Body

HOUSTON -- In a first-time disclosure of IPN60090, a small-molecule inhibitor of the metabolic enzyme glutaminase (GLS1), researchers from The University of Texas MD Anderson Cancer Center's Therapeutics Discovery division and Ipsen Biopharmaceuticals reported the preclinical discovery and early-stage clinical development of this novel drug. IPN60090, now under investigation in a Phase I trial, may hold benefit for certain patients with lung and ovarian cancers.

MD Anderson's GLS1 program was initiated and advanced by a team of scientists in the Institute for Applied Cancer Science (IACS) and Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) platforms, both engines within Therapeutics Discovery. Development of the program continues in collaboration with Ipsen, which licensed the therapeutic in 2018.

Findings and information about the ongoing trial will be presented today at the 2020 American Association for Cancer Research Virtual Annual Meeting I by Jeffrey Kovacs, Ph.D., institute group leader with TRACTION and co-leader of the GLS1 program.

"This effort is a great example of our strategy within Therapeutics Discovery, taking a comprehensive approach to personalized medicine," said Kovacs. "Our preclinical data suggest that IPN60090 may be effective in underserved groups of patients who need better treatment options, and we look forward to results from our ongoing clinical trials."

Dysregulation of cellular metabolism is a hallmark of cancer development, and the GLS1 enzyme plays a key role in many metabolic processes. Thus, it makes an attractive target for cancer therapy, explained Kovacs.

IACS drug-discovery scientists identified IPN60090 as a potent and selective inhibitor of GLS1 suitable for clinical trials, and translational researchers in TRACTION demonstrated its activity against subsets of lung and ovarian cancer preclinical models.

Further analysis revealed biomarkers of response, which have been leveraged to identify patients most likely to benefit. In lung cancers, mutations in the KEAP1 and NFE2L2 genes, which regulate response to oxidative stress, sensitize cells to treatment with IPN60090. Similarly, low expression of the metabolic protein asparagine synthetase (ASNS) in ovarian cancers predicts response to IPN60090 in preclinical models.

"Identifying these putative predictive biomarkers of response is critical for our ongoing clinical efforts to ensure that we're able to offer patients the most relevant therapies," said Timothy A. Yap, M.B.B.S., Ph.D., F.R.C.P., associate professor of Investigational Cancer Therapeutics and medical director of IACS. "These patient groups in particular, which represent distinct niches within those cancer types, are in need of more effective treatment options."

For example, patients with lung cancers harboring KEAP1/NRF2 mutations have not benefited from treatment with immune checkpoint inhibitors and have poorer outcomes overall, explained Yap, who leads the IPN60090 clinical trial at MD Anderson.

IPN60090 currently is under investigation in a Phase I dose-escalation and dose-expansion study for patients with advanced solid tumors that harbor KEAP1/NFE2L2 mutations or have low ASNS levels. The team has developed novel CLIA-certified assays to identify patients likely to benefit and monitor how effectively the drug is acting. Initial data from the clinical trial indicate that IPN60090 is effectively inhibiting GLS1 activity in peripheral blood mononuclear cells from patients.

Future trial cohorts plan to investigate IPN60090 in combination with checkpoint inhibitors, chemotherapy and targeted therapies identified by the researchers as having potential synergistic benefits with GLS1 inhibition.

The ongoing research is supported by Ipsen through a global licensing and development agreement. The research is managed according to MD Anderson's Institutional Conflict of Interest Management and Monitoring Plan. Kovacs is a co-inventor on material and method-of-use patent applications related to IPN60090. The Therapeutics Discovery division is supported in part by MD Anderson's Moon Shots Program®.

HOUSTON - New data from the Phase III EMBRACA trial led by researchers at The University of Texas MD Anderson Cancer Center found the PARP inhibitor talazoparib did not demonstrate a statistically significant overall survival (OS) benefit for patients with metastatic HER2-negative breast cancer and mutations in the BRCA1/2 genes. Most patients included in the study went on to receive subsequent systemic therapies, which may have affected the survival outcome analysis. The research confirmed previous results showing talazoparib improved patient reported quality-of-life measures over available chemotherapies and had a tolerable safety profile.

The secondary endpoint results from the EMBRACA trial were presented today at the American Association for Cancer Research (AACR) annual meeting by Jennifer Litton, M.D., professor of Breast Medical Oncology. The primary analysis results previously were published in the New England Journal of Medicine and found that patients treated with talazoparib had significantly prolonged progression-free survival (PFS) when compared with chemotherapy, with a median PFS of 8.6 months versus 5.6 months, respectively. This led to Food and Drug Administration approval for talazoparib in 2018.

EMBRACA is the largest trial of PARP monotherapy to date in patients with germline BRCA-mutated HER2-negative advanced breast cancer. The final OS analysis was performed using the intent-to-treat population after 324 deaths had been observed. After a median follow-up of 44.9 months for talazoparib and 36.8 months for chemotherapy, 216 patients in the talazoparib group and 108 patients in the chemotherapy group had died. The effect of treatment with talazoparib also was similar regardless of BRCA status.

