Day: 03/04/2022

COVID-19 pandemic triggers 25% increase in prevalence of anxiety and depression worldwide

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Wake-up call to all countries to step up mental health services and support

In the first year of the COVID-19 pandemic, global prevalence of anxiety and depression increased by a massive 25%, according to a scientific brief released by the World Health Organization (WHO) today. The brief also highlights who has been most affected and summarizes the effect of the pandemic on the availability of mental health services and how this has changed during the pandemic.

Concerns about potential increases in mental health conditions had already prompted 90% of countries surveyed to include mental health and psychosocial support in their COVID-19 response plans, but major gaps and concerns remain.

“The information we have now about the impact of COVID-19 on the world’s mental health is just the tip of the iceberg,” said Dr Tedros Adhanom Ghebreyesus, WHO Director-General. “This is a wake-up call to all countries to pay more attention to mental health and do a better job of supporting their populations’ mental health.”

Multiple stress factors

One major explanation for the increase is the unprecedented stress caused by the social isolation resulting from the pandemic. Linked to this were constraints on people’s ability to work, seek support from loved ones and engage in their communities.

Loneliness, fear of infection, suffering and death for oneself and for loved ones, grief after bereavement and financial worries have also all been cited as stressors leading to anxiety and depression. Among health workers, exhaustion has been a major trigger for suicidal thinking.

Young people and women worst hit

The brief, which is informed by a comprehensive review of existing evidence about the impact of COVID-19 on mental health and mental health services, and includes estimates from the latest Global Burden of Disease study, shows that the pandemic has affected the mental health of young people and that they are disproportionally at risk of suicidal and self-harming behaviours. It also indicates that women have been more severely impacted than men and that people with pre-existing physical health conditions, such as asthma, cancer and heart disease, were more likely to develop symptoms of mental disorders.

Data suggests that people with pre-existing mental disorders do not appear to be disproportionately vulnerable to COVID-19 infection. Yet, when these people do become infected, they are more likely to suffer hospitalization, severe illness and death compared with people without mental disorders. People with more severe mental disorders, such as psychoses, and young people with mental disorders, are particularly at risk.

Gaps in care

This increase in the prevalence of mental health problems has coincided with severe disruptions to mental health services, leaving huge gaps in care for those who need it most. For much of the pandemic, services for mental, neurological and substance use conditions were the most disrupted among all essential health services reported by WHO Member States. Many countries also reported major disruptions in life-saving services for mental health, including for suicide prevention.

By the end of 2021 the situation had somewhat improved but today too many people remain unable to get the care and support they need for both pre-existing and newly developed mental health conditions.

Unable to access face-to-face care, many people have sought support online, signaling an urgent need to make reliable and effective digital tools available and easily accessible. However, developing and deploying digital interventions remains a major challenge in resource-limited countries and settings.

WHO and country action

Since the early days of the pandemic, WHO and partners have worked to develop and disseminate resources in multiple languages and formats to help different groups cope with and respond to the mental health impacts of COVID-19. For example, WHO produced a story book for 6-11-year-olds, My Hero is You, now available in 142 languages and 61 multimedia adaptations, as well as a toolkit for supporting older adults available in 16 languages.

At the same time, the Organization has worked with partners, including other United Nations agencies, international nongovernmental organizations and the Red Cross and Red Crescent Societies, to lead an interagency mental health and psychosocial response to COVID-19. Throughout the pandemic, WHO  has also worked to promote the integration of mental health and psychosocial support across and within all aspects of the global response. 

WHO Member States have recognized the impact of COVID-19 on mental health and are taking action. WHO’s most recent pulse survey on continuity of essential health services indicated that 90% of countries are working to provide mental health and psychosocial support to COVID-19 patients and responders alike. Moreover, at last year’s World Health Assembly, countries emphasized the need to develop and strengthen mental health and psychosocial support services as part of strengthening preparedness, response and resilience to COVID-19 and future public health emergencies. They adopted the updated Comprehensive Mental Health Action Plan 2013-2030, which includes an indicator on preparedness for mental health and psychosocial support in public health emergencies.

Step up investment

However, this commitment to mental health needs to be accompanied by a global step up in investment. Unfortunately, the situation underscores a chronic global shortage of mental health resources that continues today. WHO’s most recent Mental Health Atlas showed that in 2020, governments worldwide spent on average just over 2% of their health budgets on mental health and many low-income countries reported having fewer than 1 mental health worker per 100 000 people.

Dévora Kestel, Director of the Department of Mental Health and Substance Use at WHO, sums up the situation: ”While the pandemic has generated interest in and concern for mental health, it has also revealed historical under-investment in mental health services. Countries must act urgently to ensure that mental health support is available to all.”

Covid-19: Sanofi and GSK to seek regulatory authorisation for protein based vaccine

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Sanofi and GlaxoSmithKline’s covid-19 vaccine has 57.9% (95% confidence interval 26.5% to 76.7%) efficacy against any symptomatic disease, the companies have reported.

In a phase 3 trial in which more than 10 000 adults were randomised to receive two doses of the vaccine or placebo, 21 days apart, researchers found it to have 100% efficacy against severe disease and hospital admission (0 v 10 cases in placebo group after one dose, 0 v 4 cases after two doses) and 75% efficacy against moderate or severe disease (3 v 11 cases).

