Body

May 27, 2020 - For patients with diabetes - especially those with lower incomes - preventive drug lists (PDLs) of essential medications available with no deductible can reduce out-of-pocket costs while increasing use of important treatments, reports a study in a June supplement to Medical Care. The journal is published in the Lippincott portfolio by Wolters Kluwer.

The special issue presents a series of "natural experiments" - evaluating how changes in healthcare policy or practice affect real-world outcomes in patients with diabetes - from the Natural Experiments for Translation in Diabetes 2.0 (NEXT-D2) Network. "Natural experiments are permitting us to take advantage of the rapid proliferation of big data to rigorously study the impact of policies that otherwise would go unevaluated," comments Edward Gregg, PhD, of Imperial College, London, one of the co-leaders of the NEXT-D2 Network.

As Out-of-Pocket Costs Go Down, Use of Essential Treatments Goes Up

A growing number of Americans are covered by high-deductible health plans (HDHPs) - insurance plans with annual deductibles of $1,000 or higher - designed to reduce unnecessary care and promote higher-value care. But HDHPs include annual deductibles, copayments and other forms of cost-sharing, which can adversely impact treatment for diabetes and other chronic diseases, including use of needed medications. Adverse effects on medication use may be particularly large in federally regulated HDHPs linked to Health Savings Accounts (HSAs) that require patients to pay the full cost of medications until their annual deductible amounts are met.

To address this issue, some employers and insurers have developed PDLs specifying medications exempt from deductibles or copayments. Dennis Ross-Degnan, ScD, and colleagues of Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, evaluated a natural experiment to determine how these PDLs have affected out-of-pocket costs and use of clinically essential medications for patients with diabetes.

The study included 1,744 patients with diabetes enrolled in HDHPs with HSAs, whose employers switched all employees to PDL coverage. The switch meant that key medications and supplies for preventing the long-term adverse effects of chronic illness - including antidiabetic drugs, insulin, test strips, and blood pressure- and cholesterol-lowering drugs - became available with no or limited cost-sharing.

Analysis of insurance claims found that the PDLs led to a significant decrease in out-of-pocket medication costs: an average savings of $612 per year for patients with diabetes. This was accompanied by a sharp increase in preventive medication use: an average of six additional medication refills per year.

The increase in prescription refills was much larger for lower-income patients, for whom high cost-sharing may have been an important reason for previous underuse. The researchers also noted: "Overall savings in out-of-pocket spending were much larger for patients with severe diabetes, primarily due to savings on insulin."

'What Works' in Diabetes Management - NEXT-D2 Papers Provide Insights

There are many promising strategies to improve care and prevent complications for the millions of Americans affected by diabetes. The eight NEXT-D2 projects in the special issue address initiatives related to health insurance expansion, including Medicaid expansion and community health centers; healthcare financing and payment models, such as HDHPs and new Medicare/Medicaid initiatives; and innovations in care coordination for patients with diabetes.

"These and other natural experiments in the NEXT-D2 collaboration are using existing health data to fill the knowledge gaps in terms of what works for preventing diabetes and its complications," Dr. Gregg adds. NEXT-D2 is co-sponsored by the Centers for Disease Control and Prevention, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Patient-Centered Outcomes Research Institute.

PHILADELPHIA - With doctors and researchers around the world searching for effective treatments for COVID-19, many drugs approved to treat other diseases are being used in hopes that they'll be effective against the virus, a use that's known as "off-label." New research from the Perelman School of Medicine at the University of Pennsylvania catalogued every use documented in medical literature so far and found physicians have reported on the use of more than 100 different off-label and experimental treatments. The effort, called COvid19 Registry of Off-label & New Agents (CORONA), is an attempt to take an inventory of what's being used where, as well as to spot any evidence of treatments that warrant further investigation in a randomized clinical trial. The findings published in Infectious Diseases and Therapy today.

"We can't win this fight if we don't take stock of the tools that are already being used and search for new ones that could be effective. While off-label use is happening all over the world, there's currently no system in place to track it, so we felt like we had to create one," said the study's lead author David C. Fajgenbaum, MD, MBA, MSc, an assistant professor of Translational Medicine & Human Genetics and director of the Center for Cytokine Storm Treatment & Laboratory (CSTL) at Penn.

Fajgenbaum is also the executive director of the Castleman Disease Collaborative Network (CDCN) and a Castleman patient himself. In 2012, after failing to respond to other therapies and having relapsed multiple times after chemo, Fajgenbaum's research suggested a drug approved for other uses may be effective for his condition. Based on his own research and in consultation with his treating physician, Fajgenbaum decided to test the drug on himself and has been in remission ever since.

"With the world facing its greatest public health crisis in a century, we decided to take action, using the same approach that helped me and applying it to potentially help find promising leads in the treatment of COVID-19," Fajgenbaum said.

The team reviewed about 2,700 published papers from all over the world detailing the treatment of COVID-19. From there, they gathered data on 9,152 patients and found doctors had tried 115 different drugs. These treatments were grouped into categories - antivirals were unsurprisingly the most common, followed by antibacterials and corticosteroids. The analysis also showed the use of immunosuppressants and blood substitutes, among other treatment options. Sheila Pierson, MS, the associate director for clinical research at the CSTL, director of registry enrollment for the CDCN, and the study's senior author, led the analysis of the data.

"Our team has spent the last several years studying drugs used to control the cytokine storm in Castleman disease, so I'm glad we were able to apply these principles to COVID19. The work remains ongoing, and we are updating this drug inventory daily as we continue to compile information on other treatments as they're being reported in the medical literature," Pierson said.

