Review: Are climate change and air pollution making neurologic diseases worse?

Peer-Reviewed Publication

AMERICAN ACADEMY OF NEUROLOGY

Review: Are Climate Change and Air Pollution Making Neurologic Diseases Worse?

MINNEAPOLIS – People with neurologic diseases like headache, dementia, multiple sclerosis (MS) and Parkinson’s disease may experience worsening symptoms due to climate change, according to a scoping review of research published in the November 16, 2022, online issue of Neurology®, the medical journal of the American Academy of Neurology. The review also found that stroke may become more prevalent due to climate change.

“Although the international community seeks to reduce global temperature rise to under 2.7 ºF before 2100, irreversible environmental changes have already occurred, and as the planet warms these changes will continue to occur,” said review author Andrew Dhawan, MD, DPhil, of Cleveland Clinic in Ohio and a member of the American Academy of Neurology. “As we witness the effects of a warming planet on human health, it is imperative that neurologists anticipate how neurologic disease may change.”

For the review, researchers looked at studies published on climate change, pollutants, temperature extremes and neurologic disease between 1990 and 2022. They identified 364 relevant studies in three categories, including 289 studies on the impact of pollution, 38 studies on extreme weather events and temperature fluctuations and 37 studies on emerging neuroinfectious diseases. They included only studies on adults, not children.

The studies highlighted the relationships between temperature variability and worsening neurologic symptoms, warming climates and tick- and mosquito-borne infections, as well as airborne pollutants and cerebrovascular disease rate and severity.

The review showed extreme weather events and temperature fluctuations were associated with stroke incidence and severity, migraine headaches, hospitalization in dementia patients, and worsening of MS.

It showed for emerging neuroinfectious diseases like West Nile virus, meningococcal meningitis and tick-borne encephalitis, climate change expanded the favorable conditions beyond the traditional geographic areas, and these diseases carried by animals and insects pose the risk of disease in new populations.

The review also showed exposure to airborne pollutants, especially nitrates and fine particulate matter, also known as PM 2.5, pollutant particles of less than 2.5 microns in diameter, was associated with stroke incidence and severity, headaches, dementia risk, Parkinson’s disease, and worsening of MS.

“Climate change poses many challenges for humanity, some of which are not well-studied,” said Dhawan. “For example, our review did not find any articles related to effects on neurologic health from food and water insecurity, yet these are clearly linked to neurologic health and climate change. More studies are needed on ways to reduce neuroinfectious disease transmission, how air pollution affects the nervous system, and how to improve delivery of neurologic care in the face of climate-related disruptions."

A limitation is that the studies were conducted in resource-rich regions of the world, suggesting that the results may not apply in regions with fewer resources where such changes may be even more likely to occur.

Learn more about brain health at BrainandLife.org, home of the American Academy of Neurology’s free patient and caregiver magazine focused on the intersection of neurologic disease and brain health. Follow Brain & Life® on Facebook, Twitter and Instagram.

When posting to social media channels about this research, we encourage you to use the hashtags #Neurology and #AANscience.

The American Academy of Neurology is the world’s largest association of neurologists and neuroscience professionals, with over 38,000 members. The AAN is dedicated to promoting the highest quality patient-centered neurologic care. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as Alzheimer’s disease, stroke, migraine, multiple sclerosis, concussion, Parkinson’s disease and epilepsy.

For more information about the American Academy of Neurology, visit AAN.com or find us on Facebook, Twitter, Instagram, LinkedIn and YouTube.