Early data has also indicated 77% efficacy against any symptomatic disease associated with the delta variant, French drug company Sanofi has said. So far, details of the trial have been released only through press release, although the companies said full study results will be published later this year.

Thomas Triomphe, executive vice president of Sanofi vaccines, said, “No other global phase 3 efficacy study has been undertaken during this period with so many variants of concern, including omicron, and these efficacy data are similar to the recent clinical data from authorised vaccines.”

The protein based vaccine can be kept at refrigerator temperatures, making it easier to store and transport than some of the other vaccines, such as the mRNA vaccines (Pfizer-BioNTech and Moderna), which require shipping and long term storage at −20°C or lower.

Melanie Saville, executive director of vaccine research and development at the Coalition for Epidemic Preparedness Innovations (CEPI), told The BMJ, “Protein based vaccines like GSK-Sanofi’s updated candidate offer a new era in the global covid-19 vaccination effort … Protein based candidates may generate different immunological profiles from other covid-19 vaccine approaches, which may have a favourable profile in certain demographics, like the elderly or young populations. These vaccines are generally well tolerated.”

She added that as the vaccine is stable at refrigerator temperatures, “it doesn’t require the complex cold chains that have limited the use of other covid-19 vaccines in remote or low resource settings” and should reduce vaccine waste globally.

In a separate trial, the vaccine was tested as a booster dose for people who had previously had two doses of an mRNA or adenovirus vaccine (such as Oxford-AstraZeneca). The booster dose was found to increase neutralising antibodies 18-fold to 30-fold across different vaccine platforms and age groups.

Across both studies, the vaccine was well tolerated in younger and older adults with no safety concerns, the press release said.

The companies are now in discussions with regulatory authorities, including the US Food and Drug Administration and European Medicines Agency, and plan to submit for regulatory authorisation shortly.

GSK vaccines president, Roger Connor, said, “The evolving epidemiology of covid-19 demonstrates the need for a variety of vaccines. Our adjuvanted protein based vaccine candidate uses a well established approach that has been applied widely to prevent infection with other viruses, including pandemic flu. We are confident that this vaccine can have an important role as we continue to address this pandemic and prepare for the post-pandemic period.”

New Studies Support Wuhan Market as Pandemic’s Origin Point

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The reports’ authors say that the novel coronavirus, or SARS-CoV-2, jumped from animals sold at the market to people twice in late 2019—but some scientists want more definitive evidence

New Studies Support Wuhan Market as Pandemic's Origin Point
View of Wuhan Huanan Wholesale Seafood Market before its closure in Hankou, Wuhan city, central China’s Hubei province, 31 December 2019. C

Scientists have released three studies that reveal intriguing new clues about how the COVID-19 pandemic started. Two of the reports trace the outbreak back to a massive market that sold live animals, among other goods, in Wuhan, China and a third suggests that the coronavirus SARS-CoV-2 spilled over from animals—possibly those sold at the market—into humans at least twice in November or December 2019. Posted on 25 and 26 February, all three are preprints, and so have not been published in a peer-reviewed journal.

These analyses add weight to original suspicions that the pandemic began at the Huanan Seafood Wholesale Market, which many of the people who were infected earliest with SARS-CoV-2 had visited. The preprints contain genetic analyses of coronavirus samples collected from the market and from people infected in December 2019 and January 2020, as well as geolocation analyses connecting these samples to a section of the market where live animals were sold. Taken together, these different lines of evidence point towards the market as the source of the outbreak—much like animal markets were ground zero for the severe acute respiratory syndrome (SARS) epidemic of 2002–2004—says Kristian Andersen, a virologist at the Scripps Research Institute in La Jolla, California, and an author on two of the reports. “This is extremely strong evidence,” he says.

Still, none of the studies contain definitive evidence about what type of animal might have harbored the virus before it spread to humans. Andersen speculates that the culprits could be raccoon dogs, a squat dog-like mammal used for food and for their fur in China. One of the studies he coauthored suggests that raccoon dogs were sold in a section of the market where several positive samples were collected. And reports show that the animals are capable of harboring other types of coronaviruses.ADVERTISEMENT

Some virologists say that the new evidence pointing to the Huanan market doesn’t rule out an alternative hypothesis. Namely, they say that the market could have just been the location of a massive amplifying event, in which an infected person spread the virus to many other people, rather than the place of the original spillover.

“Analysis-wise, this is excellent work, but it remains open to interpretation,” says Vincent Munster, a virologist at the Rocky Mountain Laboratories, a division of the National Institutes of Health, in Hamilton, Montana. He says searching for SARS-CoV-2 and antibodies against it in blood samples collected from animals sold at the market, and from people who sold animals at the market, could provide more definitive evidence of COVID-19’s origins. The number of positive samples from the market suggests an animal source, Munster says. But he is frustrated that more thorough investigations haven’t already been conducted: “We are talking about a pandemic that has upended the lives of so many people.”

GROUND ZERO?