Fajgenbaum notes that the goal of this work is not to point toward the most effective treatment, but to provide a resource for what may be candidates for further study.

"We hear a lot about the same handful of drugs, but we show here that there are many more currently in use than those that have already made headlines. Anything that shows promise anecdotally still needs to be rigorously tested in a clinical trial to see if it is effective and safe," Fajgenbaum said.

Out of concern for fetal safety, pregnant people have typically been excluded from drug trials. And when human health is on the line, drug studies assessing fetal safety in animal models may be viewed as far from definitive.

Due to sheer lack of data concerning implications for fetal and maternal safety, clinicians are often unsure about prescribing drugs to pregnant patients.

That's the situation as outlined in a position paper in Nature Medicine by Anup Challa, David Aronoff, MD, and colleagues. A woeful knowledge deficit leads to undertreatment of chronic and acute illness in pregnant people, while, creepily enough, also posing additional risk of adverse drug reactions for this group.

The authors' solution: use electronic health record (EHR) data to emulate randomized controlled trials (RCTs).

Used to compare treatments, RCTs involve enrollment of subjects who undergo interventions carried out in real time. By contrast, so-called target trials are a type of observational study that painstakingly emulates an RCT through retrospective analysis of existing clinical data.

Several methods can help uncover and eliminate bias that can limit these observational studies. Provided enough data (Vanderbilt University Medical Center has EHRs from 2 million patients and counting), investigators can design and conduct "trials" that simulate not only a real trial's treatment strategies (drug versus no drug) and outcomes, but also eligibility criteria and random assignment to treatment at baseline.

Ideally, target trials can provide a basis for causal inference, the authors note. Such trials are arguably "the only ethical way to gather human drug exposure data for pregnant people on a significant scale and across all classes of drugs," the paper states.

Certain common genetic variants are known to mimic drug effects. So, in the case of drugs for which there may be insufficient prescription data in pregnant people's records, genomic data can provide a proxy for drug exposures in target trials.

So-called organ-on-a-chip technologies -- newer lab methods that recapitulate drug exposures in human tissue -- stand ready to help validate results of target trails.

According to the authors, "this is one of very few valid, ethical workflows that can accommodate large-scale drug screening. Never before in the history of medicine have we been afforded sufficient data to tackle this problem ethically and effectively."

Patients with a vascular condition called abdominal aortic aneurysm did not benefit from taking the common antibiotic doxycycline for two years to shrink the aneurysm when compared to those who took a placebo, according to a Vanderbilt University Medical Center (VUMC) study published in the Journal of the American Medical Association (JAMA).

Abdominal aortic aneurysm is a swelling or ballooning that occurs in the major blood vessel (aorta) that supplies blood from the heart to the lower half of the body. It affects about 3 percent of older Americans, most commonly men and smokers.

The condition can cause fatal internal bleeding if the aneurysm grows large enough to burst. Small aneurysms frequently cause no symptoms and are often detected when an abdominal ultrasound or CT scan is performed for other reasons.

Doctors had traditionally monitored the aneurysm growth and sometimes opt to prescribe doxycycline in an effort to forestall surgery in higher-risk patients, a practice that was based on earlier research suggesting that certain antibiotics reduce inflammation that contributes to aneurysm growth.

The study findings released today could lead doctors to stop prescribing doxycycline as a way to prevent small aneurysms from growing larger and bursting, said John Curci, MD, associate professor of Surgery in the Division of Vascular Surgery at VUMC.

"Taking doxycycline to prevent or slow the growth of small abdominal aortic aneurysms is not advised or helpful, even though it reduced circulating markers of inflammation," said Curci, whose study expertise was bio-banking and bio-specimen analysis with Vanderbilt serving as the Biomarker Core Lab.

The large multicenter NIH/NIA study included 254 patients with small aneurysms who were randomly assigned to take either 100 milligrams of doxycycline twice daily or a placebo for two years.

CT scans performed at the beginning of the study and on follow-up found no differences in aneurysm growth between those who took the drug and those who took the placebo.

"This trial will provide critical material for improved biologic understanding of aneurysm disease," Curci said. "For example, detailed study of the circulating proteins or other markers in blood from these patients might help us better understand why aneurysms grow, and allow us to look for more effective drugs."

For every ten adults in the world, four suffer from functional gastrointestinal disorders of varying severity. This is shown by a study of more than 73,000 people in 33 countries. University of Gothenburg scientists are among those now presenting these results.

Functional gastrointestinal disorders, FGIDs, is a collective term for chronic disorders in the gastrointestinal tract, with severe symptoms, for which clear explanations or connections with objective findings from routine investigations are lacking.

The symptoms may arise throughout the gastrointestinal tract. From the upper part, the esophagus and stomach, they can include heartburn, acid reflux and indigestion (dyspepsia). In everyday parlance, the latter is often called "a sensitive stomach" or "gastritis," although there is no stomach inflammation. For the lower parts (the intestines), chronic constipation, abdominal distension or bloating, and irritable bowel syndrome (IBS) are among the complaints.

The present study, published in the journal Gastroenterology, gives an overall picture of the global prevalence of FGIDs. Data were collected by means of web-based questionnaires and face-to-face (household) interviews.

Magnus Simrén, Professor of Gastroenterology at Sahlgrenska Academy, University of Gothenburg, belongs to the international steering group for the study and is in charge of its Swedish part, comprising 2,000 people.

"It's striking how similar the findings are between countries. We can see some variations but, in general, these disorders are equally common whatever the country or continent," he says.

