Body

BOSTON - A team led by researchers at Massachusetts General Hospital (MGH) has taken an important step forward in the goal of developing a potential treatment for non-alcoholic fatty liver disease (NAFLD), the most common form of chronic liver disease. There are currently no approved medications for NAFLD, but in a study published in the journal JCI Insight on August 20, 2020, investigators conducted a genetic analysis that has identified how one promising therapy may work to improve the adverse effects of this increasingly prevalent health threat.

NAFLD is an umbrella term for a spectrum of conditions that begin with a build-up of liver fat, which can set the stage for inflammation that may promote scarring known as fibrosis. Over time, fibrosis can progress to potentially fatal cirrhosis and even a form of liver cancer called hepatocellular carcinoma (HCC). Between 30 and 40 percent of adults in the United States have NAFLD, and the incidence appears to be rising.

Last year, a team led by endocrinologist Steven Grinspoon, MD, chief of the MGH Metabolism Unit, published a randomized controlled study in Lancet HIV showing that the drug tesamorelin (Egrifta) reduced liver fat and fibrosis progression in patients with HIV, who have an increased risk for NAFLD.

Tesamorelin is approved by the Food and Drug Administration (FDA) for treating excess abdominal fat in HIV-infected people, but how the drug might improve critical features of NAFLD was unknown. In collaboration with colleagues at the Harvard T.H. Chan School of Public Health and the Broad Institute, as well as with collaborators at the National Institutes of Health (NIH), Grinspoon and his team decided to find out.

Using a technique called gene set enrichment analysis (GSEA), Grinspoon and his colleagues studied liver biopsy specimens from participants in the Lancet HIV study, half of whom received tesamorelin, while the others got inactive placebos. GSEA revealed that the drug appeared to increase expression of a set of genes that are associated with burning of fat in the mitochondria--the "furnaces" in cells that play a key role in energy metabolism. In turn, increased expression of key oxidative phosphorylation genes was associated with reduced expression of fibrosis genes. "Increasing oxidative phosphyloration may be a key process by which tesamorelin reduces fat in the liver and ultimately prevents progression of fibrosis," says Grinspoon.

What's more, the study revealed that genes associated with inflammation were relatively silenced, or downregulated, in patients treated with tesamorelin compared with placebo. Likewise, genes associated with cell repair and cell division were also downregulated. "That's likely beneficial," explains Grinspoon, noting that the body may over-respond to inflammation with collagen deposits that promote fibrosis. Moreover, a high rate of cell division could increase the risk for HCC. While it's unknown whether tesamorelin prevents liver cancer, genes associated with a favorable prognosis of HCC were upregulated in patients given the drug.

The MGH group is conducting additional studies with tesamorelin in both HIV and non-HIV patients. "This treatment strategy has effects on critical NAFLD pathways that could alter the milieu of the liver in a positive way in non-HIV patients, as well," says Grinspoon.

New Rochelle, NY, August 26, 2020--Across the U.S., COVID-19 and HIV diagnoses are lowest in primarily white counties. They follow the same pattern, with diagnoses decreasing as the population of white residents in these counties increases, according to a Commentary in AIDS Patient Care and STDs, a peer-reviewed journal from Mary Ann Liebert, Inc., publishers. Click here to read the article.

"This commentary documents differing HIV and COVID-19 outcomes and service delivery by race/ethnicity and the crucial role of racial segregation," state Gregorio Millett and coauthors from Foundation for AIDS Research (amfAR). "There are multiple factors that contribute to greater COVID-19 burden in communities of color, but all stem from systemic racism.

August 26, 2020 - For patients with elongated labia, vague terms like "vaginal rejuvenation" and "designer vagina" can undermine the seriousness of the condition, which includes a variety of functional concerns. Often attributed to congenital causes, exogenous hormones, chronic irritation, childbirth, aging and external physical causes, women at nearly every age, from birth to later adulthood, have symptoms such as tugging, twisting, urinary tract infections, personal hygiene issues, dyspareunia, pain during exercise, exposure in clothing and deviation of urine stream.

For an increasing number of women who seek to alleviate these symptoms, labiaplasty, a surgical procedure that was performed more than 11,000 times in 2019 according to the American Society of Plastic Surgeons, can provide significant improvement in quality of life.

Given the persistent controversy and the limited number of prospective outcome studies looking at improvement of specific symptoms through surgery, Heather Furnas, MD, FACS, and colleagues performed a study featured in the September issue of Plastic and Reconstructive Surgery®, the official medical journal of the American Society of Plastic Surgeons (ASPS), to measure the degree of change in the incidence of specific, pre-existing functional and appearance-related symptoms after a labiaplasty.

In the prospective study, 62 women (ranging in age from 17 to 61 with an average age of 33 years) undergoing labiaplasty completed a questionnaire about symptoms related to excess vaginal tissue before the procedure in 2016-17, and again at follow-up in 2019.

The study revealed that before surgery, all of the women had at least one of 11 symptoms commonly reported by labiaplasty patients. The most common symptom was feeling self-conscious about their appearance, reported by 93.5 percent of women. Other common symptoms included problems with intimacy, including tugging during intercourse (66.1 percent); and difficulties with clothing, including twisting in tight pants (58.1 percent).

