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Orlando, Fla - Vaccination rates in the U.S. have plummeted amid COVID-19, something experts warn could lead to the next pandemic of dangerous and preventable childhood diseases. A new national survey by Orlando Health finds while the vast majority of parents (84%) believe vaccines are the best way to protect their children from infectious diseases, two-thirds are still nervous to take their kids to their pediatrician's office due to COVID-19.

"It is imperative that parents keep their routine wellness visits with their child's pediatrician," said Alix Casler, MD, a pediatrician and chair of the Department of Pediatrics for Orlando Health Physician Associates. "While we are doing as many visits as possible virtually, coming in for vaccinations is important not only for protecting your child, but also to preserve herd immunity against these terrible diseases."

Like many physicians, Casler has put protocols in place at her practice to keep patients as safe as possible. Some of these include seeing one family at a time, having patients wait in their cars rather than a waiting room and implementing COVID-19 screenings, putting patients and parents at ease and making them more likely to keep their appointments.

"All it will take is a case of measles entering our community and we will see loss of life that is completely and totally unnecessary," said Casler. "It can be hard for people to grasp just how important universal vaccinations are because they've never seen how devastating these diseases can be. Measles and whooping cough outbreaks are a thing of the past thanks to vaccines, and we'd like to keep it that way."

The survey also found that skepticism about vaccines is a major issue, with 38 percent of parents responding that they don't believe their child needs all the vaccines recommended by their pediatrician.

"The only reason that we have herd immunity against so many diseases is because upwards of 90 to 95 percent of children are vaccinated," Casler said. "Once we drop below that level, no one will be presumed safe."

It's something Cynthia Velasco worries about as her 5-year-old son AJ prepares to go to kindergarten. "He's so excited to go to what he calls 'big boy school,'" said Velasco. "And while I'm confident that the schools are doing all they can to keep students safe, it makes me nervous that his immune system has been largely untested as we were socially distant for the past several months."

Velasco says her pediatrician's office has been very helpful in reminding her when AJ is due for vaccines and ensuring they see him for a wellness visit before school starts. "Making sure that he is protected from these diseases is really important to me, and because I know our pediatrician's office is taking steps to keep their office safe, staying up to date on his vaccinations far outweighs the risk of getting sick at that appointment."

Casler says it is also very important for the whole family to get their flu shots as soon as possible this season. "The fact is that we have a safe and effective method to reduce the impact of influenza through a vaccine. We're hoping that people will be lining up to get their flu shots so we can at least take something off of the table in terms of very serious illness as the nation continues to battle this pandemic."

She is reaching out to patient families who are behind on their scheduled vaccinations to get them caught up before they go back into schools and other public places, something she says should be a priority everywhere, especially in areas hit hard by COVID-19.

CLEVELAND, Ohio (August 12, 2020)--Removal of the ovaries before natural menopause (surgical menopause) often exacerbates menopause symptoms and places women at increased risk for heart disease, osteoporosis, and cognitive decline. A new study identified the frequency of hormone therapy (HT) use and factors that determine who is more likely to use hormones after oophorectomy to manage symptoms. Study results are published online today in Menopause, the journal of The North American Menopause Society (NAMS).

Women who carry the high-risk BRCA gene may be likely to develop ovarian cancer. As a result, these women often undergo an oophorectomy to mitigate the risk. However, the preventive removal of the ovaries before a woman reaches natural menopause typically creates added problems, including severe hot flashes, sleep disturbances, mood changes, vaginal dryness, and decreased libido, in addition to potential long-term adverse effects on health.

Hormone therapy has proven to be one of the most effective means for managing these symptoms and reducing long-term risks, but its use is somewhat limited because of concerns in this population of an increased risk of breast cancer, which was shown in women with a uterus who used a combination of estrogen plus a progestin in the Women's Health Initiative trials. A new study involving nearly 800 premenopausal women who underwent a preventive oophorectomy as a result of carrying the BRCA gene sought to understand how often women use HT after surgery and what factors most influence their decision to do so.

Researchers found that 61% of study participants used HT after their oophorectomies. The clinical and demographic factors that most influenced their decision were age, education, and surgical history. In particular, women who were younger at the time of surgery, who had a higher level of education, and who had also undergone a preventive mastectomy were more likely to use HT for the management of their menopause symptoms. The researchers hope that by understanding the factors that influence women's decisions regarding therapy options, healthcare providers may be better positioned to address barriers to HT use and help improve women's overall quality of life after surgery.

Study results appear in the article "Factors associated with use of hormone therapy after preventive oophorectomy in BRCA mutation carriers."

"This study highlights some of the factors associated with hormone therapy use in younger women with BRCA gene mutations who underwent risk-reducing oophorectomy before the natural age of menopause. These findings are particularly important, given the potential long-term adverse health consequences of hormone therapy avoidance in these young women and may help clinicians individualize treatment of menopause symptoms without increasing breast cancer risk," says Dr. Stephanie Faubion, NAMS medical director.

Pregnant obese women were more at risk of experiencing early and late-onset hypertensive disorders, and that risk progressively increased in women with higher body mass indexes (BMI), according to a study led by researchers at The University of Texas Health Science Center at Houston (UTHealth).

The retrospective cohort study was recently published in Obstetrics and Gynecology.

