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Download (PDF 41.7 kb) No AbstractNo Reference information available - sign in how much does generic viagra cost for walgreens viagra price access. No Supplementary Data.No Article MediaNo MetricsDocument Type. Research ArticleAffiliations:1.

Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical how much does generic viagra cost University, Nanjing, China 2. ISGlobal Hospital Clínic, Universitat de Barcelona, Barcelona, Spain, Manhiça Health Research Hospital, Ministry of Health, National Tuberculosis Control Program, Maputo, Mozambique , Email. [email protected]Publication date:01 September 2020More about this publication?.

The International Journal of Tuberculosis and Lung Disease how much does generic viagra cost publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on lung health world-wide. To share scientific research of immediate concern as rapidly as possible, The Union is fast-tracking the publication of certain articles from the IJTLD and publishing them on The Union website, prior to their publication in the Journal.

Read fast-track articles.Certain IJTLD articles are also how much does generic viagra cost selected for translation into French, Spanish, Chinese or Russian. These are available on the Union website.Editorial BoardInformation for AuthorsSubscribe to this TitleInternational Journal of Tuberculosis and Lung DiseasePublic Health ActionIngenta Connect is not responsible for the content or availability of external websitesNo AbstractNo Reference information available - sign in for access. No Supplementary Data.No Article MediaNo MetricsDocument Type.

Research ArticleAffiliations:1 how much does generic viagra cost. Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, London, UK 2. German Central Committee against Tuberculosis, Berlin, Germany , Email.

[email protected]Publication date:01 September 2020More how much does generic viagra cost about this publication?. The International Journal of Tuberculosis and Lung Disease publishes articles on all aspects of lung health, including public health-related issues such as training programmes, cost-benefit analysis, legislation, epidemiology, intervention studies and health systems research. The IJTLD is dedicated to the continuing education of physicians and health personnel and the dissemination of information on lung health world-wide.

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A reported ransomware attack on the CompuGroup how to get viagra prescription Medical data center partner, MedNetwoRX, has impeded some customers' access to their Aprima electronic health record systems for more than can you buy viagra at cvs two weeks. According to emails forwarded to Healthcare IT News, the disruption began on April 22 – and some hosted Aprima clients are still waiting for service to be restored as of Friday."The outage has been tremendously disruptful to our ability to properly care for our patients," said Dr. Christopher Fox, a Colorado-based endocrinologist.Fox's clinic, the Alpine Center for Diabetes, Endocrinology and Metabolism, is an Aprima EHR client."We've not had access to our clinic schedule, chart notes, refill requests or incoming test results," said Fox, although he notes that they can access test results in other ways as a how to get viagra prescription workaround.

"We're unable to schedule new appointments, as availability and open time slots are unknown. We've been using our downtime protocols, however, these how to get viagra prescription were really not designed to serve a 14-day outage," he said. "I assume this is unusual for length of outage," he said.

The CompuGroup Medical brand how to get viagra prescription eMDs, which acquired Aprima in 2019, did not respond to multiple requests for comment. MedNetwoRX also did not respond to requests for comment. Two weeks of outages Email messages forwarded to Healthcare IT News suggest how to get viagra prescription weeks of uncertainty.

On April 27, eMDs sent an email signed by CompuGroup Medical CEO Derek Pickell to hosted Aprima customers detailing the incident.According to the email, "A sophisticated criminal organization carried out a ransomware attack on some of the hosting vendor’s systems, disaster recovery site, and backups." "We do not have confirmation yet that this is a data breach, and if it was, which of our clients were impacted, but the eMDs Incident Response Team continues to follow all data integrity and appropriate government, regulatory, and notification protocols," the email continued. "eMDs will be sending a written data breach notice to any customer whose data has been confirmed to have been how to get viagra prescription encrypted," it read. The email encouraged hosted customers to continue operating under HIPAA disaster protocols and contingency plans, including using paper-based workflows.

"We are working extremely closely how to get viagra prescription with the hosting vendor to ensure that APRIMA customers are prioritized for restoration," read an April 26 email, also signed by Pickell. "They have engaged additional outside technical professionals and are conducting a thorough investigation of their network. Every server at the main and secondary backup/disaster recovery sites is undergoing a thorough review process." "The goal is to remove any and all malware from the how to get viagra prescription systems, make sure all devices are clean, and to restore full functionality and data," that email continued.Some customers took to social media to discuss the effects they were experiencing.

"Our EMR (Aprima), has been down since last Thursday worldwide," wrote the Arthritis and Osteoporosis Center of Kentucky in a public Facebook post dated April 28. "Support is looking into how to get viagra prescription the issue and has assured us they are working around the clock to get us back up and running. Therefore, we are not able to log in.

Patient portal will also how to get viagra prescription not be available. "We are still operating as normal to continue providing service to our patients. We are having to do everything manually instead of electronic and much more time how to get viagra prescription consuming so please be patient," the post read.

"This is beyond our control and we are working as fast as we can on our part until our EMR is back up and running."We appreciate your understanding, but again, it is an issue world wide affecting other practices as well. We will do everything how to get viagra prescription we can on our part, to make sure you are taken care of," it continued.Commenters on that post described their own access hurdles. "Any progress?.

We also have Aprima, in how to get viagra prescription our cardiology group in Sarasota, Florida. We are still down ..." wrote one user on April 29. "We have patients that have been with us for many years and now it’s tough to help them," the user added in a different comment."I am down still will be [two] weeks this Thursday," wrote another on May 4 how to get viagra prescription.

"As a solo practitioner I expect that I am a low priority." Problems appeared to persist for some customers even after their access was restored. "We are continuing to experience issues with Aprima, our EMR," wrote the AOCK in another public Facebook post, dated May 5 how to get viagra prescription. "It is down nationwide and it is taking us quite a bit of time to open each chart as it takes several minutes to open each tab.

It is how to get viagra prescription impossible to answer [calls]," the post continued. The center did not respond to requests for comment. "We remain aware that some restored users have how to get viagra prescription been experiencing speed issues.

We are working hard with MedNetworx troubleshooting these and doing what it takes to rectify the causes," read an eMDs email, dated May 6. Still waiting As of how to get viagra prescription May 6, eMDs said in another forwarded email that about 260 customers had their system availability restored. "We are told by MedNetworx that we should have access to most of the remaining servers tomorrow," read the email, signed by Pickell.

"As you would expect, we have many processes in place to maximize the restore speed of the databases on these as soon how to get viagra prescription as we get access." "We are still on target to provide all affected customers with access to their data by Monday. We recognize that we are now [two] weeks into this and again, apologize for the disruption to your operations," continued the email. On Friday morning, Fox said his clinic was still waiting how to get viagra prescription to have access restored.

"We remain hopeful for service soon, but still nothing for us," he said. Kat Jercich how to get viagra prescription is senior editor of Healthcare IT News.Twitter. @kjercichEmail.

Kjercich@himss.orgHealthcare IT News is a HIMSS Media publication.While the last five years have seen how to get viagra prescription computing move from local networks to the cloud, especially in healthcare, the trend of edge computing is seeing organizations move back to move forward. Moving key computing and intelligence back to the point of care while still retaining the benefits of cloud computing.This not only reduces latency, which can be especially important for healthcare, but also has important implications for privacy and security.On today's episode, we welcome Tao Zhang, an IEEE Fellow and manager of emerging network technologies at NIST, to give us a primer on edge computing, and explain what it can do for healthcare organizations.This podcast is brought to you by Aruba Networks.Like what you hear?. Subscribe to the podcast on Apple Podcasts, Spotify how to get viagra prescription or Google Play!.

Talking points:What is edge computing and why is it gaining traction now?. Striking the balance between the edge and the cloud.The history of edge computing.Why the healthcare how to get viagra prescription space is turning to edge computing.Security implications of edge computing for IoT.Downsides to edge computing.More edge computing use cases. Tips for adopting edge computing.What next for edge computing?.

Edge and AI.More about this episode:NIST ResourcesHospitals embracing IoT must be prepared to secure a decentralized environmentStriking a balance between medical device security and innovationGE Healthcare unveils new edge computing tools for cliniciansNvidia launches AI edge computing platformTech Optimization. Medical device and IoT operating secretsHow Vail Health ensures consistent medical device security and firmware patchingThe Mayo Clinic released results of a trial this how to get viagra prescription week that suggests potential for artificial intelligence to assist with early diagnosis of some types of heart disease. The study, published in Nature Medicine on Thursday, found that an AI-enabled electrocardiogram increased the diagnosis of low ejection fraction.

"The AI-enabled EKG facilitated the diagnosis how to get viagra prescription of patients with low ejection fraction in a real-world setting by identifying people who previously would have slipped through the cracks," said Dr. Peter Noseworthy, a Mayo Clinic cardiac electrophysiologist who was the senior author on the study, in a press release. WHY IT MATTERS Ejection fraction is a measurement of how much blood the left ventricle pumps out with each contraction how to get viagra prescription.

A lower-than-normal ejection fraction can be a sign of heart failure. Diagnosing low ejection fraction early can be how to get viagra prescription key to effective treatment. And as the Mayo Clinic notes, an echocardiogram can do so, but it is time-consuming and resource-heavy.

By contrast, an EKG how to get viagra prescription is readily available, inexpensive and fast. The ECG AI-Guided Screening for Low Ejection Fraction, or EAGLE, was aimed at determining whether an AI-enabled EKG algorithm trial could help improve the diagnosis of this condition. Over eight months, 22,641 adult how to get viagra prescription patients received an EKG under the medical supervision of 348 primary care clinicians throughout Minnesota.

Clinicians in the intervention group were "alerted to a positive screening result for low ejection fraction via the electronic health record, prompting them to order an echocardiogram to confirm," read the press release. The AI found positive results how to get viagra prescription in 6% of the patients. Although the proportion who received an echocardiogram was similar overall, the AI intervention increased the diagnosis of low ejection fraction.

"To put it in absolute terms, for every 1,000 patients screened, the AI screening yielded five new diagnoses of low ejection fraction over usual care," said Xiaoxi Yao, a health outcomes researcher in cardiovascular diseases at Mayo Clinic and how to get viagra prescription first author on the study, in a statement. The low ejection fraction algorithm has received Food and Drug Administration breakthrough designation. "With EAGLE, the information was readily available in the electronic health record, and care teams could see the results and decide how to use that how to get viagra prescription information," said Noseworthy.

THE LARGER TRENDCompanies have developed several innovations over the past few years aimed at using AI to assist with detecting and diagnosing heart disease. In 2018, Google AI announced that it had successfully predicted cardiovascular problems using how to get viagra prescription images of the retina – a potential major breakthrough. A few years later, the FDA approved marketing authorization for AI-enabled cardiac ultrasound software to assist in diagnosis for non-expert providers.

And this past month, a study found that a new AI tool may help cardiologists select the best non-invasive diagnostic test how to get viagra prescription. ON THE RECORD "The takeaway is that we are likely to see more AI use in the practice of medicine as time goes on. It's up how to get viagra prescription to us to figure how to use this in a way that improves care and health outcomes but does not overburden front-line clinicians," said Noseworthy.

Kat Jercich is senior editor of Healthcare IT News.Twitter. @kjercichEmail. Kjercich@himss.orgHealthcare IT News is a HIMSS Media publication.The director of the Centers for Disease Control and Prevention said recently that the U.S.