In early January 2020, Chinese authorities identified the Huanan market as a potential source of a viral outbreak because the majority of people infected with COVID-19 at that time had been there in the days before they began to show symptoms, or were in contact with people who had. Hoping to stem the outbreak, Chinese authorities shuttered the market. Then researchers collected samples from poultry, snakes, badgers, giant salamanders, Siamese crocodiles and other animals sold there. They also swabbed drains, cages, toilets and vendor stalls in search of the pathogen. Following an investigation led by the World Health Organization (WHO), researchers released a report in March 2021 showing that all of the nearly 200 samples collected directly from animals were negative, but that more than 1,000 environmental samples from the stalls and other areas were positive.

A research team from China including the head of China’s Center for Disease Control and Prevention (CDC) has now genetically sequenced those positive samples, releasing the results in a preprint posted on 25 February. The scientists confirm that the samples contain SARS-CoV-2 sequences nearly identical to those that have been circulating in humans. Further, they show that the two original virus lineages circulating at the start of the pandemic, called A and B, were both present at the market.

“It’s a nice piece of work,” says Ray Yip, an epidemiologist who is a former director of the China branch of the US Centers for Disease Control and Prevention. “They’ve confirmed that the Huanan market was indeed a very important spreading location.”ADVERTISEMENT

As soon as the report from China posted online, Andersen and his colleagues rushed to post the manuscripts they had been working on for weeks.

In one, the team zeroed in on the southwestern section of the Huanan market, where live animals were sold as recently as 2019, as being the potential epicentre of the outbreak. They arrived at this conclusion by compiling information on the first known COVID-19 cases in China, as reported in various places, including the WHO investigation, newspaper articles, and from audio and video recordings of doctors and patients in Wuhan. This geospatial analysis found that 156 cases in December 2019 clustered tightly around the market and then gradually became more dispersed around Wuhan in January and February 2020.

They also examined the locations of the positive samples collected in the market, as reported in the WHO study, and fleshed out information about their potential surroundings by collecting business registration information, photographs of the market before it closed, and scientific reports that have emerged since the WHO’s investigation. For example, one paper published last year documented some 47,000 animals—including 31 protected species—sold in Wuhan markets between 2017 and 2019.

In one major finding in the new preprint, Andersen and colleagues mapped five positive samples from the market to a single stall that sold live animals, and more specifically to a metal cage, to carts used to move animals, and to a machine used to remove bird feathers. One of the coauthors on the report, virologist Eddie Holmes at the University of Sydney in Australia, had been to this stall in 2014 and snapped photographs—included in this study—of a live raccoon dog in a metal cage, stacked above crates of poultry, with the whole assembly sitting atop sewer drains. Notably, in the study from the China CDC, sewage at the market tested positive for SARS-CoV-2.

In a second report, Andersen and colleagues concluded that lineage A and lineage B of SARS-CoV-2 are too different from one another on a genetic level for one to have evolved into the other quickly in humans. Therefore, they suggest that the coronavirus must have evolved within non-human animals and that the two different lineages spread to humans separately. Because lineage B was the far more prevalent variety in January 2020, among other reasons, the authors suggest that it spilled over into humans before lineage A. Other outbreaks of coronaviruses, such as the SARS and Middle East respiratory syndrome (MERS) epidemics, also resulted from repeated introductions from wildlife, the paper notes.

Taking all of the new data together, and adding a degree of speculation, Andersen suggests that raccoon dogs could have been infected on a farm that then sold the animals at the markets in Wuhan in November or December 2019, and that the virus might have jumped to people handling them, or to buyers. At least twice, those infections could have spread from an index case to other people, he says.

‘AS GOOD AS IT GETS’

Over the past year, Michael Worobey, a virologist at the University of Arizona, in Tucson, and an author on the papers with Andersen says that his thinking on the origins of COVID-19 has shifted. Back in May 2021, he led a letter published in Science in which he and other researchers pressed the scientific community to keep an open mind about whether the pandemic stemmed from a laboratory, a controversial hypothesis suggesting that SARS-CoV-2 was either created in a lab, or was accidentally or intentionally released by researchers at the Wuhan Institute of Virology. “You want to take this kind of thing seriously,” he explains.

But since May, additional evidence has come to light that supports a zoonotic origin story similar to that of HIV, Zika virus, Ebola virus and multiple influenza viruses, he says. “When you look at all of the evidence, it is clear that this started at the market,” he says. Separate lines of analysis point to it, he says, and it’s extremely improbable that two distinct lineages of SARS-CoV-2 could have been derived from a laboratory and then coincidentally ended up at the market.

Nonetheless, Munster says he is not completely convinced of two spillover events because, alternatively, the virus might have evolved from one lineage into the other within a person who was immunocompromised. He adds that more data collected from people and animals is needed to answer this question, and to show that the first spillover occurred at the Huanan market. David Relman, a microbiologist at Stanford University in California, agrees that the preprints are not definitive, and that they exclude the possibility that people were infected prior to the outbreak at the market, but went undiagnosed.

Holmes fears that additional samples from early human cases and from animals might never materialize. Last July, for example, Chinese officials said that they planned to analyse patient blood samples from 2019, stored at the Wuhan Blood Centre—but if that study has been conducted, it has yet to be made public. “This is as good as it gets,” Holmes says. “What we should focus on now is trying to keep these events from happening again.”

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A Canadian study of more than 123,000 births found no association between epidural labor analgesia exposure and an increased risk for autism spectrum disorder in children, according to findings published in JAMA Pediatrics.