"The link between maternal obesity and late-onset hypertensive disorders has been well studied, but our research provides good evidence that obesity also plays a role in early-onset hypertensive disorders, which occur at less than 34 weeks gestation," said Matthew J. Bicocca, MD, first author and a maternal-fetal medicine fellow in the Department of Obstetrics, Gynecology and Reproductive Sciences with McGovern Medical School at UTHealth. "Previously, early-onset hypertensive disorders were thought to be an issue with the placenta and had little to do with obesity, but this study shows us that obesity likely plays a factor as well."

Preeclampsia, which along with gestational hypertension and eclampsia make up hypertensive disorders of pregnancy, is a leading cause of maternal and perinatal mortality and morbidity, according to published research.

The UTHealth research team studied birth and infant death certificates from 14 million live births from 2014 to 2017 to evaluate the relationship between BMI at delivery and hypertensive disorders. BMI was separated into three categories: class 1 obesity (BMI 30.0-34.9), class 2 (BMI 35.0-39.9), and class 3 (BMI 40.0 or greater).

Previous research shows early-onset hypertensive disorders were associated with a fivefold increased risk of infant mortality and an increased risk of severe cardiovascular, renal, or hepatic maternal morbidities compared with late-onset disease, the authors noted.

The research team also found that increasing levels of maternal obesity were associated with progressively increased risk of both early-onset and late-onset hypertensive disorders of pregnancy. Bicocca noted the same trends occurred when patients with diabetes were excluded.

With further study, this evidence could help inform guidelines for pre-pregnancy weight and recommended weight gain in pregnant obese women.

"We used BMI at time of delivery and that is a combination of pre-pregnancy BMI and weight gain, so there's still a question of which one makes a more significant difference," Bicocca said. "Once we know that, we can adjust guidelines on optimal pre-pregnancy weight, as well as weight gain recommendations during pregnancy. We could also inform whether women in different classes of obesity need different guidelines, as currently the guidelines are the same if they are in class 1, 2, or 3."

"Early onset preeclampsia, particularly when it develops at less than 30 weeks, is life-threatening to both mother and fetus," said Baha Sibai, MD, a maternal-fetal medicine specialist with UT Physicians and McGovern Medical School and international expert in preeclampsia.

"In addition, it is a major cause of fetal origin of adult disease since infants born to these pregnancies are at increased risk of metabolic syndrome including hypertension and diabetes, as well as cardiovascular disease later in life. Moreover, the pregnant women are also at increased risk for ischemic heart disease and stroke later in life. Therefore, obesity is a leading health care problem in the U.S. that has implications for future generations," Sibai said.

"In Houston obesity is prevalent, but it is really an epidemic across the U.S. and much of the developed world. Updated guidelines would be particularly important for many women and their children," Bicocca said.

Patients with undiagnosed flu symptoms who actually had COVID-19 last winter were among thousands of undetected early cases of the disease at the beginning of this year. In a new paper in The Lancet's open-access journal EClinicalMedicine, epidemiological researchers from The University of Texas at Austin estimated COVID-19 to be far more widespread in Wuhan, China, and Seattle, Washington, weeks ahead of lockdown measures in each city.

In the U.S., about a third of the estimated undiagnosed cases were among children. The researchers also concluded that the first case of COVID-19 in Seattle may have arrived as far back as Christmas or New Year's Day.

Lauren Ancel Meyers, a professor of integrative biology and statistics and data sciences who leads the UT Austin COVID-19 Modeling Consortium, worked with her team of researchers to extrapolate the extent of the COVID-19 epidemic in Wuhan and Seattle based on retested throat swabs taken from patients who were suffering from influenza-like illnesses during January in Wuhan and during late February and early March in Seattle. When the samples were analyzed later in each city, most turned out to be flu, but some turned out to be positive for SARS-CoV-2, the virus that causes COVID-19.

"Even before we realized that COVID-19 was spreading, the data imply that there was at least one case of COVID-19 for every two cases of flu," Meyers said. "Since we knew how widespread flu was at that time, we could reasonably determine the prevalence of COVID-19."

When the Chinese government locked down Wuhan on Jan. 22, there were 422 known cases. But, extrapolating the throat-swab data across the city using a new epidemiological model, Meyers and her team found that there could have been more than 12,000 undetected symptomatic cases of COVID-19. On March 9, the week when Seattle schools closed due to the virus, researchers estimate that more than 9,000 people with flu-like symptoms had COVID-19 and that about a third of that total were children. The data do not imply that health authorities were aware of these infections, rather that they may have gone unseen during the early and uncertain stages of the pandemic.

"Given that COVID-19 appears to be overwhelmingly mild in children, our high estimate for symptomatic pediatric cases in Seattle suggests that there may have been thousands more mild cases at the time," wrote Zhanwei Du, a postdoctoral researcher in Meyers' lab and first author on the study.

According to several other studies, about half of COVID-19 cases are asymptomatic, leading researchers to believe that there may have been thousands more infected people in Wuhan and Seattle before each city's respective lockdown measures went into effect.

"We can go back and piece together the history of this pandemic using a combination of investigative techniques and modeling," Meyers said. "This helps us understand how the pandemic spread so quickly around the globe and provides insight into what we may see in the coming weeks and months."

The new technique for estimating the amount of unseen COVID-19 based on the ratio of influenza cases to COVID-19 cases has also been used to determine how many children were actually infected in each city and the pace of the early pandemic in the U.S., Meyers said.

The finding in the new paper is consistent with work that Meyers and her team have done on the virus's early spread. Using travel data, she and her team estimated how far the virus had spread and concluded that there were as many as 12,000 cases of COVID-19 in Wuhan before the lockdown.