Might be finally turning a corner in the erectile dysfunction treatment viagra. It's been a relentless 16 months, and healthcare CIOs and other health IT leaders can no doubt use a breather.During the course of the past year-plus, these executives have learned many lessons spurred by the manic pacing of the viagra. Some of them center on the importance of data and analytics, the need for more patient engagement, the requirements of keeping telehealth up to par, and the need to focus technologies on enabling enterprise-wide strategic plans.In this seventh installment in Healthcare IT News' feature series, Health IT Lessons Learned During the erectile dysfunction treatment Era, four top IT executives from provider organizations nationwide share what they've learned during the past year and discuss how they're applying these lessons to improve their organizations.

(To see all the stories in the series, click here to visit the special portal.)We spoke with:Clark Averill, director of information technology at St. Luke's Regional Healthcare System, based in Duluth, Minnesota. (@StLukesDuluth)Dr.

Roxana Lupu, chief medical information officer at Sanford Health, based in Sioux Falls, South Dakota. (@SanfordHealth)Leonard T. "Skip" Rollins, CIO and CISO at Freeman Health System, based in Joplin, Missouri.

(@FreemanCares4U)Matthew Russo, IT director at Helio Health, based in Syracuse, New York. (@Helio_Health)The increased importance of data and analyticsOverall, the erectile dysfunction treatment viagra has catapulted the importance of data analytics and data in general, said Lupu of Sanford Health."At Sanford Health, the largest rural health system in the country, our leaders have always recognized the importance and the power of data, but the erectile dysfunction treatment viagra revealed the meaningful benefits of investing in the resources and infrastructure needed for a strong data analytics department," she said.For example, the data analytics team designed an algorithm to sort and pull relevant data from the records of more than 100,000 patients who had been diagnosed with erectile dysfunction treatment, identifying those at highest risk of complications from the viagra."In early November 2020, the FDA issued an emergency use authorization for the therapeutic use of monoclonal antibodies for erectile dysfunction treatment-positive patients, which had been shown to prevent hospitalizations in a limited number of trials," Lupu recalled."Our leaders have always recognized the importance and the power of data, but the erectile dysfunction treatment viagra revealed the meaningful benefits of investing in the resources and infrastructure needed for a strong data analytics department."Dr. Roxana Lupu, Sanford Health"At the time, hospitals across the Sanford Health footprint were experiencing a rapid increase in erectile dysfunction treatment hospitalizations, stretching hospital capacity and creating unprecedented challenges for our health system and its frontline workers."Staff members were able to use data analytics to proactively screen and contact patients who were at highest risk of developing complications from erectile dysfunction treatment and schedule outpatient monoclonal antibody treatments.

To date, Sanford has treated more than 2,700 patients with antibody infusions at more than 19 sites across its vast rural footprint, preventing nearly 1,000 days of hospitalization and averting at least 15 deaths, Lupu reported."We were also able to harness our data analytics in our vaccination rollout strategy to efficiently and equitably get treatments to people," she added. "Early on, when treatment supply was limited, Sanford Health followed state eligibility guidelines and then stratified the list based on patient risk factors, prioritizing the highest-risk patients and inviting them to be among the first to schedule erectile dysfunction treatment vaccination appointments."This all would have been a much tougher lesson if Sanford had not already had this infrastructure in place, she said."We see immense value in applying predictive models and risk stratification to our patient population," she said. "For example, we can leverage the data to deliver more personalized care through predictive models that take into account all aspects of patients' histories.

Data analytics also will be critical as we move toward value-based care with a focus on prevention and keeping our patients healthy rather than just treating sick patients."More, more, more patient engagementFor Averill of St. Luke's Regional Healthcare System, the impact of patient engagement using patient portal communication, virtual visits and digital appointment-scheduling provided a big lesson."St. Luke's primary use of the patient portal prior to erectile dysfunction treatment was as a tool for providing patients access to their health information, especially lab results and physician/patient messaging," he explained.

"The importance of using the portal as a patient engagement tool was highlighted when in-person patient visits were limited due to erectile dysfunction treatment protocols."Patient engagement consisted of using the portal for self-scheduling patient visits, patient messaging via the portal, remote patient monitoring, and implementing virtual visits," he continued. "We also expanded the amount of clinical information sent in real time to the portal since delivering in-person results wasn't possible."On March 5, 2020, St. Luke's had 27,305 patients enrolled in its patient portal, which was 18.92% of its patient population since going live with Meditech Expanse on May 1, 2019.

"We decided to http://counterbalancebeer.com/july-progress-report/ implement self-scheduling for the erectile dysfunction treatment. Self-scheduling has been an overwhelming success and patient satisfier."Clark Averill, St. Luke's Regional Healthcare SystemWith the expansion of virtual visits, St.

Luke's launched a major effort to increase the number of patients enrolled in the patient portal. As of April 19, 2021, St. Luke's had enrolled 63,546 patients – 34.47% of all patients.

Of patients with an assigned primary care provider, 55.51% of patients are enrolled in the portal."Patient self-scheduling became critically important as we implemented our erectile dysfunction treatment clinic," Averill noted. "As we started to receive the erectile dysfunction treatment, we struggled with the best way to schedule appointments, given the volume of patients we needed to vaccinate. Our original plan was to schedule these appointments via traditional methods, but we believed those methods couldn't scale to the volume of patients we needed to schedule."St.

Luke's had begun a pilot project of patient self-scheduling for annual wellness visits," he continued. "We decided to implement self-scheduling for the erectile dysfunction treatment. Self-scheduling has been an overwhelming success and patient satisfier.

Patients appreciate the ability to select the day and time of the appointment."St. Luke's is continuing to expand patient engagement features of the patient portal:Self-scheduling. Increasing the number of appointment types available for patients to self-schedule.Virtual visits.

Continuing to enhance the number of appointments that can be completed using virtual visit technology or including remote caregivers during an in-person visit.Remote patient monitoring. Expanding the number of patients that can be monitored away from the hospital or clinic for medical conditions in order to enhance patient care and reduce readmissions.Non-patient onboarding. This new feature of the Expanse patient portal allows people who have not been patients at St.

Luke's to enroll in the patient portal and schedule appointments.When telehealth is not up to parOne major lesson Helio Health learned last year was that its telehealth presence was not up to par. On the other hand, the health system also learned that its teams could implement a telehealth presence fairly quickly."We had to pivot quickly to be certain our patients' critical care would not be interrupted by restrictions put in place as a result of erectile dysfunction treatment," said Russo of Helio Health. "We were already using Microsoft Teams internally as our video conferencing solution, so it was a natural choice to begin to use for remote one-on-one therapy sessions and group counselling sessions as well."Helio Health equipped staff with as many laptops, headsets and webcams as it could get its hands on.

The supply chain was extremely strained, but Helio's vendors were able to come through."For our inpatient services, we procured a large quantity of iPads so that our counselors could still meet with our patients without being face to face," Russo said. "This helped during the patients' initial quarantines and for when there were active cases of erectile dysfunction treatment in any of our facilities. We upgraded our phone systems to be able to handle the increased volume of over-the-phone telehealth support.""It was really impressive to see everyone come together and work toward the same goal of providing the best care possible during one of the most challenging periods of our lives."Matthew Russo, Helio HealthHelio Health's methods evolved over the course of last summer.

It was able to quickly adjust to changes thrown at it."The IT and HIT teams at Helio Health went through some of the most intense months of our careers, but I am so proud of the team and how we were able to persevere so that our patient population would still be taken care of," Russo said. "To be fair, this was the case for our entire staff and for most of the world. It was really impressive to see everyone come together and work toward the same goal of providing the best care possible during one of the most challenging periods of our lives."He added that Helio Health is continuing to improve its posture in the areas of remote working and telehealth services and is committed to investing in new technology to help staff members be ready for anything the future throws their way.Leveraging technology to further strategyRollins of Freeman Health System said 2020 was a great year for health IT for many reasons."Many important initiatives were pushed forward and implemented in attempts to react to the ever-changing needs of our customers," he explained.

"I have always been very aggressive in staying in touch with technology and how it might further our needs. One of our fundamental directives is to understand how we can leverage technology to further Freeman's strategies. This approach has worked well when we were forced to shuffle and reshuffle priorities during 2020."The guiding principle has been to never impede Freeman's progress or response to patients' needs.

Having a firm understanding of how one's IT organization is positioned to react is very important, he added."When the CEO turns to you in a meeting and says, 'Can you do that?. ' you must be ready to provide a confident response," he stated. "Answering with, 'Let me check,' is not a good answer.""When the CEO turns to you in a meeting and says, 'Can you do that?.

' you must be ready to provide a confident response. Answering with, 'Let me check,' is not a good answer."Leonard T. "Skip" Rollins, Freeman Health SystemAll health IT leaders know how difficult it can be to get funding for new or changing technology platforms.

Flexibility in infrastructure gives CIOs the ability to have a "can do" approach to the varying needs of health systems, Rollins said."Our EHR platforms are utilitarian and are what they are. The magic happens in the echo systems around the EHRs," he said. "Maximizing the ability to pivot and use new applications or technology to solve problems can make CIOs heroes.

Not having the ability can make you look out of touch or behind the times. Get flexible. Do not commit to strategies that put you in a corner.

Stay nimble and look for opportunities to leverage your ability to react quickly."Freeman Health System always is reviewing and re-evaluating its approach to the healthcare environment. As mentioned, it is difficult to always stay the direction with strategies, Rollins said."Things change, so we annually evaluate our plans and strategies to validate they are consistent with the direction things are trending," he noted. "This process allows us to adjust and stay as close as we can to being ready to react when things change.

It's not easy, and it's not the least expensive way to operate, but it will position you better to have the right answer ready when asked, 'Can we do that?. '"Keeping strategies dynamicAnother lesson Rollins has learned over the past year is that health IT and organizational strategies must leave room to adapt to the environment."All CIOs have said, 'I really wish I knew that when I made that decision,'" he said. "Things change, as should your strategies.

Our strategies are certainly with the organization's plans, but we try to leave them open enough to adjust. We had made decisions and commitments related to mobility that had to be revisited during 2020."Rollins is being transparent when he admits he and his team missed on how many of their mobility tools would be used, and encountered limitations in some areas."Our care providers evolved, and we were not completely able to follow them because of some of the commitments we had made," he said. "This miss scared me and caused me to sit with the IT leadership team and reevaluate mobility and how we could support the direction it was headed.

We made adjustments in device management, BYOD and other components of the strategy to give us more room to ebb and flow with the ever-changing workflows and needs of the care providers."This miss was a surprise. They thought they had it figured out, but they did not. Many of their assumptions about how the equipment was going to be used were wrong, he admitted."As a result of the miss on mobility, we have evolved this strategy," Rollins said.

"On a broader scale, we have changed how we make technology decisions and built in more flexibility. The flexibility need drove us to redefine mobility and how we would provide the capability. Our big mistake was we had an idea of how the users would use the tools.

Now they are planning with us and helping us to better understand the possible uses of the tools."The moral of the story. Get closer with users, understand their workflows, and understand how they use technology before making commitments, he advised.Streamlined and efficient decision-makingOn another front, the viagra has underscored the importance of having a structured mechanism and system in place for streamlined and efficient decision-making, said Lupu of Sanford Health."Prior to erectile dysfunction treatment, if our operations teams needed to address certain topics, we worked through a committee structure to gather feedback, propose solutions and build consensus. It was not uncommon for this process to take months before a decision was reached," she said.In March 2020, Sanford Health activated its incident command and started closely monitoring erectile dysfunction treatment.