"Overall survival is always an important endpoint, but also a challenge for metastatic breast cancer patients as there are many treatment options available," said Litton. "Many of these patients also received subsequent therapies, including PARP inhibitors and platinum-based therapies, which could have potentially influenced these results."

Mutations in the BRCA1/2 genes, which account for 5 to 10% of all breast cancers, cause defects in normal DNA damage repair. PARP inhibitors block an additional DNA repair pathway, and the anti-tumor effects of PARP inhibitors can be intensified in patients with BRCA mutations. Talazoparib works by not only inhibiting the PARP enzyme, but by trapping the enzyme on DNA to further prevent DNA repair.

The international Phase III clinical trial, EMBRACA, enrolled 431 patients with locally advanced or metastatic and hereditary BRCA1/2 gene mutations. Patients with HER2-positive disease were excluded as there are approved targeted therapies for those cancers. Patients were allowed up to three previous chemotherapies, including platinum-based therapies.

Participants were randomized 2:1 to receive either talazoparib (287) or physician's choice of treatment (PCT) of single-agent therapy (144), either capecitabine, eribulin, gemcitabine or vinorelbine. Fifty-four percent of participants had HR+ disease and 46% had triple negative breast cancer; BRCA1 and BRCA2 mutations were split at 45 and 55%, respectively.

Almost half of patients in the talazoparib group received a subsequent PARP inhibitor or platinum therapy compared with almost 60% of patients in the chemotherapy group. When looking at PARP inhibitors specifically, approximately a third of patients in the chemotherapy group received a subsequent PARP inhibitor, which became increasingly available to patients either through trials or commercially during the course of this trial, compared with only 4.5% of patients who received talazoparib.

Subsequent platinum therapy was received by around 46% of patients in the talazoparib group compared with approximately 42% of patients in the chemotherapy group.

Interpretation of the OS results may have been confounded by subsequent treatments, so two sensitivity analyses accounting for subsequent PARP inhibitor and/or platinum therapy were carried out.

The analysis suggests that the OS analysis underestimated the treatment benefit of talazoparib.

Patient-reported quality-of-life measures revealed a prolonged time to deterioration of overall health, 26.3 months in the talazoparib arm compared to 6.7 months for the chemotherapy arm.

"Talazoparib remains an option for patients with advanced breast cancer and a germline BRCA mutation due to its improvements in progression free survival," said Litton "Other advantages include it being an oral once-daily option, as well as the demonstrated improvements in quality of life for metastatic breast cancer patients."

Grade 3-4 hematological adverse events (AEs) occurred in 56.6% of patients receiving talazoparib and 38.9% of those on chemotherapy. Most grade 3-4 AEs reported in the talazoparib group were hematologic and most were successfully managed by supportive care and dose modifications. The most common hematologic AE in patients receiving talazoparib was anemia, which was reported in 54.9% of patients receiving talazoparib compared with 19.0% of patients receiving chemotherapy.

Correlative studies currently are underway and analysis using the EMBRACA population to explore the effect of tumor BRCA zygosity and genomic loss-of-heterozygosity on efficacy outcomes also is being presented at AACR's annual meeting by Lida Mina, M.D., associate director of Breast Programs at Banner MD Anderson Cancer Center.

Philadelphia, April 27, 2020 - Diabetic retinopathy is one of the main vascular complications of type 2 diabetes, and the most common cause of visual deterioration in adults. A new study in The American Journal of Pathology, published by Elsevier, reports on the efficacy of a possible treatment candidate that showed anti-inflammatory and neuroprotective effects on the retina and optic nerve head in early type 2 diabetic retinopathy using a diabetic mouse model.

Diabetic retinopathy is caused by damage to the blood vessels of the light-sensitive tissue at the back of the eye. The cause is usually attributed to high blood sugar (hyperglycemia), but several studies have shown that inflammation is also an important factor in the progression of the disorder.

"Inflammation causes neurodegeneration as well as microvascular abnormalities in the retina," explained lead investigator Jin A. Choi, PhD, Department of Ophthalmology and Visual Science, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. "Diabetic retinal neurodegeneration can occur before the onset of clinical diabetic retinal microvascular abnormalities. Therefore, therapeutics for neurodegeneration may provide a novel interventional strategy in the window period between the diagnosis of type 2 diabetes and the onset of clinically manifested diabetic retinopathy."

Investigators analyzed and compared the anti-inflammatory and neuroprotective effects of the glucagon-like peptide-1 receptor agonist (GLP-1RA) lixisenatide in the retina and the optic nerve head with those of insulin in a mouse model of type 2 diabetes. They divided diabetic mice into three groups; GLP-1RA (LIX); insulin (INS) with controlled hyperglycemia based on the glucose concentration of LIX; and a control group (D-CON). Nondiabetic control mice were also characterized for comparison.

