A new commentary by infectious disease experts published in Annals of Internal Medicine says that, for patient safety, masking should continue in health care settings. This message, from authors at George Washington University School of Medicine and the National Institutes of Health (NIH), conflicts with a recent commentary from authors from 8 US institutions suggesting that the time for universal masking is over.
Masking has been a controversial mitigation strategy during the COVID pandemic because high-quality evidence of efficacy is lacking and because the topic has become highly politicised. Regardless, real-world experience demonstrates the effectiveness of mask-wearing in clinical settings where data shows that transmission from patient-to-staff and staff-to-patent, when both are masked, is uncommon. Since health care personnel report being driven to show up for work even when they are ill themselves, the argument in support of mask-wearing becomes even more compelling.
Those without symptoms may also transmit respiratory viruses, particularly SARS-CoV-2. While the Omicron strain has been milder, infection could still cause severe or life-threatening disease or prolonged illness if transmitted to at-risk patients, such as the elderly or immunocompromised. With the still-looming risks, now does not seem the time to take off masks in the health care setting. Instead, the authors advocate strongly for continued mask use for infection prevention.
A new study led by Yale School of Medicine scientists and published inBMChas pinpointed why some adults – by some estimates, at least 50% of the population after 75 years of age – develop hearing problems.
While congenital hearing impairment – usually presenting in childhood – result from rare mutations, hearing problems in adults are likely due to the cumulative effect of polygenic risk and environmental factors.
Recent genome-wide association studies have uncovered several risk genes that are implicated in hearing problems in adults, however some factors still have not adequately been investigated by large-scale genetic studies.
For instance, there is limited information about why hearing problems among older adults are more common, more severe, and with earlier onset in men than in women. It is uncertain how hearing-related polygenic risk translates among people of diverse ancestral backgrounds.
While environmental risk factors such as noise exposure and tobacco smoking are known to increase the risk of hearing problems, the molecular mechanisms underlying these associations are unclear.
Researchers sampled nearly 750 000 adults and identified 54 risk variants – including 12 novel variants – that could contribute to hearing problems. They also highlighted how hormonal regulation may play a role in the differences between hearing problems in men and women.
Analysing multiple ancestry groups, the researchers demonstrated that polygenic risk in hearing problems is shared across human populations. They also determined genes involved in brain development interact with sex, noise pollution, and tobacco smoking in relation to their associations with hearing problems.
“Our results support that large-scale genetic studies are useful instruments to understand the biology and the epidemiology of hearing problems in adults,” said Renato Polimanti, PhD, associate professor of psychiatry at Yale School of Medicine and senior author of the study.
Overall, the findings contribute to identifying possible molecular targets for drug development and define novel strategies to identify older adults at risk of losing their hearing.
The study could lead to changes in how older adults with hearing problems are assessed and treated. Hearing loss can impair communications, and that can result in social isolation with major health, psychosocial, and economic consequences, reducing the quality of life of those affected.
In the US, drug approval needs “substantial evidence” of effectiveness – but an investigation by The BMJ into the recent approval of the antibiotic Recarbrio from Merck suggests that these standards are being bypassed.
Recarbrio is a combination therapy made up of a new beta-lactamase inhibitor (relebactam) and a decades old Merck antibiotic (imipenem-cilastatin) to treat complicated infections. It costs $4000–$15 000 for a course, compared with a couple of hundred dollars for the generic version of Merck’s old antibiotic.
Peter Doshi, senior editor at The BMJ, describes how US Food and Drug Administration (FDA) scientists had serious doubts about its highly expensive Recarbrio but the agency approved it anyway.
Did the FDA break its own rules in approving this antibiotic, and what does this case tell us about problems within the agency, he asks?
In its FDA application, Merck submitted results from two clinical trials comparing Recarbrio with imipenem in adults with complicated urinary tract infections and in patients with complex intra-abdominal infections.
But FDA reviewers noted that Merck had studied the wrong patient population to evaluate the added benefits of the new drug, and said the trial for urinary tract infections showed that Recarbrio was as much as 21% less effective than the older, cheaper imipenem.
The FDA concluded that “these studies are not considered adequate and well-controlled.” And of a third clinical study, the FDA called it a “very small,” “difficult to interpret” “descriptive trial with no pre-specified plans for hypothesis testing.”
