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"Sandhusn zieht aus" hat nichts mit dem Entledigen eines männlichen Kleidungsstückes zu tun. Er hat vielmehr einen historischen Bezug. Mit dem Niedergang des Bergbaues im Erzgebirge mussten andere Erwerbsmöglichkeiten gesucht werden. Neben dem Klöppeln und der Posamentenindustrie war dies in Geyer der Verkauf von Scheuersand, der als Nebenprodukt den Kiesgruben der Umgebung anfiel. Die Kinder die "auszogen" um eben diesen Sand zu verkaufen, wurden dann "Sandhusn" genannt. Dieser Spitzname wird übrigens bis heute für jeden Bewohner in Geyer verwendet.


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After voters expanded Medicaid in conservative states like Missouri and Oklahoma, health care advocates are renewing a push for expansion in Mississippi and other Southern states where Republican leaders have long been opposed.They say the changing tide has followed rising income inequality, joblessness and pressure from hospitals in economic turmoil — issues exacerbated by the alcoholism antabuse."There antabuse pill price have been, in the last two years, votes on Medicaid expansion in some of the most conservative, find this Republican-leaning states in the country, and Medicaid expansion has never lost," said Eliot Fishman, senior director of Health Policy at Families USA, a health care advocacy organization.Fishman spoke Thursday during an online forum about Medicaid expansion hosted by the Mississippi Health Advocacy Program and the Mississippi Center for Justice.Medicaid expansion is an option under the health care overhaul that then-President Barack Obama signed into law in 2010. Many Democratic-controlled states agreed to expansion, mainly for people whose jobs don't provide health insurance.However, since Republican Donald Trump became president in January 2017, voters in Idaho, Nebraska, Utah, Oklahoma, Maine and most recently Missouri have approved antabuse pill price Medicaid expansion by ballot measures. In Virginia, legislators passed Medicaid expansion after Democrats gained power."This is clearly an issue which you can no longer shut down voter interest by just saying the word 'Obamacare,' " Fishman said.

"That power has waned."There are now 12 states — including Mississippi, Georgia, Alabama, Texas, South Carolina, North Carolina, Tennessee and antabuse pill price Florida — that have not expanded Medicaid. A newly formed collaborative, antabuse pill price "Southerners for Medicaid Expansion," is aiming to put pressure on the holdouts.Medicaid is a government health insurance program for the needy, aged, blind and disabled, and it is paid by state and federal money. Because Mississippi is poor, the federal government pays nearly 78% of the cost.Under expansion, the federal government pays 90% of the cost in any state.About 25% of Mississippi's nearly 3 million residents are already enrolled in Medicaid, and opponents have said they don't want more people taking part in a government program.Roy Mitchell, executive director of the Mississippi Health Advocacy Program, said hospitals are in desperate need of the dollars.

Uncompensated care costs in Mississippi exceed $600 million annually, according to a 2019 statement from the antabuse pill price Mississippi Hospital Association."Let's face it, providers are businessmen. Despite their marketing, they are inherently out to make a profit, and they are going to have to wake up in Mississippi," Mitchell said. "I'm sure alcoholism treatment did a good job of doing antabuse pill price that."Addressing ailing hospitals has been controversial.

Republican Gov antabuse pill price. Tate Reeves and leaders in the Republican-controlled Mississippi Legislature have opposed Medicaid expansion. Reeves has said money should go instead to federally funded community health centers that help people in need.Reeves has said repeatedly that the antabuse antabuse pill price has not changed his mind about expansion.

And Republican House Speaker Philip Gunn told reporters this month that he also remains opposed.The Mississippi Hospital Association in 2019 proposed "Mississippi Cares," which it called Medicaid reform but not expansion. It was modeled after an Indiana program antabuse pill price enacted under then-Gov. Mike Pence antabuse pill price.

It would expand Medicaid eligibility while setting $20 monthly premium payments and copays. The proposal gained no traction during this year's Mississippi legislative session.While advocates for Medicaid expansion say they are hopeful, they acknowledge difficulties.Out of the 12 nonexpansion states, Mississippi and Florida are the only two with a ballot initiative process.Mississippi law says that antabuse pill price for an initiative to be placed on the ballot, at least 106,190 certified signatures must be gathered, and those must be evenly divided among the five congressional districts that Mississippi used 20 years ago. Even if signature-gathering is successful, the earliest a proposal is likely to be on the ballot is November 2022."For all the stars to align in a ballot initiative ...

There's got to be a commitment on the part of providers in Mississippi, I think, and we have to also look realistically at the amount of resources that it takes to do a ballot initiative," antabuse pill price Mitchell said. "But it is certainly not out of reach."Consultations via tablets, laptops and phones linked patients and doctors when society antabuse pill price shut down in early spring. Telehealth visits dropped with the reopening, but they're still far more common than before and now there's a push to make them widely available in the future.Permanently expanding access will involve striking a balance between costs and quality, dealing with privacy concerns and potential fraud, and figuring out how telehealth can reach marginalized patients, including people with mental health problems."I don't think it is ever going to replace in-person visits, because sometimes a doctor needs to put hands on a patient," said CMS Administrator Seema Verma, the Trump administration's leading advocate for telehealth.Caveats aside, "it's almost a modern-day house call," she added."It's fair to say that telemedicine was in its infancy prior to the antabuse, but it's come of age this year," said Murray Aitken of the data firm IQVIA, which tracks the impact.In the depths of the alcoholism shutdown, telehealth accounted for more than 40% of primary care visits for patients with traditional Medicare, up from a tiny 0.1% sliver before the public health emergency.

As the government's flagship health care program, Medicare covers more than 60 million people, including those age 65 and older, and younger disabled people.A recent poll of older adults by the University of Michigan Institute for Healthcare antabuse pill price Policy &. Innovation found that more than 7 in 10 are interested in using telehealth for follow-ups with their doctor, and nearly 2 out of 3 feel comfortable with video conferences.But privacy was an issue, especially for those who hadn't tried telehealth antabuse pill price. The poll found 27% of older adults who had not had a telemedicine visit were concerned about privacy, compared with 17% of those who tried it.Those who tried telehealth weren't completely sold.