A multidisciplinary team from across the organization sat around the table – including health system leaders and operators, medical directors, advanced practice providers, nursing, pharmacy, enterprise data analytics, clinical informatics and clinical research. They were able to make decisions, pivot and then implement new protocols in real time, she said."For example, on Friday, April 16, the FDA revoked the EUA that allowed for the monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild to moderate erectile dysfunction treatment, due to ongoing analysis of emerging scientific data around its resistance to new variants," she recalled. "With the support of our revamped reporting and decision-making structure, we were able to immediately make the necessary changes in the electronic record and notify our providers, pharmacists and operational leaders in real time to ensure we remained in compliance and protected the health and safety of our patients."Sanford Health now has restructured its optimization committees to improve efficiency in the decision-making process.

It sees the value in having a more streamlined way of expediting issues that need to be addressed."Before erectile dysfunction treatment, if colleagues were not present at our optimization committee meeting, we'd have to follow up and have a back-and-forth discussion before moving ahead with a decision or resolution," Lupu said. "Now we have a more centralized approach to our committees, with a clearer structure and pathways to lift up issues and execute change."Standardized processes and equipmentAnother lesson Helio Health has learned is the need for standardization of equipment and processes, Russo said."The vast majority of our computers were desktop PCs," he noted. "With a grant from the FCC, we were able to standardize our outpatient facilities with Microsoft laptops, which allow us to work and provide support from anywhere.

Users are able to come and go, from remote work to in-person work, easily."With a recent merger between Helio Health and two other organizations, much of the hardware from the other organizations was dissimilar to Helio Health's standards."We are upgrading them and shifting them to our standards," said Russo. "This includes standardizing computer models, Ruckus cloud wireless, bringing them into our eLAN through Spectrum, implementing Ricoh Follow Me print, etc. "With everyone on the same platform, it is easier to troubleshoot issues," he added.

"The Ricoh Follow Me print is a pretty neat feature we are implementing across the organization. You can basically press print, and then go to any printer or copier in the organization and release your print job by authenticating with an RFID badge."The lesson learned, he concluded, is to be on the cutting edge of hardware, software and security so that an organization can be ready for anything that life throws at it.Twitter. @SiwickiHealthITEmail the writer.

Bsiwicki@himss.orgHealthcare IT News is a HIMSS Media publication.Philips hosted a virtual round table with industry leaders to discuss the findings of the newly-released Future Health Index 2021 (FHI). Philips’ chief medical officer, Jan Kimpen, hosted the discussion between Professor Wim van Harten, CEO of Rijnstate Hospital in the Netherlands, and Dr Aaron Neinstein, director of clinical informatics at UCSF Center for Digital Health Innovation in the US, to discuss the future of healthcare post-viagra.In its sixth year, the FHI is an original research report conducted by Philips to analyse and determine the current and future priorities of healthcare leaders across the globe. The report, titled ‘A Resilient Future.

Healthcare leaders look beyond the crisis’, surveyed almost 3,000 healthcare leaders across 14 countries to determine the readiness of countries to address the global challenges in healthcare and see how they are working to build resilient healthcare systems.WHY IT MATTERSThe FHI identified three key trends for post-viagra healthcare. The acceleration of virtual care delivery. A stepwise approach in digital transformation from telehealth to AI adoption.

And an increased focus on building sustainable healthcare systems.Despite conducting the research in the throes of the viagra, the report showed that healthcare leaders were already looking ahead.“What was surprising at the beginning was that, while we were expecting a pessimistic view of healthcare, this was not the case,” said Kimpen during the roundtable. €œHealthcare leaders are optimistic. They are energised during this crisis and they are optimistic, 75% of them think that their hospital and their healthcare system will be able to deliver quality care three years from now, starting today.”Part of this optimism was directed towards the increased prominence of telehealth in healthcare systems, which, the report stated, is expected to make up 23% of routine care delivery three years from now.Van Harten, who has been integral in bringing telehealth and value-based care strategies to the region around Arnhem, reflected how Rijnstate had to redefine the timelines of the digital strategy they had set pre-viagra.“We had been working as a hospital with 750 beds for about half a million people and we changed our paradigm to say that ‘we are a hospital with half a million beds and it doesn’t matter anymore where patients should be treated’.

The horizon that we had was about five to ten years and I think the trends that we see will make this happen a lot sooner.”The acceleration of virtual care services also means an improvement of the organisation’s processes and business information.Neinstein added that the main obstacle for telehealth adoption that was overcome during the viagra was the cultural expectations about care delivery. As patients have become accustomed to receiving care virtually, their expectations of how care is delivered have changed, which is an accelerant for virtual care transformation.The FHI found, however, that the current focus on telehealth will likely move to investment in AI in the next three years. This could be used not only to improve processes and workflows but also clinical decision making.“When people think of AI in healthcare, they imagine a robot replacing the doctor,” said Neinstein.

€œThat is the last thing that will happen when leveraging and implementing AI in healthcare. What we are looking at is creating lots of efficiencies. We are reliant on cumbersome workflows and a lot of human effort to touch every part of the care journey and there are a lot of opportunities to layer in machine learning and AI in ways that are not risky but really save people a lot of time and energy.”Van Harten acknowledged that, as a teaching hospital with limited funds, investment in AI had as much to do with making the right alignments and partnerships with institutions and startups to drive digital innovation as it had to do with the implementation itself.A surprising finding from the FHI was a commitment to environmental sustainability, despite being in the midst of a viagra.

With just 4% of those surveyed reporting that their facility currently prioritised sustainable healthcare systems, 58% expected to see this as a priority three years from now. €œThe care and the patient are always in the first place but, looking at the environment, it is inevitable that you as a hospital invest in these types of activities,” said van Harten. He underlined that, alongside goals such as ensuring a percentage of green energy was used in hospitals and climate control in operating rooms, sustainability was a priority when building new facilities.

€œWe [are building] a new site in about two years and this will be the first site in the Netherlands to be hydrogen-powered. We are really proud and rather confident that we will succeed in achieving that.”Neinstein highlighted the potential of technology in creating more sustainable healthcare systems, particularly focusing on the role of measurement and analytics to identify the “low hanging fruit for sustainability”, as well as the further integration of remote care as a means of reducing unnecessary travel emissions for patients.THE LARGER PICTUREAs the threat of the viagra decreases and vaccination programmes roll out across the world, the disparities and health inequities that were illuminated have affected political change. The accelerated uptake of digital tools and virtual care over the last year, for instance, has been seen as a way to close the digital divide, but it must maintain the quality of care.

Recently in conversation with HIMSS TV, Franka Cadée, president of the International Confederation of Midwives, highlighted the need for digital tools to foster human-to-human interaction and compassionate care. €œWhen you use digital means, it’s important to use them in the right balance and to make sure you build on the human trust. Then you can use digital means but you need to keep that trust as well and make sure you invest in that.”.

A reported ransomware attack on the CompuGroup Medical data center partner, MedNetwoRX, has impeded some customers' access to how much does generic viagra cost their Aprima electronic health record systems for more than two click over here weeks. According to emails forwarded to Healthcare IT News, the disruption began on April 22 – and some hosted Aprima clients are still waiting for service to be restored as of Friday."The outage has been tremendously disruptful to our ability to properly care for our patients," said Dr. Christopher Fox, a Colorado-based endocrinologist.Fox's clinic, the how much does generic viagra cost Alpine Center for Diabetes, Endocrinology and Metabolism, is an Aprima EHR client."We've not had access to our clinic schedule, chart notes, refill requests or incoming test results," said Fox, although he notes that they can access test results in other ways as a workaround. "We're unable to schedule new appointments, as availability and open time slots are unknown. We've been using our downtime protocols, however, these were really not designed to serve a how much does generic viagra cost 14-day outage," he said.

"I assume this is unusual for length of outage," he said. The CompuGroup Medical brand eMDs, which acquired Aprima in 2019, did not respond how much does generic viagra cost to multiple requests for comment. MedNetwoRX also did not respond to requests for comment. Two weeks of outages Email messages how much does generic viagra cost forwarded to Healthcare IT News suggest weeks of uncertainty. On April 27, eMDs sent an email signed by CompuGroup Medical CEO Derek Pickell to hosted Aprima customers detailing the incident.According to the email, "A sophisticated criminal organization carried out a ransomware attack on some of the hosting vendor’s systems, disaster recovery site, and backups." "We do not have confirmation yet that this is a data breach, and if it was, which of our clients were impacted, but the eMDs Incident Response Team continues to follow all data integrity and appropriate government, regulatory, and notification protocols," the email continued.

"eMDs will be sending a written how much does generic viagra cost data breach notice to any customer whose data has been confirmed to have been encrypted," it read. The email encouraged hosted customers to continue operating under HIPAA disaster protocols and contingency plans, including using paper-based workflows. "We are working extremely closely with the hosting vendor to ensure that APRIMA customers are prioritized for how much does generic viagra cost restoration," read an April 26 email, also signed by Pickell. "They have engaged additional outside technical professionals and are conducting a thorough investigation of their network. Every server at the main and secondary backup/disaster recovery sites is undergoing a how much does generic viagra cost thorough review process." "The goal is to remove any and all malware from the systems, make sure all devices are clean, and to restore full functionality and data," that email continued.Some customers took to social media to discuss the effects they were experiencing.

"Our EMR (Aprima), has been down since last Thursday worldwide," wrote the Arthritis and Osteoporosis Center of Kentucky in a public Facebook post dated April 28. "Support is looking into the how much does generic viagra cost issue and has assured us they are working around the clock to get us back up and running. Therefore, we are not able to log in. Patient portal how much does generic viagra cost will also not be available. "We are still operating as normal to continue providing service to our patients.

We are having to do everything manually how much does generic viagra cost instead of electronic and much more time consuming so please be patient," the post read. "This is beyond our control and we are working as fast as we can on our part until our EMR is back up and running."We appreciate your understanding, but again, it is an issue world wide affecting other practices as well. We will do everything we can on our part, to make sure you are taken care how much does generic viagra cost of," it continued.Commenters on that post described their own access hurdles. "Any progress?. We also have Aprima, in our cardiology group in Sarasota, how much does generic viagra cost Florida.

We are still down ..." wrote one user on April 29. "We have patients that have been with us for many years and now how much does generic viagra cost it’s tough to help them," the user added in a different comment."I am down still will be [two] weeks this Thursday," wrote another on May 4. "As a solo practitioner I expect that I am a low priority." Problems appeared to persist for some customers even after their access was restored. "We are continuing to experience issues how much does generic viagra cost with Aprima, our EMR," wrote the AOCK in another public Facebook post, dated May 5. "It is down nationwide and it is taking us quite a bit of time to open each chart as it takes several minutes to open each tab.

It is how much does generic viagra cost impossible to answer [calls]," the post continued. The center did not respond to requests for comment. "We remain aware that how much does generic viagra cost some restored users have been experiencing speed issues. We are working hard with MedNetworx troubleshooting these and doing what it takes to rectify the causes," read an eMDs email, dated May 6. Still waiting As of May 6, eMDs said in another forwarded how much does generic viagra cost email that about 260 customers had their system availability restored.

"We are told by MedNetworx that we should have access to most of the remaining servers tomorrow," read the email, signed by Pickell. "As you would expect, we have many processes in place to maximize the restore speed of the databases on these as soon as we get access." "We are still on target to provide all affected customers with access to their how much does generic viagra cost data by Monday. We recognize that we are now [two] weeks into this and again, apologize for the disruption to your operations," continued the email. On Friday how much does generic viagra cost morning, Fox said his clinic was still waiting to have access restored. "We remain hopeful for service soon, but still nothing for us," he said.