The questions posed to the respondents were based on the diagnostic criteria for IBS and other FGIDs. Particulars of other diseases and symptoms, living conditions, quality of life, healthcare consumption, etc. were also requested.

The prevalence of FGIDs was higher in women than in men, and clearly associated with lower quality of life. According to the questionnaire responses, 49 percent of the women and 37 percent of the men met the diagnostic criteria for at least one FGID.

The severity of the disorders varied, from mild discomfort to symptoms that adversely affected quality of life to a high degree. The prevalence of FGIDs was also strongly associated with high consumption of healthcare, such as visits to the doctor and use of medication, but also surgery.

Web-based questionnaires were used in most of the countries in the study, including Sweden. In some countries, instead, the respondents were asked to reply to the questions when an interviewer read them aloud. In two countries, both methods were used in parallel, and the interviewees were found to report fewer symptoms.

"We don't know why we're seeing this difference, but one reason might be that people think it's embarrassing to talk about stomach and bowel symptoms to someone sitting in front of them, and that they therefore underreport them compared with those who give their responses anonymously on an online form," Simrén says.

The study is the first of a series in this area. The initiative for the massive data collection came from the Rome Foundation, a committee to which Magnus Simrén belongs, which develops diagnostic criteria for FGIDs.

The novel coronavirus (COVID-19) pandemic not only affects patients who have the virus, but strikes the entire healthcare system including the care for patients with cancer. Aggressive cancers, such as pancreatic cancer, require the continuation of oncological care during the pandemic. However, pursuing care exposes both healthcare professionals and vulnerable patients to COVID-19.

Today, new research published in Annals of Surgery from the University of Colorado Department of Surgery at the Anschutz Medical Campus provides guidance on clinical decision-making in regards to treating pancreatic cancer patients during the COVID-19 pandemic.

"The inability to receive medical or surgical care during a pandemic can be an equal or sometimes worse threat for pancreatic cancer patients," said Marco Del Chiaro, MD, PhD, FACS, Chief of Surgical Oncology and Director of the National Pancreas Foundation Center of Excellence at the Anschutz Medical Campus..

Del Chiaro continues, "The goal of our research is to optimize safety for patients and clinicians, as well as safeguard healthcare capacity. Given the aggressive biology of pancreatic cancer, it's critical that there is a strategy to support healthcare professionals in decision-making during this time."

The researchers sent an online survey to members of seven international pancreatic associations and study groups to investigate the impact of the current pandemic on pancreatic surgery. In April of 2020, 337 respondents from 267 centers and 37 countries spanning five continents completed the survey.

Nearly all of the respondents were surgeons who worked in an academic center. The biggest takeaway from the surgeons was that pancreatic surgery should be prioritized for patients with non-COVID-19 pancreatic diseases during the pandemic.

Other key findings:

The majority of centers (62 percent) performed less pancreatic surgery because of the COVID-19 pandemic.

Prior to pancreatic surgery, most centers screened their patients for symptoms of COVID-19. However, no consensus was reached to recommend COVID-19 preoperative testing/screening.

Based on consensus, patients who undergo pancreatic surgery should be informed about the following additional risks: COVID-19 infection during hospitalization, possible non-optimal postoperative management (i.e. shortage of ICU beds), increased risk of COVID-19 related mortality due to surgery or the cancer condition.

Furthermore, this survey convincingly recommends that operating room (OR) personnel have to wear adequate protective features during surgery, considering their increased risk for COVID-19 infection during surgical procedures.

Additionally, prioritization of COVID-19 patients with a better prognosis over pancreatic cancer patients, adhering to the process of triage for hospital resources and ICU beds, did not reach 60 percent agreement. On the other hand, the difficulty to prioritize between patients with severe COVID-19 or resectable pancreatic cancer is conceivable.

"The era of the COVID-19 pandemic underlines the need for an international survey with clear statements, aiming to guide clinicians in their clinical decision-making," said Atsushi Oba, MD, PhD, research associate for surgical oncology, University of Colorado Department of Surgery, and co-author of the paper. "This survey revealed several consensus statements as well as statements that need further discussion."

The survey consisted of 36 questions on baseline characteristics, the local impact of the COVID-19 pandemic on pancreatic surgery (i.e. number of pancreatic resections, triage, and screening), and 21 statements about the role of pancreatic surgery in the current era of the COVID-19 pandemic.

"This project is an example of how to be strategic and appropriately use resources during a pandemic to keep our patients as safe as possible," said, Richard Schulick, MD, MBA, FACS, Chair of the Department of Surgery and Director of the University of Colorado Cancer Center on the campus. "I could not be prouder of the members of the Department of Surgery on the Anschutz Medical Campus, who continue to provide appropriate world-class cancer care to our patients during a pandemic - sometimes even risking their own health."

United States has been facing a serious problem of drug abuse and addiction, and has seen around 700,000 deaths within a span of 20 years (1999 to 2017) due to drug overdose. Opioid abuse, among other drugs, has been a prime cause of deaths due to overdose and misuse. In order to control this opioid epidemic, Highmark Inc., a national health plan and the second largest integrated delivery and financing system in USA devised, implemented and assessed a series of quality management-focused opioid interventions with the help of a three-pronged public health strategy.

Dr. Oralia Dominic, the Chief Medical Officer (CMO), Highmark Inc., Pittsburgh, PA, USA, defined the three-pronged public health strategy that was implemented in Delaware, Pennsylvania, and West Virginia, to curtail the use and abuse of opioid. The strategy was designed with the following objectives.