About 4 in 5 were concerned the doctor couldn't physically examine them, and 64% worried the quality wasn't as good."After the initial excitement, in the afterglow, patients realize 'I can't get my treatment,' or 'You can't see this antabuse pill price thing in the back of my throat over the computer,' " said Dr. Gary LeRoy of Dayton, Ohio, a primary care doctor and president of the American Academy of Family Physicians.For Medicare beneficiary Jean Grady of Westford, Vermont, telemedicine was a relief. She needed a checkup required by Medicare to continue receiving supplies for her wearable antabuse pill price insulin pump.

Being in a high risk group for alcoholism treatment, Grady worried about potential exposure in a doctor's waiting room, and even more about losing her diabetes supplies if she missed Medicare's checkup deadline."I would have had to go back to antabuse pill price taking insulin by syringe," she said.Grady prepared for the virtual visit by calling her clinician's tech department and downloading teleconference software. She says she would do some future visits by video, but not all. For example, people with diabetes need periodic blood tests, and their feet must be checked for signs of circulatory problems.Still, quite a few follow-ups "could be done very efficiently and be just as useful to the physician and myself as going in and seeing them in person," Grady said.Many private insurance plans, including those in Medicare Advantage, offer some level of telemedicine coverage.But traditional Medicare antabuse pill price has restricted it to rural residents, who generally had to travel to specially designated sites to connect.Under the alcoholism public health emergency, the administration temporarily waived Medicare's restrictions so enrollees anywhere could use telemedicine.

Patients could connect from home. Making such changes permanent would require antabuse pill price legislation from Congress, but there's bipartisan interest.Sen. Lamar Alexander, chairman of the Senate Health, Education, Labor and Pensions Committee, says he'd antabuse pill price like to see broader access, without breaking the bank."Our job should be to ensure that change is done with the goals of better outcomes and better patient experiences, at a lower cost," said Alexander, R-Tenn.That's a tall order.Payment will be a sticky obstacle.

For now, Medicare is paying clinicians on par for virtual and in-person visits."Policymakers seems to be in a rush to pass legislation, but I think it is worth taking a little more time," said Juliette Cubanski, a Medicare expert with the nonpartisan Kaiser Family Foundation. "Fraud is one big area that policymakers need to be cognizant of."Fraud-busters agree.Telehealth antabuse pill price is so new that "we don't have at this point a real sense of where the huge risks lie," said Andrew VanLandingham, a senior lawyer with the Health and Human Services inspector general's office. "We are sort of in an experimental phase."Despite the risks, advocates see opportunities.Expanded Medicare telehealth could:help move the nation closer to a long-sought goal of treating mental health the same as physical conditions.

Sen. Ron Wyden, D-Ore., wants to use telemedicine as a springboard to improve mental health care. IQVIA data shows 60% of psychiatric consults took place by telehealth during the shutdown.increase access for people living in remote communities, in low-income urban areas and even nursing homes.

Medicare's research shows low-income beneficiaries have had similar patterns of using telehealth for primary care as program enrollees overall.improve coordination of care for people with chronic health conditions, a goal that requires patient and persistent monitoring. Chronic care accounts for most program spending.University of Michigan health policy expert Mark Fendrick says Medicare should figure out what services add value for patients' health and taxpayers' wallets, and pay just for those.Telehealth "was an overnight sensation," said Fendrick. "Hopefully it's not a one-hit wonder."As the wind howled and the rain slammed down, a team of nurses, respiratory therapists and a doctor worked through the night to care for 19 tiny babies as Hurricane Laura slammed southwestern Louisiana.The babies, some on ventilators or eating through a feeding tube, seemed to weather the storm just fine, said Dr.

Juan Bossano, the medical director of the neonatal intensive care unit at Lake Charles Memorial Hospital for Women. "They did very well. They tolerated it very well.

We had a very good day," he said.Laura made landfall early Thursday morning as a Category 4 storm, packing top winds of 150 mph (241 kph), and pushing a storm surge as high as 15 feet in some areas.Hours before it made landfall, officials had to move the babies from the women's hospital to the main hospital in the system after it became clear that storm surge could inundate the women's hospital, located on the southern end of Lake Charles. The hospital has its own generator and hospital administrator Alesha Alford said it was built to withstand hurricane force winds. But in the single story facility, there's no room to move up and storm surge in that area was expected to hit nine feet.

In a roughly two-hour operation the babies in the intensive care unit were transferred by ambulance to Lake Charles Memorial Hospital, a ten-story facility on the northern side of the city. Trucks carried needed equipment such as incubators.Alford said the storm hadn't yet hit but "the skies looked very ominous." She said everyone pitched in to get supplies moved to the other hospital."It went as smooth as could be because we had everyone helping," she said.Alford said three mothers who couldn't be discharged from the women's hospital were also transferred. Two of them had their newborns with them while the child of the third mom was in the intensive care unit.

Parents of the other children in the neonatal intensive care unit couldn't stay with them during the storm because there wasn't enough room so Bossano said one nurse was tasked with calling parents to keep them informed of how their children were doing. Bossano occasionally posted updates on Facebook.Once they got situated at the larger hospital and the winds picked up, Alford said the patients were moved into the hallways. To "protect our babies," mattresses were pushed up against the windows to prevent flying glass although none of the windows ended up breaking.She said as huge gusts of wind started coming in, they could feel the building vibrate.

In addition to Bossano, the medical staff consisted of two neonatal nurse practitioners, 14 nurses and three respiratory therapists who worked on 12-hour shifts. Some of the staff slept on air mattresses in the hallway, Alford said. After making it through the hurricane, the plan was to have the babies stay in Lake Charles.

While electricity was out in the city, the hospital has its own generator. But Alford said the city's water system has been so heavily damaged that it ultimately forced them to transfer the babies as well as other patients to other hospitals around the state Friday.Both Alford and Bossano repeatedly praised the nursing staff for their work in caring for the babies that in some cases were born weighing only a pound or two. Some of the nursing staff lost their houses in the storm, and they were worried about their own families, but they put those concerns aside to care for their tiny patients."Really the nurses and the respiratory therapists are the heroes here," Bosanno said.