Kat Jercich is senior editor of Healthcare how much does generic viagra cost IT News.Twitter. @kjercichEmail. Kjercich@himss.orgHealthcare IT News is a HIMSS Media publication.While the last five years have seen computing move from local networks to the cloud, especially in healthcare, the how much does generic viagra cost trend of edge computing is seeing organizations move back to move forward. Moving key computing and intelligence back to the point of care while still retaining the benefits of cloud computing.This not only reduces latency, which can be especially important for healthcare, but also has important implications for privacy and security.On today's episode, we welcome Tao Zhang, an IEEE Fellow and manager of emerging network technologies at NIST, to give us a primer on edge computing, and explain what it can do for healthcare organizations.This podcast is brought to you by Aruba Networks.Like what you hear?. Subscribe to the podcast on Apple Podcasts, Spotify or Google Play! how much does generic viagra cost.

Talking points:What is edge computing and why is it gaining traction now?. Striking the balance how much does generic viagra cost between the edge and the cloud.The history of edge computing.Why the healthcare space is turning to edge computing.Security implications of edge computing for IoT.Downsides to edge computing.More edge computing use cases. Tips for adopting edge computing.What next for edge computing?. Edge and AI.More about this episode:NIST ResourcesHospitals embracing IoT must be prepared to secure a decentralized environmentStriking a balance between medical device security and innovationGE Healthcare unveils new edge computing tools for cliniciansNvidia launches AI edge computing platformTech Optimization. Medical device and IoT operating secretsHow Vail Health ensures consistent medical device security and firmware patchingThe Mayo Clinic released results of a trial this week that suggests potential for artificial intelligence to assist with early diagnosis of some types of how much does generic viagra cost heart disease.

The study, published in Nature Medicine on Thursday, found that an AI-enabled electrocardiogram increased the diagnosis of low ejection fraction. "The AI-enabled EKG facilitated the diagnosis of patients with low ejection fraction in a real-world how much does generic viagra cost setting by identifying people who previously would have slipped through the cracks," said Dr. Peter Noseworthy, a Mayo Clinic cardiac electrophysiologist who was the senior author on the study, in a press release. WHY IT MATTERS Ejection fraction is a measurement of how much blood the how much does generic viagra cost left ventricle pumps out with each contraction. A lower-than-normal ejection fraction can be a sign of heart failure.

Diagnosing low ejection fraction how much does generic viagra cost early can be key to effective treatment. And as the Mayo Clinic notes, an echocardiogram can do so, but it is time-consuming and resource-heavy. By contrast, an EKG is how much does generic viagra cost readily available, inexpensive and fast. The ECG AI-Guided Screening for Low Ejection Fraction, or EAGLE, was aimed at determining whether an AI-enabled EKG algorithm trial could help improve the diagnosis of this condition. Over eight months, 22,641 adult patients received an EKG how much does generic viagra cost under the medical supervision of 348 primary care clinicians throughout Minnesota.

Clinicians in the intervention group were "alerted to a positive screening result for low ejection fraction via the electronic health record, prompting them to order an echocardiogram to confirm," read the press release. The AI found positive results in 6% of how much does generic viagra cost the patients. Although the proportion who received an echocardiogram was similar overall, the AI intervention increased the diagnosis of low ejection fraction. "To put it in absolute terms, for every 1,000 patients screened, the AI screening yielded five new diagnoses of low ejection fraction over usual care," said Xiaoxi Yao, a health outcomes researcher in cardiovascular diseases at Mayo Clinic and first author on the study, how much does generic viagra cost in a statement. The low ejection fraction algorithm has received Food and Drug Administration breakthrough designation.

"With EAGLE, the information how much does generic viagra cost was readily available in the electronic health record, and care teams could see the results and decide how to use that information," said Noseworthy. THE LARGER TRENDCompanies have developed several innovations over the past few years aimed at using AI to assist with detecting and diagnosing heart disease. In 2018, Google AI announced that it had successfully predicted cardiovascular problems using images how much does generic viagra cost of the retina – a potential major breakthrough. A few years later, the FDA approved marketing authorization for AI-enabled cardiac ultrasound software to assist in diagnosis for non-expert providers. And this how much does generic viagra cost past month, a study found that a new AI tool may help cardiologists select the best non-invasive diagnostic test.

ON THE RECORD "The takeaway is that we are likely to see more AI use in the practice of medicine as time goes on. It's up to how much does generic viagra cost us to figure how to use this in a way that improves care and health outcomes but does not overburden front-line clinicians," said Noseworthy. Kat Jercich is senior editor of Healthcare IT News.Twitter. @kjercichEmail. Kjercich@himss.orgHealthcare IT News is a HIMSS Media publication.The director of the Centers for Disease Control and Prevention said recently that the U.S.

Might be finally turning a corner in the erectile dysfunction treatment viagra. It's been a relentless 16 months, and healthcare CIOs and other health IT leaders can no doubt use a breather.During the course of the past year-plus, these executives have learned many lessons spurred by the manic pacing of the viagra. Some of them center on the importance of data and analytics, the need for more patient engagement, the requirements of keeping telehealth up to par, and the need to focus technologies on enabling enterprise-wide strategic plans.In this seventh installment in Healthcare IT News' feature series, Health IT Lessons Learned During the erectile dysfunction treatment Era, four top IT executives from provider organizations nationwide share what they've learned during the past year and discuss how they're applying these lessons to improve their organizations. (To see all the stories in the series, click here to visit the special portal.)We spoke with:Clark Averill, director of information technology at St. Luke's Regional Healthcare System, based in Duluth, Minnesota.

(@StLukesDuluth)Dr. Roxana Lupu, chief medical information officer at Sanford Health, based in Sioux Falls, South Dakota. (@SanfordHealth)Leonard T. "Skip" Rollins, CIO and CISO at Freeman Health System, based in Joplin, Missouri. (@FreemanCares4U)Matthew Russo, IT director at Helio Health, based in Syracuse, New York.

(@Helio_Health)The increased importance of data and analyticsOverall, the erectile dysfunction treatment viagra has catapulted the importance of data analytics and data in general, said Lupu of Sanford Health."At Sanford Health, the largest rural health system in the country, our leaders have always recognized the importance and the power of data, but the erectile dysfunction treatment viagra revealed the meaningful benefits of investing in the resources and infrastructure needed for a strong data analytics department," she said.For example, the data analytics team designed an algorithm to sort and pull relevant data from the records of more than 100,000 patients who had been diagnosed with erectile dysfunction treatment, identifying those at highest risk of complications from the viagra."In early November 2020, the FDA issued an emergency use authorization for the therapeutic use of monoclonal antibodies for erectile dysfunction treatment-positive patients, which had been shown to prevent hospitalizations in a limited number of trials," Lupu recalled."Our leaders have always recognized the importance and the power of data, but the erectile dysfunction treatment viagra revealed the meaningful benefits of investing in the resources and infrastructure needed for a strong data analytics department."Dr. Roxana Lupu, Sanford Health"At the time, hospitals across the Sanford Health footprint were experiencing a rapid increase in erectile dysfunction treatment hospitalizations, stretching hospital capacity and creating unprecedented challenges for our health system and its frontline workers."Staff members were able to use data analytics to proactively screen and contact patients who were at highest risk of developing complications from erectile dysfunction treatment and schedule outpatient monoclonal antibody treatments. To date, Sanford has treated more than 2,700 patients with antibody infusions at more than 19 sites across its vast rural footprint, preventing nearly 1,000 days of hospitalization and averting at least 15 deaths, Lupu reported."We were also able to harness our data analytics in our vaccination rollout strategy to efficiently and equitably get treatments to people," she added. "Early on, when treatment supply was limited, Sanford Health followed state eligibility guidelines and then stratified the list based on patient risk factors, prioritizing the highest-risk patients and inviting them to be among the first to schedule erectile dysfunction treatment vaccination appointments."This all would have been a much tougher lesson if Sanford had not already had this infrastructure in place, she said."We see immense value in applying predictive models and risk stratification to our patient population," she said. "For example, we can leverage the data to deliver more personalized care through predictive models that take into account all aspects of patients' histories.

Data analytics also will be critical as we move toward value-based care with a focus on prevention and keeping our patients healthy rather than just treating sick patients."More, more, more patient engagementFor Averill of St. Luke's Regional Healthcare System, the impact of patient engagement using patient portal communication, virtual visits and digital appointment-scheduling provided a big lesson."St. Luke's primary use of the patient portal prior to erectile dysfunction treatment was as a tool for providing patients access to their health information, especially lab results and physician/patient messaging," he explained. "The importance of using the portal as a patient engagement tool was highlighted when in-person patient visits were limited due to erectile dysfunction treatment protocols."Patient engagement consisted of using the portal for self-scheduling patient visits, patient messaging via the portal, remote patient monitoring, and implementing virtual visits," he continued. "We also expanded the amount of clinical information sent in real time to the portal since delivering in-person results wasn't possible."On March 5, 2020, St.

Luke's had 27,305 patients enrolled in its patient portal, which was 18.92% of its patient population since going live with Meditech Expanse on May 1, 2019. "We decided to implement self-scheduling for the erectile dysfunction treatment. Self-scheduling has been an overwhelming success and patient satisfier."Clark Averill, St. Luke's Regional Healthcare SystemWith the expansion of virtual visits, St. Luke's launched a major effort to increase the number of patients enrolled in the patient portal.

As of April 19, 2021, St. Luke's had enrolled 63,546 patients – 34.47% of all patients. Of patients with an assigned primary care provider, 55.51% of patients are enrolled in the portal."Patient self-scheduling became critically important as we implemented our erectile dysfunction treatment clinic," Averill noted. "As we started to receive the erectile dysfunction treatment, we struggled with the best way to schedule appointments, given the volume of patients we needed to vaccinate. Our original plan was to schedule these appointments via traditional methods, but we believed those methods couldn't scale to the volume of patients we needed to schedule."St.

Luke's had begun a pilot project of patient self-scheduling for annual wellness visits," he continued. "We decided to implement self-scheduling for the erectile dysfunction treatment. Self-scheduling has been an overwhelming success and patient satisfier. Patients appreciate the ability to select the day and time of the appointment."St. Luke's is continuing to expand patient engagement features of the patient portal:Self-scheduling.

Increasing the number of appointment types available for patients to self-schedule.Virtual visits. Continuing to enhance the number of appointments that can be completed using virtual visit technology or including remote caregivers during an in-person visit.Remote patient monitoring. Expanding the number of patients that can be monitored away from the hospital or clinic for medical conditions in order to enhance patient care and reduce readmissions.Non-patient onboarding. This new feature of the Expanse patient portal allows people who have not been patients at St. Luke's to enroll in the patient portal and schedule appointments.When telehealth is not up to parOne major lesson Helio Health learned last year was that its telehealth presence was not up to par.

On the other hand, the health system also learned that its teams could implement a telehealth presence fairly quickly."We had to pivot quickly to be certain our patients' critical care would not be interrupted by restrictions put in place as a result of erectile dysfunction treatment," said Russo of Helio Health. "We were already using Microsoft Teams internally as our video conferencing solution, so it was a natural choice to begin to use for remote one-on-one therapy sessions and group counselling sessions as well."Helio Health equipped staff with as many laptops, headsets and webcams as it could get its hands on. The supply chain was extremely strained, but Helio's vendors were able to come through."For our inpatient services, we procured a large quantity of iPads so that our counselors could still meet with our patients without being face to face," Russo said. "This helped during the patients' initial quarantines and for when there were active cases of erectile dysfunction treatment in any of our facilities. We upgraded our phone systems to be able to handle the increased volume of over-the-phone telehealth support.""It was really impressive to see everyone come together and work toward the same goal of providing the best care possible during one of the most challenging periods of our lives."Matthew Russo, Helio HealthHelio Health's methods evolved over the course of last summer.