PROVIDENCE, R.I. [Brown University] -- Across the globe, COVID-19 has infected more than 18 million people to date and has killed hundreds of thousands -- and the United States has been hit especially hard. Although the U.S. comprises just 4.2% of the global population, it accounted for approximately 33% of all reported infections by the end of April.

However, the majority of U.S. states eventually imposed stay-at-home orders, and those orders appear to have significantly slowed the spread of the disease for the nation as a whole.

These findings -- along with a state-by-state breakdown of how quickly COVID-19 spread before and after lockdown orders -- were published in the Journal of Infectious Diseases on Saturday, Aug. 1.

"Understanding the trajectory of the epidemic in the U.S. is critical, and measuring the impact of stay-at-home orders on epidemic growth offers evidence for current and future COVID-19 control and containment measures," said Mark Lurie, an associate professor of epidemiology at Brown University. "While this was not a randomized trial, and therefore we cannot establish causation, what was clear in our study is that stay-at-home orders were significantly associated with slowing epidemic growth rates."

Lurie was the lead co-author for the study as part of a team of researchers from Brown's School of Public Health and Warren Alpert School of Medicine.

The study calculated the pandemic doubling time -- the amount of time it takes for the number of cases to double -- on both a national level and for individual states. An increase in doubling time indicates a slowing pandemic.

This map highlights the percentage increase in epidemic doubling time between pre-stay-at-home order and during stay-at-home order time periods, by state.

Before the effects of widespread lockdowns became apparent -- from March 4 until April 4 -- the national pandemic doubling time was 2.68 days. This doubling time increased significantly, to an average of 15 days, in the period between April 5 and April 30. In other words, the number of cases doubled in less than three days before mitigation measures were put into place. In contrast, after mitigation measures, the number of cases took more than two weeks to double.

But while doubling time increased in all states, the rate of increase varied. On average, the 45 states with stay-at-home orders in place added about 12.27 days to their doubling time, indicating significant slowing of disease spread. Meanwhile, the five states without stay-at-home orders -- Arkansas, Iowa, Nebraska, North Dakota and South Dakota -- added only about six days to their doubling time, and four of these states exhibited some of the worst doubling rates in the nation.

"We hope that these findings contribute to a growing body of evidence aimed at studying the full course of COVID-19 in America," said Joe Silva, a Ph.D. student at Brown's School of Public Health and another lead co-author on the study. "This study does not imply stay-at-home orders were the sole factor that drove the observed increase in epidemic doubling time, but the data may be representative of the impact of multiple public health measures."

As the researchers published their findings, they did so aware that the U.S. is far from having successfully addressed the COVID-19 pandemic, he added.

"Our study period included data through the end of April, and since then cases have increased beyond what was previously thought to be the peak of the pandemic within our borders," Silva said. "During this time, states have also removed stay-at-home orders, and it will be just as important to study the potential impacts on disease spread after these measures were no longer in place."

PITTSBURGH, August 13, 2020 - Men at particular risk for HIV are very likely to consistently take prevention medication during vacations when their odds of contracting the virus are higher, according to a new study led by scientists at the University of Pittsburgh Graduate School of Public Health, The Fenway Institute and Harvard University.

The findings, published online and to be reported Saturday in the print issue of the Journal of Acquired Immune Deficiency Syndromes, indicate that short-term use of pre-exposure prophylaxis (PrEP) medication could be a highly successful way to prevent the spread of HIV in men who have sex with men and have difficulty with long-term PrEP use. It may also work to transition men to long-term PrEP use, which has been shown to be highly effective in reducing HIV transmission.

"We started this as a feasibility study to see if we could identify barriers to short-term PrEP use and make adjustments. But we were excited when we got the results and discovered that almost all the participants were adherent to the point of protection against HIV," said lead author James Egan, Ph.D., M.P.H., assistant professor of behavioral and community health sciences at Pitt Public Health. "This gives us a promising strategy to pursue in engaging at-risk men in HIV prevention efforts that work for them."

When taken as a daily pill, PrEP reduces the risk of getting HIV from sex by about 99%, according to the Centers for Disease Control and Prevention. However, adhering to a daily medication regimen doesn't work for everyone for reasons that include cost and individual concerns about the biological consequences of long-term medication.

Previous studies have shown that there are certain periods when men who have sex with men are more vulnerable to contracting HIV, including when traveling, on vacation, moving to a new city or after a break-up. Egan and his team set out to explore whether these men might be more receptive to adhering to PrEP treatment during these times.

The team followed 48 adult men from Pittsburgh or Boston who have sex with men in a pilot program to test the daily use of PrEP for 30 days that included an out-of-town vacation, with the men starting the medication seven days before the trip and continuing for at least seven days after vacation. The men were also given a brief session introducing them to the use of PrEP.

After their vacations, 94% of the men had blood concentrations protective against HIV, consistent with regular use of the medication. Almost 75% reported condomless sex during vacation, and about a third reported recreational drug use. None of the men contracted HIV during their vacation, though one of the men contracted the virus during the three-month post-vacation follow-up period when he'd had a lapse in use of PrEP associated with loss of health insurance and a move to a new city.

Additionally, 70% of the participants indicated an interest in continuing daily PrEP use long-term.

"That really stood out to us," said senior author Kenneth Mayer, M.D., medical research director at The Fenway Institute at Fenway Health in Boston and professor of medicine at Harvard. "It shows us that introducing short-term use of PrEP before a vacation could lead to longer-term use. This presents an enticing opportunity to reduce HIV transmission."