"They showed that very clearly the way they performed."There aren’t many hospital visitors amid the alcoholism treatment antabuse. But, if you were to walk through intensive-care units at one New York City hospital, you’d see internet-connected speakers—about the size of a stack of Post-it Notes—affixed to the bedrails of some patient beds.It’s part of a project by two Weill Cornell Medicine doctors to help family members speak with ICU patients, often intubated or otherwise not able to hold up a phone themselves, from afar.“The patients could be completely sedated, they could be in a coma,” but families still want to be there with them, said Dr. Marc Schiffman, an interventional radiologist and one of the doctors who spearheaded bringing the devices into ICUs.The speakers, now in 11 units at Weill Cornell, are part of a two-way communication system from company Relay, originally developed as a walkie-talkie system of sorts for children to stay in touch with their parents throughout the day.

Users on one end record snippets of conversation using a mobile app, which are automatically played out loud through the small speaker.Users on the other end push a button on the device to record a response.“Whenever (families) have a story they want to recount, they can just talk into their phone,” Schiffman said. €œIt gives the families a sense of autonomy (and) connection,” even when the patient can’t respond.The effort, dubbed the VoiceLove Project, began about four months ago, at the height of the alcoholism treatment antabuse in New York City.Families and other visitors were no longer allowed inside Weill Cornell, but still wanted a way to connect with patients who were sick with alcoholism treatment. Initially, that involved a nurse standing in the ICU and holding up a phone or tablet so families could see the patient—a task that took time out of their already busy day, potentially exposed them to alcoholism treatment and often meant using scarce personal protective equipment.“It really wasn’t a practical solution,” said Dr.

Tamatha Fenster, a minimally invasive gynecologic surgeon.So Fenster and Schiffman began brainstorming hands-free technologies they could install directly at the bedside. Schiffman drove to a local Target store and bought a few Relay walkie-talkie devices. After testing it with families and patients in the ICU, the two decided it was a “grand slam,” Schiffman said.Since March, hospitals have been trying new ways to keep patients connected to families at home, said Bill Flatley, senior service delivery manager at consulting firm OST.

He said he’s mainly seen hospitals repurpose technology usually used for telemedicine, like tablets and cameras mounted on telemedicine carts.It’s likely hospitals will have to continue to restrict visitors, at least as long as there’s uncertainty around alcoholism treatment. So it’s integral for staff to figure out processes that make it easy for families to talk to patients—without putting an additional burden on clinicians or expecting them to serve as tech support.For Fenster and Schiffman, deploying walkie-talkies in the ICU for the first time took some leg work.To scale the walkie-talkie system, Schiffman reached out to Relay’s team via the company’s website, and the company agreed to donate roughly 130 devices and waived the per-user subscription fee. The doctors and Relay have continued to work together on best practices for using the devices in ICUs, a use case Relay is marketing and could sell to other hospitals, according to Jon Schniepp, Relay’s senior vice president of marketing.But Fenster and Schiffman couldn’t just bring walkie-talkies into the ICU.

In the hospital setting, there are additional quality and privacy concerns. To address those, the doctors created a disposable case, which made it easier to keep the device sterile and blocked passersby from accidentally pressing the button that would transmit sounds to a family’s Relay app.The two spent thousands of dollars out of their own pockets to devise the best case design, Fenster said, working with an industrial designer in New Jersey to 3D print different models. The final plastic case, customized with the phrase “VoiceLove” on the front, costs about $10 per case to print and ship.

They’ve started reaching out to acute-care and post-acute facilities in California, Texas and other alcoholism treatment hot spots to explain how the VoiceLove Project works, hoping to connect other groups with Relay and share the case design. But the doctors say they’re still working out the logistics of getting the equipment to interested organizationsWhen Dr. George Wanna saw how devastated St.

George Hospital University Medical Center was by an explosion that shook Beirut, he felt a need to help his hometown. The Aug. 4 blast in the city’s harbor ravaged St.

George’s, so Wanna launched a GoFundMe page to help the hospital, where a good friend of his, Dr. Alexander Nehme, is chief medical officer.At deadline, more than $86,600 had been raised, with a goal of $100,000. €œThis is the first time in their 140-year history when St.

George’s Hospital was damaged so severely that it is unable to function,” said Wanna, chair of the otolaryngology department at New York Eye and Ear Infirmary of Mount Sinai and Mount Sinai Beth Israel in New York. €¨St. George Hospital even remained open during Lebanon’s 15-year civil war, a conflict that wracked Beirut and forced Wanna to spend much of his childhood in bomb shelters.

Wanna is also working with Mount Sinai to send medical supplies. €œSt. George Hospital is in need of everything needed to run a hospital—beds, ventilators, protective equipment.” The tragedy also affected Wanna’s family.

His parents weren’t home when the blast struck and were unharmed. But “my parents’ home was severely damaged by the blast. Sadly, we lost the lives of several of my dad’s relatives,” he said via email.

Wanna, who spent his residency at Mount Sinai, is grateful to the system. €œThey have given me a chance to have the kind of life I could never have hoped for—they helped me build a home and a life in this great country.”.

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IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in http://www.kampfirejournal.com/?post_type=feedback&p=1000 cohorts of patients suspected best online antabuse to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation in Science and Technology (EU COST) action BM1303 ‘A systematic elucidation of differences of sex development’ has been a platform to achieve European agreement on harmonisation of clinical management and laboratory practices.15–17 Another such initiative involved an update of the 2006 DSD 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 best online antabuse. 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 best online antabuse part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured healthcare systems and similar resources. Within the guideline there is agreement that optimisation of expertise and care can be achieved through centralisation, for example, by limiting analysis of next-generation sequencing (NGS)-based diagnostic panels to only a few centres and by centralising pathological review of gonadal tissues. International networks such as the European Reference Network for rare endocrine conditions (EndoERN), in which DSD is best online antabuse embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

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

Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the best online antabuse 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 best online antabuse 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 best online antabuse line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, 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, best online antabuse 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 best online antabuse.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft best online antabuse was discussed by the 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, the final version was presented to the paediatric and genetic associations for approval best online antabuse. 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 best online antabuse 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 best online antabuse 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 best online antabuse 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 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 best online antabuse 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 best online antabuse findings and the limitations of this technique. The procedure(s) that can be followed, including the risks associated with an amniocentesis.