It was able to quickly adjust to changes thrown at it."The IT and HIT teams at Helio Health went through some of the most intense months of our careers, but I am so proud of the team and how we were able to persevere so that our patient population would still be taken care of," Russo said. "To be fair, this was the case for our entire staff and for most of the world. It was really impressive to see everyone come together and work toward the same goal of providing the best care possible during one of the most challenging periods of our lives."He added that Helio Health is continuing to improve its posture in the areas of remote working and telehealth services and is committed to investing in new technology to help staff members be ready for anything the future throws their way.Leveraging technology to further strategyRollins of Freeman Health System said 2020 was a great year for health IT for many reasons."Many important initiatives were pushed forward and implemented in attempts to react to the ever-changing needs of our customers," he explained. "I have always been very aggressive in staying in touch with technology and how it might further our needs. One of our fundamental directives is to understand how we can leverage technology to further Freeman's strategies.

This approach has worked well when we were forced to shuffle and reshuffle priorities during 2020."The guiding principle has been to never impede Freeman's progress or response to patients' needs. Having a firm understanding of how one's IT organization is positioned to react is very important, he added."When the CEO turns to you in a meeting and says, 'Can you do that?. ' you must be ready to provide a confident response," he stated. "Answering with, 'Let me check,' is not a good answer.""When the CEO turns to you in a meeting and says, 'Can you do that?. ' you must be ready to provide a confident response.

Answering with, 'Let me check,' is not a good answer."Leonard T. "Skip" Rollins, Freeman Health SystemAll health IT leaders know how difficult it can be to get funding for new or changing technology platforms. Flexibility in infrastructure gives CIOs the ability to have a "can do" approach to the varying needs of health systems, Rollins said."Our EHR platforms are utilitarian and are what they are. The magic happens in the echo systems around the EHRs," he said. "Maximizing the ability to pivot and use new applications or technology to solve problems can make CIOs heroes.

Not having the ability can make you look out of touch or behind the times. Get flexible. Do not commit to strategies that put you in a corner. Stay nimble and look for opportunities to leverage your ability to react quickly."Freeman Health System always is reviewing and re-evaluating its approach to the healthcare environment. As mentioned, it is difficult to always stay the direction with strategies, Rollins said."Things change, so we annually evaluate our plans and strategies to validate they are consistent with the direction things are trending," he noted.

"This process allows us to adjust and stay as close as we can to being ready to react when things change. It's not easy, and it's not the least expensive way to operate, but it will position you better to have the right answer ready when asked, 'Can we do that?. '"Keeping strategies dynamicAnother lesson Rollins has learned over the past year is that health IT and organizational strategies must leave room to adapt to the environment."All CIOs have said, 'I really wish I knew that when I made that decision,'" he said. "Things change, as should your strategies. Our strategies are certainly with the organization's plans, but we try to leave them open enough to adjust.

We had made decisions and commitments related to mobility that had to be revisited during 2020."Rollins is being transparent when he admits he and his team missed on how many of their mobility tools would be used, and encountered limitations in some areas."Our care providers evolved, and we were not completely able to follow them because of some of the commitments we had made," he said. "This miss scared me and caused me to sit with the IT leadership team and reevaluate mobility and how we could support the direction it was headed. We made adjustments in device management, BYOD and other components of the strategy to give us more room to ebb and flow with the ever-changing workflows and needs of the care providers."This miss was a surprise. They thought they had it figured out, but they did not. Many of their assumptions about how the equipment was going to be used were wrong, he admitted."As a result of the miss on mobility, we have evolved this strategy," Rollins said.

"On a broader scale, we have changed how we make technology decisions and built in more flexibility. The flexibility need drove us to redefine mobility and how we would provide the capability. Our big mistake was we had an idea of how the users would use the tools. Now they are planning with us and helping us to better understand the possible uses of the tools."The moral of the story. Get closer with users, understand their workflows, and understand how they use technology before making commitments, he advised.Streamlined and efficient decision-makingOn another front, the viagra has underscored the importance of having a structured mechanism and system in place for streamlined and efficient decision-making, said Lupu of Sanford Health."Prior to erectile dysfunction treatment, if our operations teams needed to address certain topics, we worked through a committee structure to gather feedback, propose solutions and build consensus.

It was not uncommon for this process to take months before a decision was reached," she said.In March 2020, Sanford Health activated its incident command and started closely monitoring erectile dysfunction treatment. A multidisciplinary team from across the organization sat around the table – including health system leaders and operators, medical directors, advanced practice providers, nursing, pharmacy, enterprise data analytics, clinical informatics and clinical research. They were able to make decisions, pivot and then implement new protocols in real time, she said."For example, on Friday, April 16, the FDA revoked the EUA that allowed for the monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild to moderate erectile dysfunction treatment, due to ongoing analysis of emerging scientific data around its resistance to new variants," she recalled. "With the support of our revamped reporting and decision-making structure, we were able to immediately make the necessary changes in the electronic record and notify our providers, pharmacists and operational leaders in real time to ensure we remained in compliance and protected the health and safety of our patients."Sanford Health now has restructured its optimization committees to improve efficiency in the decision-making process. It sees the value in having a more streamlined way of expediting issues that need to be addressed."Before erectile dysfunction treatment, if colleagues were not present at our optimization committee meeting, we'd have to follow up and have a back-and-forth discussion before moving ahead with a decision or resolution," Lupu said.

"Now we have a more centralized approach to our committees, with a clearer structure and pathways to lift up issues and execute change."Standardized processes and equipmentAnother lesson Helio Health has learned is the need for standardization of equipment and processes, Russo said."The vast majority of our computers were desktop PCs," he noted. "With a grant from the FCC, we were able to standardize our outpatient facilities with Microsoft laptops, which allow us to work and provide support from anywhere. Users are able to come and go, from remote work to in-person work, easily."With a recent merger between Helio Health and two other organizations, much of the hardware from the other organizations was dissimilar to Helio Health's standards."We are upgrading them and shifting them to our standards," said Russo. "This includes standardizing computer models, Ruckus cloud wireless, bringing them into our eLAN through Spectrum, implementing Ricoh Follow Me print, etc. "With everyone on the same platform, it is easier to troubleshoot issues," he added.

"The Ricoh Follow Me print is a pretty neat feature we are implementing across the organization. You can basically press print, and then go to any printer or copier in the organization and release your print job by authenticating with an RFID badge."The lesson learned, he concluded, is to be on the cutting edge of hardware, software and security so that an organization can be ready for anything that life throws at it.Twitter. @SiwickiHealthITEmail the writer. Bsiwicki@himss.orgHealthcare IT News is a HIMSS Media publication.Philips hosted a virtual round table with industry leaders to discuss the findings of the newly-released Future Health Index 2021 (FHI). Philips’ chief medical officer, Jan Kimpen, hosted the discussion between Professor Wim van Harten, CEO of Rijnstate Hospital in the Netherlands, and Dr Aaron Neinstein, director of clinical informatics at UCSF Center for Digital Health Innovation in the US, to discuss the future of healthcare post-viagra.In its sixth year, the FHI is an original research report conducted by Philips to analyse and determine the current and future priorities of healthcare leaders across the globe.

The report, titled ‘A Resilient Future. Healthcare leaders look beyond the crisis’, surveyed almost 3,000 healthcare leaders across 14 countries to determine the readiness of countries to address the global challenges in healthcare and see how they are working to build resilient healthcare systems.WHY IT MATTERSThe FHI identified three key trends for post-viagra healthcare. The acceleration of virtual care delivery. A stepwise approach in digital transformation from telehealth to AI adoption. And an increased focus on building sustainable healthcare systems.Despite conducting the research in the throes of the viagra, the report showed that healthcare leaders were already looking ahead.“What was surprising at the beginning was that, while we were expecting a pessimistic view of healthcare, this was not the case,” said Kimpen during the roundtable.

€œHealthcare leaders are optimistic. They are energised during this crisis and they are optimistic, 75% of them think that their hospital and their healthcare system will be able to deliver quality care three years from now, starting today.”Part of this optimism was directed towards the increased prominence of telehealth in healthcare systems, which, the report stated, is expected to make up 23% of routine care delivery three years from now.Van Harten, who has been integral in bringing telehealth and value-based care strategies to the region around Arnhem, reflected how Rijnstate had to redefine the timelines of the digital strategy they had set pre-viagra.“We had been working as a hospital with 750 beds for about half a million people and we changed our paradigm to say that ‘we are a hospital with half a million beds and it doesn’t matter anymore where patients should be treated’. The horizon that we had was about five to ten years and I think the trends that we see will make this happen a lot sooner.”The acceleration of virtual care services also means an improvement of the organisation’s processes and business information.Neinstein added that the main obstacle for telehealth adoption that was overcome during the viagra was the cultural expectations about care delivery. As patients have become accustomed to receiving care virtually, their expectations of how care is delivered have changed, which is an accelerant for virtual care transformation.The FHI found, however, that the current focus on telehealth will likely move to investment in AI in the next three years. This could be used not only to improve processes and workflows but also clinical decision making.“When people think of AI in healthcare, they imagine a robot replacing the doctor,” said Neinstein.

€œThat is the last thing that will happen when leveraging and implementing AI in healthcare. What we are looking at is creating lots of efficiencies. We are reliant on cumbersome workflows and a lot of human effort to touch every part of the care journey and there are a lot of opportunities to layer in machine learning and AI in ways that are not risky but really save people a lot of time and energy.”Van Harten acknowledged that, as a teaching hospital with limited funds, investment in AI had as much to do with making the right alignments and partnerships with institutions and startups to drive digital innovation as it had to do with the implementation itself.A surprising finding from the FHI was a commitment to environmental sustainability, despite being in the midst of a viagra. With just 4% of those surveyed reporting that their facility currently prioritised sustainable healthcare systems, 58% expected to see this as a priority three years from now. €œThe care and the patient are always in the first place but, looking at the environment, it is inevitable that you as a hospital invest in these types of activities,” said van Harten.

He underlined that, alongside goals such as ensuring a percentage of green energy was used in hospitals and climate control in operating rooms, sustainability was a priority when building new facilities. €œWe [are building] a new site in about two years and this will be the first site in the Netherlands to be hydrogen-powered. We are really proud and rather confident that we will succeed in achieving that.”Neinstein highlighted the potential of technology in creating more sustainable healthcare systems, particularly focusing on the role of measurement and analytics to identify the “low hanging fruit for sustainability”, as well as the further integration of remote care as a means of reducing unnecessary travel emissions for patients.THE LARGER PICTUREAs the threat of the viagra decreases and vaccination programmes roll out across the world, the disparities and health inequities that were illuminated have affected political change. The accelerated uptake of digital tools and virtual care over the last year, for instance, has been seen as a way to close the digital divide, but it must maintain the quality of care. Recently in conversation with HIMSS TV, Franka Cadée, president of the International Confederation of Midwives, highlighted the need for digital tools to foster human-to-human interaction and compassionate care.

€œWhen you use digital means, it’s important to use them in the right balance and to make sure you build on the human trust. Then you can use digital means but you need to keep that trust as well and make sure you invest in that.”.

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Under the stewardship of the MidMichigan Health where to get viagra Foundation, this year, 23 area students will received scholarship awards from the Tolfree Scholarship, the Dr does viagra lower your blood pressure. George Schaiberger, does viagra lower your blood pressure Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Scholarship, and the Paul does viagra lower your blood pressure A.

Poling Memorial Scholarship.Awardees receiving the Dr. George Schaiberger, does viagra lower your blood pressure Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink does viagra lower your blood pressure Medical Staff Memorial Scholarship are.