However, the scientists pointed out, the study included men who were motivated to enroll and did not address the likelihood of physicians prescribing PrEP for short-term use, the ease of obtaining PrEP for use only during vacations or the impact of the study's brief counseling on the use of PrEP.

"These are all areas that our findings suggest warrant future explorations," Egan said. "Our study tells us short-term adherence to PrEP during high-risk periods is tolerable in men who have sex with men, and that it could lead to long-term use. Now we need to determine how to make it possible in the real-world setting."

BOSTON - Adults with the chronic skin condition atopic dermatitis can rest easy in the knowledge that two topical immunosuppressant medications commonly prescribed to treat the condition do not appear to increase the risk for the most common forms of skin cancer, despite package label warnings to the contrary, researchers from Massachusetts General Hospital (MGH) found.

Looking at data on nearly 94,000 people diagnosed with dermatitis in general or more specifically atopic dermatitis -- Maryam M. Asgari, MD, MPH, Professor of Dermatology at MGH and colleagues found that patients who were prescribed topical tacrolimus or pimecrolimus did not have a greater risk for either basal cell or squamous cell carcinomas compared with patients who received prescription topical corticosteroids, the most common topical treatment for dermatitis.

Their findings are published online in JAMA Dermatology.

Tacrolimus and pimecrolimus belong to a class of drugs known as topical calcineurin inhibitors (TCI). The US Food and Drug Administration (FDA) requires that TCI medications carry a "black box" warning about increased risk for skin cancer, although previously published studies have shown conflicting results regarding the use of TCIs and skin cancer risk. The FDA has mandated long-term studies of patients with atopic dermatitis who use these products to get a better handle on their potential for increasing skin cancer risk.

"I thought that the data implicating increased skin cancer risk with TCIs was not robust, and that prompted me to get involved in studying it " Asgari said.

The MGH researchers took advantage of the comprehensive database maintained by Kaiser Permanente Northern California in Oakland, which contains integrated pharmacy and pathology data on 93,746 adults age 40 and older who were diagnosed by a clinician with atopic dermatitis or dermatitis from January 2002 through December 2013.

Since nearly all Kaiser Permanente patients use the health plan's pharmacy, Asgari and colleagues were able to determine the proportions of patients who received prescriptions for TCIs vs. topical corticosteroids, and then compared those data with pathology-verified skin cancer diagnoses.

They found that there was no association between TCI use and risk for either keratinocyte carcinomas overall, or for squamous cell or basal cell carcinomas individually. Looking at different doses, frequency, and duration of TCI use did not change the findings.

"We analyzed the data with multiple sensitivity analyses to explore the association of TCI use and skin cancer risk in detail, which revealed no association each time, so that was very reassuring" Asgari says.

COLUMBIA, Mo. - More than 380,000 babies are born prematurely in the United States each year, according to the March of Dimes. "Preemies" can be severely underweight babies and struggle to get the nutrients they need from breast milk alone, so neonatal intensive care units provide an additional milk fortifier, either in the form of cow's milk or manufactured from donor breast milk, to keep them healthy.

Now, a new research study from the University of Missouri and University College in London suggests that using a human-based milk fortifier has better health outcomes for severely underweight, premature babies compared to traditional, cow-based milk fortifiers.

Jan Sherman, a professor in the MU Sinclair School of Nursing, collaborated with Alan Lucas, a professor at University College in London, to perform a meta-analysis on various studies involving more than 450 severely underweight, premature babies in the United States, Canada and Austria who received either traditional cow-based milk fortifiers or human-based milk fortifiers.

By comparing their health outcomes, they found that the babies who were fed cow milk fortifiers were more than three times as likely to develop necrotizing enterocolitis, a life-threatening intestine disease, and more than twice as likely to develop retinopathy of prematurity, an eye disorder that can lead to blindness.

"Everyone wants what's best for these underweight, premature babies, and choosing the best type of milk fortifiers for feeding can help lead to improved health outcomes," said Sherman. "Nearly half of neonatal intensive care units in the United States, including the one at MU Children's Hospital, are already using human-based milk fortifiers. If we can reduce these cases of necrotizing enterocolitis, if we can preserve their eye sight and reduce the risk of infection, that will benefit the babies' health in the long term."

Neonatal intensive care units can use this research in evaluating the nutritional supplements they give to severely underweight, premature babies, who have a higher risk of death or disease than babies born after a full nine-month pregnancy.

"Our research is geared toward better understanding if we can avoid cow's milk fortifiers while still feeding premature infants well," said Lucas. "The most current evidence suggests that a diet with entirely human milk and enriched feeds manufactured from donated human milk will meet the nutritional needs of the baby without the potential negative health effects that can come with a cow milk fortifier."

DALLAS - Aug. 12, 2020 - In an animal model of multiple sclerosis (MS), decreasing the amount of a protein made in the liver significantly protected against development of the disease's characteristic symptoms and promoted recovery in symptomatic animals, UTSW scientists report.

The findings, published online today by Science Translational Medicine, could lead to a new treatment strategy for this neurological disease and other conditions marked by chronic inflammation.

In 1997, researchers discovered a protein secreted in the brain called Reelin. Subsequent work showed that Reelin appears to help the brain organize itself during development and assist in forming connections between brain cells during adulthood. However, as researchers learned more about Reelin, they discovered that large amounts of it are produced in the liver and that cells lining blood vessels have receptors for this protein.