 

JOURNAL

Neurology

SUBJECT OF RESEARCH

People

ARTICLE PUBLICATION DATE

16-Nov-2022

Lung infections caused by soil fungi are a problem nationwide

Outdated maps of disease-causing fungi may lead to delayed, missed diagnoses

Peer-Reviewed Publication

WASHINGTON UNIVERSITY SCHOOL OF MEDICINE

 

IMAGE: THE FUNGUS HISTOPLASMA, WHICH CAUSES LUNG INFECTIONS, WAS CONCENTRATED IN THE MIDWEST IN THE 1950S AND 60S (TOP MAP), BUT NOW CAUSES SIGNIFICANT DISEASE THROUGHOUT MUCH OF THE COUNTRY (BOTTOM). RESEARCHERS AT WASHINGTON UNIVERSITY SCHOOL OF MEDICINE IN ST. LOUIS DISCOVERED THAT THE THREE MAIN KINDS OF SOIL FUNGI THAT CAUSE LUNG INFECTIONS HAVE ALL EXPANDED THEIR RANGES IN RECENT DECADES. RELIANCE ON OUTDATED MAPS COULD BE CAUSING DELAYED OR MISSED DIAGNOSES. view more 

CREDIT: PATRICK MAZI AND ANDREJ SPEC/WASHINGTON UNIVERSITY

Fungi in the soil cause a significant number of serious lung infections in 48 out of 50 states and the District of Columbia, including many areas long thought to be free of deadly environmental fungi, according to a study by researchers at Washington University School of Medicine in St. Louis.

Studies from the 1950s and 60s indicated that fungal lung infections were a problem only in certain parts of the country. The new study, available online in Clinical Infectious Diseases, shows that is no longer the case. Doctors who rely on outdated maps of disease-causing fungi may miss the signs of a fungal lung infection, resulting in delayed or incorrect diagnoses, the researchers said.

“Every few weeks I get a call from a doctor in the Boston area – a different doctor every time – about a case they can’t solve,” said senior author Andrej Spec, MD, an associate professor of medicine and a specialist in fungal infections. “They always start by saying, ‘We don’t have histo here, but it really kind of looks like histo.’ I say, ‘You guys call me all the time about this. You do have histo.’”

Histoplasma, or histo, is one of the three main species of soil fungi that cause lung infections in the U.S. Historically, Histoplasma was found in the Midwest and parts of the East, Coccidioides in the Southwest, and Blastomyces in the Midwest and the South. But a growing number of case reports and anecdotes suggest that all three have expanded out of their traditional ranges in recent decades, most likely due to climate change.

People develop fungal lung infections after breathing in spores from fungi in the soil. The spores become airborne when the ground is disturbed by farming, landscaping, construction or even just by people walking around in fungi-rich environments such as caves. Most healthy adults and children can fight off a fungal infection handily, but infants, older adults and people with compromised immune systems may develop fever, cough, fatigue and other symptoms. Fungal lung infections easily can be mistaken for bacterial or viral lung infections such as COVID-19, bacterial pneumonia and tuberculosis.

“People with fungal lung infection often spend weeks trying to get the right diagnosis and appropriate treatment, and the whole time they’re feeling terrible,” said lead author Patrick B. Mazi, MD, a clinical fellow in infectious diseases. “They usually have multiple health-care visits with multiple opportunities for testing and diagnosis, but the doctor just doesn’t consider a fungal infection until they’ve exhausted all other possibilities.”

Spec, Mazi and colleagues set out to determine where soil fungi are sickening people today. The Centers for Disease Control and Prevention (CDC) last revised its maps of disease-causing fungi in 1969.

The researchers calculated the number of fungal lung infections nationwide from 2007 to 2016 using Medicare fee-for-service claims from all 50 states and the District of Columbia. Using the patients’ home addresses to identify counties of residence, they calculated the number of cases per 100,000 person-years for each county. (Person-years are a way to correct for the fact that counties can have wildly different population sizes; one person on Medicare for one year is one person-year). Counties with more than 100 cases caused by Histoplasma or Coccidioides, or 50 cases caused by Blastomyces, per 100,000 person-years were defined as having a meaningful number of fungal lung infections.

Of the 3,143 counties in the U.S., 1,806 had meaningful numbers of lung infections caused by Histoplasma, 339 of Coccidioides and 547 of Blastomyces. These counties were distributed across the majority of the U.S. Across the 50 states plus DC, 94% had at least one county with a problem with Histoplasma lung infections, 69% with Coccidioides and 78% with Blastomyces.