Allie Morand, Camden Groff, Nicholas Morse, Anna Erickson, Emily Terry, Brooke Chenette, Tyler Walters, Austin Raymond, Jordan Williams, Andrew Waack, does viagra lower your blood pressure Rylie Alward, Nicholas Thomas and Madison Nachtrieb. Those receiving the Tolfree Scholarship are. Allie Morand, does viagra lower your blood pressure Nicholas Morse, Anna Erickson, Emily Terry and Andrew Waack. Lastly, awardees receiving the Paul A.Poling Memorial Scholarship are Emily Terry, Anna Erickson, Nicholas Morse, Allie Morand and Andrew Waack.“The intent of our generous donors in creating these scholarships is to provide our rural counties, particularly those served by MidMichigan Medical Center – West Branch, with future generations of excellent health care professionals,” said Nicole Potter, director, MidMichigan Health Foundation.

€œWe congratulate does viagra lower your blood pressure all of this year’s recipients, as well as the parents and teachers who help them arrive at this major milestone in these students’ lives. We wish each one of them the best of success and hope to see them back again in a few years serving the people of their own hometown.”Examples of the health professions being pursued by these individuals include physical therapy, pre-medicine, nursing, health administration, sports medicine, neuroscience and human biology.Applications for the 2021-2022 school year will be accepted from Dec. 1, 2020, does viagra lower your blood pressure through March 1, 2021. Those interested in reviewing the eligibility guidelines, including a scholarship application, may visit www.midmichigan.org/scholarships or call (989) 343-3694.Growers donate produce to staff and patients at MidMichigan Health Park – Bay.Residents in the Bay does viagra lower your blood pressure area have an additional opportunity to embrace healthy lifestyles near MidMichigan Health Park – Bay.

Produce by the Park, a community garden that began late last year with a donation from MidMichigan Health Foundation, is flourishing, allowing patients, friends and neighbors to literally enjoy the fruits of their labor.Brenda Turner, director, MidMichigan Physicians Group, has a farming background and dreamt of a garden for her community for years. When the Health Park was built with ample property behind and support from the Foundation, does viagra lower your blood pressure that dream was brought to life.“We are so pleased to be able to support this project as it represents very well MidMichigan Health’s purpose of building healthy communities – together,” said Denise O’Keefe, executive director, MidMichigan Health Foundation.Other local organizations came on board to offer help. Tri-County Equipment of Saginaw donated dirt, and the Agriscience classes at John Glenn High School volunteered to get plots prepared for gardening. The Building Trades program at Bay Arenac ISD built and installed a tool shed does viagra lower your blood pressure.

Woodchips from Weiler Tree Service were donated to cut down on weeding, and Nature’s Own Landscaping and Irrigation hooked up a spigot in a central location so that all gardeners could access it easily.“During our first season, we had just a few plots of our two-acre garden assigned and less than ten participants,” said Ashleigh Palmer, practice manager, MidMichigan Health Park – Bay. €œThis year, does viagra lower your blood pressure we have all plots filled with more than 40 participants. We have couples, families and individuals who share their experience, produce does viagra lower your blood pressure and recipes with each other. It’s a lot of fun to see the friendships that have developed among our gardeners.

The ground is fertile, so produce is thriving, does viagra lower your blood pressure and excess vegetables are being donated to patients of the facility.”Jarod Morse, 21, saw the garden information on Facebook and is excited to be participating. €œMy whole family - brother, sister and her fiancé, mom, and Papa - are working on the garden together,” Morse stated. A few of the does viagra lower your blood pressure items they are growing are cabbage, cauliflower and a variety of peppers. €œThe best part,” he added, “is getting to share knowledge and smiles with other members of the garden.”Rows of produce growing in the community garden, Produce by the Park.MidMichigan Health staffers Shelby Kuch and Kellie Picard do much of the organizing, serving as “garden ambassadors.” They are excited to see it thriving.“It has been fun to see how each person has their own unique approach to gardening and harvesting,” said Kuch.

€œThere are so does viagra lower your blood pressure many things being grown. Cabbage, corn, potatoes, broccoli, does viagra lower your blood pressure tomatoes, and beautiful sunflowers. You wouldn’t believe the variety and the willingness to share what is harvested with other gardeners, members of the community and patients.”Picard is pleased to see elderly residents becoming involved. €œMany don’t have the room to does viagra lower your blood pressure plant where they live,” she explained.

€œThis place gives them a chance to be outside, grow their own food, socialize with others and get some exercise. It’s inspiring to see their work pay off in so many ways.”Those who are interested in securing a plot must fill out an application and waiver, and agree does viagra lower your blood pressure to the terms set by Produce by the Park. All skill levels are welcome and there is no cost associated with securing a plot.“Our goal has evolved,” said Palmer. €œWe hope to build upon this year’s successes to increase does viagra lower your blood pressure food security by providing access to fresh, healthy foods while reinforcing ties to the environment and encouraging community members to work together.

I think we are well on our way.”Those interested in more information on the Produce by the Park or to request an application may visit www.midmichigan.org/bay/garden or contact Palmer at (989) 778-2888 or ashleigh.palmer@midmichigan.org..

Under the stewardship of how much does generic viagra cost the MidMichigan Health Foundation, this year, 23 area students the original source will received scholarship awards from the Tolfree Scholarship, the Dr. George Schaiberger, Sr., how much does generic viagra cost Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Scholarship, and the Paul A how much does generic viagra cost. Poling Memorial Scholarship.Awardees receiving the Dr.

George Schaiberger, how much does generic viagra cost Sr., Dr. Howard VanOosten and Dr. Lloyd Wiegerink Medical Staff Memorial Scholarship are how much does generic viagra cost. Allie Morand, Camden Groff, Nicholas Morse, Anna Erickson, Emily Terry, Brooke Chenette, Tyler Walters, Austin Raymond, Jordan Williams, Andrew Waack, Rylie Alward, Nicholas Thomas and Madison how much does generic viagra cost Nachtrieb. Those receiving the Tolfree Scholarship are.

Allie Morand, Nicholas Morse, Anna Erickson, how much does generic viagra cost Emily Terry and Andrew Waack. Lastly, awardees receiving the Paul A.Poling Memorial Scholarship are Emily Terry, Anna Erickson, Nicholas Morse, Allie Morand and Andrew Waack.“The intent of our generous donors in creating these scholarships is to provide our rural counties, particularly those served by MidMichigan Medical Center – West Branch, with future generations of excellent health care professionals,” said Nicole Potter, director, MidMichigan Health Foundation. €œWe congratulate all of this year’s recipients, as well as the parents and teachers how much does generic viagra cost who help them arrive at this major milestone in these students’ lives. We wish each one of them the best of success and hope to see them back again in a few years serving the people of their own hometown.”Examples of the health professions being pursued by these individuals include physical therapy, pre-medicine, nursing, health administration, sports medicine, neuroscience and human biology.Applications for the 2021-2022 school year will be accepted from Dec. 1, 2020, through March 1, 2021 how much does generic viagra cost.

Those interested in reviewing the eligibility guidelines, including a scholarship application, may visit www.midmichigan.org/scholarships or call (989) 343-3694.Growers donate produce to staff and patients at MidMichigan Health Park – Bay.Residents in the Bay area have an additional opportunity to embrace healthy lifestyles near how much does generic viagra cost MidMichigan Health Park – Bay. Produce by the Park, a community garden that began late last year with a donation from MidMichigan Health Foundation, is flourishing, allowing patients, friends and neighbors to literally enjoy the fruits of their labor.Brenda Turner, director, MidMichigan Physicians Group, has a farming background and dreamt of a garden for her community for years. When the Health Park was built with ample property behind and support from the Foundation, that dream was brought to life.“We are so pleased to be able to support this project as it represents very well MidMichigan Health’s purpose of building healthy communities – together,” said Denise O’Keefe, executive director, MidMichigan Health Foundation.Other local organizations came on how much does generic viagra cost board to offer help. Tri-County Equipment of Saginaw donated dirt, and the Agriscience classes how to get viagra at John Glenn High School volunteered to get plots prepared for gardening. The Building Trades program at Bay how much does generic viagra cost Arenac ISD built and installed a tool shed.

Woodchips from Weiler Tree Service were donated to cut down on weeding, and Nature’s Own Landscaping and Irrigation hooked up a spigot in a central location so that all gardeners could access it easily.“During our first season, we had just a few plots of our two-acre garden assigned and less than ten participants,” said Ashleigh Palmer, practice manager, MidMichigan Health Park – Bay. €œThis year, we have all plots filled with more than 40 participants how much does generic viagra cost. We have how much does generic viagra cost couples, families and individuals who share their experience, produce and recipes with each other. It’s a lot of fun to see the friendships that have developed among our gardeners. The ground is fertile, so how much does generic viagra cost produce is thriving, and excess vegetables are being donated to patients of the facility.”Jarod Morse, 21, saw the garden information on Facebook and is excited to be participating.

€œMy whole family - brother, sister and her fiancé, mom, and Papa - are working on the garden together,” Morse stated. A few of the items they are growing are cabbage, cauliflower how much does generic viagra cost and a variety of peppers. €œThe best part,” he added, “is getting to share knowledge and smiles with other members of the garden.”Rows of produce growing in the community garden, Produce by the Park.MidMichigan Health staffers Shelby Kuch and Kellie Picard do much of the organizing, serving as “garden ambassadors.” They are excited to see it thriving.“It has been fun to see how each person has their own unique approach to gardening and harvesting,” said Kuch. €œThere are so many how much does generic viagra cost things being grown. Cabbage, corn, potatoes, broccoli, tomatoes, and how much does generic viagra cost beautiful sunflowers.

You wouldn’t believe the variety and the willingness to share what is harvested with other gardeners, members of the community and patients.”Picard is pleased to see elderly residents becoming involved. €œMany don’t how much does generic viagra cost have the room to plant where they live,” she explained. €œThis place gives them a chance to be outside, grow their own food, socialize with others and get some exercise. It’s inspiring to see their work pay off in how much does generic viagra cost so many ways.”Those who are interested in securing a plot must fill out an application and waiver, and agree to the terms set by Produce by the Park. All skill levels are welcome and there is no cost associated with securing a plot.“Our goal has evolved,” said Palmer.

€œWe hope to build upon this year’s successes to increase food security by providing access to fresh, healthy foods while reinforcing ties to the environment and encouraging community members how much does generic viagra cost to work together. I think we are well on our way.”Those interested in more information on the Produce by the Park or to request an application may visit www.midmichigan.org/bay/garden or contact Palmer at (989) 778-2888 or ashleigh.palmer@midmichigan.org..

Dosis de viagra segun edad

Although, the primary goal in patients dosis de viagra segun edad with an acute myocardial infarction (AMI) is to can you get viagra without a prescription reduce mortality and major adverse events, patient centred measures such as long-term health-related quality of life (HRQoL) also are important. The benefits of exercise for mortality reduction after AMI are well known but the effect on HRQoL has received less attention. In this issue of Heart, Hurdus and colleagues1 examined the dosis de viagra segun edad temporal association of HRQoL with physical activity levels and cardiac rehabilitation in 4570 patients at 30 days, 6 and 12 months after AMI.