And the type of information genetic testing can and cannot provide best online antabuse. 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 best online antabuse to allow parents to make a well-informed decision about whether or not to continue the pregnancy.

Termination of pregnancy can be considered, for instance, in best online antabuse 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 best online antabuse and uncertainty about the diagnosis, 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 decline prenatal testing (personal best online antabuse 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 best online antabuse 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 neurological anomalies best online antabuse 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 of sex development best online antabuse (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 http://diamaritorres.com/2012/08/30/endulge-in-typography/ 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 their explanation have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for antabuse pill price 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 antabuse pill price financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them. Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to antabuse pill price 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 embedded, may facilitate the expansion of this kind of collaboration across Europe.This antabuse pill price 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 antabuse pill price 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 the adult team requires optimal communication between the antabuse pill price 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 antabuse pill price 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 Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines antabuse pill price 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 antabuse pill price 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 antabuse pill price were excluded, as were articles that were not open access or retrievable through institutional access. Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft antabuse pill price was discussed by the 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, the final version was presented to the paediatric and genetic associations for antabuse pill price 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 antabuse pill price 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 antabuse pill price 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 antabuse pill price analysis and reports.

If the X and Y chromosomes are included, it is important to realise that the presence of a Y-chromosome does not necessarily imply male fetal development. At the time that NIPT is performed (usually 11–13 weeks), genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their antabuse pill price 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 antabuse pill price the ultrasound findings and the limitations of this technique.

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

Termination of pregnancy can be considered, for antabuse pill price 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, treatment and prognosis antabuse pill price 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 antabuse pill price during pregnancy and having a contact person before birth.After expert prenatal counselling, a significant number of pregnant couples decline prenatal testing (personal experience IALG, MK, ABD, YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist. The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery antabuse pill price 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 seen, the geneticist can consider specific gene defects that may underlie a known antabuse pill price 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 of sex development antabuse pill price (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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SALT LAKE CITY, taking antabuse after drinking Sept. 09, 2020 (GLOBE NEWSWIRE) -- Health Catalyst, Inc. ("Health Catalyst", taking antabuse after drinking Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that Patrick Nelli, Chief Financial Officer, and Adam Brown, Senior Vice President, Investor Relations, will participate in the 2020 Cantor Global Virtual Healthcare Conference on Tuesday, September 15, 2020, which will include a fireside chat presentation at 1:20 p.m.

ET. A live audio webcast and replay of this presentation will be available at https://ir.healthcatalyst.com/investor-relations.About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Investor Relations Contact:Adam BrownSenior Vice President, Investor Relations+1 (855)-309-6800ir@healthcatalyst.comHealth Catalyst Media Contact:Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.com Source.

Health Catalyst, Inc.SALT LAKE CITY, Sept. 8, 2020 /PRNewswire/ -- Health Catalyst, Inc. ("Health Catalyst," Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that it has completed its seventh annual and first ever virtual Healthcare Analytics Summit (HAS), with record registration of more than 3,500 attendees.

Keynotes included Dr. Amy Abernethy, Principal Deputy Commissioner and Acting CIO of the U.S. Food and Drug Administration, Michael Dowling, CEO of Northwell Health, Vice Admiral Raquel Bono, MD, and many others. Other business updates include:The Vitalware, LLC ("VitalWare"), transaction has closed, and integration is underway of the Yakima, Washington-based provider of revenue workflow optimization and analytics SaaS technology solutions for health organizations.

This is another example of Health Catalyst's ability to scale software on top of its cloud-based Data Operating System (DOS™). DOS will further enhance the analytics insights made available by Vitalware's technology by combining charge and revenue data with claims, cost, and quality data. Vitalware's flagship offering is a Best in KLAS chargemaster management solution that delivers results for the complex regulatory and compliance functions needed by all healthcare provider systems. "As announced on August 11, 2020, we entered into an acquisition agreement to acquire Vitalware and expected to close the acquisition in Q3 or Q4 of 2020.

We are pleased to announce that we closed the acquisition on September 1, 2020. We are thrilled to formalize the combination of our solutions for the benefit of our customers and the industry," said CEO Dan Burton. On its upcoming Q3 2020 earnings call, Health Catalyst will share the impact of Vitalware on its Q3 2020 financial performance, which will not be significant given the timing of the acquisition, as well as update its full year 2020 guidance to include the impact of Vitalware. Health Catalyst Co-Founder Steve Barlow has returned from his three-year full-time volunteer mission for the Church of Jesus Christ of Latter-Day Saints, having served as Mission President of the Ecuador Quito Mission.

He has rejoined Health Catalyst's companywide Leadership Team as a Senior Vice President, responsible for some of the company's largest customer relationships. Dan Burton said, "We couldn't be more excited about Steve's return to Health Catalyst. His energy, dedication and commitment to transforming healthcare launched our journey and will continue to make us better and stronger. Steve is leading and overseeing all aspects of our partnerships with some of our largest and longest-standing customers.

Steve's extraordinary experience and capability enable him to be a critical partner and leader in enabling these customers' continued improvement and success." "My experience over the past three years in Ecuador reinforced for me how fortunate I am to be in a country with high-quality healthcare," said Barlow. "It has been invigorating to return to Health Catalyst and witness the incredible growth and expansion that has occurred over the past few years. We are better positioned than ever before to achieve our mission of being the catalyst for massive, measurable, data-informed healthcare improvement. I am grateful to be reunited with our longstanding team members and customers, and I'm thrilled to get to know and work alongside our new customers and teammates in this critical work." Effective October 1, 2020, Chief Technology Officer Dale Sanders will be transitioning to a Senior Advisor role with Health Catalyst, and the company is pleased to announce that one of Dale's longtime protégés and colleagues, Bryan Hinton, will serve as Health Catalyst's next Chief Technology Officer.