Other common symptoms included feeling less attractive and negative effects on self-esteem. Overall, the women reported on average of 6.5 symptoms per patient. Most patients (82.2 percent) had a trim labiaplasty, wherein the excess part of labia minora is removed and sutured so that it is symmetrical with the labia majora, and the rest (17.7 percent) had a wedge, wherein a partial thickness wedge is removed from the thickest part of the labia minora.

"The decision to perform a trim or a wedge labiaplasty was a mutual decision made after a discussion with the patient about the anatomic characteristics of her labia minora and clitoral hood and according to her goals," Dr. Furnas and colleagues wrote. "The discussion covered pigmentation, thickness of each labium, roughness of the mucosa, asymmetry, and morphology of the clitoral hood."

"Patients wishing for rough, textured and darkly pigmented mucosa to be removed or for the central lamina to be thinned chose the trim approach," according to the study. "Patients generally chose a wedge when the mucosa along the edge of the labia had qualities they wished to maintain."

The preoperative survey indicated that all patients had at least 1 of 11 specific symptoms. After surgery, 58 of the 62 patients (93.5 percent) were symptom-free. Nearly all patients were self-conscious (93 percent), and afterwards only 6.5 percent reported the same issue. Preoperatively, 66.1 percent experienced tugging with intercourse and an equal 66.1 percent felt less attractive; both symptoms were eliminated after surgery.

Over half of patients surveyed experienced a negative impact on self-esteem (64.5 percent) and intimacy (62.9 percent), which dropped to 1.6 and 0 percent respectfully; twisting in clothing (58.1 percent) dropped to 3.2 percent; tight pants being uncomfortable (56.5 percent) dropped to 4.8 percent; and restriction of clothing choice (54.8 percent) dropped to 3.2 percent. In addition, the 46.8 percent with visibility in tight exercise clothing dropped to 1.6 percent; the 43.5 percent experiencing pain with intercourse dropped to 1.6 percent; and the 38.7 percent noting exposure in a bathing suit dropped to 1.6 percent after surgery.

The new study is one of the few to track changes in individual symptoms from before to after labiaplasty, showing positive effects on a wide range of physical and psychosocial symptoms. "Our paper establishes the dramatic quality-of-life benefits of labiaplasty," Dr Furnas comments. "It provides new evidence that the current, common recommendation of nonsurgical treatments is inadequate to improve women's symptoms related to excess vaginal tissue."

HOUSTON -- For patients with non-small cell lung cancers (NSCLC) marked by RET gene fusions, the targeted therapy selpercatinib was well tolerated and achieved durable objective responses, or tumor shrinkage, in the majority of participants in the Phase I/II LIBRETTO-001 trial, according to researchers from The University of Texas MD Anderson Cancer Center.

Among previously untreated patients, the objective response rate (ORR) was 85%, and those receiving at least prior platinum-based chemotherapy had an ORR of 64%. For patients with brain metastases, there was a 91% ORR in the brain.

Results from LIBRETTO-001, published today in the New England Journal of Medicine, led to the approval of selpercatinib in May by the Food and Drug Administration for RET-altered lung and thyroid cancers.

"Genome-guided precision oncology has altered the landscape of multiple kinase-driven tumors, with lung cancer being the poster child. However, we previously did not have any drug approved specifically for RET-fusion positive non-small cell lung cancer," said senior author Vivek Subbiah, M.D., associate professor of Investigational Cancer Therapeutics. "Moving from the first-in-human Phase I trial to FDA approval in less than three years is a testament to the fact that patients benefited a great deal from this treatment and had no effective options."

Evaluating selective RET inhibitor to answer significant unmet need

RET fusions occur when a portion of the chromosome containing the RET gene breaks and rejoins with another piece of chromosome, creating a fusion protein capable of fueling cancer growth. RET alterations occur in roughly 2% of NSCLC, 10-20% of papillary thyroid cancers (PTC) and the vast majority of medullary thyroid cancers (MTC). Up to half of all RET fusion-positive cancers metastasize to the brain.

Several targeted therapies, such as cabozantinib and vandetanib, have ancillary activity against RET alterations, but clinical trials found that NSCLC patients saw only limited benefit from these drugs, explained Subbiah, who is co-principal investigator of the trial.

The study reports findings from 144 patients with advanced NSCLC enrolled on the open-label, international trial. The primary endpoint was ORR assessed by an independent review committee, and secondary endpoints included safety, intracranial response, duration of response, and progression-free survival (PFS). Results from investigator assessments were not significantly different from that of independent reviewers.

The trial included previously untreated patients (39) and patients having received at least platinum-based chemotherapy (105). Previously treated patients had a median of three prior lines of therapy, including immune checkpoint blockade in more than half. Across both cohorts, trial participants were 57.6% Caucasian, 32.6% Asian, 5.6% Black, 2.8% other and 1.4% unknown. The median age was 61, with women accounting for 58.3% and men 41.7% of participants.

Among previously treated patients, 2% had a complete response, 62% had a partial response and 29% had stable disease. The median duration of response was 17.5 months and 63% of responses were ongoing at a median follow-up of 12 months. Median PFS was 16.5 months.

In previously untreated patients, 85% had a partial response and 10% had stable disease. At six months, 90% of responses were ongoing, and neither median duration of response nor median PFS has been reached at the time of analysis.

On the study, 11 patients had measurable brain metastases. Ten of these patients (91%) saw an objective response in the brain, including three complete responses. The median duration of CNS response was 10.1 months.