1) The first and foremost objective has been to manage pain more effectively in order to reduce the need for opioids (primary prevention)

2) Secondly, when required, prescription of opioids should be according to safe prescribing guidelines (secondary prevention)

3) Lastly, to ensure access to effective treatment for the ones with Opioid Use Disorder (OUD) to help reduce morbidity / mortality through opioid abuse (tertiary prevention)

Dr. Dominic and the team engaged in this healthcare plan deployed a series of evidence-based and data-driven interventions with the help of clinical guidelines, integrated and coordinated infrastructures, and community-based participatory research frameworks within the service areas in the three states of USA. Through thorough primary and secondary research utilizing all the data available and collected, the strategy was implemented and evaluated to assess the success of the interventions.

The results of this three-pronged opioid intervention strategy, during the period of 2013 to 2017, have been promising, as there has been a significant decrease of 19% of opioid use as prescription drug. A decrease in the duration of opioid use (number of days of opioid use) was observed. The plan also helped reduce the number of members on higher strength 20+ MME (Morphine Milligram Equivalents) opioids.

Growing evidence suggests that SARS-CoV-2, the novel coronavirus that causes COVID-19, can be spread by asymptomatic people via aerosols -- a reality that deeply underscores the ongoing importance of regular widespread testing, wearing masks and physical distancing to reduce the spread of the virus, say Kimberly Prather and colleagues in a new Perspective. The World Health Organization (WHO) recommendations for social distancing of 6 feet and hand washing to reduce the spread of SARS-CoV-2 are based on studies of respiratory droplets carried out in the 1930s. When these studies were conducted, the technology did not exist for detecting submicron aerosols. More recently, measurements show that intense coughs and sneezes that propel larger virus droplets more than 20 feet can also create thousands of aerosols that can travel even further. Recent studies of SARS-CoV-2 have shown that in addition to droplets, SARS-CoV-2 may also be transmitted through aerosols. One recent study estimated that a single minute of loud speaking might generate between 1,000-100,000 virion-containing aerosols or virus particles suspended in the air, for example. These infectious aerosols can accumulate in indoor, uncirculating air for hours, where they can be more easily inhaled deeply into the lungs. Given how little is known about the airborne behavior of infectious aerosols, it's difficult to define a safe distance for physical distancing, the authors say. Properly fitted masks provide a critical physical barrier, reducing the number of infectious viruses in the exhaled breath of asymptomatic individuals. Countries that have been most effective in limiting the spread of COVID-19 have implemented universal masking, they note. It is particularly important to wear masks in locations with conditions that can accumulate high concentrations of viruses, such as health care settings, airplanes, restaurants, and other crowded places with reduced ventilation.

DALLAS, May 27, 2020 -- Palliative care is valuable for heart failure patients, and, for those who are hospitalized, it can significantly lower the risk of repeated hospital admissions and the need for invasive procedures such as mechanical ventilation and defibrillator implantation, according to new research published today in the Journal of the American Heart Association, an open access journal of the American Heart Association.

Palliative care focuses on pain relief, emotional support and maximizing a patient's quality of life. Unlike hospice services, however, palliative care does not limit life-prolonging therapy. Yet continuing aggressive medical treatment is not always appropriate, especially when it eclipses a patient's most basic need - to make the most out of the time they have left.

As heart failure progresses, patients experience high symptom burden that negatively impacts their ability to function, creates suffering and increases risk of death. By 2030, the prevalence of heart failure will grow resulting in millions of adults living with the condition.

"There is a misunderstanding about when palliative care would be beneficial, even within the medical community. There's a perception that it's provided only at the very end of life, and that's not true," said James L. Rudolph, M.D., S.M., study co-author and the director of the Center of Innovation in Geriatric Services at the Providence VA Medical Center, professor of medicine at the Warren Alpert Medical School at Brown University and professor of health policy at Brown University School of Public Health in Providence, Rhode Island. "Palliative care added to heart failure treatment plans especially when a patient is hospitalized can have a big impact on the patient and the entire health system."

Using data from the Veterans Affairs (VA) External Peer Review Program, researchers identified more than 57,000 patients who had been hospitalized for heart failure at any of the 124 VA medical centers between 2010 and 2015. Among those, about 1,400 patients received palliative care prior to and during hospitalization for heart failure. Patients were matched for age, gender and similar health conditions with the same number of patients who did not receive palliative care (control group).

Researchers examined how often within six months after hospital discharge patients were readmitted, went to the intensive care unit and received procedures such as mechanical ventilation, pacemaker implantation or defibrillator implantation.

Researchers found:

Palliative care reduced the rates of multiple rehospitalizations. Overall, 31% of patients in the palliative care group experienced repeated hospital readmissions, compared to 40% of patients in the control group.

Mechanical ventilation and defibrillator implantation were significantly lower in the palliative care group (2.8% for palliative care versus 5.4% in the control group; and 2.1% for palliative care versus 3.6% in the control group, respectively).

After adjusting for hospital differences around the country, palliative care reduced the chance of hospital readmission or being put on mechanical ventilation by about 25%.

"Palliative care can be delivered along with aggressive heart failure treatment. In our study, palliative care patients still got defibrillators, went to the ICU and received mechanical ventilation," Rudolph said. "The team-based approach to palliative care seems to enable patients to make difficult decisions about life-limiting conditions such as heart failure."

The major limitation of this study is that patients receiving palliative care were a little older and sicker than those in the control group. Additionally, missing electronic medical record data varied by VA site.