“Fungal infections are much more common than people realize, and they’re spreading,” Spec said. “The scientific community has underinvested in studying and developing treatments for fungal infections. I think that’s beginning to change, but slowly. It’s important for the medical community to realize these fungi are essentially everywhere these days and that we need to take them seriously and include them in considering diagnoses.”

The three main species of fungi that cause lung infections in the U.S. — Histoplasma (red), Blastomyces (blue) and Coccidioides (green) — have all expanded their ranges in recent decades. These maps were created based on data from 1955 (top row) and 2007-2016 (bottom row). Reliance on outdated maps may lead to delayed or missed diagnoses.

CREDIT

Patrick Mazi and Andrej Spec/Washington University

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JOURNAL

Clinical Infectious Diseases

DOI

10.1093/cid/ciac882 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

The Geographic Distribution of Dimorphic Mycoses in the United States for the Modern Era.

ARTICLE PUBLICATION DATE

11-Nov-2022

COI STATEMENT

P.B.M., A.M.R, J.M.S., A.C.R., M.P. report no conflicts. M.A.O. reports grants, consulting fees, and personal fees from Pfizer. W.G.P. reports grants and personal fees from Merck and Co, and National Institute for Health (not directly related to this work), personal fees from Gilead Sciences. A.S. reports grants from Astellas Global Development Pharma, Inc., grants from Scynexis, grants from Cidara, grants and personal fees from Mayne Pharma. A.C.R. reports grants or contracts from Metabolic Skeletal Disorders Training Grant through the National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR060719, Funding for author PhD stipend 2020-2022 though Washington University School of Medicine) and support for attending CSHL Mechanisms of Aging Meeting 2022 (Division of Bone and Mineral Diseases, Washington University in St. Louis). M.P reports consulting fees from Clinton health Access initiative (external consulting as web developer).

More U.S. adults carrying loaded handguns daily, study finds

Peer-Reviewed Publication

UNIVERSITY OF WASHINGTON

 

IMAGE: THIS CHART SHOWS A VAST MAJORITY OF HANDGUN OWNERS REPORT CARRYING A HANDGUN FOR PROTECTION AGAINST ANOTHER PERSON. view more 

CREDIT: ROWHANI-RAHBAR ET AL./AMERICAN JOURNAL OF PUBLIC HEALTH

The number of U.S. adult handgun owners carrying a loaded handgun on their person doubled from 2015 to 2019, according to new research led by the University of Washington.

Data come from the 2019 National Firearms Survey (NFS), an online survey of U.S. adults living in households with firearms, including nearly 2,400 handgun owners. Compared to estimates from prior UW-led research, the new study suggests that in 2019 approximately 16 million adult handgun owners had carried a loaded handgun on their person in the past month (up from 9 million in 2015) and 6 million carried every day (twice as many as carried daily in 2015).

Published Nov. 16 in the American Journal of Public Health, the study also found that a larger proportion of handgun owners carried handguns in states with less restrictive carrying regulations: In these states, approximately one-third of handgun owners reported carrying in the past month, whereas in states with more restrictive regulations, only about one-fifth did.

“Between increases in the number of people who own handguns and the number of people who carry every day, there has been a striking increase in handgun carrying in the U.S.,” said lead author Dr. Ali Rowhani-Rahbar, a professor of epidemiology and Bartley Dobb Professor for the Study and Prevention of Violence at the UW.

Among the other findings reported in the new study:

• About 7 in 10 handgun owners said they carried a loaded handgun as protection against another person, dwarfing the number who said they carried as protection against an animal, for example, or for work
• 4 in 5 handgun owners who reported carrying were male, 3 in 4 were white, and a majority were between the ages of 18 and 44

Researchers pointed to some limitations of the study: Respondents were asked if they carried, and how often, but not where. It is possible that a person residing in a state with one type of permitting restrictions (or none) could have carried their handgun in another state with different laws. The study also did not ask whether the respondent carried a handgun openly or concealed.