Hinton joined Health Catalyst in 2012 and currently serves as the Senior Vice President and General Manager of the DOS Platform Business. He will continue to lead this business in addition to assuming the responsibilities of CTO. He has been instrumental in the development and integration of DOS and has been working directly with Dale and other technology leaders at Health Catalyst for many years. His experience prior to joining Health Catalyst includes four years with the .NET Development Center of Excellence at The Church of Jesus Christ of Latter-Day Saints, where he established the architectural guidance of all .NET projects.

Previously, at Intel, he was responsible for the development and implementation of Intel's factory data warehouse product installed at Intel global factories. Hinton graduated from Brigham Young University with a BS in Computer Science. "Dale has been central to Health Catalyst's growth and success and we are grateful to him for his many years of service to our company and to the broader healthcare industry," said Dan Burton, CEO of Health Catalyst. "Thanks to Dale's vision, passion, innovative thinking and broad-based industry experience and perspective, Health Catalyst has grown from a handful of clients to a large number of organizations relying on us as their digital transformation partner, helping the healthcare ecosystem to constantly learn and improve.

Dale's technology leadership was critical to the company's overall maturation, and I am convinced that we could not have grown and scaled as we have without Dale's foundational leadership and contributions. We are grateful to continue our association with Dale in the months and years ahead in his next role as a Senior Advisor to the company." Burton added, "We are thrilled to see Bryan Hinton take on this added role after having demonstrated his technology leadership prowess during the course of his tenure at Health Catalyst and having been mentored by Dale for many years. Bryan is well-prepared and ready for this additional responsibility, and we extend our congratulations to him." "I feel like a parent saying goodbye to my kids at their college graduation," said Dale Sanders. "Many of the concepts we first developed and applied over 20 years ago at Intermountain and then later refined during my tenure as CIO at Northwestern had a big influence on our technology and products at Health Catalyst.

The vision of the Data Operating System and its application ecosystem originated in the real-world healthcare operations and research trenches of Northwestern. At Health Catalyst, I had the wonderful opportunity to lead the teams who made that vision a reality for the benefit of the entire industry. None of it would have been possible without Bryan Hinton leading the DOS team and Eric Just and Dan Unger leading the application development teams. We've been working side-by-side for many years to make the vision real.

Bryan is the consummate modern CTO from outside of healthcare that healthcare needs. I've always described Eric as having a manufacturing engineer's mindset with a healthcare data and software engineer's skills, with Dan Unger leveraging his deep domain expertise in financial transformation to oversee the development of meaningful applications and solutions so relevant for CFOs. I'm honored and thrilled to step aside and turn the future over to their very capable hands. Under their leadership, the best is yet to come for Health Catalyst's technology." About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations, and is committed to being the catalyst for massive, measurable, data-informed healthcare improvement.

Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Media Contact:Kristen BerrySenior Vice President, Public Relations+1 (617) 234-4123HealthCatalyst@we-worldwide.com View original content to download multimedia:http://www.prnewswire.com/news-releases/health-catalyst-completes-hosting-of-the-largest-ever-healthcare-analytics-summit-and-announces-the-close-of-the-vitalware-acquisition-301125125.htmlSOURCE Health Catalyst.

SALT LAKE click over here CITY, antabuse pill price Sept. 09, 2020 (GLOBE NEWSWIRE) -- Health Catalyst, Inc. ("Health Catalyst", antabuse pill price Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that Patrick Nelli, Chief Financial Officer, and Adam Brown, Senior Vice President, Investor Relations, will participate in the 2020 Cantor Global Virtual Healthcare Conference on Tuesday, September 15, 2020, which will include a fireside chat presentation at 1:20 p.m.

ET. A live audio webcast and replay of this presentation will be available at https://ir.healthcatalyst.com/investor-relations.About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations committed to being the catalyst for massive, measurable, data-informed healthcare improvement. Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial, and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Investor Relations Contact:Adam BrownSenior Vice President, Investor Relations+1 (855)-309-6800ir@healthcatalyst.comHealth Catalyst Media Contact:Kristen BerryVice President, Public Relations+1 (617) 234-4123+1 (774) 573-0455 (m)kberry@we-worldwide.com Source.

Health Catalyst, Inc.SALT LAKE CITY, Sept. 8, 2020 /PRNewswire/ -- Health Catalyst, Inc. ("Health Catalyst," Nasdaq. HCAT), a leading provider of data and analytics technology and services to healthcare organizations, today announced that it has completed its seventh annual and first ever virtual Healthcare Analytics Summit (HAS), with record registration of more than 3,500 attendees.

Keynotes included Dr. Amy Abernethy, Principal Deputy Commissioner and Acting CIO of the U.S. Food and Drug Administration, Michael Dowling, CEO of Northwell Health, Vice Admiral Raquel Bono, MD, and many others. Other business updates include:The Vitalware, LLC ("VitalWare"), transaction has closed, and integration is underway of the Yakima, Washington-based provider of revenue workflow optimization and analytics SaaS technology solutions for health organizations.

This is another example of Health Catalyst's ability to scale software on top of its cloud-based Data Operating System (DOS™). DOS will further enhance the analytics insights made available by Vitalware's technology by combining charge and revenue data with claims, cost, and quality data. Vitalware's flagship offering is a Best in KLAS chargemaster management solution that delivers results for the complex regulatory and compliance functions needed by all healthcare provider systems. "As announced on August 11, 2020, we entered into an acquisition agreement to acquire Vitalware and expected to close the acquisition in Q3 or Q4 of 2020.

We are pleased to announce that we closed the acquisition on September 1, 2020. We are thrilled to formalize the combination of our solutions for the benefit of our customers and the industry," said CEO Dan Burton. On its upcoming Q3 2020 earnings call, Health Catalyst will share the impact of Vitalware on its Q3 2020 financial performance, which will not be significant given the timing of the acquisition, as well as update its full year 2020 guidance to include the impact of Vitalware. Health Catalyst Co-Founder Steve Barlow has returned from his three-year full-time volunteer mission for the Church of Jesus Christ of Latter-Day Saints, having served as Mission President of the Ecuador Quito Mission.

