows us to extend the timeline for publication of the final rule. As of August 26, 2020, the timeline for publication of the final rule to finalize the provisions of the October 17, 2019 proposed rule (84 FR 55766) is extended until August 31, 2021. Start Further Info zithromax and wine Lisa O. Wilson, (410) 786-8852.

End Further Info End Preamble Start Supplemental Information In the October 17, 2019 Federal Register (84 FR 55766), we published a proposed rule that addressed undue regulatory impact and burden of the physician self-referral law. The proposed rule was issued in conjunction with the Centers for Medicare zithromax and wine &. Medicaid Services' (CMS) Patients over Paperwork initiative and the Department of Health and Human Services' (the Department or HHS) Regulatory Sprint to Coordinated Care. In the proposed rule, we proposed exceptions to the physician self-referral law for certain value-based compensation arrangements between or among physicians, providers, and suppliers. A new exception zithromax and wine for certain arrangements under which a physician receives limited remuneration for items or services actually provided by the physician.

A new exception for donations of cybersecurity technology and related services. And amendments to the existing exception for electronic health records (EHR) items and services. The proposed rule also provides critically zithromax and wine necessary guidance for physicians and health care providers and suppliers whose financial relationships are governed by the physician self-referral statute and regulations. This notice announces an extension of the timeline for publication of the final rule and the continuation of effectiveness of the proposed rule. Section 1871(a)(3)(A) of the Social Security Act (the Act) requires us to establish and publish a regular timeline for the publication of final regulations based on the previous publication of a proposed regulation.

In accordance with section 1871(a)(3)(B) of the Act, the timeline may vary among different regulations based on differences in the complexity of the regulation, the number and scope of comments received, and other relevant factors, but may not be zithromax and wine longer than 3 years except under exceptional circumstances. In addition, in accordance with section 1871(a)(3)(B) of the Act, the Secretary may extend the initial targeted publication date of the final regulation if the Secretary, no later than the regulation's previously established proposed publication date, publishes a notice with the new target date, and such notice includes a brief explanation of the justification for the variation. We announced in the Spring 2020 Unified Agenda (June 30, 2020, www.reginfo.gov) that we would issue the final rule in August 2020. However, we are still working through the Start Printed Page 52941complexity of the issues raised by comments received on the proposed rule and therefore we are zithromax and wine not able to meet the announced publication target date. This notice extends the timeline for publication of the final rule until August 31, 2021.

Start Signature Dated. August 24, 2020 zithromax and wine. Wilma M. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human Services. End Signature End Supplemental Information zithromax and wine [FR Doc.

2020-18867 Filed 8-26-20. 8:45 am]BILLING CODE 4120-01-PThe Centers for Medicare &. Medicaid Services (CMS) today announced efforts underway to support Louisiana and Texas in response to Hurricane zithromax and wine Laura. On August 26, 2020, Department of Health and Human Services (HHS) Secretary Alex Azar declared public health emergencies (PHEs) in these states, retroactive to August 22, 2020 for the state of Louisiana and to August 23, 2020 for the state of Texas. CMS is working to ensure hospitals and other facilities can continue operations and provide access to care despite the effects of Hurricane Laura.

CMS provided numerous waivers to health care providers during the current coronavirus zithromax and wine disease 2019 (COVID-19) pandemic to meet the needs of beneficiaries and providers. The waivers already in place will be available to health care providers to use during the duration of the COVID-19 PHE determination timeframe and for the Hurricane Laura PHE. CMS may waive certain additional Medicare, Medicaid, and Children’s Health Insurance Program (CHIP) requirements, create special enrollment opportunities for individuals to access healthcare quickly, and take steps to ensure dialysis patients obtain critical life-saving services. “Our thoughts are with everyone who is in the path zithromax and wine of this powerful and dangerous hurricane and CMS is doing everything within its authority to provide assistance and relief to all who are affected,” said CMS Administrator Seema Verma. €œWe will partner and coordinate with state, federal, and local officials to make sure that in the midst of all of the uncertainty a natural disaster can bring, our beneficiaries will not have to worry about access to healthcare and other crucial life-saving and sustaining services they may need.” Below are key administrative actions CMS will be taking in response to the PHEs declared in Louisiana and Texas.

Waivers and Flexibilities for Hospitals and Other Healthcare Facilities. CMS has already waived many Medicare, Medicaid, and zithromax and wine CHIP requirements for facilities. The CMS Dallas Survey &. Enforcement Division, under the Survey Operations Group, will grant other provider-specific requests for specific types of hospitals and other facilities in Louisiana and Texas. These waivers, once issued, will help provide continued access zithromax and wine to care for beneficiaries.