Elizabeth Wall-Wieler, PhD, an assistant professor of community health services at the University of Manitoba, and colleagues conducted a longitudinal cohort study of vaginal deliveries of singleton live infants born from April 1, 2005, through March 31, 2016, from a population-based data set linking information from health care databases in Manitoba.

Source: Adobe Stock
Source: Adobe Stock

Wall-Wieler and colleagues cited a study published last year by Qui and colleagues that suggested there may be an association between epidural analgesia for vaginal delivery and autism in children.

The current study included 123,175 births, a majority of which were male infants (50.9%; 62,647). Of the total, 80,459 infants had at least one sibling. Wall-Wieler and colleagues classified a diagnoses of autism spectrum disorder (ASD) by the presence of at least one diagnosis by age 18 months. Of the total births, 47,011 infants (38.2%) were exposed to epidural labor analgesia (ELA).

By April 1, 2019, 2.1% (985 of 47,011) of infants exposed to ELA were diagnosed with ASD compared with 1.7% (1,272 of 76,164) of infants not exposed to ELA (HR = 1.25; 95% CI, 1.15-1.36), Wall-Wieler and colleagues reported. There also was no association after adjustment for perinatal covariates (inverse probability of treatment-weighted HR = 1.08; 95% CI, 0.97-1.2).

ELA-exposed offspring faced a slightly higher risk in a sibling cohort (HR = 1.25; 95% CI, 1.12-1.39).

“Our findings suggest that ELA use is not associated with an increased offspring risk of ASD,” the authors wrote.

In a related editorial, Gillian E. Hanley, PhD, a postdoctoral fellow at the University of British Columbia, and colleagues called for further research into the issue.

“Epidural labor analgesia is an extremely effective approach to obstetric analgesia, and we have a collective responsibility to understand whether it is a safe option that sets a healthy developmental pathway well into childhood,” Hanley and colleagues wrote. “Women have the right to make a truly informed choice about their pain relief during labor: for their health and that of her

BRCA mutations linked to increased risk for pancreatic, male breast, other cancers

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Pathogenic variants in BRCA1 and BRCA2 appeared associated with increased risks for prostate cancer, pancreatic cancer, male breast cancer and possibly stomach cancer, according to research published in Journal of Clinical Oncology.

Results of the international, collaborative study should enable researchers to better optimize screening and early detection strategies for both women and men with these mutations, they wrote.

Relative risk ratios.
Data derived from Li S, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02112.

“The findings suggest that in families with BRCA1 and BRCA2 mutations, relatives — men and women — should be informed about their individual cancer risk and be encouraged to be tested for BRCA1 and BRCA2,” Antonis C. Antoniou, PhD, professor of cancer risk prediction in the department of public health and primary care at University of Cambridge, told Healio.

Background

Although associations of BRCA1 and BRCA2 mutations with increased risk for breast and ovarian cancers in women have been well-documented, studies examining possible links to other cancers have been limited due to small sample sizes, resulting in imprecise estimates of cancer risk, Antoniou said.

Antonis C. Antoniou, PhD

Antonis C. Antoniou

“Having accurate risk estimates is critical for counseling of women and men with genetic faults [on] prevention and screening,” Antoniou said. “We were able to have data on the largest number of families with BRCA1 and BRCA2 genetic faults to date. That enabled us to study these links with greater precision than previously possible.”

Methodology

The analysis included data from 5,341 families in the Consortium of Investigators of Modifiers of BRCA1/2 with one or more members who had a BRCA1 (n = 3,184) or BRCA2 (n = 2,157) mutation. Antoniou and colleagues estimated age-specific relative and absolute risks for 22 first primary cancer types and adjusted for family ascertainment.

Researchers collected the following data from each adult family member for their analysis: familial relationship, BRCA1/2 pathogenic variant status, sex, year of birth, years or age at pedigree data collection, death and cancer diagnoses.

Key findings

Results showed associations of BRCA1 pathogenic variants with risks for male breast cancer (RR = 4.3; 95% CI, 1.09-16.96), pancreatic cancer (RR = 2.36; 95% CI, 1.51-3.68) and stomach cancer (RR = 2.17; 95% CI, 1.25-3.77). The data also suggested associations of these mutations with risks for colorectal and gallbladder cancers.

Researchers reported associations of BRCA2 pathogenic variants with risks for male breast cancer (RR = 44; 95% CI, 21.3-90.9), stomach cancer (RR = 3.69; 95% CI, 2.4-5.67), pancreatic cancer (RR = 3.34; 95% CI, 2.21-5.06) and prostate cancer (RR = 2.22; 95% CI, 1.63-3.03). They observed a higher RR for stomach cancer among women vs. men (6.89 vs. 2.76) but noted the small data set for this rare cancer.

Absolute risks to age 80 years ranged from 0.4% for male breast cancer to approximately 2.5% for pancreatic cancer for BRCA1 carriers, and from approximately 2.5% for pancreatic cancer to 27% for prostate cancer for BRCA2 carriers. Results showed no strong link between BRCA2 and melanoma.

“One finding, which in fact is reassuring for families, is that there was no strong link between BRCA1 and BRCA2 genetic faults and several other cancers that had been previously reported in smaller studies,” Antoniou said.