He has rejoined Health Catalyst's companywide Leadership Team as a Senior Vice President, responsible for some of the company's largest customer relationships. Dan Burton said, "We couldn't be more excited about Steve's return to Health Catalyst. His energy, dedication and commitment to transforming healthcare launched our journey and will continue to make us better and stronger. Steve is leading and overseeing all aspects of our partnerships with some of our largest and longest-standing customers.

Steve's extraordinary experience and capability enable him to be a critical partner and leader in enabling these customers' continued improvement and success." "My experience over the past three years in Ecuador reinforced for me how fortunate I am to be in a country with high-quality healthcare," said Barlow. "It has been invigorating to return to Health Catalyst and witness the incredible growth and expansion that has occurred over the past few years. We are better positioned than ever before to achieve our mission of being the catalyst for massive, measurable, data-informed healthcare improvement. I am grateful to be reunited with our longstanding team members and customers, and I'm thrilled to get to know and work alongside our new customers and teammates in this critical work." Effective October 1, 2020, Chief Technology Officer Dale Sanders will be transitioning to a Senior Advisor role with Health Catalyst, and the company is pleased to announce that one of Dale's longtime protégés and colleagues, Bryan Hinton, will serve as Health Catalyst's next Chief Technology Officer.

Hinton joined Health Catalyst in 2012 and currently serves as the Senior Vice President and General Manager of the DOS Platform Business. He will continue to lead this business in addition to assuming the responsibilities of CTO. He has been instrumental in the development and integration of DOS and has been working directly with Dale and other technology leaders at Health Catalyst for many years. His experience prior to joining Health Catalyst includes four years with the .NET Development Center of Excellence at The Church of Jesus Christ of Latter-Day Saints, where he established the architectural guidance of all .NET projects.

Previously, at Intel, he was responsible for the development and implementation of Intel's factory data warehouse product installed at Intel global factories. Hinton graduated from Brigham Young University with a BS in Computer Science. "Dale has been central to Health Catalyst's growth and success and we are grateful to him for his many years of service to our company and to the broader healthcare industry," said Dan Burton, CEO of Health Catalyst. "Thanks to Dale's vision, passion, innovative thinking and broad-based industry experience and perspective, Health Catalyst has grown from a handful of clients to a large number of organizations relying on us as their digital transformation partner, helping the healthcare ecosystem to constantly learn and improve.

Dale's technology leadership was critical to the company's overall maturation, and I am convinced that we could not have grown and scaled as we have without Dale's foundational leadership and contributions. We are grateful to continue our association with Dale in the months and years ahead in his next role as a Senior Advisor to the company." Burton added, "We are thrilled to see Bryan Hinton take on this added role after having demonstrated his technology leadership prowess during the course of his tenure at Health Catalyst and having been mentored by Dale for many years. Bryan is well-prepared and ready for this additional responsibility, and we extend our congratulations to him." "I feel like a parent saying goodbye to my kids at their college graduation," said Dale Sanders. "Many of the concepts we first developed and applied over 20 years ago at Intermountain and then later refined during my tenure as CIO at Northwestern had a big influence on our technology and products at Health Catalyst.

The vision of the Data Operating System and its application ecosystem originated in the real-world healthcare operations and research trenches of Northwestern. At Health Catalyst, I had the wonderful opportunity to lead the teams who made that vision a reality for the benefit of the entire industry. None of it would have been possible without Bryan Hinton leading the DOS team and Eric Just and Dan Unger leading the application development teams. We've been working side-by-side for many years to make the vision real.

Bryan is the consummate modern CTO from outside of healthcare that healthcare needs. I've always described Eric as having a manufacturing engineer's mindset with a healthcare data and software engineer's skills, with Dan Unger leveraging his deep domain expertise in financial transformation to oversee the development of meaningful applications and solutions so relevant for CFOs. I'm honored and thrilled to step aside and turn the future over to their very capable hands. Under their leadership, the best is yet to come for Health Catalyst's technology." About Health CatalystHealth Catalyst is a leading provider of data and analytics technology and services to healthcare organizations, and is committed to being the catalyst for massive, measurable, data-informed healthcare improvement.

Its customers leverage the cloud-based data platform—powered by data from more than 100 million patient records and encompassing trillions of facts—as well as its analytics software and professional services expertise to make data-informed decisions and realize measurable clinical, financial and operational improvements. Health Catalyst envisions a future in which all healthcare decisions are data informed.Health Catalyst Media Contact:Kristen BerrySenior Vice President, Public Relations+1 (617) 234-4123HealthCatalyst@we-worldwide.com View original content to download multimedia:http://www.prnewswire.com/news-releases/health-catalyst-completes-hosting-of-the-largest-ever-healthcare-analytics-summit-and-announces-the-close-of-the-vitalware-acquisition-301125125.htmlSOURCE Health Catalyst.

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As alcoholism continues its global spread, it’s possible that one of the pillars of alcoholism treatment antabuse control — universal facial masking — might help reduce the severity antabuse cost per pill of disease and ensure that a greater proportion of new s are asymptomatic buy antabuse with free samples. If this hypothesis is borne out, universal masking could become a form of “variolation” that would generate immunity and thereby slow the spread of the antabuse in the United States and elsewhere, as we await a treatment.One important reason for population-wide facial masking became apparent in March, when reports started to circulate describing the high rates of alcoholism viral shedding from the noses and mouths of patients who were presymptomatic or asymptomatic — shedding rates equivalent to those among symptomatic patients.1 Universal facial masking seemed to be a possible way to prevent transmission from asymptomatic infected people. The Centers for Disease Control and Prevention (CDC) therefore recommended on April 3 that the public wear cloth face coverings in areas with high rates of community transmission — a recommendation that has been unevenly followed across the United States.Past evidence related to other respiratory antabusees indicates that facial masking can also protect the wearer from becoming infected, by blocking viral particles from entering the nose and mouth.2 Epidemiologic investigations conducted around the world — especially in Asian countries antabuse cost per pill that became accustomed to population-wide masking during the 2003 SARS antabuse — have suggested that there is a strong relationship between public masking and antabuse control. Recent data from Boston demonstrate that alcoholism s decreased among health care workers after universal masking was implemented in municipal hospitals in late March.alcoholism has the protean ability to cause myriad clinical manifestations, ranging from a complete lack of symptoms to pneumonia, acute respiratory distress syndrome, and death.