Both cardiac rehabilitation and self-reported physical activity of at least 150 min/week were positively associated in improvements in HRQoL at each time point, with an additive effect for physical activity even in those receiving cardiac rehabilitation (figure 1).Health-related quality of life trajectories of patients with acute myocardial infarction according to their attendance at cardiac rehabilitation and/or self-reported physical activity of ≥150 min/week. EQ-VAS, EuroQol 5-Visual Analogue Scale" data-icon-position data-hide-link-title="0">Figure 1 Health-related quality of life trajectories of patients with acute myocardial infarction according to their attendance at cardiac rehabilitation and/or self-reported physical activity of ≥150 min/week. EQ-VAS, EuroQol 5-Visual Analogue ScaleIn an editorial, Taylor and Dalal2 point out that ‘When we ask our patients why they want to participate in cardiac rehabilitation (CR), the response that we invariably hear is that they do so because they want to be able to better undertake their activities and roles of daily life—in other words, patients undertake CR to improve their HRQoL.’ Although the results of the study reported in this issue of Heart,1 ‘require dosis de viagra segun edad confirmation in a randomised trial, robust scientific methods were employed by this study group, with potential selection bias and confounding minimised by use of a weighted propensity score analysis.’ Clearly, we need to incorporate relevant measures of HRQoL in future clinical trials whenever possible.Prevention of stroke in patients with atrial fibrillation (AF) has been enhanced by the use of non-vitamin K antagonist oral anticoagulants (NOACs).

However, effectiveness depends not only on ensuring physicians prescribe NOACs appropriately but also on patients adhering to the recommended therapy. In this issue of Heart, Capiau and colleagues3 explored how patient’s actual intake of medication (implementation adherence) was related to their experiences with and beliefs about NOACs. In a series of 766 patients with a mean age of 76 years, almost 21% reported dosis de viagra segun edad non-adherence, most often due to forgetfulness.

Overall, about half the study population failed to take their NOAC on at least 17 days per year, despite a high level of acceptance of the need for therapy (figure 2).Scatter plot of the necessity (X-axis) and concerns (Y-axis) scores of the study population. Every dot on the scatter plot corresponds with one necessity/concerns score combination but dosis de viagra segun edad can include multiple patients. The range of the number of patients per score is indicated with different dot styles.

BMQ, beliefs about medicines questionnaire. MPR, medication possession ratio." dosis de viagra segun edad data-icon-position data-hide-link-title="0">Figure 2 Scatter plot of the necessity (X-axis) and concerns (Y-axis) scores of the study population. Every dot on the scatter plot corresponds with one necessity/concerns score combination but can include multiple patients.

The range of the number of patients per score is indicated with dosis de viagra segun edad different dot styles. BMQ, beliefs about medicines questionnaire. MPR, medication possession ratio.Hendriks and colleagues4 propose approaches to improving adherence with NOAC therapy.

€˜As patients dosis de viagra segun edad age, multimorbidity increases, and cognitive decline and dementia associated with AF may affect the ability to self-manage medications. Integrated care models in which multiple specialists work closely together can help to identify these changes, and assist patients to receive the help they need. For some increased carer support may suffice, while for others text or phone messaging may have a place or the use of dose administration aids may be indicated.’An ambulatory ECG is a common diagnostic test for patients with palpitations or syncope but the information obtained needs to be interpreted in the context of the normal variation in heart rhythm across the age spectrum.

In a meta-analysis of 33 studies than included 6466 healthy adults with ambulatory ECG recordings, Williams and colleagues5 found that:Sinus pauses over 3 s in length occurred in <1% of subjects.Any supraventricular or ventricular ectopy was common and increased in prevalence with age.In patients aged dosis de viagra segun edad 60–79 years, frequent supraventricular ectopy (>1000/24 hours) was seen in 6%, supraventricular tachycardiac in 28%, frequent ventricular ectopy (>1000/24 hours) in 5% and non-sustained ventricular tachycardia in only 2%.Johnson and Conen6 summarise this data (figure 3), discuss the definition of ‘normal’ and suggest that additional work is needed in understanding the prevalence and prognostic value of these variations in cardiac rhythm. €˜Only then we can reliably interpret ambulatory ECG recordings and start thinking about reliable interventions to improve patient outcomes.’(A) Prevalence of arrhythmias by age groups. (B) Schematic overview of possible inter-relationships between normal physiology, SVE, AF and complications.

AF, atrial dosis de viagra segun edad http://subwaycaterstampa.com/product/6-inch-combo-downtown/ fibrillation. AV, atrioventricular. NSVT, non-sustained ventricular dosis de viagra segun edad tachycardia.

SVE, supraventricular ectopy. SVT, sustained ventricular tachycardia. VE, ventricular ectopy." data-icon-position data-hide-link-title="0">Figure 3 (A) Prevalence of arrhythmias by age groups dosis de viagra segun edad.

(B) Schematic overview of possible inter-relationships between normal physiology, SVE, AF and complications. AF, atrial fibrillation. AV, atrioventricular dosis de viagra segun edad.

NSVT, non-sustained ventricular tachycardia. SVE, supraventricular dosis de viagra segun edad ectopy. SVT, sustained ventricular tachycardia.

VE, ventricular ectopy.The Education in Heart article in this issue provides a quick tutorial on the role of imaging for evaluation of aortic and mitral regurgitation.7 Key steps in imaging are to identify the mechanism of regurgitation, measure the severity of regurgitation using a multiparametric approach, and assess the consequences of regurgitation, including adverse changes in left ventricular size and function and in pulmonary pressures.A review article on positron emission tomography provides a concise introduction for clinicians of the emerging uses of this advanced imaging modality in clinical diagnosis of patients with ischaemic heart disease, heart failure, prosthetic valve endocarditis and cardio-oncology8 (figure 4).Potential scope of PET imaging in cardiovascular disease. CVD, cardiovascular disease dosis de viagra segun edad. ICD, implantable cardioverter difibrillator.

PET, positron dosis de viagra segun edad emission tomography. VT, ventricular tachycardia." data-icon-position data-hide-link-title="0">Figure 4 Potential scope of PET imaging in cardiovascular disease. CVD, cardiovascular disease.

ICD, implantable dosis de viagra segun edad cardioverter difibrillator. PET, positron emission tomography. VT, ventricular tachycardia.The Cardiology in Focus article in this issue is the second of a two-part topic on computer programming for the clinician.9It’s not the years in your life that matter, it’s the life in your years.This (mis)quote neatly captures the importance of quality of life.

Indeed, our quality of life has perhaps never been so important than during these unprecedented dosis de viagra segun edad times of the erectile dysfunction treatment viagra.Although limited, there is some empirical evidence to support the value that people with heart disease attach to their health-related quality of life (HRQoL). An innovative study asked 99 people with advanced heart failure to complete a time trade-off (TTO) tool to quantify their willingness to trade time (length of life) for better health (HRQoL).1 TTO scores can range from 1.0 (no willingness to trade off length of life for health) to 0 (complete willingness to trade off length of life for health). Importantly, the study authors found that patients were prepared to trade off time for health, and interestingly this trade-off was greatest for those with the poorest HRQoL (eg, patients with an New York Heart ….

Although, the primary goal in patients with can you get viagra without a prescription an acute myocardial infarction (AMI) is to reduce mortality and major adverse events, patient centred measures such as long-term health-related quality of life (HRQoL) also how much does generic viagra cost are important. The benefits of exercise for mortality reduction after AMI are well known but the effect on HRQoL has received less attention. In this issue of Heart, Hurdus and colleagues1 examined the temporal association of HRQoL with physical activity levels and cardiac rehabilitation in 4570 patients at how much does generic viagra cost 30 days, 6 and 12 months after AMI. Both cardiac rehabilitation and self-reported physical activity of at least 150 min/week were positively associated in improvements in HRQoL at each time point, with an additive effect for physical activity even in those receiving cardiac rehabilitation (figure 1).Health-related quality of life trajectories of patients with acute myocardial infarction according to their attendance at cardiac rehabilitation and/or self-reported physical activity of ≥150 min/week.

EQ-VAS, EuroQol 5-Visual Analogue Scale" data-icon-position data-hide-link-title="0">Figure 1 Health-related quality of life trajectories of patients with acute myocardial infarction according to their attendance at cardiac rehabilitation and/or self-reported physical activity of ≥150 min/week. EQ-VAS, EuroQol 5-Visual Analogue ScaleIn an editorial, Taylor and Dalal2 point out that ‘When we ask our patients why they want to participate in cardiac rehabilitation (CR), the response that we invariably hear is that they do so because they want to be able to better undertake their activities and roles of daily life—in other words, patients undertake CR to improve their HRQoL.’ Although the results of the study reported in this issue how much does generic viagra cost of Heart,1 ‘require confirmation in a randomised trial, robust scientific methods were employed by this study group, with potential selection bias and confounding minimised by use of a weighted propensity score analysis.’ Clearly, we need to incorporate relevant measures of HRQoL in future clinical trials whenever possible.Prevention of stroke in patients with atrial fibrillation (AF) has been enhanced by the use of non-vitamin K antagonist oral anticoagulants (NOACs). However, effectiveness depends not only on ensuring physicians prescribe NOACs appropriately but also on patients adhering to the recommended therapy. In this issue of Heart, Capiau and colleagues3 explored how patient’s actual intake of medication (implementation adherence) was related to their experiences with and beliefs about NOACs.

In a series of 766 patients with a mean age of 76 years, almost 21% reported how much does generic viagra cost non-adherence, most often due to forgetfulness. Overall, about half the study population failed to take their NOAC on at least 17 days per year, despite a high level of acceptance of the need for therapy (figure 2).Scatter plot of the necessity (X-axis) and concerns (Y-axis) scores of the study population. Every dot on the scatter plot corresponds with how much does generic viagra cost one necessity/concerns score combination but can include multiple patients. The range of the number of patients per score is indicated with different dot styles.

BMQ, beliefs about medicines questionnaire. MPR, medication possession ratio." data-icon-position data-hide-link-title="0">Figure 2 Scatter plot of the necessity (X-axis) and concerns (Y-axis) scores of the study population how much does generic viagra cost. Every dot on the scatter plot corresponds with one necessity/concerns score combination but can include multiple patients. The range how much does generic viagra cost of the number of patients per score is indicated with different dot styles.

BMQ, beliefs about medicines questionnaire. MPR, medication possession ratio.Hendriks and colleagues4 propose approaches to improving adherence with NOAC therapy. €˜As patients age, multimorbidity increases, and cognitive decline and dementia how much does generic viagra cost associated with AF may affect the ability to self-manage medications. Integrated care models in which multiple specialists work closely together can help to identify these changes, and assist patients to receive the help they need.

For some increased carer support may suffice, while for others text or phone messaging may have a place or the use of dose administration aids may be indicated.’An ambulatory ECG is a common diagnostic test for patients with palpitations or syncope but the information obtained needs to be interpreted in the context of the normal variation in heart rhythm across the age spectrum. In a meta-analysis of 33 studies than included 6466 healthy adults with ambulatory ECG recordings, Williams and colleagues5 found that:Sinus pauses over 3 s in length occurred in <1% of subjects.Any supraventricular or ventricular ectopy was common and increased in prevalence with age.In patients aged 60–79 years, frequent supraventricular ectopy (>1000/24 hours) was seen in 6%, supraventricular tachycardiac in 28%, frequent ventricular ectopy (>1000/24 hours) in 5% and non-sustained ventricular tachycardia in only 2%.Johnson and Conen6 summarise this data (figure 3), discuss the definition of ‘normal’ and suggest that additional how much does generic viagra cost work is needed in understanding the prevalence and prognostic value of these variations in cardiac rhythm. €˜Only then we can reliably interpret ambulatory ECG recordings and start thinking about reliable interventions to improve patient outcomes.’(A) Prevalence of arrhythmias by age groups. (B) Schematic overview of possible inter-relationships between normal physiology, SVE, AF and complications.

AF, atrial how much does generic viagra cost fibrillation. AV, atrioventricular. NSVT, non-sustained ventricular tachycardia how much does generic viagra cost. SVE, supraventricular ectopy.