Researchers from the group of Hans Clevers at the Hubrecht Institute have modeled the development and progression of high-grade serous ovarian cancer in mini-versions of the female reproductive organs of the mouse. They found out that the cells of the oviduct, the equivalent of fallopian tubes in humans, are more prone to develop into tumors than those of the ovarian surface epithelium, the outer layer of the ovaries. In the future, such mini-versions, or organoids, of human tissue may be used to better understand how this disease, that is often diagnosed very late, develops. The researchers published their results in the scientific journal Nature Communications on the 27th of May.

High-grade serous ovarian cancer (hereafter referred to as simply "ovarian cancer") is the most common type of ovarian cancer and has the lowest rate of survival. It is often only diagnosed when it has already spread within the pelvis and abdomen, making it harder to treat. Because the early stages of ovarian cancer are not often observed, much is still unknown about the early development of the disease. We do know that ovarian cancer cells often have mutations, or mistakes, in certain genes, such as Trp53, a gene that is often mutated in many types of cancer, Brca1, a gene often mutated in breast cancer, Nf1 and Pten.

Organoids

Researchers in the group of Hans Clevers at the Hubrecht Institute used mini-versions of two parts of female reproductive tract of mice to study the early development of ovarian cancer. They grew mini-versions, or organoids, of the oviducts (in humans called the fallopian tubes) that transport the egg from the ovary to the uterus, and of the ovarian surface epithelium, the outer layer of the ovaries, in the lab from small pieces of tissue from mice. In these organoids, they recreated the mutations found in ovarian cancer. Using the state-of-the-art CRISPR-Cas9 genome editing approach, they mutated the genes Trp53, Brca1, Nf1 and Pten to study how these genes contribute to the development of a tumor.

Mutations

When mutations were introduced in three of the four genes, namely Trp53, Brca1 and either Nf1 or Pten, the organoids acquired characteristics of tumors, such as more densely packed cells and changes in chromosome number. In addition, when these organoids were transplanted back into mice, they developed into tumors that are similar to ovarian cancer tumors in humans.

The researchers found out that organoids from the oviduct were more likely to develop into tumors, grew faster and grew into larger tumors than the organoids from the ovarian surface epithelium. This suggests that ovarian cancer is more likely to originate in the oviduct, or the fallopian tube in humans, compared to the ovarian surface epithelium.

Earlier diagnosis and preventive care

Studying the development and progress of ovarian cancer in such organoid models may help to better understand how ovarian cancer develops in the body. Researchers in the group of Hans Clevers have previously shown that organoids can also be made from the human fallopian tube and the human ovarian surface epithelium. In the future, the researchers may also introduce the specific mutations found in ovarian cancer in these human organoids to further study the development of this disease.

Patients with a mutation in one of the Brca genes are at a high risk of ovarian cancer and can receive preventive treatment. This includes radical surgery in which both ovaries as well as the fallopian tubes are removed, leading to premature menopause in these women. The results in this study support the emerging view that the fallopian tube, not the ovarian surface epithelium around the ovaries, are the main origin for ovarian cancer, which may direct future changes in (preventive) treatment. For example, the Dutch Gynecological Oncology Group recently launched a clinical trial to study whether early removal of only the fallopian tubes and later removal of the ovaries can improve the quality of life for these patients, while also reducing the risk of ovarian cancer.

Knowing more about the development and progression of ovarian cancer may help doctors to better recognize ovarian cancer in the future, enabling earlier treatment and a higher chance of survival.

Publication

Assessing the origin of high-grade serous ovarian cancer using CRISPR-modification of mouse organoids. Kadi Lõhmussaar*, Oded Kopper*, Jeroen Korving, Harry Begthel, Celien P. H. Vreuls, Johan H. van Es, Hans Clevers. Nature Communications 2020.

*These authors contributed equally to this work

Hans Clevers is group leader at the Hubrecht Institute and the Princess Máxima Center for Pediatric Oncology, professor of Molecular Genetics at the UMC Utrecht and Utrecht University, and Oncode Investigator.

About the Hubrecht Institute

The Hubrecht Institute is a research institute focused on developmental and stem cell biology. It encompasses 23 research groups that perform fundamental and multidisciplinary research, both in healthy systems and disease models. The Hubrecht Institute is a research institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), situated on Utrecht Science Park. Since 2008, the institute is affiliated with the UMC Utrecht, advancing the translation of research to the clinic. The Hubrecht Institute has a partnership with the European Molecular Biology Laboratory (EMBL). For more information, visit http://www.hubrecht.eu.

Journal

Nature Communications

DOI

10.1038/s41467-020-16432-0

Rehabilitation clinicians and other health care professionals now have a framework for assessing and managing people who may have serious spinal pathologies. Detailed in a position statement about red flags for serious spinal injuries and disease, this new guidance for clinical practice was developed for the International Federation of Orthopaedic Manipulative Physical Therapists (IFOMPT) and published online this month in the Journal of Orthopaedic & Sports Physical Therapy® (JOSPT®).

"While rare, serious spinal pathology can have devastating and life-changing consequences, and must be identified early and managed appropriately," says Laura M. Finucane, MSc, BSc, FCSP, FMACP, lead author of the statement and vice president of IFOMPT. "This framework is intended to provide clinicians with a clinical-reasoning pathway to clarify the role of red flags in recognizing spinal injuries and disease."

IFOMPT drew on the expertise of 100 experts from 19 countries to synthesize current research and reach consensus on the framework. Seventy clinicians from 13 countries, supported by patient partners, reviewed the information and approved the final version of the framework and its decision tools.