Recent virologic, epidemiologic, and ecologic data have led to the hypothesis that facial masking may also reduce the severity of disease among people who do antabuse cost per pill become infected.3 This possibility is consistent with a long-standing theory of viral pathogenesis, which holds that the severity of disease is proportionate to the viral inoculum received. Since 1938, researchers have explored, primarily in animal models, the concept of the lethal dose of a antabuse — or the dose at which 50% of exposed hosts die (LD50). With viral s in antabuse cost per pill which host immune responses play a predominant role in viral pathogenesis, such as alcoholism, high doses of viral inoculum can overwhelm and dysregulate innate immune defenses, increasing the severity of disease. Indeed, down-regulating immunopathology is one mechanism by which dexamethasone improves outcomes in severe alcoholism treatment .

As proof of concept of viral inocula influencing disease manifestations, higher doses of administered antabuse led to more severe manifestations of alcoholism treatment in a Syrian hamster model of alcoholism .4If the viral inoculum matters in determining the severity of alcoholism , an additional hypothesized reason for wearing facial masks would be to reduce the viral antabuse cost per pill inoculum to which the wearer is exposed and the subsequent clinical impact of the disease. Since masks can filter out some antabuse-containing droplets (with filtering capacity determined by mask type),2 masking might reduce the inoculum that an exposed person inhales. If this theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence,2 antabuse cost per pill might contribute to increasing the proportion of alcoholism s that are asymptomatic. The typical rate of asymptomatic with alcoholism was estimated to be 40% by the CDC in mid-July, but asymptomatic rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evidence for this hypothesis.

Countries that have adopted population-wide masking have fared better in terms of rates of severe alcoholism treatment-related illnesses and death, which, in environments with limited testing, suggests a shift from symptomatic to asymptomatic antabuse cost per pill s. Another experiment in the Syrian hamster model simulated surgical masking of the animals and showed that with simulated masking, hamsters were less likely to get infected, and if they did get infected, they either were asymptomatic or had milder symptoms than unmasked hamsters.The most obvious way to spare society the devastating effects of alcoholism treatment is to promote measures to reduce both transmission and severity of illness. But alcoholism is highly transmissible, cannot be contained by syndromic-based surveillance alone,1 and is proving antabuse cost per pill difficult to eradicate, even in regions that implemented strict initial control measures. Efforts to increase testing and containment in the United States have been ongoing and variably successful, owing in part to the recent increase in demand for testing.The hopes for treatments are pinned not just on prevention.

Most treatment trials include a secondary outcome of decreasing the severity of illness, since increasing the proportion of cases in which disease is mild antabuse cost per pill or asymptomatic would be a public health victory. Universal masking seems to reduce the rate of new s. We hypothesize that by reducing the viral inoculum, it would also increase the proportion of infected people who remain asymptomatic.3In an outbreak on a closed Argentinian cruise ship, for example, where passengers were provided with surgical masks and staff with N95 masks, the rate of asymptomatic was 81% (as compared with 20% in earlier cruise ship outbreaks without universal antabuse cost per pill masking). In two recent outbreaks in U.S.

Food-processing plants, where all workers were issued masks each day and were required to wear them, the proportion of asymptomatic antabuse cost per pill s among the more than 500 people who became infected was 95%, with only 5% in each outbreak experiencing mild-to-moderate symptoms.3 Case-fatality rates in countries with mandatory or enforced population-wide masking have remained low, even with resurgences of cases after lockdowns were lifted.Variolation was a process whereby people who were susceptible to smallpox were inoculated with material taken from a vesicle of a person with smallpox, with the intent of causing a mild and subsequent immunity. Variolation was practiced only until the introduction of the variola treatment, which ultimately eradicated smallpox. Despite concerns regarding safety, worldwide distribution, and eventual uptake, the world has high hopes for a highly effective alcoholism treatment, and as of early September, 34 treatment candidates were in clinical evaluation, with hundreds more in development.While we await the results of treatment antabuse cost per pill trials, however, any public health measure that could increase the proportion of asymptomatic alcoholism s may both make the less deadly and increase population-wide immunity without severe illnesses and deaths. Re with alcoholism seems to be rare, despite more than 8 months of circulation worldwide and as suggested by a macaque model.

The scientific community has been clarifying for some time the humoral and cell-mediated antabuse cost per pill components of the adaptive immune response to alcoholism and the inadequacy of antibody-based seroprevalence studies to estimate the level of more durable T-cell and memory B-cell immunity to alcoholism. Promising data have been emerging in recent weeks suggesting that strong cell-mediated immunity results from even mild or asymptomatic alcoholism ,5 so any public health strategy that could reduce the severity of disease should increase population-wide immunity as well.To test our hypothesis that population-wide masking is one of those strategies, we need further studies comparing the rate of asymptomatic in areas with and areas without universal masking. To test the variolation hypothesis, we will need more studies comparing the strength and durability of alcoholism–specific T-cell immunity between people with asymptomatic and those with symptomatic , as well as a demonstration of the natural slowing of alcoholism antabuse cost per pill spread in areas with a high proportion of asymptomatic s.Ultimately, combating the antabuse will involve driving down both transmission rates and severity of disease. Increasing evidence suggests that population-wide facial masking might benefit both components of the response..