The most common adverse events of grade 3 or higher were hypertension (14%), increased aminotransferase (13%), increased aspartate aminotransferase (10%), hyponatremia (6%) and lymphopenia (6%). Four patients discontinued selpercatinib treatment due to treatment-related adverse events.

Strong response also reported in patients with thyroid cancers

In additional cohorts of LIBRETTO-001, selpercatinib also showed activity in RET-altered thyroid cancers, including MTC with RET mutations and papillary/anaplastic thyroid cancers with RET fusions, with a similar safety profile.

Among patients with MTC, there was a 73% ORR in previously untreated patients and 69% ORR in those receiving prior targeted therapies. In patients with previously treated papillary/anaplastic thyroid cancer, the ORR was 79%. These data also were published today in New England Journal of Medicine, with Subbiah and Maria Cabanillas, M.D., professor of Endocrine Neoplasia and Hormonal Disorders, as co-senior authors.

"The data show these patients benefit from this treatment and it is safe compared with multi-kinase inhibitors and chemotherapy," said Subbiah. "The continued implementation of a robust molecular screening strategy in frontline lung and thyroid cancers with the ability to detect RET and other gene fusions will be critical for identifying patients who may benefit from specifically targeted therapies like selpercatinib."

Scientists at the University of Missouri have discovered possible biological markers that they hope could one day help identify the presence of an opioid use disorder during human pregnancy.

Cheryl S. Rosenfeld, an author on the study, said women often take opioids for pain regulation during pregnancy, including oxycodone, so it's important to understand the effects of these drugs on the fetal placenta, a temporary organ that is essential in providing nutrients from a mother to her unborn child. Rosenfeld is a professor of biomedical sciences in the College of Veterinary Medicine, investigator in the Christopher S. Bond Life Sciences Center and research faculty member in the Thompson Center for Autism and Neurodevelopmental Disorders.

According to the Centers for Disease Control and Prevention, the number of pregnant women diagnosed with an opioid use disorder has quadrupled between 1999 and 2014.

"Many pregnant women are being prescribed opioids -- in particular OxyContin, or oxycodone -- to help with the pain they can experience during pregnancy, and this can lead to opioid use disorders," Rosenfeld said. "Many women also don't want to admit to taking these drugs, and we know that children born from mothers who have taken opioids during pregnancy experience post-birth conditions, such as low-birth weight. But, so far no one has studied the potential ramifications of opioid use during fetal life. Thus, we focused on the placenta because it is the main communication organ between the mother and her unborn child."

Previous studies examining these effects have used human cell cultures, but this is one of the first studies to use an animal model to examine how developmental exposure to these drugs affect the conceptus. In the study, Rosenfeld and her colleagues focused on how a mother's use of oxycodone during her pregnancy can affect a mouse's placenta. Mouse and human placentas are similar in many ways, including having placenta-specific cells in direct contact with a mother's blood. They found the use of this drug during pregnancy can negatively affect the placenta's structure, such as reducing and killing cells that produce by-products needed for normal brain development. In addition, Rosenfeld said their findings show specific differences in genetic expressions between female and male placentas in response to maternal oxycodone exposure.

"Our results show when mothers take oxycodone during pregnancy, it causes severe placental disruptions, including elevation of certain gene expressions," Rosenfeld said. "We know what the normal levels should be and if there are any changes, then we know something might have triggered such effects. For instance, in response to material oxycodone exposure, female placentas start increasing production of key genes essential in regulating material physiology. However, in male placentas, we see some of these same genes are reduced in expression. These expression patterns could be potential biomarkers for detecting exposure to oxycodone use."

Rosenfeld said by studying this in an animal model, it allows scientists to see these changes quicker than if they were completing a comparable study in people, because a pregnant mouse can give birth in 21 days compared to about nine months in people.

"This also allows us to easily study other regions of the body, especially the brain of exposed offspring, that would be affected by taking these opioids," Rosenfeld said. "We can then use this information to help epidemiologists identify behaviors that people should be looking at in children whose mothers have taken these opioids."

Rosenfeld suggests that opioids should be added to other widely discussed warning factors during pregnancy, such as smoking and drinking alcohol. She said short-term use of opioids by pregnant women, such as someone who has kidney stones, might not cause much of an effect on their pregnancy, but that likely depends on when the mother is taking the drug while pregnant. Future plans for this study include analyzing how offspring are affected once they are born.

Rosenfeld's research is an example of an early step in translational medicine, or research that aims to improve human health by determining the relevance of animal science discoveries to people. This research can provide the foundation for precision medicine, or personalized human health care. Precision medicine will be a key component of the NextGen Precision Health Initiative -- the University of Missouri System's top priority -- by helping to accelerate medical breakthroughs for both patients in Missouri and beyond.

In one out of 100,000 infants, a mutation in the GALC gene causes an incurable, always fatal disorder known as infantile Krabbe disease, or globoid cell leukodystrophy. Most children with the condition die before they turn 2.

A parallel condition also naturally affects dogs, who typically show symptoms of the disease at six weeks old and succumb to it within a few months. A study in the Journal of Clinical Investigation (JCI), led by the School of Veterinary Medicine's Charles Vite, describes an effective gene therapy for Krabbe disease in dogs with lasting impact. Dogs that received the treatment have lived to 4 years of age and beyond with no significant symptoms. The work highlights the potential for a similar treatment approach in children.