For more information on the waivers CMS has granted, visit. Www.cms.gov/emergency straight from the source. Special Enrollment Opportunities for Hurricane Victims. CMS will make available special enrollment periods for certain Medicare beneficiaries and certain individuals seeking health plans offered through the Federal zithromax and wine Health Insurance Exchange. This gives people impacted by the hurricane the opportunity to change their Medicare health and prescription drug plans and gain access to health coverage on the Exchange if eligible for the special enrollment period.

For more information, please visit. Disaster Preparedness zithromax and wine Toolkit for State Medicaid Agencies. CMS developed an inventory of Medicaid and CHIP flexibilities and authorities available to states in the event of a disaster. For more information and to access the toolkit, visit. Https://www.medicaid.gov/state-resource-center/disaster-response-toolkit/index.html.

Dialysis Care. CMS is helping patients obtain access to critical life-saving services. The Kidney Community Emergency Response (KCER) program has been activated and is working with the End Stage Renal Disease (ESRD) Network, Network 13 – Louisiana, and Network 14 - Texas, to assess the status of dialysis facilities in the potentially impacted areas related to generators, alternate water supplies, education and materials for patients and more. The KCER is also assisting patients who evacuated ahead of the storm to receive dialysis services in the location to which they evacuated. Patients have been educated to have an emergency supply kit on hand including important personal, medical and insurance information.

Contact information for their facility, the ESRD Network hotline number, and contact information of those with whom they may stay or for out-of-state contacts in a waterproof bag. They have also been instructed to have supplies on hand to follow a three-day emergency diet. The ESRD Network 8 – Mississippi hotline is 1-800-638-8299, Network 13 – Louisiana hotline is 800-472-7139, the ESRD Network 14 - Texas hotline is 877-886-4435, and the KCER hotline is 866-901-3773. Additional information is available on the KCER website www.kcercoalition.com. During the 2017 and 2018 hurricane seasons, CMS approved special purpose renal dialysis facilities in several states to furnish dialysis on a short-term basis at designated locations to serve ESRD patients under emergency circumstances in which there were limited dialysis resources or access-to-care problems due to the emergency circumstances.

Medical equipment and supplies replacements. Under the COVD-19 waivers, CMS suspended certain requirements necessary for Medicare beneficiaries who have lost or realized damage to their durable medical equipment, prosthetics, orthotics and supplies as a result of the PHE. This will help to make sure that beneficiaries can continue to access the needed medical equipment and supplies they rely on each day. Medicare beneficiaries can contact 1-800-MEDICARE (1-800-633-4227) for assistance. Ensuring Access to Care in Medicare Advantage and Part D.

During a public health emergency, Medicare Advantage Organizations and Part D Plan sponsors must take steps to maintain access to covered benefits for beneficiaries in affected areas. These steps include allowing Part A/B and supplemental Part C plan benefits to be furnished at specified non-contracted facilities and waiving, in full, requirements for gatekeeper referrals where applicable. Emergency Preparedness Requirements. Providers and suppliers are expected to have emergency preparedness programs based on an all-hazards approach. To assist in the understanding of the emergency preparedness requirements, CMS Central Office and the Regional Offices hosted two webinars in 2018 regarding Emergency Preparedness requirements and provider expectations.

One was an all provider training on June 19, 2018 with more than 3,000 provider participants and the other an all-surveyor training on August 8, 2018. Both presentations covered the emergency preparedness final rule which included emergency power supply. 1135 waiver process. Best practices and lessons learned from past disasters. And helpful resources and more.

Both webinars are available at https://qsep.cms.gov/welcome.aspx. CMS also compiled a list of Frequently Asked Questions (FAQs) and useful national emergency preparedness resources to assist state Survey Agencies (SAs), their state, tribal, regional, local emergency management partners and health care providers to develop effective and robust emergency plans and tool kits to assure compliance with the emergency preparedness rules. The tools can be located at. CMS Regional Offices have provided specific emergency preparedness information to Medicare providers and suppliers through meetings, dialogue and presentations. The regional offices also provide regular technical assistance in emergency preparedness to state agencies and staff, who, since November 2017, have been regularly surveying providers and suppliers for compliance with emergency preparedness regulations.

Additional information on the emergency preparedness requirements can be found here. Https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_z_emergprep.pdf CMS will continue to work with all geographic areas impacted by Hurricane Laura. We encourage beneficiaries and providers of healthcare services that have been impacted to seek help by visiting CMS’ emergency webpage (www.cms.gov/emergency).