After eight weeks of treatment, neuroinflammation caused by type 2 diabetes was significantly reduced in GLP-1RA-treated retinas and optic nerve heads compared with untreated or even insulin-treated retinas of early type 2 diabetic mice, showing that the outcomes are independent of the glucose-lowering effect of GLP-1RA.

"This study can provide a possible therapeutic strategy to prevent visual deterioration by using GLP-1RA in early type 2 diabetic retinopathy," noted first author Yeon Woong Chung, MD, Department of Ophthalmology and Visual Science, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea. "GLP-1RA significantly suppressed neuroinflammation in the early diabetic retinopathy, whereas insulin had little or no suppressive effect in this study."

"Retinal ganglion cells start to die even before clinical changes such as hemorrhages in diabetic retinopathy occur," commented Dr. Choi. "Thus, for better visual prognosis, we need to focus on the treatment of the retina in early type 2 diabetes before the clinical onset of diabetic retinopathy. The diabetic mouse group in our study who were treated with GLP-1RA showed significantly decreased cell death compared to those with insulin treatment."

A first-of-its-kind randomized clinical trial offers strong and perhaps surprising evidence that a combination of two targeted melanoma drugs when given continuously keeps patients' cancer from growing or spreading longer when compared with intermittent treatment, according to study results to be presented at the 2020 virtual annual meeting of the American Association for Cancer Research.

The findings will be presented at the AACR's opening clinical plenary on Monday, April 27 at 10:25 a.m. EDT by Alain Algazi, MD, an associate professor in the Department of Medicine at University of California San Francisco and the study chair with SWOG Cancer Research Network, which led the research. SWOG is a cancer clinical trials network funded by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH), and a member of the oldest and largest publicly-funded research network in the nation.

Algazi's study, SWOG S1320, focuses on treatment for melanomas with mutations in the BRAF gene, changes that cause cancer cells to grow rapidly. About half of all melanomas diagnosed involve a BRAF mutation, and Algazi's study focused on treatments for patients with the most common melanoma mutations - BRAFV600E and BRAFV600K. These cancers can be difficult to treat because they often become resistant to drugs designed to target BRAF mutations, and can return months after treatment even more difficult to defeat. In 2013, results of a high-profile study in mice were published that suggested giving the standard drug combination intermittently may be a way to beat this cunning cancer and help patients live longer before their cancer grew or spread, an outcome known as progression-free survival. Algazi wanted to test this idea in humans, and his phase II randomized trial is the first do so.

SWOG is part of the NCI's National Clinical Trials Network (NCTN), which includes more than 2,000 cancer centers, university hospitals, and community sites in the U.S. and abroad. Using this network, Algazi's team enrolled 249 eligible melanoma patients from 68 clinical sites over a five-year period. Of the 249 patients, 206 were randomized. Every patient was given the commonly prescribed BRAF and MEK inhibitor combination regimen of dabrafenib and trametinib. One group of patients took the combination of pills each day until their cancer progressed. Another group took the same daily combination for five weeks, then took a three-week break, then resumed treatment for another five weeks, then took a break, and so on, until their cancer progressed. During the treatment period, each patient had a CT scan every eight weeks to measure their tumor size. Patients also gave blood and tumor samples.

Results showed that the patients who received continuous drug doses were, on average, did not have their cancer progress for nine months. Patients who received intermittent doses, on average, did not have their cancer progress for five months.

So continuous dosing was more effective in this study. And the positive results on intermittent dosing found in mice - now the subject of dozens of clinical trials - did not appear to hold up in humans, SWOG results show.

"What works in pre-clinical studies doesn't always work in real-world clinical studies," Algazi said. "In melanoma research, we're all trying to figure out ways to optimize these targeted drugs and find a way around resistance so people live longer. We're going to have to keep at it because the current standard of continuous dosing seems to hold the most benefit."

Why continuous treatment proved more effective isn't clear, although Algazi said the tissue and blood samples taken during the trial may hold clues and can be used for further study. While measuring overall survival was not the primary research objective of the trial, Algazi's team also found that, regardless of their dosing schedule, melanoma patients on the trial have lived about the same amount of time. About half of the patients who participated in the trial have died over the course of the study, which continues to follow those who are still alive.

Antoni Ribas, MD, PhD, is the senior leader on the trial, the former chair of the melanoma research committee at SWOG, and the AACR president. He is also a professor of medicine at the David Geffen School of Medicine at the University of California Los Angeles, director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program, and director of the Parker Institute for Cancer Immunotherapy Center at UCLA.

"The idea of prescribing therapy intermittently made sense," Ribas said. "Cancer cells wouldn't have enough time to get used to it, and become resistant - a notion that was supported scientifically by well-conducted studies in the laboratory. This clinical study illustrates the importance of ultimately testing hypotheses in human patients, which is the underlying reason for the existence of NCI-funded groups like SWOG."

Bethesda, MD - Findings from a new animal study suggest that maternal nicotine exposure during breastfeeding could be linked to problems with skull and face development. Although widespread research has focused on the effects of cigarettes, little work has examined nicotine alone.