A 2016 study by Joachim Herz, M.D., director of the Center for Translational Neurodegeneration Research and professor in the departments of molecular genetics, neurology and neurotherapeutics, and neuroscience at UTSW, and his colleagues showed that depleting levels of circulating Reelin protected mice from atherosclerosis. Probing deeper into the mechanism behind this phenomenon, they found that Reelin appears to regulate the production of adhesion molecules on blood vessel walls that capture circulating monocytes, a type of inflammation-inducing immune cell. When the scientists decreased Reelin in animal models, levels of these adhesion molecules also declined, preventing them from capturing monocytes and causing inflammation.

Wondering if Reelin plays a similar role in other inflammatory diseases, Herz, along with Laurent Calvier, Ph.D., an instructor in the department of molecular genetics at UTSW, and their colleagues investigated this protein's role in MS, a neurodegenerative disease that affects an estimated 2.3 million people worldwide. They started by examining blood concentrations of Reelin in patients with relapsing-remitting MS, the most common form of the disease. They found that while Reelin concentrations were about the same in patients in remission as those without the disease, concentrations were elevated in patients during relapse. These findings suggest that circulating Reelin levels might correlate with MS severity and stages, and that lowering Reelin levels might be a novel way to treat MS.

Investigating further, Herz, Calvier, and their colleagues worked with mice affected by a disease called experimental autoimmune encephalomyelitis (EAE), a condition that mimics human MS. When these animals were genetically modified so that the researchers could control Reelin production, they found that eliminating this protein substantially mitigated the disease's typical paralysis or even eliminated it altogether, in contrast to mice with normal Reelin levels. These effects appeared to stem from the lack of monocyte adhesion on the altered animals' blood vessel walls, which prevented entry into the central nervous system.

The researchers had further success preventing paralysis when unaltered animals with EAE received antibodies that inactivated Reelin. This strategy was even effective in animals that already displayed symptoms of the disease - a situation that more closely mimics human patients diagnosed with MS - reducing paralysis severity and promoting healing.

Herz and Calvier suggest that reducing immune cells' ability to accumulate and cause inflammation by altering Reelin levels could represent a new strategy for treating patients with MS, a disease for which several effective drugs exist that nevertheless can have significant side effects. Additionally, they say, reducing Reelin could alter the course of several other conditions marked by chronic inflammation, including psoriasis, Crohn's disease, and rheumatoid arthritis.

"We think we can use this intervention for a wide range of inflammatory diseases that have been difficult to therapeutically address," Herz says. "We are now in the process of testing this in animal models for these human diseases. In preparation for future human clinical trials, we are also working at humanizing a monoclonal antibody that can clear Reelin from human blood."

Herz holds the Presbyterian Village North Foundation Distinguished Chair in Alzheimer's Disease Therapeutic Research and the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer's Disease Research.

New treatment regimens for multidrug-resistant tuberculosis (MDR-TB) have shown early effectiveness in 85 percent of patients in a cohort that included many people with serious comorbidities that would have excluded them from clinical trials, according to the results of a new international study.

The results, based on observational data from a diverse cohort of patients in 17 countries, underscore the need for expanded access to the recently developed TB medicines bedaquiline and delamanid. By contrast, the historical standard of care, still in use in much of the world, has approximately 60 percent treatment efficacy globally.

The study was published July 24, 2020, in the American Journal of Respiratory and Critical Care Medicine.

"This is important evidence that these new regimens will work well for the true population suffering from this disease," said lead study author Molly Franke, associate professor of global health and social medicine in the Blavatnik Institute at Harvard Medical School.

The research was conducted as part of endTB, an international partnership with leaders from HMS, Partners In Health, Médecins Sans Frontières, Interactive Research & Development, the Institute of Tropical Medicine in Antwerp and Epicentre.

"Our findings underscore the need for urgent expanded access to these drugs," said Carole Mitnick, associate professor of global health and social medicine in the Blavatnik Institute at HMS and a co-author of the study. While recent announcements of a price reduction for bedaquiline and an expected reduction for delamanid are welcome, the researchers said, more must be done to improve treatment guidelines worldwide and to scale up treatment with these new regimens.

The need for better treatments for MDR-TB is dire. The WHO estimates that there are nearly 500,000 new cases of MDR-TB per year and that nearly 200,000 people die of the disease each year . In 2018, only one out of three patients were given an effective treatment, and only half of these were cured.

In the early 2010s, regulatory agencies approved the first new TB drugs in 50 years, bedaquiline and delamanid, offering hope for more effective and less toxic MDR-TB treatment. With the historical standard of care and some newer regimens, certain subgroups of patients, including those with HIV or hepatitis C or diabetes experience worse treatment outcomes than patients without these conditions. In addition, these conditions preclude patients from participating in clinical trials for these drugs.

It's important to examine whether these subgroups experience any benefit from the new regimens that might be observed in healthier study participants, the researchers said. They noted that only a large cohort study has the statistical power to explore these differences.

The endTB study showed that for the new regimens, early treatment response was similar for patients without serious comorbidities or other complicating factors and for those with diabetes, hepatitis C and severe drug resistance.

Patients with severe TB disease when they started treatment had worse outcomes than patients with less severe disease. Sixty-eight percent of people with severe disease had early favorable responses to the new regimen, compared to 89 percent without severe disease. Among patients with HIV coinfection, early outcomes on the new regimens were favorable in 73 percent, compared to 84 percent in those without HIV.