Implications

The analysis makes the link between BRCA2 and prostate and pancreatic cancer much clearer, Marc Tischkowitz, MD, PhD, professor in the department of medical genetics at University of Cambridge and researcher on the study, said in a press release.

“Overall,” he said, “the results will add to our knowledge on optimizing cancer screening and early detection strategies for people who are known to carry these faulty genes.”

Antoniou said further research to confirm the associations should be conducted among cohorts of unaffected mutation carriers with long-term follow-up.

References:

Faulty BRCA genes linked to prostate and pancreatic cancers. https://www.cam.ac.uk/research/news/faulty-brca-genes-linked-to-prostate-and-pancreatic-cancers. Published Jan. 25, 2022. Accessed Feb. 3, 2022.
Li S, et al. J Clin Oncol. 2022;doi:10.1200/JCO.21.02112.

For more information:

Antonis C. Antoniou, PhD, can be reached at Center for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge CB1 8RN, United Kingdom; email: aca20@medschl.cam.ac.uk.

PERSPECTIVE

Payal D. Shah, MD)

Payal D. Shah, MD

As a medical oncologist who counsels patients with inherited pathogenic variants in cancer susceptibility genes, I am often asked a few fundamental questions: How likely am I to develop cancer? Which cancers? When?

More than 25 years after the discovery of BRCA1 and BRCA2, the risks for female breast and ovarian cancers associated with these genes are quantitatively and qualitatively well-delineated. However, less precise data have been available characterizing other BRCA1/2-associated cancer risks. For this reason, the work by Antoniou and colleagues is incredibly informative.

The findings are in part confirmatory with respect to our current understanding of BRCA1/2-associated cancer risks: individuals with pathogenic variants in these genes have an increased risk for male breast and pancreatic cancers. Interestingly, the male breast cancer risk reported is slightly lower than what has been published previously. As it stands, the National Comprehensive Cancer Network has not been firm on mammography in male BRCA1/2 carriers due to limited supporting data, so this finding is unlikely to alter clinical practice.

The pancreatic cancer risks observed in the present study are quantitatively consistent with prior reports, although the elevated relative risk for BRCA2 carriers aged younger than 65 years is interesting. The NCCN recommends consideration of pancreatic cancer screening for individuals with BRCA1/2 pathogenic germline variants and a family history of the disease. The recommended age for screening initiation is 50 years, barring a young family diagnosis, and this recommendation seems in line with the authors’ findings of pancreatic cancer diagnoses under age 65 years.

Another valuable finding from this study is the absence of an association between BRCA1 and overall prostate cancer risk. These data may eventually contribute to the removal of prostate cancer screening as a consideration for men with BRCA1 mutations from NCCN guidelines. I think this would be fair, although it should be mentioned that for a biological male with a BRCA1 germline pathogenic variant, a prostate cancer risk estimate should incorporate other risk factors, including family history, rather than automatically defaulting to population risk.

Among the authors’ findings, I found the BRCA1/2-associated stomach cancer risk most noteworthy. Given the morbidity and mortality associated with stomach cancer, I agree with the authors’ assertion that screening of the upper gastrointestinal tract, including the full stomach in addition to the pancreas, is important in BRCA1/2 carriers. The best modality, age at initiation and frequency of this screening will need to be optimized as data emerge. The illumination of BRCA1/2-associated stomach cancer risk also highlights the significance of cascade testing of male family members.

Although this was a large study, only 3.3% of probands who reported ethnicity data were Hispanic and 1.2% were Black. This is a clear target for improvement given that in many countries, Hispanics and Blacks represent larger proportions of the overall population and are underrepresented in medical research.

Finally, it is important to note that the findings above are as robust and precise as they are due to the large sample size and ability to control for ascertainment bias. This study by Antoniou and colleagues underscores the importance of multicenter collaborations in moving forward advances in genetic syndromes, and the authors are to be congratulated for their joint efforts on this work.

Payal D. Shah, MD

University of Pennsylvania

Vaginal delivery with neuraxial analgesia lowers risk for severe maternal morbidity

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Using neuraxial analgesia in women undergoing their first vaginal delivery was associated with a reduced risk for severe maternal morbidity, according to a retrospective cross-sectional study in JAMA Network Open.

“An old study conducted in France suggested that epidural analgesia during childbirth resulted in a decreased risk of postpartum hemorrhage — the first cause of preventable maternal morbidity and mortality,” Jean Guglielminotti, MD, PhD, assistant professor of anesthesiology at Columbia University Vagelos College of Physicians and Surgeons, told Healio. “We believed it was important to replicate this study in the United States because of the advances in obstetric and anesthesia care practices during the last 15 years, and because of the marked differences in the health care systems between the United States and France.”

Data derived from Guglielminotti J, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.0137.
Data derived from Guglielminotti J, et al. JAMA Netw Open. 2022;doi:10.1001/jamanetworkopen.2022.0137.

Data collection

Guglielminotti and colleagues analyzed the medical records of 575,524 women (mean age, 28 years; 44.9% non-Hispanic white) who were hospitalized for vaginal delivery from January 2010 to December 2017 available through the New York State Inpatient Database. They noted whether patients received no anesthesia or neuraxial analgesia (47.4%), as well as the incidence of severe maternal morbidity (SMM) — defined by the CDC — and postpartum hemorrhage (PPH).