"This disease has no good therapy," says Vite, a professor of neurology and senior author on the new work. "We've been looking at this disease in dogs since the 1990s, but it was really the shift over to a new gene therapy vector that gave us a chance to treat it with a big effect on the nervous system."

Krabbe disease is among a group of conditions known as lysosomal storage diseases, characterized by a buildup of materials in small containers called lysosomes within cells. Normally, the GALC gene encodes an enzyme that breaks down lipids in the body. In Krabbe disease, the mutated GALC causes lipids to build up, resulting in deformed growth of the lipid-containing coating of nerve cells, the myelin sheath, leading to impaired nerve cell signaling. As a result, children with Krabbe disease experience progressive neurological symptoms, including blindness, deafness, and paralysis.

A bone marrow transplant within the first month of life can prevent symptoms from arising in about 30% of infants, but the procedure is exceedingly risky. "A new treatment is really needed," Vite says.

Krabbe disease was one of the first pediatric genetic diseases for which a parallel inherited disorder was found in dogs. Canines with the condition are part of Penn Vet's Referral Center for Animal Models of Human Genetic Disease, allowing for the investigation of new therapies.

To blunt the effects of the disease, the researchers knew that getting a healthy version of the GALC gene to the brain was crucial. They were able to make progress in doing so by using a particular vector to deliver GALC gene, the AAV9 vector, which has been used effectively in experimental gene therapies for other neurological diseases and appears the best candidate for FDA approval.

The site of delivery was also important. "We decided we would inject into the spinal fluid via the back of the head, which is the most effective means of getting to the brain," says Vite.

The researchers used both a high and low dose of the gene therapy, administering it to dogs that were two weeks old, before symptoms appear, or six weeks old, after neurological symptoms had begun to emerge.

Vite and colleagues were concerned that simply delivering a normal copy of GALC might not fully alleviate the condition's symptoms, which result in part due to the buildup of a toxic compound called psychosine from the errant metabolism of the mutant GALC enzyme. But the team was excited by the dramatic results.

Dogs that received the high dose gene therapy before the onset of symptoms not only had healthy myelination in their brains, but the gene therapy also maintained myelination of the peripheral nervous system. "That was a huge surprise for us," Vite says. "That injecting a gene therapy in the spinal fluid can positively affect both the central and the peripheral nervous system was really exciting." These dogs have also lived symptom-free for upward of four years.

Even dogs treated after they began to show symptoms lived significantly longer with the therapy than without it. The lower dose of gene therapy, however, resulted in an intermediate form of the disease, underscoring the importance of pinpointing the correct dose when translating the findings to children.

Allison Bradbury, Vite's former postdoctoral researcher and the lead author on the JCI paper, is now an investigator at Nationwide Children's Hospital and will be following up on the work to understand how psychosine levels are tamped down by the therapy throughout the body.

Vite's group, meanwhile, hopes to determine how differences in size and biology between dogs and children can be used to identify an effective dose for both.

And given the effect of the therapy the team observed in the peripheral nerves, Vite is energized by the prospects of such an approach not only in Krabbe disease but in other diseases that involve the peripheral nervous system.

"The hope is to use the model as a method to understand the mechanisms at work in peripheral nerves and how we can target peripheral neuropathies," says Vite.

Sophia Antipolis, France -26 Aug 2020: Many believe that lying down for a snooze is a harmless activity. But today, scientists show that drifting off for more than one hour could be risky. The study is presented at ESC Congress 2020.1

"Daytime napping is common all over the world and is generally considered a healthy habit," said study author Dr. Zhe Pan of Guangzhou Medical University, China. "A common view is that napping improves performance and counteracts the negative consequences of 'sleep debt'. Our study challenges these widely held opinions."

Previous research on the link between daytime naps and death or cardiovascular disease has produced conflicting results. In addition, it did not account for the duration of night-time sleep.

This study summarised the available evidence to assess the relationship between napping and the risks of all-cause death and cardiovascular disease. A total of 313,651 participants from more than 20 studies were included in the analysis. Some 39% of participants took naps.

The analysis found that long naps (more than 60 mins) were associated with a 30% greater risk of all-cause death and 34% higher likelihood of cardiovascular disease compared to no napping. When night-time sleep was taken into account, long naps were linked with an elevated risk of death only in those who slept more than six hours per night.

Overall, naps of any length were linked with a 19% elevated risk of death. The connection was more pronounced in women, who had a 22% greater likelihood of death with napping compared to no napping, and older participants, whose risk rose by 17% with naps.

Short naps (less than 60 minutes) were not risky for developing cardiovascular disease. Dr. Pan said: "The results suggest that shorter naps (especially those less than 30 to 45 minutes) might improve heart health in people who sleep insufficiently at night."

The reasons why napping affects the body are still uncertain, said Dr. Pan, but some studies have suggested that long snoozes are linked with higher levels of inflammation, which is risky for heart health and longevity. Other research has connected napping with high blood pressure, diabetes, and poor overall physical health.

He concluded: "If you want to take a siesta, our study indicates it's safest to keep it under an hour. For those of us not in the habit of a daytime slumber, there is no convincing evidence to start."

More frequent seizures during the menstrual cycle in women with genetic generalized epilepsy have been linked for the first time to drug-resistant epilepsy, when anti-seizure medications don't work, according to a Rutgers coauthored study that may help lead to tailored treatments.