The results are based on an analysis of early treatment results from more than 1,000 MDR-TB patients who were enrolled in the study between April 2015 and March 2018. The study examines outcomes after 6 months in a treatment that lasts 15 months or longer. Long-term effectiveness will be measured at the end of treatment and during follow-up.

For this study, the researchers counted how many of those patients, within the first six months of treatment with regimens containing bedaquiline, delamanid, or both, experienced culture conversion, a state in which the bacteria that cause TB can no longer be found on a sample. Previous studies have shown this to be a strong predictor of successful treatment outcomes.

Confirmation with end-of-treatment outcomes will be important and more work needs to be done to ensure successful treatment in these populations, the researchers said.

"The early results from these studies offer convincing evidence that these new regimens offer a very promising alternative to the historical regimens that achieve approximately 60 percent success at end of treatment, and to other new treatments that are becoming available," said Mitnick, who is a senior researcher at Partners In Health and co-principal investigator of the clinical trials being conducted by endTB.

"We're eager to follow these patients as they progress through treatment in order to verify the effectiveness of these new regimens," she added.

Observational research makes so many important contributions to improving treatment outcomes for complex illnesses in complicated populations that it is critical to continue research efforts past the stage of clinical trials in illnesses like tuberculosis, the researchers said.

While tuberculosis has nearly disappeared in wealthier populations, it remains a critical threat in communities with fewer resources. A big part of the challenge of treating MDR-TB is finding regimens that will work in low-resource settings with complex populations that often include great diversity and many people who might be undernourished or sick with other illnesses.

The partnership is also studying the safety of the new regimens. Preliminary results suggest that side effects from the new regimen may be much less severe than those seen with the historical treatment, which has been known to cause deafness and psychosis.

"TB is well-controlled where control is easy," Mitnick said. "We need to find better ways to treat it where it's difficult."

The global reach of endTB has now provided clinicians with invaluable hands-on experience with bedaquiline and delamanid and helped change country guidelines, getting the new drugs registered for use in more than half of the17 endTB countries, the researchers said. The endTB observational study has contrinuted to changing global guidelines, including new recommendations for concomitant use of bedaquiline and delamanid and extended use of each drug.

The endTB partnership is using the same model for promoting innovation to prepare for what researchers hope will be the next change on the horizon in care for MDR-TB: all-oral, shortened regimens, which are being studied in the current phase of endTB's clinical trial. While the implementation program continues to roll out and reaches new patients, the endTB trial has enrolled 465 patients with MDR-TB in new all-oral regimens that could transform care for MDR-TB.

The all-oral regimens used in the endTB observational study and the all-oral, shortened regimens studied in the trials would be particularly helpful during international health crises like the coronavirus pandemic, the researchers noted. These all-oral regimens are much easier to deliver in routine times and especially so in times of extreme crisis that burden health systems.

"If the ongoing trials demonstrate reduced toxicity of the all-oral, shortened regimens, this is another huge benefit for their delivery in good times and bad," Mitnick said.

The project also transformed the landscape for TB trials by running in six countries (Georgia, Kazakhstan, Lesotho, Pakistan, Peru, South Africa) on four continents. This is the first time a clinical trial has taken place in some of these sites, the researchers said.

"In global health we see many vicious cycles, where poverty and lack of access to care combine to make diseases worse," Franke said. "On the other hand, bringing care delivery, training and research together the way we are in the endTB project can be a kind of virtuous cycle, where each turn of the wheel brings better care, improved health and greater well-being."

A team of researchers led by neuroscientists at Harvard Medical School has successfully used acupuncture to tame cytokine storm in mice with systemic inflammation.

In the study, published Aug. 12 in Neuron, acupuncture activated different signaling pathways that triggered either a pro-inflammatory or an anti-inflammatory response in animals with bacterially induced systemic inflammation.

Further, the team found that three factors determined how acupuncture affected response: site, intensity and timing of treatment. Where in the body the stimulation occurred, how strong it was and when the stimulation was administered yielded dramatically different effects on inflammatory markers and survival.

The team's experiments represent a critical step toward defining the neuroanatomical mechanisms underlying acupuncture and offer a roadmap for harnessing the approach for the treatment of inflammatory diseases.

The scientists caution, however, that before any therapeutic use, the observations must be confirmed in further research--in animals as well as in humans--and the optimal parameters for acupuncture stimulation must be carefully defined.

"Our findings represent an important step in ongoing efforts not only to understand the neuroanatomy of acupuncture but to identify ways to incorporate it into the treatment arsenal of inflammatory diseases, including sepsis," said study principal investigator Qiufu Ma, professor of neurobiology in the Blavatnik Institute at Harvard Medical School and a researcher at Dana-Farber Cancer Institute.

In the study, acupuncture stimulation influenced how animals coped with cytokine storm--the rapid release of large amounts of cytokines, inflammation-fueling molecules. The phenomenon has gained mainstream attention as a complication of severe COVID-19, but this aberrant immune reaction can occur in the setting of any infection and has been long known to physicians as a hallmark of sepsis, an organ-damaging, often-fatal inflammatory response to infection. Sepsis is estimated to affect 1.7 million people in the United States and 30 million people worldwide each year.

Acupuncture, rooted in traditional Chinese medicine, has recently grown more integrated into Western medicine, particularly for the treatment of chronic pain and gastrointestinal disorders. The approach involves mechanical stimulation of certain points on the body's surface--known as acupoints. The stimulation purportedly triggers nerve signaling and remotely affects the function of internal organs corresponding to specific acupoints.