Yet despite all three clinical studies not providing substantial evidence of effectiveness, FDA approved Recarbrio.
“Instead of basing its decision on the clinical trials in Merck’s application, FDA’s determination of Recarbrio’s efficacy was justified on past evidence that imipenem was effective, plus – to justify the new relebactam component – in vitro (lab) studies and animal models of infection rather than evidence from human trials as required by law,” writes Doshi.
Others are concerned that Recarbrio’s approval essentially amounts to a return to a way of regulating medicines that the FDA abandoned a half century ago prior to the agency’s “substantial evidence” standard.
Doshi explains that, under specific circumstances, the Director of the Center for Drug Evaluation and Research (CDER) can waive in whole or in part the FDA’s “adequate and well-controlled studies” approval criteria. But the FDA told The BMJ ”there was no center director memo in the file” for Recarbrio.
And when The BMJ contacted Janet Woodcock, CDER Director at the time, and now the FDA’s Principal Deputy Commissioner, she said she was not aware that clinical studies showed Recarbrio did not provide substantial evidence of effectiveness.
Woodcock was also unable to confirm that approvals of new drugs require at least one clinical study of the drug itself that demonstrates substantial evidence – evidence lacking in the case of Recarbrio.
A spokesperson for CDER told The BMJ that FDA “applied regulatory flexibility” in approving Recarbrio.
It is unclear whether this regulatory flexibility enabled FDA to conclude Recarbrio had met the legal “substantial evidence” standard without “adequate and well-controlled investigations” of Recarbrio, says Doshi. FDA declined to answer the question, saying “We have no additional information to provide.”
The decline of science at the FDA has become unmanageable, argues David Ross, associate clinical professor of medicine at George Washington University, School of Medicine and Health Sciences, and former FDA medical reviewer, in a linked commentary.
He describes Recarbrio’s approval as “shocking” and says while much of the blame must go to the FDA’s reliance on industry paid user fees for around two-thirds of its annual drugs budget, “the corruption of the FDA’s scientific culture remains the primary culprit driving the deterioration of safety and effectiveness standards.”
To address this “dismal situation” he suggests tapering the FDA’s dependence on user fees and improving public access to the information received by the FDA, its reasoning, and its decisions.
“The Recarbrio approval is a sentinel event, warning of a return to an era when drug effectiveness was an afterthought,” argues Ross. “Although the FDA crowed about this approval, it would have been better advised to remember that “for a successful technology, reality must take precedence over public relations, for nature cannot be fooled,” he concludes.
With the administration of the first COVID vaccines two years ago, public health officials found an increase in cases of myocarditis, particularly among young males who had been vaccinated with mRNA vaccines. The underlying cause of these reactions remained a mystery.
Now Yale scientists have identified the immune signature of these heart inflammation cases. Published in the journal Science Immunology, their findings eliminate some of the theorised causes of the heart inflammation and point to the consequences of a slightly over-stimulated immune system.
Myocarditis is a generally mild inflammation of heart tissue which can cause scarring but is usually resolved within days. The increased incidence of myocarditis during vaccination was seen primarily in males in their teens or early 20s, who had been vaccinated with mRNA vaccines, which are designed to elicit immune responses specifically to the SARS-CoV-2 virus.
According to the Centers for Disease Control and Prevention (CDC), among males aged 12 to 17, about 22 to 36 per 100 000 experienced myocarditis within 21 days after receiving a second vaccine dose. The incidence of myocarditis was 50.1 to 64.9 cases per 100 000 after infection with the COVID virus among males in this age group.
For the new study, the Yale research team conducted a detailed analysis of immune system responses in those rare cases of myocarditis among vaccinated individuals. They found that the heart inflammation was not caused by antibodies created by the vaccine, but rather by a more generalised response involving immune cells and inflammation.
“The immune systems of these individuals get a little too revved up and over-produce cytokine and cellular responses,” said team leader Carrie Lucas, associate professor of immunobiology.
Earlier research had suggested that increasing the time between vaccination shots from four to eight weeks may reduce risk of developing myocarditis.
Lucas noted that, according to CDC findings, the risk of myocarditis is significantly greater in unvaccinated individuals who contract COVID than in the vaccinated. She emphasised that vaccination offers the best protection from COVID-related disease.