The framework covers four serious spine pathologies: cauda equina syndrome, compression of the nerve roots at the base of the spinal cord; spinal fracture, which accounts for the largest number of serious pathologies of the spine; spinal malignancy, which includes cancers that have spread from a primary cancer site to bone; and spinal infection, which includes infectious disease affecting spinal structures. For each pathology, decision tools summarize the red flags; outline the risk factors, symptoms, signs, and initial investigations; and offer a series of scenarios illustrating how red flags may raise suspicion of that condition.

The framework identifies the level of concern clinicians should have and the clinical action they should take, based on available pathways for therapy or referral to specialist care.

"While they often lack high-quality empirical evidence, red flags remain the best tools available to the clinician to raise suspicion of serious spinal pathology when used in the context of a thorough, subjective patient history and physical examination," Finucane says. As a result, the framework's authors urge clinicians to consider both the evidence to support red flags and the individual profile of their patient to decide how concerned they are that a serious condition exists.

CHICAGO (May 27, 2020): As health care providers observe Coronavirus Disease 2019 (COVID-19) affecting children differently than adults, pediatric surgeons in Chicago have modified an evaluation tool for use in pediatric patients that allows surgeons in every pediatric specialty to prioritize nonemergency ("elective") operations during all phases of the pandemic. The new pediatric-specific scoring system is presented in an "article in press" on the Journal of the American College of Surgeons (JACS) website ahead of print.

Called the Pediatric Medically Necessary Time-Sensitive, or pMeNTS, scoring system, the new index score created by researchers at The University of Chicago (UChicago) Medicine adapts the adult MeNTS approach. That original surgical prioritization approach was published on April 9 in a scientific article on the JACS website amid COVID-19-related resource constraints and nationwide recommendations to postpone elective operations.1

Pediatric surgeons at UChicago Medicine found that the adult MeNTS scoring system needed revisions for optimal use in pediatric surgery, according to Mark B. Slidell, MD, MPH, FACS, the lead investigator and associate professor of surgery at UChicago Medicine.

"It was very important to create a pediatric-specific system that recognizes there are big differences between adults and children," Dr. Slidell said.

Need for revised scoring system

Among the differences is that many children testing positive for COVID-19 appear asymptomatic (have no symptoms).2 Also, recent reports noted a new serious complication of COVID-19 in some infected children, including those who were unaware they had the virus: an inflammatory syndrome that can lead to severe involvement of multiple organs.2

Dr. Slidell's coauthor, Grace Z. Mak, MD, FACS, UChicago Medicine associate professor of pediatrics and surgery, said users of the pMeNTS scoring worksheet can adapt it to include new COVID-19 developments.

"Part of what we took into account is that asymptomatic COVID-positive patients in the pediatric population could very well have a worse outcome, and multisystem organ failure is a good example," Dr. Mak said.

As the pandemic changes the concept of elective operations, pMeNTS focuses on an operation's medical necessity and time-sensitivity--the effect of treatment delay on the patient's disease. Plus, it assesses COVID-19 factors such as infection risk for the patient and providers as well as projected use of hospital resources, including protective gear, beds, blood products, and staffing. The tool, which Dr. Slidell emphasizes is not a risk calculator, systematically evaluates factors related to the procedure, the patient's disease, and the patient's individual risks. Users rate each factor on a five-point scale and total the scores. A lower overall pMeNTS score indicates a more favorable surgical risk, less risk to personnel, and less resource utilization, and can be used to determine a higher priority for the procedure.

The hospital's surgical department leaders review the assigned scores for each surgical case and can shift the scoring cutoff each day for high-priority operations depending on available resources, Dr. Mak stated.

Unlike the adult scoring system, pMeNTS accounts for chronic diseases of childhood and birth defects such as prematurity or congenital heart and lung diseases that may raise susceptibility to more severe COVID-19 infection. It omits chronic illnesses of adulthood that are rare in children such as coronary artery disease and chronic obstructive pulmonary disease.

Another key change was pediatric age brackets reflecting the impact of age on a procedure. For instance, Dr. Mak said a hernia repair is a more difficult operation in a premature infant than a 14-year-old patient. In the adult MeNTS system, both patients would have the same score, but pMeNTS accounts for the child's age and assigns the infant a higher number, she explained.

Testing the system

The investigators tested pMeNTS in 101 pediatric patients scheduled for operations at UChicago Comer Children's Hospital from March 23 to April 19. In the article, they reported the system to be "a safe, equitable, transparent, and ethical strategy to prioritize children's surgical procedures."

During that month, they analyzed a sample of 53 deferred cases and 48 cases that were allowed to proceed as scheduled. Procedures they deemed time-sensitive included cancer biopsies and operations needed for discharge from the intensive care unit (ICU), thus freeing ICU beds, Dr. Mak said.

The researchers also compared scores of a sample of 21 patients using both the pediatric and adult scoring systems. Most children, they found, had higher scores with the adult MeNTS. Dr. Slidell said pMeNTS successfully captured the various factors that are unique to children.

Strengths of the pMeNTS tool, according to Dr. Slidell, include the flexibility to adapt to changes in the health care system now and during recovery from the pandemic. Because the tool received input from many different specialists, he said it works well across various pediatric surgical subspecialties.

The transparency of the pMeNTS tool has reduced surgeons' moral dilemmas in the difficult decision-making process of which sick children can proceed with their scheduled operations, Dr. Slidell noted.
He said, "This is one of the most important questions to ask any time we are scheduling a procedure during a time like this: 'Am I making the best decision with the information I have for the patient, for the hospital, for the workers in the hospital, and for the community at large?'"