"Unlike many other studies, we isolated the common constituent of cigarettes, vaping technologies and many nicotine replacement therapies to specifically understand how nicotine by itself might alter development," said research team leader James Cray, PhD, associate professor of anatomy at The Ohio State University. "Our findings suggest that mothers who vape while breastfeeding are likely exposing their infants to nicotine and that this can disturb growth much like cigarette exposure."

Amr Mohi, BDS, a teaching assistant and graduate student in Cray's lab, was scheduled to present this research at the American Association for Anatomy annual meeting in San Diego this month. Though the meeting, to be held in conjunction with the 2020 Experimental Biology conference, was canceled in response to the COVID-19 outbreak, the research team's abstract was published in this month's issue of The FASEB Journal.

Maternal exposure to nicotine has been linked to increased craniofacial abnormalities such as craniosynostosis, a birth defect in which the bones in a baby's skull fuse too early. To better understand the timing involved in this exposure, the researchers used an imaging method known as microCT to measure skull and face bones in mouse offspring after maternal nicotine exposure during pregnancy or lactation.

The researchers found that exposure during lactation alone--comparable to the time a mother would breastfeed her infant--was associated with abnormalities in craniofacial development.

"Our findings suggest that nicotine alone can alter craniofacial development and show that nicotine cannot be viewed as a relatively safe chemical that only acts on addiction," said Cray.

The researchers plan to build on these findings by looking more closely at nicotine exposures from vaping. In one study, they are using cell models to better understand how nicotine and carrier components used for vaping may alter cellular processes.

Rockville, Md. --Obesity has been shown to place physical stress on the body, but new research suggests that excess weight may also cause mental fatigue. The research, originally slated for presentation at the APS annual meeting at Experimental Biology (canceled due to the coronavirus), is published in the April issue of The FASEB Journal.

Obesity can increase the risk of high blood sugar (glucose), which may develop into type 2 diabetes and other metabolic disorders if untreated. Impaired exercise capacity or physical stamina may also be a problem for people who are overweight. Compromised cognitive function, however, has not been associated as strongly with obesity as physical limitations.

Researchers at Southern Illinois University Edwardsville aimed to learn more about the onset of obesity and its impact on both physical and mental abilities by studying two groups of rats. One group was fed a high-fat diet, and the other ate a standard diet for six weeks. The research team measured the rats' weight, blood glucose and ketone levels twice a week. Ketones are chemicals made by the liver when there is not enough insulin in the body to convert glucose into energy. In the fifth week, the researchers administered an open-field test, which measures speed and distance as the animals move through a maze in a given time frame and determines physical exhaustion. A novel object recognition test, which measures mental exhaustion by analyzing the time the rats spend examining new and familiar objects, was given in the final week of the trial.

Both rat groups gained weight during the trial, but the high-fat diet group, not surprisingly, gained more than the control group. Blood glucose levels fluctuated more in the high-fat diet group as well. There was no significant difference in the average glucose levels or ketones between the two groups.

The high-fat diet group performed poorly on the novel recognition test when compared with the control group. "Although we were not fully surprised by this finding, this is the first study, to our knowledge, to be reporting mental exhaustion in high-fat diet-induced obese rats," explained Chaya Gopalan, PhD, principal investigator of the study.

"One message from this study is to avoid [a] high-fat diet, which not only makes one become obese, but also has consequences on cognitive capability," the authors wrote.

Gopalan's team was slated to present "The effects of diet-induced obesity in male Sprague Dawley rats on blood glucose, ketones and markers of mental and physical fatigue" at the APS annual meeting at Experimental Biology. Although the meeting was canceled in response to the COVID-19 outbreak, the research team's abstract is published in this month's issue of The FASEB Journal.

The COVID-19 pandemic has hit some nursing homes especially hard - including in the hotspot state of Michigan.
Hundreds of deaths of residents in homes from Seattle to Boston have raised concerns about how well facilities are protecting the 1.3 million older Americans who live in them. Those concerns have prompted new federal and state requirements about testing and transparency.

But it might have been worse.

New data suggests that at least in Michigan, nursing homes that responded to a survey were far better prepared for this pandemic than they were for the last one. The study includes responses from 130 nursing homes to a survey performed during the week the state announced its first documented case of COVID-19.

It shows that nearly all had a pandemic plan in place. That's compared with just over half of the 280 nursing homes that answered the same survey in 2007. Nearly all said they now have at least one staff member in charge of pandemic preparedness.

The findings are reported in the Journal of the American Geriatrics Society by a team from the University of Michigan that has studied and worked to improve nursing home infection prevention for years.

Members of the team have several other recent publications with direct or indirect relevance to the COVID-19 pandemic, including putting forth recommendations for nursing homes and other housing facilities for older adults to use in planning how they will respond to pandemics such as COVID-19.