While the data are from 2019, researchers say the findings are timely, following the U.S. Supreme Court ruling in June that struck down a New York state handgun-carrying law. States, in general, have become less restrictive over the years regarding handgun carrying — more than 20 do not require permits to carry today, compared to only one such state in 1990. The differences highlighted in this study suggest that this behavior may be responsive to the types of laws governing carrying that pertain in a state.

“The Supreme Court ruling has already resulted in some states’ loosening of laws related to handgun carrying,” Rowhani-Rahbar said. “In light of that ruling, our study reinforces the importance of studying the implications of handgun carrying for public health and public safety.”

The study was funded by the Joyce Foundation and the New Venture Fund. Co-authors were Amy Gallagher, now of the Centers for Disease Control and Prevention, previously of the Firearm Injury & Policy Research Program at the UW; Deborah Azrael of Harvard University; and Matthew Miller of Northeastern University.

For more information, contact Rowhani-Rahbar at rowhani@uw.edu.

1968

JOURNAL

American Journal of Public Health

DOI

10.2105/AJPH.2022.307094 

ARTICLE PUBLICATION DATE

16-Nov-2022

Ultrasound-guided surgery is quicker, less painful and more effective for treating early form of breast cancer

Reports and Proceedings

EUROPEAN ORGANISATION FOR RESEARCH AND TREATMENT OF CANCER

 

IMAGE: ANTONIO ESGUEVA USING IOUS TO GUIDE BREAST SURGERY view more 

CREDIT: ANTONIO ESGUEGA / EORTC

Barcelona, Spain: Using ultrasound to guide surgery for patients with ductal carcinoma in situ (DCIS) gives better results than the standard technique of using a wire inserted into the breast, according to research presented at the 13th European Breast Cancer Conference.

The technique, known as intraoperative ultrasound, or IOUS, enables surgeons to remove a smaller quantity of breast tissue, while still removing all the of DCIS tissue. Using IOUS improves the chance of having no cancer cells at the outer edge of the tissue that was removed (known as positive margins), reducing the risk of patients needing a second operation.

Because IOUS negates the need for inserting a guide wire, this technique could also reduce pain and preoperative stress for patients and save time for medical staff.

The research was carried out by a team at Clinica Universidad de Navarra in Madrid, Spain, and was presented by Dr Antonio J. Esgueva. He said: “DCIS is a common form of early breast cancer that can develop into a more serious, invasive cancer. To ensure it does not progress, patients are usually offered surgery. Because DCIS does not usually create lumps in the breast, we need a good technique to guide surgery and make it accurate as possible.”

The research involved 108 people who were diagnosed with DCIS and treated at the Clinica Universidad de Navarra between February 2018 and December 2021. Forty-one were treated with IOUS-guided surgery while 67 were treated with surgery guided by wire localisation (WL).

Following each operation, the tissue removed was analysed to see how much was removed and whether there were ‘positive margins’. This means that DCIS cells were found at the edge of the tissue removed, suggesting some DCIS cells could have been left behind and patients would probably need a second operation.

Among those treated using WL, seven (10.4%) had positive margins and needed a second operation while in those treated using IOUS, there were only two patients (4.8%) with positive margins who needed a second operation.

The patients have been followed up for a year and half so far and cancer has only recurred in one (who was treated with WL).

Dr Esgueva said: “As breast surgeons, we want to perform the very best oncological surgery in terms of removing any trace of DCIS but also removing as little of the breast tissue as possible in order to have the best cosmetic result possible. At the same time, we also want to improve patients' experience during treatment by using less invasive techniques and reducing their anxiety. Our research suggests that using intraoperative ultrasound, a quicker and less invasive technique, is effective for guiding DCIS surgery.”

The researchers plan to continue gathering information about patients having surgery for DCIS in the hopes of seeing long-term benefits of using IOUS.