The researchers also stratified their analysis according to race and ethnicity and whether the women were at low or high risk based on the comorbidity index for obstetric patients (CMI-OB). The low-risk CMI-OB group comprised 69.6% of the study population.

Analysis of SMM risk

SMM occurred in 7,712 women (1.3%; 95% CI, 1.31-1.37), 2,748 (35.6%) of whom had PPH. In an unadjusted analysis, women with neuraxial analgesia had a lower risk of SMM compared with those who underwent labor without it (risk difference, 0.12%; 95% CI, 0.17 to 0.07). Even after the researchers adjusted their analysis, the odds remained lower for women with neuraxial analgesia (adjusted OR = 0.86; 95% CI, 0.82-0.9).

Neuraxial analgesia reduced risk of SMM similarly across high- and low-risk patients, as well as across races and ethnicities.

Jean Guglielminotti, MD, PhD

Jean Guglielminotti

“We suggest that increasing access to and utilization of epidural during childbirth, especially for racial and ethnic minority women, could be a feasible strategy to improve maternal health and reduce disparities in maternal health,” Guglielminotti said.

However, according to the researchers, the decreased risk for PPH accounted for only 21% (95% CI, 14%-28%) of the protective association between neuraxial analgesia and SMM risk.

“Other possible mechanisms [responsible for this association] may include sustained intrapartum hemodynamic monitoring of parturient women with neuraxial analgesia, which enhances maternal monitoring and early detection of blood loss immediately after delivery; adequate intravenous access and fluid resuscitation; and continuous anesthesia availability and oversight of the process of labor and delivery and preparedness for acute events,” Guglielminotti and colleagues wrote in the study.

The researchers cautioned that the study was limited by its observational design — suggesting that the associations between neuraxial analgesia and SMM are not necessarily causal — and they did not specifically assess the risk for SMM by race because of the low number of cases in some patient groups. Moreover, they said the study did not examine neuraxial techniques, lacked specific data on hospital staffing, excluded women who had an intrapartum cesarean delivery and did not account for SMM occurring after discharge.

Despite these limitations, Guglielminotti called for “more research on the effect of possible interventions to increase the use of epidural analgesia during labor.”

Reference:

Routine use of typhoid conjugate vaccine could prevent millions of cases

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Routine use of a typhoid conjugate vaccine with a catch-up campaign through age 15 years could prevent approximately 67 million cases and 826,000 deaths caused by typhoid fever over 10 years, according to a study.

WHO prequalified the first typhoid conjugate vaccine in 2018, making it accessible in areas where it is most needed, and recent evidence demonstrated its effectiveness even as Salmonella Typhi increasingly develops resistance.

Birger R, et al. Lancet Infect Dis. 2022;doi:10.1016/S1473-3099(21)00627-7.
Birger R, et al. Lancet Infect Dis. 2022;doi:10.1016/S1473-3099(21)00627-7.

Virginia E. Pitzer

“Drug resistance is a major problem for typhoid fever,” Virginia E. Pitzer, ScD, associate professor of epidemiology at the Yale School of Public Health, told Healio.

Pitzer said recently developed typhoid conjugate vaccines (TCVs) “have the potential to prevent drug-resistant typhoid fever and have been recommended by the WHO for introduction into routine immunization schedule in countries with a high incidence of typhoid fever and/or a high prevalence of drug resistance.”

“We previously analyzed the cost-effectiveness of vaccination strategies in countries eligible for GAVI support,” Pitzer said. “Here, we wanted to further emphasize the potential value of TCV introduction by estimating how many cases of drug-resistant typhoid could be prevented.”

Pitzer and colleagues predicted the burden of antimicrobial-resistant typhoid fever in 73 lower-income countries by combining output from mathematical models of typhoid transmission with estimates of antimicrobial resistance from meta-analyses. They based the effect of vaccination on forecasts of vaccine coverage.

The study showed that the introduction of routine immunization with TCV at 9 months with a catch-up campaign going up to age 15 years of age could prevent approximately two out of every three cases of drug-resistant typhoid fever and prevent approximately 67 million cases and 826,000 deaths in the 73 countries over 10 years.

Additionally, vaccination was predicted to reduce the relative prevalence of antimicrobial-resistant typhoid fever by 16% (95% prediction interval, 0-49) over 10 years following introduction.

“Vaccines have enormous potential to tackle the emergence of drug resistance by preventing people from being infected with drug-resistant strains,” Pitzer said.

FDA approves first drug-eluting contact lens

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Johnson & Johnson Vision Care announced that the FDA has approved its Acuvue Theravision with Ketotifen daily disposable contact lenses.

Each lens is made of etafilcon A material and contains 19 mcg of the antihistamine ketotifen, the company said in a press release. Already available to patients in Japan and Canada, these are the first drug-eluting contact lenses approved by the FDA.

The company stated that Acuvue Theravision with Ketotifen daily disposable lenses are “indicated for the prevention of ocular itch due to allergic conjunctivitis and provide vision correction in patients who do not have red eyes, who are suitable for contact lens wear and who do not have more than 1.00 D of astigmatism.”