Lona Mody, M.D., M.Sc., a geriatrician at Michigan Medicine, U-M's academic medical center, and the VA Ann Arbor Healthcare System, is senior author of both of the new publications. She's a professor of internal medicine, the associate director for clinical and translational research at the U-M Geriatrics Center, and director of the Infection Prevention in Aging research group.

"Our nursing homes house some of the most vulnerable in our society," says Mody. "This virus unfortunately is very contagious, the disease it causes has incredibly poor outcomes in older adults with comorbidities, and nursing homes are communal settings with shared spaces and resource limitations. This creates a perfect storm of sorts. Being novel, we learn as go and have to learn really quickly."

Mody heads the PRIISM, or Preventing Resistance and Infection by Integrating Systems in Michigan, project, which partners with skilled nursing facilities, hospitals and public health agencies across the state to perform research and create and test education and training materials for nursing home staff. The program's website has many free materials for use by nursing homes everywhere.

Pandemic planning

The new survey data show Michigan's nursing homes have done a lot to prepare for pandemics since the last time the U-M team performed the survey. That previous survey was taken before the H1N1 influenza pandemic of 2009, but after the H5N1 "bird flu" pandemic of 2005 raised national awareness of the importance of pandemic preparedness. Mody and colleagues published pandemic preparedness guidance for nursing homes at that time.

In mid-March of this year, 85% of nursing homes said they had stockpiled supplies before COVID-19 hit, compared with 57% after the H5N1 pandemic. Most of those that had stockpiled supplies had focused on surgical masks, gloves and hand sanitizer. Less than half had stockpiled N95 respirator masks, which are recommended by national and global health authorities for health care workers performing certain types of care on a COVID-19 patient.

Still, 42% of the nursing homes that answered a question about COVID-19-specific concerns said they were worried about running short of personal protective gear.

"Although the size and severity of COVID-19 outbreaks in some nursing homes have taken everyone by surprise, just as so much about this pandemic has, in general nursing homes knew exactly what their challenges were going to be in a pandemic - PPE shortages, staff shortages and worries that they did not have the capacity to care for COVID patients after their hospital stay."

Nearly all now said they had trained staff on how their facility would respond in a pandemic, up from 42% in 2007. But only one-third had conducted a pandemic drill. And Mody notes that nursing homes have a much higher rate of staff turnover than hospitals - meaning that training on infection prevention and pandemic response has to be offered whenever a new person joins the organization.

Michigan's nursing homes appear to have gotten better connected to the broader health care system in the past decade, with significantly more saying they now have communication lines established with local hospitals and public health departments.

Many also said they were drawing COVID-19 guidance not just from the Centers for Disease Control and Prevention, but also from state and local health departments. Half also received guidance from their home's corporate parent.

And while half of the nursing homes surveyed this year said they expected significant staff shortages due to COVID-19, most of them said they had a plan to deal with that. Most planned to ask existing clinical staff to work more hours, and to redeploy non-clinical staff. Two-thirds expected they'd need to require staff to work overtime.

The survey also explored the potential for nursing homes to relieve the burden on hospitals. In all, 82% said they'd be willing to take non-pandemic patients from overburdened hospitals now, compared with 53% in 2007. But the percent that said they'd be able to accept patients with the pandemic disease stayed the same, at one-third of responding homes.

Additional guidance

Mody and her colleagues John P. Mills, M.D. and Keith Kaye, M.D. from the U-M Division of Infectious Diseases recently published some recommendations regarding COVID-19 and older adults in the journal JCI Insight. Mody and Kaye are members of the U-M Institute for Healthcare Policy and Innovation.

They note that it's not just nursing homes with long-term residents that need to be ready to care for vulnerable older adults during pandemics.

In fact, the trend over the past decade to use nursing homes more often for short-term stays by patients who have been discharged from a hospital, and to create state and local programs that allow older adults to 'age in place' instead of moving to nursing homes for the long-term, have led to potential gaps for pandemic responses to help older adults.

They call for policymakers to address those gaps, by creating pandemic-specific plans for community-dwelling older adults, especially those with health needs.

As for nursing homes, they recommend that in areas where COVID-19 is spreading widely in the community, facilities should take these steps, and others:

place patients with known or suspected disease in the same area of the facility, away from others

perform rapid COVID-19 tests on all patients, both short-stay and long-stay

screen healthcare workers and other staff for symptoms including checking temperatures

limit visitors and group activities

require everyone wear a surgical mask

require additional protective gear for clinical staff

The limits on group activities tie in to other research by Mody and her colleagues, published in JAGS in December.

That study sampled surfaces, and the hands of patients and staff, in the common areas and rehabilitation gyms with in nursing homes, and looked for drug-resistant bacteria that can cause dangerous infections. Though the team didn't look for the presence of viruses in these areas, they did find that half of the samples taken in rehab gyms contained at least one type of bacteria that was resistant to several types of antibiotics.

In addition to stockpiling PPE and cleaning supplies, the team recommends that nursing homes should use "burn calculators" to predict how quickly they'll use those supplies based on their patient population.