A potential blood-based biomarker for Alzheimer's and other neurodegenerative diseases seems even more promising thanks to new research from a Massachusetts General Hospital-led study. According to this team's work, neurofilament light chain (NfL) has great potential as a biomarker for early detection of Alzheimer's disease and could be also useful for monitoring treatment response for that condition.

The study was carried out by a team co-led by Yakeel T. Quiroz, PhD, Assistant Professor at Harvard Medical School, and Director of the Familial Dementia Neuroimaging Lab at Massachusetts General Hospital (MGH). Their work was published recently in The Lancet Neurology.

Additional co-first authors were Henrik Zetterberg, PhD, of Sahlgrenska University Hospital in Sweden, and Eric Reiman, MD, from the University of Arizona.

"We wanted to determine the earliest age at which plasma NfL levels could distinguish individuals at high risk of Alzheimer's," says Quiroz, who is also an MGH Research Scholar 2020-2025.

They found that NfL levels increased with age among people at genetic risk because of a specific mutation (PSEN1 E280A) and began to differentiate carriers from noncarriers at age 22, an average of 22 years before their estimated age of cognitive impairment (age 44).

Neurofilament light chain (NfL) is a biomarker of neurodegeneration - damage to neurons. Measures of NfL concentrations in cerebral spinal fluid (CSF) and blood have been used to detect and track neurodegeneration in individuals with Alzheimer's disease and other brain disorders.

The team used an ultra-sensitive single molecule array immunoassay to measure NfL concentrations in serum and plasma. Earlier studies have shown close correlations between blood-based and CSF measurements in people and animal models of neurodegenerative diseases.

The team studied over 2,000 members of the world's largest kindred with familial Alzheimer's because of a single mutation (PSEN1 E280A) --the familial Alzheimer's disease Colombian kindred, which were aged 8-75 years and had no other neurological or health conditions.

Next they used a single molecule array immunoassay to examine the relationship between plasma NfL concentrations and age to establish the earliest age at which NfL concentrations start to diverge between mutation carriers and non-carriers. The team enrolled 1070 PSEN1 E280A mutation carriers and 1074 non-carriers with baseline assessments.

Plasma NfL measurements increased with age in both groups (p

"Our findings add to the growing evidence that blood-based NfL can be useful in detecting neurodegeneration, starting with very early, subtle elevations way before the onset of clinical symptoms. We need more studies to further explore NfL as a way to inform prognosis and evaluate treatments in Alzheimer's disease," says Quiroz.

An analysis of the 2018-2019 measles outbreak in New York City--the largest such outbreak in the United States in nearly three decades--identifies factors that made the outbreak so severe: delayed vaccination of young children combined with increased contact among this age group, likely through "measles parties" designed to purposely infect children. The study by Wan Yang, PhD, assistant professor of epidemiology at Columbia University Mailman School of Public Health, has implications for the future, as vaccination rates plummet during the COVID-19 pandemic.

The findings are published in the journal Science Advances.

"Measles Parties" Accelerated Measles Spread

Yang, an infectious disease modeler who previously published analyses on the spread of influenza and COVID-19, designed a computer model to simulate the transmission of measles in an Orthodox Jewish community in New York City from October 2018 to July 2019 based on city data of measles cases. Around a quarter of young children aged 1 to 4 were estimated to be susceptible to measles at the onset of the outbreak, likely due to delayed vaccination. However, the high number of infections would have been very unlikely without the increased contact between children aged 1 to 4--likely through measles parties.

Vaccination Campaigns Averted Huge Spike in Cases

To contain the outbreak, the New York City Department of Health and Mental Hygiene launched extensive vaccination campaigns and ordered mandatory vaccination of all individuals living, working, or going to school in the affected zip codes. As a result, over 32,000 individuals under 19 years were vaccinated with the measles, mumps, and rubella (MMR) vaccine during October 2018 to July 2019, and the outbreak subsided.

The new study finds that without these campaigns, the measles outbreak could have infected 6,500-8,100 people compared to 649 actual cases. These infections would have largely occurred in young children aged 1 to 4 years and infants under age 1. At least 100 infants were infected during the 10-month outbreak period, despite extensive infection and transmission control efforts, including vaccinating infants 6 months or older and post-exposure prophylaxis with immune globulin given to those under 6 months.

"These findings demonstrate the rippling effects of vaccine hesitancy to all susceptible age groups, particularly to infants too young to receive their first dose of MMR vaccine," says Yang. "Administration of the first dose of the routine MMR vaccine earlier than the current guideline of 1 year may be needed to protect infants if high levels of vaccine hesitancy persist." (The World Health Organization recommends administering the first dose of measles vaccine at 9 to 12 months of age for routine vaccination programs and as early as 6 months for settings such as during an outbreak.)

Implications for COVID-19 Period

According to New York City Mayor Bill de Blasio, MMR vaccination rates in New York City have dropped by 63 percent for all children and 91 percent among those over age 2 in recent weeks--greatly increasing the potential for a future outbreak of measles and other childhood infections.

"At the moment, chances of an immediate measles outbreak in the City remain low thanks to the recent vaccination campaigns and current social distancing practice. But as the number of unvaccinated children increases and contact resumes, there would be a much greater risk of disease spread. " says Yang. "Social distancing is needed to protect the population from COVID-19 while researchers work to develop a vaccine. Thankfully, for many other life-threatening infections such as measles, mumps, and rubella, we already have vaccinations to protect children from those diseases. It’s crucial that parents work with their doctors to make sure their children are vaccinated in a timely fashion."