Yet, the basic mechanisms underlying acupuncture's action and effect have not been fully elucidated.

The new study is an important step in mapping the neuroanatomy of acupuncture, the research team said.

As a neurobiologist who studies the fundamental mechanisms of pain, Ma has been curious about the biology of acupuncture for years. He was intrigued by a 2014 paper which showed that using acupuncture in mice could alleviate systemic inflammation by stimulating the vagal-adrenal axis--a signaling pathway in which the vagus nerve carries signals to the adrenal glands--to trigger the glands to release dopamine. Ma's curiosity was further intensified by work published in 2016 showing that vagus-nerve stimulation tamed the activity of inflammatory molecules and lessened symptoms of rheumatoid arthritis.

In the current study, researchers used electroacupuncture--a modern version of the traditional manual approach that involves the insertion of ultra-thin needles just under the skin in various areas of the body. Instead of needles, electroacupuncture uses very thin electrodes inserted into the skin and into the connective tissue, offering better control of stimulation intensities.

Building on previous research pointing to neurotransmitters' role in inflammation regulation, the researchers focused on two specific cell types known to secrete them--chromaffin cells that reside in the adrenal glands and noradrenergic neurons that are located in the peripheral nerve system and directly connected to the spleen through an abundance of nerve fibers. Chromaffin cells are the body's main producers of the stress hormones adrenaline and noradrenaline and of dopamine, while noradrenergic neurons release noradrenaline. In addition to their well-established functions, adrenaline, noradrenaline and dopamine, the researchers said, appear to play a role in inflammation response--an observation that's been borne out in previous research and is now reaffirmed in the experiments of the current study.

The team wanted to determine the precise role these nerve cells play in the inflammatory response. To do so, they used a novel genetic tool to ablate chromaffin cells or noradrenergic neurons. This allowed them to compare the response to inflammation in mice with and without these cells to determine just whether and how they were involved in modulating inflammation. The markedly different response in mice with and without such cells conclusively pinpointed these nerve cells as key regulators of inflammation.

In one set of experiments, researchers applied low-intensity electroacupuncture (0.5 milliamperes) to a specific point on the hind legs of mice with cytokine storm caused by a bacterial toxin. This stimulation activated the vagus-adrenal axis, inducing secretion of dopamine from the chromaffin cells of the adrenal glands. Animals treated this way had lower levels of three key types of inflammation-inducing cytokines and had greater survival than control mice--60 percent of acupuncture-treated animals survived, compared with 20 percent of untreated animals. Intriguingly, the researchers observed, the vagus-adrenal axis could be activated through hindlimb electroacupuncture but not from abdominal acupoints--a finding that shows the importance of acupoint selectivity in driving specific anti-inflammatory pathways.

In another experiment, the team delivered high-intensity electroacupuncture (3 milliamperes) to the same hindleg acupoint as well as to an acupoint on the abdomen of mice with sepsis. That stimulation activated noradrenergic nerve fibers in the spleen. The timing of treatment was critical, the researchers observed. High-intensity stimulation of the abdomen produced markedly different outcomes depending on when treatment occurred.

Animals treated with acupuncture immediately before they developed cytokine storm, experienced lower levels of inflammation during subsequent disease and fared better. This preventive measure of high-intensity stimulation increased survival from 20 to 80 percent. By contrast, animals that received acupuncture after disease onset and during the peak of cytokine storm experienced worse inflammation and more severe disease.

The findings demonstrate how the same stimulus could produce dramatically different results depending on location, timing and intensity.

"This observation underscores the idea that if practiced inappropriately, acupuncture could have detrimental results, which I don't think is something people necessarily appreciate," Ma said.

If borne out in further work, Ma added, the findings suggest the possibility that electroacupuncture could one day be used as a versatile treatment modality--from adjunct therapy for sepsis in the intensive care unit to more targeted treatment of site-specific inflammation, such as in inflammatory diseases of the gastrointestinal tract.

Another possible use, Ma said, would be to help modulate inflammation resulting from cancer immune therapy, which while lifesaving can sometimes trigger cytokine storm due to overstimulation of the immune system. Acupuncture is already used as part of integrative cancer treatment to help patients cope with side effects of chemotherapy and other cancer treatments.

What The Study Did: How common lupus anticoagulant (LA) positivity is in patients with COVID-19 was assessed in this observational study, which also examined the association of LA positivity with patient outcomes.

Authors: Morayma Reyes Gil, M.D., Ph.D., of Montefiore Medical Center in 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/jamanetworkopen.2020.17539)

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

New Haven, Conn. -- Mental stress and anger may have clinical implications for patients with heart failure according to a new report published in the Journal of Cardiac Failure.

Heart failure is a life-threatening cardiovascular disease in which the heart is damaged or weakened. This can lead to a reduced ejection fraction, in which the heart muscle pumps out a lower amount of blood than is typical with each contraction.

In this study of patients who had heart failure with reduced ejection fraction, the authors -- including researchers at Yale -- evaluated the effects of stress and anger on diastolic function. Diastolic function describes the ability of the heart to relax and refill between muscle contractions and is predictive of mortality risk.

For one week, participants completed daily questionnaires about their experiences of stress, anger, and negative emotions during the previous 24 hours. Participants then completed a standardized "mental stress" protocol in which they solved challenging arithmetic problems and described a recent stressful experience. Echocardiograms were performed to assess diastolic function at rest and during the stress task.