If nursing homes and other residential facilities for older adults haven't already done so, they should establish lines of communication with local health departments in advance of any outbreak of COVID-19 in their facility. They should also focus on staff retention, including providing for generous sick leave policies so that staff can stay home when ill, and hazard pay for those who can come to work.

And, the team says, nursing homes should make sure they have an infection prevention plan in place for staff when a patient has died of COVID-19.

Another gap in preparedness that the COVID-19 pandemic is revealing, Mody says, is a gap in communication with patients and their families. Keeping families informed, and enabling them to connect virtually with their loved ones when they can't visit in person, is crucial, she says.

What The Essay Says: The author describes her experience being pregnant during the coronavirus disease 2019 pandemic.

Authors: Coral Olazagasti, M.D., of the Zucker School of Medicine at Hofstra/Northwell Health in New Hyde Park, New York, is the corresponding author.

To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/

(doi:10.1001/jamaoncol.2020.1652)

Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.

In a Nature Reviews Endocrinology "Comment" authors from the German Center for Diabetes Research (DZD), the Boston Children's Hospital and the Harvard T.H. Chan School of Public Health call for more research about the relationships of obesity, disproportionate fat distribution and impaired metabolic health with the severity of COVID-19.

The authors raise the point that most of the studies that have reported comorbidities in patients with COVID-19 did not provide data on body weight and height, which are used to estimate adipose tissue mass, by calculating the BMI. In their Comment they also briefly summarize novel research findings, deriving in part from articles which have not yet undergone peer-review, indicating that overweight and, particularly, obesity may associate with a substantial risk of a severe course of COVID-19. Importantly, these studies suggest that this risk is independent of cardiometabolic diseases and other comorbidities.

The authors then discuss possible mechanisms explaining this relationship. Among them respiratory dysfunction in obesity may result in hypoventilation-associated pneumonia and hypoxia-induced cardiac stress. Furthermore, they highlight that not only the calculation of the BMI, but also the measurement of the waist circumference and of glucose and insulin levels, which can be used to determine the presence of prediabetes and insulin resistance, may be important, as these parameters are independent determinants of cardiometabolic diseases, pneumonia and mortality.

Several tests have been developed for detecting the genetic material of the SARS-CoV-2 coronavirus that causes COVID-19, but these generally only allow detection of the virus during acute infection. Antibody, or serological, tests are urgently needed to determine the real rate of infection, to understand individuals' antibody responses to the virus, and to identify people who are potentially immune to re-infection. As described in a paper published in Current Protocols in Microbiology, investigators have now developed such a test.

The published article provides a step-by-step protocol with enough detail for other researchers to replicate in their laboratories. The protocol involves expressing and purifying segments of a key SARS-CoV-2 protein that are then used in blood tests for the presence of antiviral antibodies.

"Serological assays can be used to identify individuals who were infected (including severe, mild, and asymptomatic cases) and who are now potentially immune, which means that they are unlikely to transmit the virus to others," the authors wrote. "As an example, healthcare workers who are immune could potentially care for COVID19 patients with minimal risk to themselves, their colleagues, and other patients."

OKLAHOMA CITY - OU Medicine, the OU Health Sciences Center and the Oklahoma Medical Research Foundation collaborated to create a new test for COVID-19 using technology and reagents from Fluidigm Corporation, an innovative biotechnology tools provider. The test is intended for large-scale testing of patients across the OU Medicine healthcare system, with the capacity to test 180,000 samples over the next 90 days.

High-complexity laboratories like OU Medicine's that are certified by CLIA (Clinical Laboratory Improvement Amendments) are eligible to create their own diagnostic test for COVID-19, according to new guidance issued by the U.S. Food and Drug Administration. OU Medicine has applied for Emergency Use Authorization for the test from the FDA.

"We are grateful for the collaboration and leadership of the researchers at OU Health Sciences Center and OMRF. This partnership with three Oklahoma healthcare leaders and Fluidigm makes it possible for OU Medicine to offer this unique testing capability to our state," said Chuck Spicer, FACHE, President and CEO of OU Medicine, Inc. "We believe this greatly increased number of tests will serve as a turning point in our battle against the COVID-19 pandemic.

"Readily accessible and rapid testing for COVID-19 not only expedites treatment for patients who test positive, but it allows healthcare providers to be routinely tested to ensure their safety and that of everyone they encounter," Spicer added. "Increased testing will also allow more patients without COVID-19 to access specialty care at OU Medicine, including surgeries, procedures and other diagnostic testing."

The testing platform will produce results quickly - in about six hours - which will allow physicians to promptly begin treatment on patients who test positive, and will help public health officials gain a more accurate picture of the spread of the virus in Oklahoma.

OMRF's experience with Fluidigm's microfluidics technology and its Fluidigm Biomark™ HD system was a crucial component in the creation and validation of the test. The FAA Civil Aerospace Medical Institute in Oklahoma City also provided a Biomark™ HD system for use in the testing. Microfluidics technology generates more data and uses a fraction of limited testing reagents per sample compared with more traditional technology.