The ocean is a messy and turbulent space, where winds and weather kick up waves in all directions. When an object or person goes missing at sea, the complex, constantly changing conditions of the ocean can confound and delay critical search-and-rescue operations.

Now researchers at MIT, the Swiss Federal Institute of Technology (ETH), the Woods Hole Oceanographic Institution (WHOI), and Virginia Tech have developed a technique that they hope will help first responders quickly zero in on regions of the sea where missing objects or people are likely to be.

The technique is a new algorithm that analyzes ocean conditions such as the strength and direction of ocean currents, surface winds, and waves , and identifies in real-time the most attracting regions of the ocean where floating objects are likely to converge.

The team demonstrated the technique in several field experiments in which they deployed drifters and human-shaped manikins in various locations in the ocean. They found that over the course of a few hours, the objects migrated to the regions that the algorithm predicted would be strongly attracting, based on the present ocean conditions.

The algorithm can be applied to existing models of ocean conditions in a way that allows rescue teams to quickly uncover hidden "traps" where the ocean may be steering missing people at a given time.

"This new tool we've provided can be run on various models to see where these traps are predicted to be, and thus the most likely locations for a stranded vessel or missing person," says Thomas Peacock, professor of mechanical engineering at MIT. "This method uses data in a way that it hasn't been used before, so it provides first responders with a new perspective."

Peacock and Pierre Lermusiaux, also a professor of mechanical engineering at MIT, who oversaw the project, and their colleagues report their results in a study published today in the journal Nature Communications. Their coauthors are lead author Mattia Serra and corresponding author George Haller of ETH Zurich, Irina Rypina and Anthony Kirincich of WHOI, Shane Ross of Virginia Tech, Arthur Allen of the U.S. Coast Guard, and Pratik Sathe of the University of California at Los Angeles.

Hidden traps

Today's search-and-rescue operations combine weather forecasts with models of both ocean dynamics and the ways in which objects can drift through the ocean, to map out a search plan, or regions where teams should concentrate their search.

But the ocean is a complicated space of unsteady, ever-changing flow patterns. Coupled with the fact that a missing person has likely been continuously floating through this unsteady flow field for some time, Peacock and his colleagues say that significant errors can accumulate in predicting where to look first, when using a simple approach that directly predicts the trajectories of a few drifting objects.

Instead, the team developed a method to interpret the ocean's complex flows using advanced, data-driven ocean modeling and prediction systems. They used a novel "Eulerian" approach, in contrast to more commonly used "Lagrangian" approaches -- mathematical techniques that involve integrating snapshots of the ocean velocity due to waves and currents to slowly generate an uncertain trajectory for where a missing person or object may have been carried.

The new Eulerian approach uses the most reliable velocity forecast snapshots, close to the point where a missing person or object was last seen, and quickly uncovers the most attracting regions of the ocean at a given time. These Eulerian predictions are then continuously updated when the next batch of updated velocity information becomes available.

The team has named their approach TRAPS, for its goal of identifying TRansient Attracting Profiles, or short-lived regions where water may converge and be likely to pull objects or people. The method is based on a recent mathematical theory,
developed by Serra and Haller at ETH Zurich, to uncover hidden attracting structures in highly unsteady flow data.

"We were a bit skeptical whether a mathematical theory like this would work out on a ship, in real time," Haller says. "We were all pleasantly surprised to see how well it repeatedly did."

"We can think of these 'traps' as moving magnets, attracting a set of coins thrown on a table. The Lagrangian trajectories of coins are very uncertain, yet the strongest Eulerian magnets predict the coin positions over short times," Serra says.

"The key thing is, the traps may not have any signature in the ocean current field," Peacock adds. "If you do this processing for the traps, they might pop up in very different places from where you're seeing the ocean current projecting where you might go. So you have to do this other level of processing to pull out these structures. They're not immediately visible."

Out at sea

Led by WHOI sea-going experts, the researchers tested the TRAPS approach in several experiments out at sea. "As with any new theoretical technique, it is important to test how well it works in the real ocean," Rypina says.

In 2017 and 2018, the team sailed a small research vessel several hours out off the coast of Martha's Vineyard, where they deployed at various locations, an array of small round buoys, and manikins.

"These objects tend to travel differently relative to the ocean because different shapes feel the wind and currents differently," Peacock says. "Even so, the traps are so strongly attracting and robust to uncertainties that they should overcome these differences and pull everything onto them."

The team ran their modeling and prediction systems, forecasting the ocean's behavior and currents, and used the TRAPS algorithm to map out strongly attracting regions over the course of the experiment. The researchers let the objects drift freely with the currents for a few hours, and recorded their positions via GPS trackers, before retrieving the objects at the end of the day.

"With the GPS trackers, we could see where everything was going, in real-time," Peacock says. "So we laid out this initial, widespread pattern of the drifters, and saw that, in the end, they converged on these traps."

The researchers are planning to share the TRAPS method with first responders such as the U.S. Coast Guard, as a way to speed up search-and-rescue algorithms, and potentially save many more people lost at sea.

"People like Coast Guard are constantly running simulations and models of what the ocean currents are doing at any particular time and they're updating them with the best data that inform that model," Peacock says. "Using this method, they can have knowledge right now of where the traps currently are, with the data they have available. So if there's an accident in the last hour, they can immediately look and see where the sea traps are. That's important for when there's a limited time window in which they have to respond, in hopes of a successful outcome."