Women with a form of genetic generalized epilepsy called catamenial epilepsy - when seizure frequency increases during their menstrual cycle - were nearly four times more likely to have drug-resistant epilepsy than women who experience no changes in frequency, according to the study in the journal Neurology. This association was found in two independent samples.

"Typically, genetic generalized epilepsy is thought to respond better to anti-seizure medications than focal epilepsy. However, previous studies suggest a minority of individuals, between 18 percent and 36 percent, with genetic generalized epilepsy do not respond well to these medications," said senior author Gary A. Heiman, an associate professor in the Department of Genetics in the School of Arts and Sciences at Rutgers University-New Brunswick. "It is unclear why seizures in these individuals do not respond well, and we sought to investigate why. We found a surprising association between women's menstrual cycle and those with drug-resistant genetic generalized epilepsy. Understanding the reasons for this association could lead to alternative, personalized treatment options for at least some patients."

In generalized epilepsy, seizures begin on both sides of the brain, while focal epilepsy seizures start in only one part of the brain.

In 2015, about 3.4 million people, including 470,000 children, had epilepsy in the United States, according to the U.S. Centers for Disease Control and Prevention. Anti-seizure drugs limit the spread of seizures in the brain and work for about two-thirds of people with epilepsy. Other options include surgery.

The study included 589 patients with or without drug-resistant genetic generalized epilepsy at Columbia Comprehensive Epilepsy Center and 66 patients at Yale Comprehensive Epilepsy Center. The goal was to develop and validate a model for predicting generalized epilepsy that resists drug treatment.

Such models may allow healthcare professionals to identify patients who may benefit from more aggressive or different kinds of treatment.

"Women whose seizures increase during their menstrual cycle and have drug-resistant genetic generalized epilepsy may represent a homogeneous group with a specific cause," Heiman said. "Genetic and treatment studies of these women could uncover the reason, and tailored treatment could be developed. Although our study sample is one of the largest to date and found in two independent samples, further investigation using larger sample sizes is required."

ROCHESTER, Minn. - Heart patients who undergo percutaneous coronary intervention (PCI) or stent placement? nonsurgical procedures to improve blood flow to the heart - are typically prescribed anti-platelet therapy to avoid blood clots that can lead to a heart attack or stroke. New research from the international TAILOR-PCI trial, the largest pharmacogenetics clinical trial in cardiology, suggests that genetic testing could potentially be a useful tool to help select antiplatelet medication. Pharmacogenetics is the use of a patient's genetic makeup in prescribing treatments that are likely to be most successful.

The trial, led by Naveen Pereira, M.D., and Michael Farkouh, M.D., is published in JAMA. Dr. Pereira is a cardiovascular disease specialist at Mayo Clinic and Dr. Farkouh is a cardiologist from the Peter Munk Cardiac Centre, University Health Network. The trial originated from a Mayo Clinic study catalyzed by Mayo Clinic's Center for Individualized Medicine and Department of Cardiovascular Diseases in 2012.

Clopidogrel is the most commonly used antiplatelet drug, but about 30% of Americans carry variants in the CYP2C19 gene, which interfere with the metabolism of clopidogrel. These patients are in a high-risk category due to their genetic makeup, but they can be identified with a simple point-of-care genetic test. Patients who have the CYP2C19 gene variants may be good candidates for alternative anti-platelet therapy.

The trial focused on people with the loss of function CYP2C19 gene variants who underwent percutaneous coronary intervention to see if genotype-guided therapy in that group would be more beneficial than giving clopidogrel to all. Mayo Clinic was the clinical coordinating center and data coordinating center for the five-year clinical trial, which spanned 40 centers in Canada, Mexico, South Korea and the U.S. The data coordinating center was led by Kent Bailey, Ph.D., a Mayo Clinic statistician, and the chair of the steering committee was Charanjit Rihal, M.D., a Mayo Clinic interventional cardiologist.

The trial enrolled 5,302 patients who had been treated for artery blockage with one or more stents, and followed them for one year. Half of the group was randomized to be tested for the CYP2C19 gene variation and the carriers (35%) were treated with the alternative anti-platelet medication, ticagrelor. The remainder of the group was given clopidogrel, as was the entire other randomized half that consisted of the control group of patients who did not receive genetic testing.

The results showed a statistically not significant 34% reduction in blood clotting events in the loss of function CYP2C19 gene carrier patients assigned to ticagrelor in the genotype-guided group. The loss of function CYP2C19 gene carrier patients that received clopidogrel showed a 5.9% event rate versus a 4.4% event rate in those who received genotype-guided ticagrelor treatment. The study narrowly missed its statistical goal, which was a 50% reduction in blood clotting events.

"Although these results fell short of the effect size that we predicted, they nevertheless provide a signal that offers support for the benefit of genetic testing, with approximately one-third fewer adverse events in the patients who received genetically guided treatment, compared with those who did not," says Dr. Pereira.

Dr. Pereira explains that the standard of care following coronary angioplasty and stent placement has evolved and greatly improved since the study was designed in 2012. The advent of drug-coated stents and other medical treatments improved care by reducing the expected rate of adverse events for patients in a year, but at the same time made it more difficult for the trial to reach its goal. The National Heart, Lung and Blood Institute has funded an extended follow-up study of TAILOR-PCI to determine if genetic-guided treatment will benefit longer-term outcomes.