“I hope this new knowledge will enable further optimising mRNA vaccines, which, in addition to offering clear health benefits during the pandemic, have a tremendous potential to save lives across numerous future applications,” said Anis Barmada, an MD/PhD student at Yale School of Medicine, who is a co-first author of the paper with Jon Klein, also a Yale MD/PhD student.
Postmenopausal women with atherosclerosis are at higher risk of heart attacks than men of similar age, according to research presented at EACVI 2023, a scientific congress of the European Society of Cardiology (ESC), and published in European Heart Journal – Cardiovascular Imaging. Researchers used imaging techniques to examine the arteries of nearly 25 000 patients and followed them for heart attacks and death.
“The study suggests that a given burden of atherosclerosis is riskier in postmenopausal women than it is in men of that age,” said study author Dr Sophie van Rosendael of Leiden University Medical Centre. “Since atherosclerotic plaque burden is emerging as a target to decide the intensity of therapy to prevent heart attacks, the findings may impact treatment. Our results indicate that after menopause, women may need a higher dose of statins or the addition of another lipid-lowering drug. More studies are needed to confirm these findings.”
While young women do have heart attacks, in general, women develop atherosclerosis (narrowing of arteries due to plaque buildup) later in life than men and have heart attacks at an older age than men, in part because of the protective effect of oestrogen. This study examined whether the prognostic importance of atherosclerotic plaques are the same for women and men at different ages as this could be important for selecting treatments to prevent heart attacks.
The study included 24 950 patients referred for coronary computed tomography angiography (CCTA) and enrolled in the CONFIRM registry, which was conducted in six countries in North America, Europe, and Asia. CCTA is used to obtain 3D images of the arteries in the heart.
Total atherosclerotic burden was rated using the Leiden CCTA score, which incorporates the following items for each coronary segment: plaque presence (yes/no), composition (calcified, noncalcified or mixed), location, and severity of narrowing, for a final value of 0 to 42. Patients were divided into three categories previously found to predict the risk myocardial infarction: low atherosclerotic burden (0 to 5), medium (6 to 20) and high (over 20). In addition, obstructive coronary artery disease was defined as 50% narrowing or more.
The primary outcome was the difference in Leiden CCTA score between women and men of similar age. The investigators also analysed sex differences in the rates of major adverse cardiovascular events (MACE), which included all-cause death and myocardial infarction, after adjusting for age and cardiovascular risk factors (hypertension, high cholesterol, diabetes, current smoking and family history of coronary artery disease).
A total of 11 678 women (average age 58.5 years) and 13 272 men (average age 55.6 years) were followed for 3.7 years. Regarding the primary outcome, the study showed an approximately 12 year delay in the onset of coronary atherosclerosis in women: the median Leiden CCTA risk score was above zero at age 64 to 68 years in women versus 52 to 56 years in men (p<0.001). In addition, the overall plaque burden as quantified by the Leiden CCTA score was significantly lower in women, who had more non-obstructive disease.
Dr. van Rosendael said: “The results confirm the previously reported delay in the start of atherosclerosis in women. We also found that women are more likely to have non-obstructive disease. It was formerly thought that only obstructive atherosclerosis caused myocardial infarction but we now know that non-obstructive disease is also risky.”
The burden of atherosclerosis was equally predictive of MACE in premenopausal women (aged under 55 years) and men of the same age group. However, in postmenopausal women (age 55 years and older), the risk of MACE was higher than men for a given score. In postmenopausal women, compared to those with a low burden, those with a medium and high burden had 2.21-fold and 6.11-fold higher risks of MACE. While in men aged 55 years and older, compared to those with a low burden, those with a medium and high burden had 1.57-fold and 2.25-fold greater risks of MACE.
Dr van Rosendael said: “In this study, the elevated risk for women versus men was especially observed in postmenopausal women with the highest Leiden CCTA score. This could be partly because the inner diameter of coronary arteries is smaller in women, meaning that the same amount of plaque could have a larger impact on blood flow. Our findings link the known acceleration of atherosclerosis development after menopause with a significant increase in relative risk for women compared to men, despite a similar burden of atherosclerotic disease. This may have implications for the intensity of medical treatment.”