SVT, sustained ventricular tachycardia. VE, ventricular ectopy." data-icon-position how much does generic viagra cost data-hide-link-title="0">Figure 3 (A) Prevalence of arrhythmias by age groups. (B) Schematic overview of possible inter-relationships between normal physiology, SVE, AF and complications. AF, atrial fibrillation.

AV, atrioventricular how much does generic viagra cost. NSVT, non-sustained ventricular tachycardia. SVE, supraventricular how much does generic viagra cost ectopy. SVT, sustained ventricular tachycardia.

VE, ventricular ectopy.The Education in Heart article in this issue provides a quick tutorial on the role of imaging for evaluation of aortic and mitral regurgitation.7 Key steps in imaging are to identify the mechanism of regurgitation, measure the severity of regurgitation using a multiparametric approach, and assess the consequences of regurgitation, including adverse changes in left ventricular size and function and in pulmonary pressures.A review article on positron emission tomography provides a concise introduction for clinicians of the emerging uses of this advanced imaging modality in clinical diagnosis of patients with ischaemic heart disease, heart failure, prosthetic valve endocarditis and cardio-oncology8 (figure 4).Potential scope of PET imaging in cardiovascular disease. CVD, cardiovascular disease how much does generic viagra cost. ICD, implantable cardioverter difibrillator. PET, positron emission tomography how much does generic viagra cost.

VT, ventricular tachycardia." data-icon-position data-hide-link-title="0">Figure 4 Potential scope of PET imaging in cardiovascular disease. CVD, cardiovascular disease. ICD, implantable cardioverter difibrillator how much does generic viagra cost. PET, positron emission tomography.

VT, ventricular tachycardia.The Cardiology in Focus article in this issue is the second of a two-part topic on computer programming for the clinician.9It’s not the years in your life that matter, it’s the life in your years.This (mis)quote neatly captures the importance of quality of life. Indeed, our quality of life has perhaps never been how much does generic viagra cost so important than during these unprecedented times of the erectile dysfunction treatment viagra.Although limited, there is some empirical evidence to support the value that people with heart disease attach to their health-related quality of life (HRQoL). An innovative study asked 99 people with advanced heart failure to complete a time trade-off (TTO) tool to quantify their willingness to trade time (length of life) for better health (HRQoL).1 TTO scores can range from 1.0 (no willingness to trade off length of life for health) to 0 (complete willingness to trade off length of life for health). Importantly, the study authors found that patients were prepared to trade off time for health, and interestingly this trade-off was greatest for those with the poorest HRQoL (eg, patients with an New York Heart ….

Does viagra work the first time

IntroductionIn recent years, many studies have been published on new diagnostic possibilities and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the does viagra work the first time 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 does viagra work the first time highlighted how cultural and financial aspects and the availability of resources differ significantly between countries and societies, a situation that hampers supranational agreement on common diagnostic protocols. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational does viagra work the first time 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 paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving does viagra work the first time 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 does viagra work the first time sex development and why this may warrant referral to a specialised team may be challenging, especially for professionals with limited experience in DSD.22 23 Therefore, a section of the Dutch-Flemish guideline was written for these healthcare providers. Moreover, this enables DSD specialists to refer to the guideline when advising a referral.

Transition from the prenatal to the postnatal team and from the paediatric to the adult team requires optimal communication between the specialists involved does viagra work the first time. 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 does viagra work the first time 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 does viagra work the first time in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, 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, does viagra work the first time review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were does viagra work the first time 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 was discussed by the writing committee and, after having obtained agreement on remaining points of does viagra work the first time 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 does viagra work the first time associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the does viagra work the first time 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic sex and the phenotypic sex seen by ultrasound.

In certified laboratories, the possibility of a sample switch is extremely low but should be ruled out immediately. More often, the discrepancy will be due to sex-chromosome mosaicism or a true form of DSD.A situation now occurring with increasing frequency is a discrepancy between the genotypic sex revealed by non-invasive prenatal testing (NIPT), which is now available to high-risk pregnant does viagra work the first time 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 does viagra work the first time 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), does viagra work the first time genital development cannot be reliably appreciated by ultrasound, so any discrepancy or atypical aspect of the genitalia will only be noticed later in pregnancy and should prompt further evaluation.Counselling and diagnosticsIf a DSD is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

After confirming an atypical genital on ultrasound, the specialist team should offer the couple a referral for genetic counselling to discuss the possibility of performing invasive prenatal testing (usually an amniocentesis) to identify an underlying cause that fits the ultrasound findings.22 23 To enable the parents to make a well-informed decision, prenatal counselling should, in our opinion, include. Information on does viagra work the first time 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 genetic testing can and cannot does viagra work the first time provide. Knowing which information has been provided and what words have been used by the prenatal specialist is very helpful for those involved in postnatal care.It is important that parents understand that the biological sex of a baby is determined by a complex interplay of chromosomes, genes and hormones, and thus that assessment of the presence or absence of a Y-chromosome alone is insufficient to assign the sex of their unborn child or, as in any unborn child, say anything about the child’s future gender identity.Expecting parents can be counselled by the clinical geneticist and the psychologist from the DSD team, although other DSD specialists can also be involved. The clinical geneticist should be experienced in prenatal counselling and well informed about the diagnostic possibilities given the limited time span in which test results need to be available to allow parents to make a well-informed decision about whether or not to does viagra work the first time continue the pregnancy.

Termination of pregnancy can be considered, for instance, in a syndromic form of DSD with multiple malformations, but when the DSD occurs as does viagra work the first time 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 does viagra work the first time 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 experience IALG, MK, ABD, YvB, MC does viagra work the first time 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 does viagra work the first time 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 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 does viagra work the first time 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 does viagra work the first time of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

IntroductionIn recent years, many studies have been published on new diagnostic possibilities how much does generic viagra cost and management approaches in cohorts of patients suspected to have a disorder/difference of sex development (DSD).1–13 Based on these studies, it has become clear that services and institutions still differ in the composition of the multidisciplinary teams that provide care for patients who have a DSD.11 14 Several projects have now worked to resolve this variability in care. The European Cooperation how much does generic viagra cost 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. As only a few national guidelines have been published in international journals, comparison of these guidelines is difficult even though such a comparison is necessary to capture the differences and initiate actions to overcome them.

Nonetheless, four DSD (expert) centres located in the Netherlands and Flanders (the Dutch-speaking Northern part of Belgium) have collaborated to produce a detailed guideline on diagnostics in DSD.19 This shows that a supranational guideline can be a reasonable approach for countries with similarly structured how much does generic viagra cost 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 how much does generic viagra cost European Reference Network for rare endocrine conditions (EndoERN), in which DSD is embedded, may facilitate the expansion of this kind of collaboration across Europe.This paper highlights key discussion points in the Dutch-Flemish guideline that have been insufficiently addressed in the literature thus far because they reflect evolving technologies or less visible stakeholders.

For example, prenatal observation of an atypical aspect of the genitalia indicating a possible DSD is becoming increasingly common, and we discuss appropriate counselling and a diagnostic approach for these cases, including the option of using NGS-based genetic testing. So far, little attention has been paid to this process.20 21 Furthermore, informing patients and/or their parents about atypical sex development and why this may warrant referral to a specialised team may how much does generic viagra cost 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 specialists involved how much does generic viagra cost. Application of NGS-based techniques may lead to a higher diagnostic yield, providing a molecular genetic diagnosis in previously unsolved cases.16 We address the timing of this testing and the problems associated with this technique such as the interpretation of variants of unknown clinical significance (VUS). Similarly, histopathological interpretation and classification of removed gonadal tissue is challenging and would benefit from international collaboration and centralisation of expertise.MethodsFor the guideline revision, an interdisciplinary multicentre group was formed how much does generic viagra cost with all members responsible for updating the literature for a specific part of the guideline.

Literature search in PubMed was not systematic, but rather intended to be broad in order to cover all areas and follow expert opinions. This approach is more in line with the Clinical Practice Advisory Document method described by Burke et al24 for guidelines involving genetic practice because it is often troublesome to substantiate such guidelines with sufficient evidence due to the rapid changes in testing methods, for example, gene panels how much does generic viagra cost. 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 how much does generic viagra cost be written in English and were identified using a broad range of Medical Subject Headings terms (eg, DSD, genetic, review, diagnosis, diagnostics, 46,XX DSD, 46,XY DSD, guideline, multidisciplinary care). Next, potentially relevant papers on diagnostic procedures in DSD were selected. Case reports were excluded, as were articles that were not open access or retrievable through how much does generic viagra cost institutional access.

Based on this, a draft guideline was produced that was in line with the international principles of good diagnostic care in DSD. This draft was how much does generic viagra cost 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 how much does generic viagra cost to the paediatric and genetic associations for approval. After approval by the members of the paediatric (NVK), clinical genetic (VKGN) and genetic laboratory (VKGL) associations, the guideline was published on their respective websites.19 Although Turner syndrome and Klinefelter syndrome are considered to be part of the DSD spectrum, they are not extensively discussed in this diagnostic guideline as guidelines dedicated to these syndromes already exist.25 26 However, some individuals with Turner syndrome or Klinefelter syndrome may present with ambiguous or atypical genitalia and may therefore initially follow the DSD diagnostic process.Guideline highlightsPrenatal settingPresentationThe most frequent prenatal presentation of a DSD condition is atypical genitalia found on prenatal ultrasound as an isolated finding or in combination with other structural anomalies. This usually occurs after the 20-week routine medical ultrasound for screening of congenital anomalies, but may also occur earlier, for example, when a commercial ultrasound is performed at the request of the parents.Another way DSD can be diagnosed before birth is when invasive prenatal genetic testing carried out for a different reason, for example, due to suspicion of other structural anomalies, reveals a discrepancy between the genotypic how much does generic viagra cost 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 discrepancy between the genotypic sex revealed how much does generic viagra cost 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 how much does generic viagra cost 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 how much does generic viagra cost is suspected, first-line sonographers and obstetricians should refer the couple to their colleague prenatal specialists working with or in a DSD team.

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

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

Termination of pregnancy can be considered, for instance, in a how much does generic viagra cost 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 how much does generic viagra cost 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 experience IALG, MK, ABD, how much does generic viagra cost YvB, MC and HC-vdG). At birth, umbilical cord blood is a good source for (molecular) karyotyping and storage of DNA and can be obtained by the obstetrician, midwife or neonatologist.

The terminology used in communication with parents should be carefully chosen,22 23 and midwives and staff of neonatal and delivery units should be clearly instructed to use gender-neutral and non-stigmatising vocabulary (eg, ‘your baby’) as long as sex assignment is pending.An algorithm for diagnostic evaluation how much does generic viagra cost 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 genetic how much does generic viagra cost 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 how much does generic viagra cost the analysis well before the expected delivery.Disorders/differences of sex development (DSD) in the prenatal setting. A diagnostic algorithm.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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However, Chinese medical graduates are not fully trained doctors when they leave school due to lack of enough clinical practice and how much does generic viagra cost training. Therefore, resident training is a key stage for medical graduates to acquire skills and knowledge before becoming professionals.2 As is known to all, Chinese government has made great efforts to meet how much does generic viagra cost the growing demand for medical services and improve the work performance of senior doctors and residents in the past decades.2 Among these attempts, the standardised training system for residents (STSR) started in 2014 is particularly important. The STSR, how much does generic viagra cost jointly issued by the National Health Commission of the People’s Republic of China with six other departments, is a national project that provides systematic and standardised training for residents, and is also one of the important steps in the reform of Chinese medical system.3 The STSR is mandatory and will take up to 3 years depending on the educational level of participants.

In detail, the training period of Medical Bachelor (MB), Master ….

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