Phase 3 clinical trials showed a “clinically and statistically meaningful reduction in itchy allergy eyes as quickly as 3 minutes after lens insertion and lasting up to 12 hours; however, the lens may be worn longer than 12 hours for vision correction,” according to the release.

“Ocular allergic itch in contact lens wearers may soon be an issue of the past thanks to the decision of the FDA in approving Acuvue Theravision with Ketotifen,” Brian Pall, OD, MS, FAAO, director of clinical science for Johnson & Johnson Vision Care, said in the release. “These new lenses may help keep more people in contact lenses, since they relieve allergic eye itch for up to 12 hours, without the need for allergy drops, and provide vision correction.”

J&J North American President Thomas Swinnen commented in the release: “This approval marks another significant milestone in Johnson & Johnson Vision’s legacy of rethinking what’s possible with contact lenses to meet the visual and eye health needs of people around the world.”

The company did not comment on when the lenses would be available for eye care providers to prescribe.

PERSPECTIVE

Kerry Giedd, OD, MS, FAAO)

Kerry Giedd, OD, MS, FAAO

Ketotifen and etafilcon A have independently enjoyed decades of proven, successful use in millions of eyes around the world, and now a marriage of the two brings the first drug-eluting contact lens to reality. I can’t deny this long-awaited launch of a new market category deserves a level of excitement and curiosity, and there is security in using these familiar, time-tested components with our patients. At the same time, I also can’t help but wonder if Acuvue Theravision with Ketotifen is outdated before it even hits office shelves. Although ketotifen and etafilcon A are still widely used, neither of these elicits a sense of innovation or best-in-class status in the mind of today’s clinician. Undoubtedly, this lone drug-eluting contact lens option will be appealing to patients who are highly motivated to find drop-free eye allergy relief, and, in turn, there will be a definite place for Acuvue Theravision in our practices. However, in many cases – even in patients who would prefer to not use eye drops – I’m not yet convinced that fitting a patient in Acuvue Theravision will prove to be an all-around easier or more effective approach for the eye care provider or the patient than choosing one of the many contemporary lens designs (not limited to spherical single vision lenses in a hydrogel material) along with, for example, a dose of a newer antihistamine prior to lens insertion.

It is always a win to have new tools in our toolbox to address patient symptoms and to potentially improve our patients’ contact lens wearing experience. As such, I’ll welcome this latest addition to the Acuvue family. Time will tell, but Acuvue Theravision’s ultimate value to eye care may lie in simply being the first in a new category, launched by a large, global company who has the reach to bring awareness to this new category. Acuvue Theravision will help pave the way and define a market space for better products to come.

Kerry Giedd, OD, MS, FAAO

Eola Eyes

Orlando, Fla.

Editorial Board Member

Healio.com/Optometry

WHO provides critical health care to Ukraine, neighboring countries amid war with Russia

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Russia’s invasion of Ukraine is hindering humanitarian access and disrupting medical supply chains that are critical to health care in the besieged country, according to WHO.

“As the situation evolves, that access is decreasing,” Jarno Habicht, MD, PhD, a WHO representative in Ukraine, said during a press conference.

“The sanctity and neutrality of health care … and the right to safe access to care must be respected and protected.”

The current situation is preventing WHO from providing necessary health care to Ukrainians, he said.

Some supplies were prepositioned into Ukraine prior to the conflict, including emergency supplies to 23 hospitals. However, these resources are not currently accessible, he added.

As the war continues in the country, supply shortages need to be addressed, Habicht said. There is a critical shortage of oxygen, as three oxygen plants in Ukraine have now closed, according to WHO Director General Tedros Adhanom Ghebreyesus, PhD, MSc. Moreover, shortages of other critical supplies such as insulin, hypertensive medicines and reproductive and sexual health care can result in “really grave” situations, a senior emergency officer at WHO said. The oxygen shortage will have an impact on Ukraine’s ability to treat patients with COVID-19 and other conditions. WHO is assessing how to safely transport oxygen and other supplies from neighboring countries into Ukraine, officials said.

Meanwhile, WHO officials are currently verifying reports that Russia has attacked hospitals and other health infrastructures in Ukraine, which would be a violation of international humanitarian law, according to Tedros.

“The sanctity and neutrality of health care, including of health care workers, patients, supplies, transport and facilities and the right to safe access to care, must be respected and protected,” Tedros said.

WHO said the first shipment of supplies will arrive in Poland on March 3, including supplies for trauma care and emergency surgery to meet the needs of 1,000 patients, as well as other health care supplies for 150,000 people, according to Tedros.

WHO estimates that about $45 million is needed to assist Ukraine and about $12.5 million to support neighboring countries caring for refugees.

The consequences of infectious diseases such as COVID-19 among displaced people are exploitive, according to Michael Ryan, MPH, the executive director of the WHO Health Emergencies Program. WHO has recently prioritized Ukraine to receive critical COVID-19 treatments such as antivirals.

Refugees fleeing the conflict in Ukraine “will need access to primary health care,” and attention needs to be paid to other infectious diseases such as polio and measles as well as water sanitation and hygiene, said Heather Papowitz, MD, MPH, an emergency management specialist at WHO.

Officials are also concerned about the growing need for mental health care in addition to immediate lifesaving care.