Patients who reported experiencing anger in the week prior to the laboratory mental stress protocol exhibited worse baseline resting diastolic pressure, the researchers said. Furthermore, most patients demonstrated stress-provoked changes in diastolic function, including decreased early relaxation and increased diastolic pressure.

"Mental stress is common in patients with heart failure due in part to the complexities of disease self-management, progressively worsening functional limitations, and frequent symptom exacerbations and hospitalizations," said the lead author Kristie Harris, a postdoctoral associate in cardiovascular medicine at Yale.

"We have evidence that patients who experience chronically elevated levels of stress experience a more burdensome disease course with diminished quality of life and increased risk for adverse events. Clarifying the relevant behavioral and physiological pathways is especially important in the era of COVID-19 when the typical stressors of heart failure may be further compounded by pandemic-related stressors," Harris said.

"Factors such as mental stress and anger often go unrecognized and are under-addressed," said Matthew Burg, a Yale clinical psychologist and senior author of the study. "This study contributes to the extensive literature showing that stress and anger affect clinical outcomes for patients with heart disease, adding chronic heart failure to the list that includes ischemic heart disease (narrowed arteries) and arrhythmic disease."

Burg said that while stress management and related techniques have been shown to reduce risk for adverse events among patients with ischemic heart disease (narrowed arteries), further work is needed to identify factors that increase vulnerability to the effects of stress in heart failure, and to determine whether stress management can improve outcomes for

WASHINGTON, D.C.--Despite the nation's growing reliance on emergency departments, large areas of rural America are experiencing shortages emergency physicians, according to a new emergency medicine workforce analysis in Annals of Emergency Medicine.

"The number of emergency physicians is increasing but there is a clear unmet need for emergency physicians in rural areas," said Christopher Bennett, MD, MA, assistant professor of emergency medicine at Stanford University School of Medicine and lead study author. "Policymakers and health leaders should prioritize opportunities to make sure that emergency departments across the country are led by appropriately trained and certified emergency physicians."

According to the "National Study of the Emergency Physician Workforce, 2020," the nation's rural emergency physician shortage is expected to worsen in the coming years, the authors note. Of the 48,835 clinically active emergency physicians in the United States, 92 percent (44,908) practice in urban areas with just 8 percent (3,927) practicing in rural communities, down from 10 percent in 2008.

The analysis also shows that the rural emergency physician workforce is aging. Nearly all (96 percent) of the emergency medicine residency or fellowship graduates within the last four years practice in more urban areas. Conversely, emergency physicians in rural communities tend to be closer to retirement age, with more than 70 percent having completed their medical training more than 20 years ago.
While the median age for an urban emergency physician is 50 years old, the median age in large rural communities is 58 years old and 62 years old in smaller rural communities.

Still, there are signs of growth in the specialty. As older emergency physicians prepare to leave the workforce, the nation's residency programs continue to expand. There were 4,565 residents in 145 programs in 2008, and today there are 7,940 residents in 247 programs. Nearly a third (28 percent) of practicing emergency physicians today are women--a modest increase from 22 percent in 2008.

One in five Americans lives in a rural area, and the American College of Emergency Physicians (ACEP) recognizes that action is needed to address emergency physician shortages and other challenges facing rural emergency care. This research underscores ACEP's concerns and complements a developing analysis from its Emergency Medicine Workforce Task Force that will help identify best practices, site supervision requirements, and funding mechanisms to support research, cost savings, and promotion of residency training programs with more focus on rural emergency care.

"Demand for emergency care in rural areas will remain high while emergency physician shortages in these communities continues to pose significant challenges for health systems and patients," said Dr. Bennett. "There are reasons to be optimistic about the pipeline of residents and trainees, however; we need to encourage a larger percentage of these individuals to work in rural America."

Given current events, many people are wearing face masks to protect themselves and others. But that same face mask could someday also collect useful health information. Researchers reporting in ACS' Analytical Chemistry have demonstrated that a fiber inserted into an ordinary N95 face mask can collect compounds in exhaled breath aerosols for analysis. The new method could allow screening for disease biomarkers on a large scale.

Exhaled breath is an aerosol that contains a variety of volatile and non-volatile compounds dissolved in microdroplets. Some of these molecules could provide important health information, such as whether a person has a certain disease, or how their body metabolizes medications they're taking. Mass spectrometry is a sensitive technique that can help identify these compounds. But first, sufficient amounts of the molecules must be collected, which often requires tedious procedures such as breathing into a tube or bag. Bin Hu and colleagues wondered if they could find a way to use face masks, which many people are wearing anyway, to collect and concentrate compounds exhaled in breath for later mass spectrometry analysis.

To test their idea, the researchers clipped a solid-phase microextraction (SPME) fiber inside an N95 face mask. SPME fibers have been used previously to extract compounds from breath collected by other methods. Volunteers performed many different activities, including eating a banana or garlic, smoking a cigarette or drinking a cup of coffee. Then, the volunteers wore the masks for 2 hours, and the researchers removed the SPME fibers and analyzed them by mass spectrometry. For each activity, the researchers detected specific compounds, even some that were present at trace amounts: for example, volatile sulfur compounds from eating garlic, nicotine from smoking and caffeine from drinking coffee. The researchers hope that the method will inspire biomarker studies for respiratory illnesses that require people to wear masks in everyday life.