As of August buy zithromax pills 26, 2020, the timeline for publication of the final rule to finalize the provisions of the October 17, 2019 proposed rule (84 FR 55766) is extended until August 31, 2021. Start Further Info Lisa O. Wilson, (410) 786-8852. End Further Info End Preamble Start Supplemental Information In the October 17, 2019 Federal Register (84 buy zithromax pills FR 55766), we published a proposed rule that addressed undue regulatory impact and burden of the physician self-referral law.

The proposed rule was issued in conjunction with the Centers for Medicare &. Medicaid Services' (CMS) Patients over Paperwork initiative and the Department of Health and Human Services' (the Department or HHS) Regulatory Sprint to Coordinated Care. In the proposed rule, we proposed exceptions to the physician self-referral law for certain value-based compensation arrangements between buy zithromax pills or among physicians, providers, and suppliers. A new exception for certain arrangements under which a physician receives limited remuneration for items or services actually provided by the physician.

A new exception for donations of cybersecurity technology and related services. And amendments to the existing exception for electronic health records buy zithromax pills (EHR) items and services. The proposed rule also provides critically necessary guidance for physicians and health care providers and suppliers whose financial relationships are governed by the physician self-referral statute and regulations. This notice announces an extension of the timeline for publication of the final rule and the continuation of effectiveness of the proposed rule.

Section 1871(a)(3)(A) of the Social Security Act (the Act) requires us to establish buy zithromax pills and publish a regular timeline for the publication of final regulations based on the previous publication of a proposed regulation. In accordance with section 1871(a)(3)(B) of the Act, the timeline may vary among different regulations based on differences in the complexity of the regulation, the number and scope of comments received, and other relevant factors, but may not be longer than 3 years except under exceptional circumstances. In addition, in accordance with section 1871(a)(3)(B) of the Act, the Secretary may extend the initial targeted publication date of the final regulation if the Secretary, no later than the regulation's previously established proposed publication date, publishes a notice with the new target date, and such notice includes a brief explanation of the justification for the variation. We announced in the Spring 2020 Unified Agenda (June 30, 2020, www.reginfo.gov) that we would issue the final rule in August 2020 buy zithromax pills.

However, we are still working through the Start Printed Page 52941complexity of the issues raised by comments received on the proposed rule and therefore we are not able to meet the announced publication target date. This notice extends the timeline for publication of the final rule until August 31, 2021. Start Signature Dated buy zithromax pills. August 24, 2020.

Wilma M. Robinson, Deputy Executive Secretary to the Department, Department of Health and Human buy zithromax pills Services. End Signature End Supplemental Information [FR Doc. 2020-18867 Filed 8-26-20.

8:45 am]BILLING CODE 4120-01-PThe Centers for Medicare & buy zithromax pills. Medicaid Services (CMS) today announced efforts underway to support Louisiana and Texas in response to Hurricane Laura. On August 26, 2020, Department of Health and Human Services (HHS) Secretary Alex Azar declared public health emergencies (PHEs) in these states, retroactive to August 22, 2020 for the state of Louisiana and to August 23, 2020 for the state of Texas. CMS is working to ensure hospitals and other facilities buy zithromax pills can continue operations and provide access to care despite the effects of Hurricane Laura.

CMS provided numerous waivers to health care providers during the current coronavirus disease 2019 (COVID-19) pandemic to meet the needs of beneficiaries and providers. The waivers already in place will be available to health care providers to use during the duration of the COVID-19 PHE determination timeframe and for the Hurricane Laura PHE. CMS may waive certain additional Medicare, Medicaid, and Children’s Health Insurance Program (CHIP) requirements, create special enrollment opportunities for individuals to buy zithromax pills access healthcare quickly, and take steps to ensure dialysis patients obtain critical life-saving services. “Our thoughts are with everyone who is in the path of this powerful and dangerous hurricane and CMS is doing everything within its authority to provide assistance and relief to all who are affected,” said CMS Administrator Seema Verma.

€œWe will partner and coordinate with state, federal, and local officials to make sure that in the midst of all of the uncertainty a natural disaster can bring, our beneficiaries will not have to worry about access to healthcare and other crucial life-saving and sustaining services they may need.” Below are key administrative actions CMS will be taking in response to the PHEs declared in Louisiana and Texas. Waivers and Flexibilities for Hospitals buy zithromax pills and Other Healthcare Facilities. CMS has already waived many Medicare, Medicaid, and CHIP requirements for facilities. The CMS Dallas Survey &.

Enforcement Division, under the Survey Operations Group, will buy zithromax pills grant other provider-specific requests for specific types of hospitals and other facilities in Louisiana and Texas. These waivers, once issued, will help provide continued access to care for beneficiaries. For more information on the waivers CMS has granted, visit. Www.cms.gov/emergency.