The trial was positioned for patient evaluation at one year and just missed statistical significance. However, data at the three-month mark hold important implications for pharmacogenetics. In the first three months after the procedure, TAILOR-PCI showed an 80% risk reduction in patients with the CYP2C19 gene variation who were given ticagrelor. Furthermore, when evaluating the total number of events experienced per patient, genetic-guided treatment showed a statistically significant 40% reduction in events, compared to those who received standard treatment.

"Clopidogrel offers many advantages, but for those who can't metabolize the drug, this trial demonstrates the potential effectiveness of a personalized medicine approach," says Dr. Farkouh. "For patients who do not have a loss of function variation, it may be cost-effective to use clopidogrel, as it's widely available and has a favorable safety profile. We plan to report a cost-effective analysis in a separate manuscript."

"TAILOR PCI represents an important public-private partnership in advancing science and therapeutics for the benefit of patients. We will continue to seek more follow-up data and ascertain clinical endpoints," says Dr. Rihal.

"The TAILOR-PCI trial is an example of the rigorous testing needed to explore personalized, genetic-guided treatment and whether it can improve patients' outcomes," says Yves Rosenberg, M.D. "The results suggest potential value of a personalized, pharmacogenomic approach to the management of patients with heart disease undergoing coronary stenting." Dr. Rosenberg leads the National Heart, Lung, and Blood Institute's Atherothrombosis and Coronary Artery Disease Branch and is a co-author on the study.

Patients hospitalized with COVID-19 who had a combination of high blood pressure, obesity and diabetes were over three times more likely to die from the disease, according to a new Tulane University study.

The study, published in the journal Diabetes Care, is the first to look at the impact of metabolic syndrome on outcomes for COVID-19 patients. Metabolic syndrome is a cluster of at least three of five conditions -- hypertension, high blood sugar, obesity, high triglycerides and low HDL cholesterol -- that increases risk for cardiovascular disease.

"Together, obesity, diabetes and pre-diabetes, high blood pressure and abnormal cholesterol levels are all predictive of higher incidents of death in these patients. The more of these diagnoses that you have, the worse the outcomes," said lead author Dr. Joshua Denson, assistant professor of medicine and pulmonary and critical care medicine physician at Tulane University School of Medicine. "The underlying inflammation that is seen with metabolic syndrome may be the driver that is leading to these more severe cases."

Researchers followed outcomes for 287 patients hospitalized for COVID-19 at Tulane Medical Center and University Medical Center New Orleans from March 30 to April 5, which was at the peak of the pandemic in New Orleans. More than 85 percent of patients in the study identified as non-Hispanic Black. The mean age was 61 years old and almost 57 percent were women.

The most common conditions were hypertension (80%), obesity (65%), diabetes (54%), and low HDL (39%).

Researchers looked at two groups -- those diagnosed with metabolic syndrome and those who weren't. They tracked outcomes including if patients were admitted to an intensive care unit, placed on a ventilator, developed acute respiratory distress syndrome (ARDS) or died from the disease.

Almost 66% of the patients in the study had metabolic syndrome. When these cases were compared with patients without the condition, 56% vs 24% required the ICU, 48% vs 18% required a ventilator, 37% vs 11% developed ARDS, and 26% vs 10% died.

Importantly, after accounting for age, sex, race, hospital location, and other conditions, the patients with metabolic syndrome were 3.4 times more likely to die from COVID-19 than those who didn't have the condition. These patients were also nearly five times more likely to be admitted to an ICU, need a ventilator, or develop ARDS.

The study didn't find an increase in mortality for patients when only one of the conditions clustered with metabolic syndrome were examined alone. However, being obese or having diabetes was associated with increased odds of ICU admission and being put on a ventilator.

"Metabolic syndrome should be considered a composite predictor of COVID-19 lethal outcome, increasing the odds of mortality by the combined effects of its individual components," Denson said.

He would advise anyone who meets the criteria for metabolic syndrome to be vigilant in taking measures to reduce risk or exposure to the coronavirus.

"It doesn't matter if you're young or old -- we took that into account," he said. "You really should be extra careful. I would say it should impact both preventing your exposures and, if you end up getting sick, you should probably see your doctor sooner."

Radiotherapy is a cornerstone of today's cancer treatment. About half of all people suffering from cancer with a so-called radiotherapy. For this, patients are usually irradiated daily for several weeks. Although this therapy contributes to healing in many people, others hardly benefit from it at all. The precise causes for these differences are unclear.

Using genetic testing methods, a team led by Prof. Sven Rottenberg from the University of Bern and in close cooperation with the Netherlands Cancer Institute in Amsterdam has now identified genes that play an important role in this process.

"For many cancer patients, their relatives and treating physicians, it is incredibly frustrating when there is no success after a painstaking radiotherapy that takes weeks," said Rottenberg. "We hope that our findings contribute to better predicting the chance of therapy success." The findings can also be used to develop new drugs that could improve the efficacy of radiotherapy. The results of the study have been published in the Cell Reports journal.

Key genes for therapeutic success

The aim of radiation therapy is to damage the DNA of the cancer cells, i.e. their blueprint. This contains mutations that cause uncontrolled growth. The tumor growth is to be stopped by destroying the cancer cells' DNA. But like all cells in our body, cancer cells also have the tools to repair this DNA damage. There are fundamental differences between individual cancer patients' tumors as to which tools are available. These are related to the genes that encrypt the information for these tools. Rottenberg's researchers used genetic screening to investigate the cancer cells' self-repair. In the process, they encountered crucial weaknesses: If certain repair genes are missing in cancer cells, they are unable to repair themselves after irradiation. The researchers were able to prove this in an animal model as well as in human cells. If these genes are missing, there is therefore a good chance that the radiotherapy will be successful. "Our findings show the importance of personalized cancer therapy that takes the genetic predisposition of the people affected into account," said Rottenberg.