"Solutions that offer scale and high-speed processing are critically important in ramping up testing capabilities for COVID-19," said OMRF President Stephen Prescott, M.D. "We anticipate that the test will generate several thousand test results per day, and it comes online at a particularly critical time for COVID-19 patients in Oklahoma."

Rapid, high-capacity testing will continue to be critical for contact tracing - determining how many people have been exposed to an infected person. Testing will remain fully functional for as long as patients and the residents of Oklahoma need to be tested. That capability will help the state determine when and how Oklahomans can begin returning to work and their daily lives following the peak of the pandemic.

"The remarkable volume of testing made available through the tireless work of our OU Health Sciences Center researchers and partners at OU Medicine, OMRF, and Fluidigm is, simply put, game-changing," said OU Interim President Joseph Harroz Jr. "As this innovative testing platform ramps into full capacity, we will be able to ensure Oklahoma has consistent testing for the current environment and for possible future outbreaks, as well as demographic and geographic sampling that can help contain further spread."

Because Fluidigm technology employs a different approach than other testing platforms, OU Medicine is able to benefit from its speed and scale capabilities.

"Since the beginning of the COVID-19 outbreak, adequate resources for testing have been a serious challenge for healthcare systems around the world," said Chris Linthwaite, President and CEO of Fluidigm. "Speed, scale and automation are critical components to delivering timely results.

"We are excited to support OU Medicine, the Oklahoma Medical Research Foundation and the OU Health Sciences Center in this incredibly important program," Linthwaite added. "In parallel with this scaling of testing capacity, Fluidigm products are providing vital information on immune response to COVID-19 exposure. This information is essential for evaluation of patient management approaches and effective vaccine and therapeutic candidate development. The COVID-19 testing program underway in Oklahoma City positions their community at the forefront of pandemic preparation efforts in the global fight against this virus."

Computed tomography scans for people at risk for lung cancer lead to earlier diagnoses and improve survival rates, but they can also lead to overtreatment when suspicious nodules turn out to be benign.

A study published in American Journal of Respiratory and Critical Care Medicine indicates that an artificial intelligence strategy can correctly assess and categorize these indeterminate pulmonary nodules (IPNs). When compared to the conventional risk models clinicians currently use, the algorithm developed by the team of researchers in a very large dataset (15,693 nodules) reclassified IPNs into low-risk or high-risk categories in over a third of cancers and benign nodules.

"These results suggest the potential clinical utility of this deep learning algorithm to revise the probability of cancer among IPNs aiming to decrease invasive procedures and shorten time to diagnosis," said Pierre Massion, MD, Cornelius Vanderbilt Chair in Medicine at Vanderbilt University, the study's lead author.

Currently, clinicians refer to guidelines issued by the American College of Radiology and the American College of Chest Physicians. Adherence to these guidelines can be variable, and how patient cases are classified can be subjective. With the goal of providing clinicians with an unbiased assessment tool, the researchers developed an algorithm based on datasets from the National Lung Screening Trial, Vanderbilt University Medical Center and Oxford University Hospital. Their study is the first to validate a risk stratification tool on multiple independent cohorts and to show reclassification performance that is significantly superior to existing risk models.

With IPNs, clinicians are often faced with the dilemma of weighing whether to advise a patient to undergo an invasive surgical procedure, which may be unnecessary, against a watch and wait strategy, which may result in delaying needed cancer treatment. A definitive diagnosis of an IPN can take up to two years.

Better assessment tools are needed by clinicians as screenings for patients at risk for lung cancer increase. Lung cancer is the leading cause of cancer-related death in the United States and globally. The overall five-year survival rate is 21.7%, but it is much greater (92%) for those patients who receive an early diagnosis of stage IA1 non-small cell cancer.

BINGHAMTON, N.Y. - High-altitude adaptations in the Himalayas may lower risk for some chronic diseases, according to a research team including faculty from Binghamton University, State University of New York, the University of New Mexico, and the Fudan University School of Life Sciences.

The Mosuo, a Tibetan-descended population living in the mountains of Southwest China, were found to be at lower risk for hypertension and diabetes-associated anemia than low-altitude Han populations.

"Understanding of high-altitude adaptations in human populations has grown tremendously in the last decade," said Katherine Wander, assistant professor of anthropology at Binghamton University. "This explosion of information led us to ask how such adaptations affect chronic disease risk. Our research suggests that Himalayan adaptations to high altitude have additional effects beyond helping people cope with low oxygen availability; they also seem to lower risk for hypertension and, among diabetics, anemia."