Special Enrollment Opportunities for Hurricane Victims. CMS will make available special enrollment periods for certain Medicare beneficiaries and certain individuals seeking health plans offered through the Federal Health Insurance Exchange. This gives people impacted by the hurricane the opportunity to change their Medicare health and prescription drug plans and gain access to health coverage on the Exchange if eligible for the special enrollment period. For more information, please visit.

Disaster Preparedness Toolkit for State Medicaid Agencies. CMS developed an inventory of Medicaid and CHIP flexibilities and authorities available to states in the event of a disaster. For more information and to access the toolkit, visit. Https://www.medicaid.gov/state-resource-center/disaster-response-toolkit/index.html.

Dialysis Care. CMS is helping patients obtain access to critical life-saving services. The Kidney Community Emergency Response (KCER) program has been activated and is working with the End Stage Renal Disease (ESRD) Network, Network 13 – Louisiana, and Network 14 - Texas, to assess the status of dialysis facilities in the potentially impacted areas related to generators, alternate water supplies, education and materials for patients and more. The KCER is also assisting patients who evacuated ahead of the storm to receive dialysis services in the location to which they evacuated.

Patients have been educated to have an emergency supply kit on hand including important personal, medical and insurance information. Contact information for their facility, the ESRD Network hotline number, and contact information of those with whom they may stay or for out-of-state contacts in a waterproof bag. They have also been instructed to have supplies on hand to follow a three-day emergency diet. The ESRD Network 8 – Mississippi hotline is 1-800-638-8299, Network 13 – Louisiana hotline is 800-472-7139, the ESRD Network 14 - Texas hotline is 877-886-4435, and the KCER hotline is 866-901-3773.

Additional information is available on the KCER website www.kcercoalition.com. During the 2017 and 2018 hurricane seasons, CMS approved special purpose renal dialysis facilities in several states to furnish dialysis on a short-term basis at designated locations to serve ESRD patients under emergency circumstances in which there were limited dialysis resources or access-to-care problems due to the emergency circumstances. Medical equipment and supplies replacements. Under the COVD-19 waivers, CMS suspended certain requirements necessary for Medicare beneficiaries who have lost or realized damage to their durable medical equipment, prosthetics, orthotics and supplies as a result of the PHE.

This will help to make sure that beneficiaries can continue to access the needed medical equipment and supplies they rely on each day. Medicare beneficiaries can contact 1-800-MEDICARE (1-800-633-4227) for assistance. Ensuring Access to Care in Medicare Advantage and Part D. During a public health emergency, Medicare Advantage Organizations and Part D Plan sponsors must take steps to maintain access to covered benefits for beneficiaries in affected areas.

These steps include allowing Part A/B and supplemental Part C plan benefits to be furnished at specified non-contracted facilities and waiving, in full, requirements for gatekeeper referrals where applicable. Emergency Preparedness Requirements. Providers and suppliers are expected to have emergency preparedness programs based on an all-hazards approach. To assist in the understanding of the emergency preparedness requirements, CMS Central Office and the Regional Offices hosted two webinars in 2018 regarding Emergency Preparedness requirements and provider expectations.

One was an all provider training on June 19, 2018 with more than 3,000 provider participants and the other an all-surveyor training on August 8, 2018. Both presentations covered the emergency preparedness final rule which included emergency power supply. 1135 waiver process. Best practices and lessons learned from past disasters.

And helpful resources and more. Both webinars are available at https://qsep.cms.gov/welcome.aspx. CMS also compiled a list of Frequently Asked Questions (FAQs) and useful national emergency preparedness resources to assist state Survey Agencies (SAs), their state, tribal, regional, local emergency management partners and health care providers to develop effective and robust emergency plans and tool kits to assure compliance with the emergency preparedness rules. The tools can be located at.

CMS Regional Offices have provided specific emergency preparedness information to Medicare providers and suppliers through meetings, dialogue and presentations. The regional offices also provide regular technical assistance in emergency preparedness to state agencies and staff, who, since November 2017, have been regularly surveying providers and suppliers for compliance with emergency preparedness regulations. Additional information on the emergency preparedness requirements can be found here. Https://www.cms.gov/Regulations-and-Guidance/Guidance/Manuals/downloads/som107ap_z_emergprep.pdf CMS will continue to work with all geographic areas impacted by Hurricane Laura.

We encourage beneficiaries and providers of healthcare services that have been impacted to seek help by visiting CMS’ emergency webpage (www.cms.gov/emergency). For more information about the HHS PHE, please visit. Https://www.hhs.gov/about/news/2020/08/26/hhs-secretary-azar-declares-public-health-emergencies-in-louisiana-and-texas-due-to-hurricane-laura.html.