Dr Laura Biganzoli is Co-Chair of the European Breast Cancer Conference and Director of the Breast Centre at Santo Stefano Hospital, Prato, Italy, and was not involved in the research. She said: "Once intervention is planned, the standard treatment for patients diagnosed with DCIS is surgery. The need for a second operation due to positive margins can be an issue. This research is promising because it shows that a kinder technique can help guide surgeons to effectively remove DCIS from the breast while minimising unwanted side-effects.”

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METHOD OF RESEARCH

Experimental study

SUBJECT OF RESEARCH

People

Rising housing cost to income ratio strongly linked to poor health, death, suicide

But state spend on unemployment and pensions can lower these risks: international study

Peer-Reviewed Publication

BMJ

The widening gap between personal disposable income and the cost of housing is strongly linked to poor health, preventable deaths, and suicide, finds an international study of developed countries accepted for publication in the Journal of Epidemiology & Community Health.

But state spend on unemployment and pensions benefits can lower these risks, as can policies such as the provision of public housing stock and rent controls, the findings indicate.

Wealthy countries have promoted home ownership through policy measures, but have paid relatively little attention to affordable housing, note the researchers.

While it’s known that unaffordable housing is associated with poor health at the personal level, it’s not clear what impact this might have at the population level, or whether social policies might alter these risks. 

In a bid to find out, the researchers drew on Organization for Economic Co-operation and Development (OECD) national stats for 27 member countries for the period 2000 to 2019, which included the global financial crisis of 2008.

The 27 countries were: Australia; Austria; Belgium; Canada; Czech Republic; Estonia; France; Finland; Germany; Greece; Hungary; Japan; Latvia; Luxembourg; Lithuania; the Netherlands; Norway; New Zealand; Poland; Portugal; Slovak Republic; Slovenia; Spain; Sweden; Switzerland; the UK; and the US.

The figures on mortality focused on avoidable deaths, classified as treatable—prevented through timely healthcare provision—and preventable—avoided through public health policy; and suicides as a proxy for ‘deaths of despair’ associated with economic hardship.

To obtain country-level data on unaffordable housing, the researchers drew on housing cost to income ratio data, to include rents; assumed rental value for owner-occupiers; and maintenance and other associated costs, as a percentage of household disposable income. 

They then looked at social spend per head of the population for each country, to include pension and unemployment benefits, healthcare, and housing.

They specifically assessed the effect of two housing policy measures on death: the size of a country’s social housing stock; and the presence of rent controls. 

Higher social housing stock was defined as more than 10% of total housing provision (5 out of the 27 countries). Rent control includes controls on initial rent charged and/or regulated and/or negotiated rents applied across rental sectors (13 out of the 27 countries).

Their analysis of all the OECD data showed that housing cost to income ratio was strongly associated with preventable and treatable deaths as well as suicide during the period following the global financial crisis (2009-17), but not in the period before (2000-08). 

The analysis also revealed that social spending on pension and unemployment benefits was  protective, lowering the death rate associated with unaffordable housing. 

In countries with higher social housing stock, the link between unaffordable housing and preventable/treatable deaths and suicide was weakened. 

Similar patterns were observed for countries with rent controls: in countries without this measure unaffordable housing was strongly linked to preventable/treatable deaths and suicide.

Unaffordable housing may affect health in various ways: by squeezing spend on good nutrition, heating, and healthcare; through psychological stress; and through unhealthy lifestyle behaviours, all of which an economic downturn, such as that experienced after the global financial crisis, is likely to worsen, suggest the researchers.

“We also demonstrated that social spending on old-age and unemployment benefits was significantly associated with lower mortality rates. This finding aligns with existing studies that social spending buffers households against economic hardship,” they point out.

Housing policy measures are also key, they add. “First, social housing for broad segments of the population appears to be associated with lower mortality risks…Second, rent controls intend to keep living costs affordable, particularly for lower income residents by limiting the amount that landlords can demand for leasing a home.