The researchers hypothesized that adaptations to high altitude might also affect the chronic disease pathways for hypertension and, among diabetics, anemia. Human populations that are adapted to the high-altitude environment of the Himalayas have higher blood flow, due dilation of their blood vessels, which can increase oxygen delivery, even if their blood oxygen content is low. The researchers hypothesized that this dilation might also lower risk for hypertension. Himalayan high-altitude populations have also lost a mechanism that normally increases red blood cell production in response to low blood oxygen, which protects them against dangerously high blood viscosity; the researchers hypothesized that this would also mitigate the risk for anemia that normally accompanies diabetes.

Both of these hypotheses were supported when patterns in hypertension and anemia were compared between the Mosuo and low-altitude Han populations: Mosuo risk for hypertension was much lower, and, although diabetics were more likely to have anemia among the Han, this was not the pattern among the Mosuo.

"As globalization continues to affect the world's populations, people's epidemiological and nutritional environments are changing. In most cases, this leads at some point to an increased burden of non-communicable diseases like hypertension, obesity, diabetes, and so on," says research-team leader Siobhan Mattison from the University of New Mexico. "Some of this is happening in the Mosuo case--there is a high incidence of diabetes, for example--but our results show that unique adaptations lead to different health consequences for the Mosuo compared to other populations."

The research suggests that, as chronic diseases continue to grow as global health concerns, it will become increasingly important to investigate how risk may be affected by genetic adaptations to the local environment.

"This is significant because it shows the importance of understanding evolution and adaptation to answering questions about health and disease," Wander said. "Obesity and other chronic diseases are an increasingly global phenomenon, and so it is important to understand how differences across populations interact with the physiology of chronic diseases--high-altitude adaptations are just one example of such an interaction."

Collecting the data for this study involved visits to hundreds of households, asking people about their livelihoods, and obtaining health information from finger-prick blood samples. "Like anyone else, the Mosuo are concerned about their health and well-being and are aware of the potential health consequences associated with non-traditional diets," says Mattison. "We learn a lot from working with our participants on issues that they're interested in."

Ethicists from Carnegie Mellon and McGill universities are calling on the global research community to resist treating the urgency of the current COVID-19 outbreak as grounds for making exceptions to rigorous research standards in pursuit of treatments and vaccines.

With hundreds of clinical studies registered on ClinicalTrials.gov, Alex John London, the Clara L. West Professor of Ethics and Philosophy and director of the Center for Ethics and Policy at Carnegie Mellon, and Jonathan Kimmelman, James McGill Professor and director of the Biomedical Ethics Unit at McGill University, caution that urgency should not be used as an excuse for lowering scientific standards. They argue that many of the deficiencies in the way medical research is conducted under normal circumstances seem to be amplified in this pandemic. Their paper, published online April 23 by the journal Science, provides recommendations for conducting clinical research during times of crises.

"Although crises present major logistical and practical challenges, the moral mission of research remains the same: to reduce uncertainty and enable care givers, health systems and policy makers to better address individual and public health," London and Kimmelman said.

Many of the first studies out of the gate in this pandemic have been poorly designed, not well justified, or reported in a biased manner. The deluge of studies registered in their wake threaten to duplicate efforts, concentrate resources on strategies that have received outsized media attention and increase the potential of generating false positive results purely by chance.

"All crises present exceptional situations in terms of the challenges they pose to health and welfare. But the idea that crises present an exception to the challenges of evaluating the effects drugs and vaccines is a mistake," London and Kimmelman said. "Rather than generating permission to carry out low-quality investigations, the urgency and scarcity of pandemics heighten the responsibility of key actors in the research enterprise to coordinate their activities to uphold the standards necessary to advance this mission."

The ethicists provide recommendations for multiple stakeholder groups involved in clinical trials:

Sponsors, research consortia and health agencies should prioritize research approaches that test multiple treatments side by side. The authors argue that "master protocols" enable multiple treatments to be tested under a common statistical framework.

Individual clinicians should avoid off-label use of unvalidated interventions that might interfere with trial recruitment and resist the urge to carry out small studies with no control groups. Instead, they should seek out opportunities to join larger, carefully orchestrated studies.

Regulatory agencies and public health authorities should play a leading role in identifying studies that meet rigorous standards and in fostering collaboration among a sufficient number of centers to ensure adequate recruitment and timely results. Rather than making public recommendations about interventions whose clinical merits remain to be established, health authorities can point stakeholders to recruitment milestones to elevate the profile and progress of high-quality studies.

"Rigorous research practices can't eliminate all uncertainty from medicine," London and Kimmelman said, "but they can represent the most efficient way to clarify the causal relationships clinicians hope to exploit in decisions with momentous consequences for patients and health systems."

What The Study Did: The association between angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and the severity of illness and death in patients with hypertension hospitalized for COVID-19 is examined in this study.

Authors: Aiping Deng, of the Central Hospital of Wuhan in China, is the corresponding author.

To access the embargoed study:  Visit our For The Media website at this link https://media.jamanetwork.com/ 

(doi:10.1001/jamacardio.2020.1624)

Editor's Note: Please see the articles for additional information, including other authors, author contributions and affiliations, conflicts of interest and financial disclosures, and funding and support.