“There are civilians being broken and the health system is going to have to put them back together again,” Ryan said.

“We need further logistic support in order to be able to continue to supply the health needs of the Ukrainian system,” he added. “But increasingly, unfortunately, these health needs are moving more and more towards battle wounds and people being caught up in a horrific conflict and all of the horrific surgical consequences of that for patients all over Ukraine.”

The clinicopathological characteristics, prognosis and immune microenvironment mapping in MSI-H/MMR-D endometrial carcinomas

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Abstract
Endometrial cancer had a relatively high prevalence of MMR deficiency. MMR-D/MSI-H endometrial cancer patients are suggested to be potential beneficiaries of PD-1/PD-L1 inhibitor therapy. Here, we explored the prognostic value of MSI subtype in endometrial cancer and its correlation with immune environment. Based on expression and clinical data of 78 POLE, 123 MSI and 299 Other EC samples from the TCGA-UCEC project, we found that the MSI tumors were identified more often in early stage, had a lower age, better patient survival, enriched CD8+ T cells, and regulatory T cells and less M2 macrophages and activated dendritic cells than the Other group, and shared a relatively similar expression profile with POLE group by differential analysis. In addition, we established the immune landscape of an MMR-D endometrial cancer tissue using unbiased single-cell RNA-seq analysis of 3371 cells. By immunohistochemistry analysis, we found that the MMR-D tumors showed a higher trend of CD20+ B cells infiltration. Our study might expand our understanding of the role of immune subsets in MSI endometrial carcinomas and provide guidance of immunotherapy for endometrial cancer.

Discussion

Distinct factors affect the prognosis of endometrial cancer such as tumor type, grade and stage status [28, 29]. MMR-D subtype has been reported to be related with a good prognosis in endometrial cancer patients [14]. Moreover, promising clinical trials of immunotherapy (anti-PD-1/anti-PD-L1) indicate good response in advanced MMR-D/MSI-H EC patients [30, 31]. But the underlying mechanism between the MMR-D status and endometrial cancer patient prognosis is not well investigated and understood. In this study, we related the molecular subtype to clinical data and prognosis of EC patients based on 78 POLE, 123 MSI and 299 Other EC samples in the TCGA-UCEC project. The tumors in MSI subgroup were identified more often in early stage, had a lower age, better patient survival and enriched immune infiltrates than the Other subgroup. Besides, using the unbiased single-cell RNA-seq analysis for an MMR-D endometrial cancer tissue, an immune atlas was established.

Tumors with defects in MMR proteins indicated higher mutation frequency, and were suggested to harbor more tumor-specific neoantigens and higher lymphocytes infiltrates [24]. Here, our enrichment analysis of up-regulated genes in POLE and MSI subtype also suggested the enrichment of immune-related functions. Diversity of tumor infiltrating immune cells in tumor influences tumor development, progression, and treatment response to targeted agents. CD8+ T cells are essential for successful tumor killing. Regulatory T cells suppress anti-tumor immune response, and are usually associated with poor clinical outcomes [32]. A previous study reported that tumor-associated macrophages (TAMs) revealed a pro-tumor role in endometrial cancer [33]. Dendritic cells could be modulated by tumor cells, and thus drive immune tolerance [34]. In this study, both CD8+ T cells and regulatory T cells showed high infiltration in MSI subtype and were related with good OS. M2 macrophages and activated dendritic cells were found to be negatively correlated with MSI subtype and patient prognosis. The high infiltration of regulatory T cells might result from high neoantigens. Further investigations are necessary to clarify the exact functions of regulatory T cells and activated dendritic cells in EC.

B cells are the other major type of tumor-infiltrating lymphocytes (TILs) besides T cells. Several studies unveil that B cells suppress the progression of tumor. B cell depletion enhanced melanoma growth in mice [35]. Activation of B cells play an anti-tumor role by secreting immunoglobulins, promoting T cell response, and killing cancer cells directly [36, 37]. In this study, we tested MMR status of 98 EC patients, and identified 15 MMR-D cases. By comparing the infiltration of CD20+ B cells between 15 pairs of MMR-D and MMR-I EC tumors, we found that the MMR-D tumors showed a higher trend in the number of CD20+ B cells and that higher expression of CD20 (MS4A1) was associated with good prognosis. Two major subtypes of B cells and their versatile functions in non-small cell lung cancer have been reported [38]. Studies on B cell subtypes in EC are sparse, and the subsets and functions of B cells in the tumor microenvironment (TME) of EC remain largely unknown. We found two subtypes of B cells (follicular B cells and plasma B cells) in MMR-D EC, while the functions of different B cell subtypes necessitating further investigations to answer.

Tumors are complex ecosystems characterized by different compositions and functions of tumor-infiltrating immune cells and other stromal cells [39]. The TME characteristics plays a critical role in the responsiveness of immunotherapy [40]. Single-cell RNA-seq technology allowed for the in-depth profiling of heterogeneous immune cell populations. In this study, we provided a baseline description of the immune transcriptomes by single-cell RNA-seq analysis for an MMR-D EC tumor, which formed the basis for further examination into the role of immune subsets in endometrial carcinomas. Future studies are needed to determine the specific roles these complex immune cell types play in the regulation of EC development and progression.