As alcoholism continues its global spread, it’s possible that one of the pillars of alcoholism treatment antabuse control — universal facial masking — might help reduce the severity of disease and ensure that a greater proportion of new antabuse pill price s are asymptomatic. If this hypothesis is borne out, universal masking could become a form of “variolation” that would generate immunity and thereby slow the spread of the antabuse in the United States and elsewhere, as we await a treatment.One important reason for population-wide facial masking became apparent in March, when reports started to circulate describing the high rates of alcoholism viral shedding from the noses and mouths of patients who were presymptomatic or asymptomatic — shedding rates equivalent to those among symptomatic patients.1 Universal facial masking seemed to be a possible way to prevent transmission from asymptomatic infected people. The Centers for Disease Control and Prevention (CDC) therefore recommended on April 3 that the public wear cloth face coverings in areas with high rates of community transmission — a recommendation that has been unevenly followed across the United States.Past evidence related to other respiratory antabusees indicates that facial masking can also protect the wearer from becoming infected, by blocking viral particles from entering the nose and mouth.2 Epidemiologic investigations conducted around antabuse pill price the world — especially in Asian countries that became accustomed to population-wide masking during the 2003 SARS antabuse — have suggested that there is a strong relationship between public masking and antabuse control. Recent data from Boston demonstrate that alcoholism s decreased among health care workers after universal masking was implemented in municipal hospitals in late March.alcoholism has the protean ability to cause myriad clinical manifestations, ranging from a complete lack of symptoms to pneumonia, acute respiratory distress syndrome, and death. Recent virologic, epidemiologic, and ecologic data have led to the hypothesis that facial masking may also reduce antabuse pill price the severity of disease among people who do become infected.3 This possibility is consistent with a long-standing theory of viral pathogenesis, which holds that the severity of disease is proportionate to the viral inoculum received.

Since 1938, researchers have explored, primarily in animal models, the concept of the lethal dose of a antabuse — or the dose at which 50% of exposed hosts die (LD50). With viral s in which host immune responses play a predominant role in viral pathogenesis, such as alcoholism, high doses of viral inoculum can overwhelm and dysregulate innate immune defenses, increasing antabuse pill price the severity of disease. Indeed, down-regulating immunopathology is one mechanism by which dexamethasone improves outcomes in severe alcoholism treatment . As proof of concept of viral inocula influencing disease manifestations, higher doses of administered antabuse led antabuse pill price to more severe manifestations of alcoholism treatment in a Syrian hamster model of alcoholism .4If the viral inoculum matters in determining the severity of alcoholism , an additional hypothesized reason for wearing facial masks would be to reduce the viral inoculum to which the wearer is exposed and the subsequent clinical impact of the disease. Since masks can filter out some antabuse-containing droplets (with filtering capacity determined by mask type),2 masking might reduce the inoculum that an exposed person inhales.

If this antabuse pill price theory bears out, population-wide masking, with any type of mask that increases acceptability and adherence,2 might contribute to increasing the proportion of alcoholism s that are asymptomatic. The typical rate of asymptomatic with alcoholism was estimated to be 40% by the CDC in mid-July, but asymptomatic rates are reported to be higher than 80% in settings with universal facial masking, which provides observational evidence for this hypothesis. Countries that have adopted population-wide masking have fared better in terms of rates of severe alcoholism treatment-related illnesses and death, which, in environments with limited testing, suggests a shift from antabuse pill price symptomatic to asymptomatic s. Another experiment in the Syrian hamster model simulated surgical masking of the animals and showed that with simulated masking, hamsters were less likely to get infected, and if they did get infected, they either were asymptomatic or had milder symptoms than unmasked hamsters.The most obvious way to spare society the devastating effects of alcoholism treatment is to promote measures to reduce both transmission and severity of illness. But alcoholism is highly transmissible, cannot be contained by syndromic-based surveillance alone,1 antabuse pill price and is proving difficult to eradicate, even in regions that implemented strict initial control measures.

Efforts to increase testing and containment in the United States have been ongoing and variably successful, owing in part to the recent increase in demand for testing.The hopes for treatments are pinned not just on prevention. Most treatment trials include a secondary outcome of decreasing the severity of illness, since increasing the proportion of cases in which antabuse pill price disease is mild or asymptomatic would be a public health victory. Universal masking seems to reduce the rate of new s. We hypothesize that by reducing the viral inoculum, it would antabuse pill price also increase the proportion of infected people who remain asymptomatic.3In an outbreak on a closed Argentinian cruise ship, for example, where passengers were provided with surgical masks and staff with N95 masks, the rate of asymptomatic was 81% (as compared with 20% in earlier cruise ship outbreaks without universal masking). In two recent outbreaks in U.S.

Food-processing plants, where all antabuse pill price workers were issued masks each day and were required to wear them, the proportion of asymptomatic s among the more than 500 people who became infected was 95%, with only 5% in each outbreak experiencing mild-to-moderate symptoms.3 Case-fatality rates in countries with mandatory or enforced population-wide masking have remained low, even with resurgences of cases after lockdowns were lifted.Variolation was a process whereby people who were susceptible to smallpox were inoculated with material taken from a vesicle of a person with smallpox, with the intent of causing a mild and subsequent immunity. Variolation was practiced only until the introduction of the variola treatment, which ultimately eradicated smallpox. Despite concerns regarding safety, worldwide distribution, and eventual uptake, the world has high antabuse pill price hopes for a highly effective alcoholism treatment, and as of early September, 34 treatment candidates were in clinical evaluation, with hundreds more in development.While we await the results of treatment trials, however, any public health measure that could increase the proportion of asymptomatic alcoholism s may both make the less deadly and increase population-wide immunity without severe illnesses and deaths. Re with alcoholism seems to be rare, despite more than 8 months of circulation worldwide and as suggested by a macaque model. The scientific community has been clarifying for some time the humoral and cell-mediated components of the adaptive immune response to alcoholism and the inadequacy of antibody-based seroprevalence studies to estimate the level of more durable T-cell and memory antabuse pill price B-cell immunity to alcoholism.

Promising data have been emerging in recent weeks suggesting that strong cell-mediated immunity results from even mild or asymptomatic alcoholism ,5 so any public health strategy that could reduce the severity of disease should increase population-wide immunity as well.To test our hypothesis that population-wide masking is one of those strategies, we need further studies comparing the rate of asymptomatic in areas with and areas without universal masking. To test the variolation hypothesis, we will need more studies comparing the strength and durability of alcoholism–specific T-cell immunity between people with asymptomatic and those with symptomatic , as well as a demonstration of the natural slowing of alcoholism spread in areas with a high proportion of asymptomatic s.Ultimately, combating antabuse pill price the antabuse will involve driving down both transmission rates and severity of disease. Increasing evidence suggests that population-wide facial masking might benefit both components of the response..

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Letzte Änderung: 20.11.2018 
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