“Overall, these protective measures protect households against suffering from housing cost induced stressors.”

This is an observational study, and as such, can’t establish cause. And the researchers acknowledge various limitations to their findings. These include the inability to distinguish between different socioeconomic groups or include national housing policy changes over time.

Nevertheless, they conclude: “Our findings suggest that housing cost burden can be related to population health….  Unfortunately, since there was a growing pressure to cut back on social spending after the economic crisis, an increasing number of households are faced with [it].”

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JOURNAL

Journal of Epidemiology & Community Health

DOI

10.1136/jech-2022-219545 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

The association between housing cost burden and avoidable mortality in wealthy countries: cross-national analysis of social and housing policies, 2000-201

ARTICLE PUBLICATION DATE

16-Nov-2022

Deaths among mothers almost four times higher in Slovakia and UK than in Norway and Denmark

Analysis of eight European countries shows younger, older, and minority ethnic mothers at particular risk. Better data collection systems needed for meaningful international comparisons, say researchers

Peer-Reviewed Publication

BMJ

Despite substantial declines in deaths related to pregnancy and childbirth in high income countries in recent years, mothers in Slovakia and the UK are up to four times more likely to die during pregnancy or soon after than mothers in Norway and Denmark, finds an in-depth analysis of data from eight European countries, published by The BMJ today. 

Overall, the findings show that the youngest and oldest mothers are at particular risk, along with those born abroad or from minority ethnic backgrounds.

As such, the researchers say enhanced methods to identify, document, and review maternal deaths are needed to provide reliable maternal mortality data in high income countries.

Today's findings follow a report published last week showing that the number of women dying during pregnancy or shortly after has risen sharply in the UK and Ireland (from 8.79 women per 100,000 giving birth in 2017-19 to 10.9 per 100,000 in 2018-2020), with increases steepest in the most deprived areas.

Although maternal mortality is at historic lows in high income countries, it remains an important indicator of quality of care, health system performance, and, more specifically, maternal care. 

However, previous studies comparing countries’ maternal mortality rates have been based on government death certificate data (vital statistics), which tend to underestimate maternal deaths, and give inaccurate information about cause of death, preventing meaningful international comparisons.

In response, several countries have set up enhanced maternal mortality surveillance systems to minimise differences in how information on maternal deaths is collected, providing more reliable and comparable data between countries.

In a bid to better understand maternal mortality patterns across countries, a team of researchers compared data from eight high income countries with enhanced surveillance systems: Denmark, Finland, France, Italy, the Netherlands, Norway, Slovakia, and the UK. 

The data were taken from the International Network of Obstetric Survey Systems (INOSS), an international collaboration aiming to gather data on serious illnesses in pregnancy and childbirth. 

Data from 2013 and after were collected for a three-year period for France, Italy and the UK, and a five-year period for Denmark, Finland, the Netherlands, Norway, and Slovakia, to account for the varying number of births in each country. Data from Finland were collected from 2008 to 2012. 

Deaths at any time during pregnancy and up to one year after the end of pregnancy were included in the analysis. 

A maternal mortality ratio (MMR) was calculated as the number of maternal deaths per 100,000 live births up to 42 days after the end of pregnancy, while deaths occurring between 43 days and one year after the end of pregnancy were defined as late deaths.

The data analysis found a fourfold difference in MMR between countries with the highest (Slovakia, 10.9) and lowest (Norway, 2.7) rates. And of the eight countries included in the study, the UK had the second highest MMR after Slovakia, with 9.6 deaths per 100,000.

The study also shows that vital statistics underestimate true rates of maternal mortality by at least a third in all countries bar Denmark, suggesting that they are not a valid source for surveillance of maternal mortality in high income countries.

What’s more, the researchers found that in France and the UK, the two countries where late maternal deaths were recorded, there were 10.8 and 19.1 late deaths per 100,000 live births, respectively. These late death figures account for 25% of total maternal mortality in France, and 50% in the UK. 