It's widely known that the causative agent for COVID-19, the SARS-CoV-2 virus, can spread rapidly among residents in nursing homes and other long-term care facilities, leading to high numbers of cases and deaths in a very vulnerable population. According to a new study led by researchers at Johns Hopkins Medicine, residents receiving hemodialysis for chronic kidney disease may be at even greater risk for infection from the virus.

The finding was reported in the Aug. 14, 2020, issue of the Morbidity and Mortality Weekly Report, published by the U.S. Centers for Disease Control and Prevention (CDC).

For their study, the researchers investigated an outbreak of COVID-19 that occurred in April 2020 in a 200-bed Maryland nursing home with an independently operated, on-site hemodialysis center. Of the 170 residents at the facility, 32 received dialysis treatment between April 16 and April 30. By the end of the study period, testing for exposure to SARS-CoV-2 was conducted on all but three of the residents (they refused and were counted as negative).

The researchers reported that 15 of the 32 residents (47%) on dialysis tested positive while only 22 of the other 138 residents (16%) did.

"Based on our results, we believe that nursing home residents undergoing dialysis are more likely than others in a facility to have repeated and prolonged exposures to the SARS-CoV-2 virus, and therefore may be at greater risk of infection and subsequent COVID-19," says Benjamin Bigelow, a fourth-year medical student at the Johns Hopkins University School of Medicine and the study's lead author.

"Our study suggests that to prevent COVID-19 outbreaks, nursing homes and dialysis centers need to maintain clear and constant communication to improve infection prevention practices throughout the process of transporting residents to dialysis and during the dialysis itself," says Morgan Katz, M.D., M.H.S., assistant professor of medicine at the Johns Hopkins University School of Medicine and senior author of the study. "Residents who undergo dialysis should be carefully monitored, and testing prioritization must account for any contact with dialysis staff who may have been exposed to SARS-CoV-2."

"Identifying cases early, along with aggressive infection prevention and control, are the keys to protecting those in nursing homes with chronic kidney disease and who are most at risk during the pandemic," she adds.

Scientists have launched a number of human milk and lactation studies to determine if SARS-CoV-2 can be transmitted to infants through human milk. Three scientists, including one from Washington University in St. Louis, wrote a new perspective article in the American Journal of Human Biology making the case for human milk studies co-created with the people whose milk is under investigation -- and where study findings are interpreted in the context of real-life choices and experiences.

"It is not easy to conduct human milk research during a pandemic," said E.A. Quinn, associate professor of biological anthropology in Arts & Sciences and a co-author of the new article. She leads the Biomarkers and Milk Research Lab at Washington University. "Yet, despite the consistent lack of quality evidence for transmission of viral RNA from breast milk, some leaders are pushing ahead by altering public health and clinical practice guidance."

"Breastfeeding and human milk are critical to maternal and infant health outcomes, especially during public health emergencies," said Aunchalee Palmquist, corresponding author and a medical anthropologist and assistant professor in the Department of Maternal and Child Health and the Carolina Global Breastfeeding Institute at the Gillings School of Global Public Health at the University of North Carolina, Chapel Hill.

"Unequivocal recommendations to disrupt lactation due to COVID-19 reveal a blatant disregard of the potential harms that hang in the balance for parents and infants," the authors wrote.

Co-author Ifeyinwa Asiodu, a nurse scientist and assistant professor in the Department of Family Health Care Nursing at the University of California, San Francisco School of Nursing, concurs.

"Current WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) recommendations are supportive of breastfeeding, chestfeeding and expressing human milk," Asiodu said. "Given the current science, we know that the utilization of donor human milk is also safe as coronavirus is inactivated by pasteurization techniques conducted at HMBANA (Human Milk Banking of North America milk banks. Any mixed messages may further exacerbate disparities and inequities experienced by Black, Indigenous, People of Color (BlPOC) communities."

Testing challenges

Since COVID-19 emerged, scientists around the world have scrambled to initiate new human milk studies and publish case reports, an effort the authors describe as a "liquid gold rush."

When research focuses on milk as a separate entity, the question becomes: 'Are women a risk to their milk?'

In published work, 50 COVID-19-positive individuals have had their milk tested, although some individuals have donated multiple samples over the course of infection.

Scientists have only found viral RNA in a small percentage of those samples, and repeat milk samples from the same individuals did not consistently yield identifiable viral RNA.

Complicating these efforts, the actual act of collecting milk samples for these kinds of studies also is difficult, given high risk of samples becoming contaminated through droplets in the air, skin or surfaces and containers.

"People seem drawn to fetishizing human milk as something discreet from lactation," Quinn said. "In reality, while the majority of mothers in the United States do express milk for their infants, most lactating individuals feed their infants directly."

"The way in which the research is constructed is, 'Is there infectious potential of the milk?'" she said. "It focuses on the milk as a separate entity, not as part of the relationship between a breastfeeding mother and baby.

"So the question becomes: 'Are women a risk to their milk?' Nobody has really demonstrated that," Quinn said.

Racial equity issues

The WHO has issued guidance that says that COVID-19 presents no reason to avoid or stop breastfeeding.

But certain influential global health and health-care authorities have subsequently put forth recommendations that contradict the WHO guidance. And these recommendations have the potential to impact certain people more than others.

"The science used to support hospital-based perinatal separation policies for COVID-19, including strongly advising against breastfeeding or provision of human milk with SARS-CoV-2 infection, are disproportionately harming BlPOC populations," Palmquist said. "So, when we see that there are racial/ethnic disparities in breastfeeding outcomes as a result of COVID-19, we need to recognize that structural racism affects everything in pandemics from bench science to bedside practice."

"During this public health crisis, we need evidence-based recommendations and consistent messaging that centers the health and well-being of women and lactating people, their infants and families," Asiodu said. "Human milk research is important; however, it needs to be conducted with a racial equity and reproductive justice lens."

An international team led by Professor Tian Hui from Peking University has recently measured the global magnetic field of the solar corona for the first time. The team used observations from the Coronal Multi-channel Polarimeter, an instrument designed by Dr. Steve Tomczyk at the National Center for Atmospheric Research, USA. Their results have been recently published in the magazines of Science and Science China Technological Sciences. Yang Zihao, a first-year graduate student at Peking University, is the first author of both papers.

The Sun is a magnetized star, and its magnetic field plays a critical role in shaping the solar atmosphere. The 11-year solar cycle, the spectacular solar eruptions and the million-degree solar corona are all driven or governed by the evolution of the solar magnetic field. Due to the magnetic coupling of different atmospheric layers, information on the magnetic field of the whole atmosphere is required to study the interplay between the solar plasma and magnetic field. However, routine measurements of the solar magnetic field have only been achieved at the photospheric level (solar surface). More than one century has passed since the first measurement of the solar magnetic field, we still do not have a precise knowledge of the magnetic field in the upper solar atmosphere, especially the corona, which impedes our complete understanding of the solar magnetism and its interaction with the solar plasma.

More than 20 years ago, a technique called coronal seismology or magnetoseismology has been introduced for coronal magnetic field diagnostics. This method makes use of magnetohydrodynamic (MHD) oscillations or waves that are observed in coronal loops or other coronal structures. From the MHD theory, the observed wave parameters can be used to infer the average magnitudes of the magnetic field in the oscillating structures. However, these oscillations/waves are just occasionally observed in small regions of the corona, and thus their potential for magnetic field diagnostics is limited.

CoMP is a coronagraph with a 20-cm aperture. Using the Fe XIII 1074.7 nm and 1079.8 nm infrared spectral lines, it can observe the solar corona in the range of about 1.05 to 1.35 solar radii from the solar center through imaging spectroscopy and spectropolarimetry. The Doppler image sequence obtained from CoMP observations often reveal the prevalence of propagating periodic disturbances, indicating the ubiquitous presence of transverse MHD waves in the corona. The team has successfully applied the magnetoseismology method to these pervasive waves. They have extended the previously developed wave-tracking technique to the whole field of view, and obtained the global distribution of the wave phase speed. The intensity ratio of the two Fe XIII lines is sensitive to the electron density, thus has been used to derive the global map of coronal electron density. Combing the wave-tracking and density diagnostic results, they have successfully mapped the magnetic field in the global corona.

This is the first time that a global map of the coronal magnetic field has been obtained through actual coronal observations, thus marking a leap towards solving the problem of coronal magnetic field measurements. In principle, with this technique, global coronal magnetic field maps could now be routinely obtained, filling in the missing part of the measurements of the Sun's global magnetism. Together with simultaneously measured photospheric magnetograms, these synoptic coronal magnetograms will provide critical information to advance our understanding of the magnetic coupling between different atmospheric layers as well as the physical mechanisms responsible for solar eruptions and solar cycle.

Leesburg, VA, August 25, 2020--An open-access article in ARRS' American Journal of Roentgenology (AJR) established a foundation for the use of virtual imaging trials in effective assessment and optimization of CT and radiography acquisitions and analysis tools to help manage the coronavirus disease (COVID-19) pandemic.

Virtual imaging trials have two main components--representative models of targeted subjects and realistic models of imaging scanners--and the authors of this AJR article developed the first computational models of patients with COVID-19, while showing, as proof of principle, how they can be combined with imaging simulators for COVID-19 imaging studies.

"For the body habitus of the models," lead author Ehsan Abadi explained, "we used the 4D extended cardiac-torso (XCAT) model that was developed at Duke University."

Abadi and his Duke colleagues then segmented the morphologic features of COVID-19 abnormalities from 20 CT images of patients with multidiagnostic confirmation of SARS-CoV-2 infection and incorporated them into XCAT models.

"Within a given disease area, the texture and material of the lung parenchyma in the XCAT were modified to match the properties observed in the clinical images," Abadi et al. continued.

Using a specific CT scanner (Definition Flash, Siemens Healthineers) and validated radiography simulator (DukeSim) to help illustrate utility, the team virtually imaged three developed COVID-19 computational phantoms.

"Subjectively," the authors concluded, "the simulated abnormalities were realistic in terms of shape and texture," adding their preliminary results showed that the contrast-to-noise ratios in the abnormal regions were 1.6, 3.0, and 3.6 for 5-, 25-, and 50-mAs images, respectively.