The results also showed that in all countries but Norway, the maternal mortality rate was at least 50% higher for women born abroad or with a minority ethnic background.

A pooled analysis of the data by age revealed that maternal death rates were highest for both the youngest and the oldest mothers in all countries except the Netherlands. For example, women under 20 were at twice the risk of death compared with women aged 20-29, and those aged 40 years or over were at almost four times the risk of death. 

And cardiovascular diseases and suicide were found to be the leading causes of maternal deaths in most countries. This, say the researchers, “underlines the importance of women’s mental and cardiovascular health and the need to develop strategies before, during, and after pregnancy to prevent the morbidity and mortality these problems can cause.”

This is an observational study, so no firm conclusions can be drawn about cause and effect, and the researchers acknowledge some limitations that may have influenced their results, including differences in baseline characteristics of pregnant women and classification of maternal deaths, particularly late deaths.
 
The researchers also acknowledge that some of the discrepancies between countries may stem from national privacy laws, for example, in the Netherlands, where deaths and birth certificates are not linked.
 
However, they are confident in the data, saying differences in maternal mortality profiles between countries “are not at all or very little related to measurement variations.” 
 
“Variations in maternal mortality ratios exist between high income European countries with enhanced surveillance systems,” they write. 
 
To further reduce maternal mortality by learning from best practices and each other, the researchers suggest that “in-depth analyses of differences in quality of care and health system performance at national levels are needed.”
 
And they stress that “cardiovascular diseases and mental health in women during and after pregnancy need to be prioritised in all countries.”
 
In a linked editorial, Professor Andrew Shennan and colleagues argue that variations in maternal mortality “remain one of the starkest health injustices in the world” and say accurate surveillance of maternal deaths is an international priority.
 
They stress that “the relatively low maternal mortality ratios identified in this study are striking compared with those recorded globally, with many countries still reporting more than 500 per 100 000 live births despite focused efforts.”
 
“Ultimately, all countries should have dedicated surveillance systems; meaningful comparisons in absolute numbers of deaths by specific causes will allow strategies and policy makers to direct efforts appropriately. This latest comparison is a valuable start and could lead the way in efforts to align methods of data collection internationally”, they add. 
 

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-070621 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Maternal mortality in eight European countries with enhanced surveillance systems: descriptive population based study

ARTICLE PUBLICATION DATE

16-Nov-2022

Studies provide latest ‘real world’ evidence on effectiveness of covid-19 treatments

Results show substantially lower risk of severe illness with an antibody treatment compared with an antiviral, but no benefit found for common heart drugs

Peer-Reviewed Publication

BMJ

Two studies published by The BMJ today provide up to date evidence on the effectiveness of both currently licensed and possible covid-19 treatments under everyday (‘real world’) conditions, helping to shed more light on whether these drugs can prevent people from becoming seriously ill.

The first is an observational study carried out in England between December 2021 and February 2022. Researchers used hospital records and death certificates for high-risk adults with covid-19 (average age 52) to compare the effectiveness of the antibody treatment sotrovimab with the antiviral drug molnupiravir.

The researchers found that those who received sotrovimab were at a substantially lower (46%) risk of severe covid-19 outcomes than those receiving molnupiravir, within 28 days of treatment.

Results were consistent when restricted to fully vaccinated people and also after further analysis of patients treated between February and May 2022 when the BA.2 omicron variant of covid-19 was dominant in England, suggesting that they are relevant to current clinical care.

There is currently ongoing discussion about the effectiveness of different antibody and antiviral treatments for covid-19 with recent World Health Organization guidance recommending against use of sotrovimab. However, both drugs are currently available for use in England.

The researchers say that their “real-world findings within a time period when both drugs were frequently prescribed and when new variants of covid-19 were circulating provide evidence of current effectiveness of  sotrovimab over molnupiravir.” 

Their analysis also “supports the conclusion that sotrovimab remains beneficial in fully vaccinated patients, which now represent the majority of the covid-19 patient population in many settings,” they add.

The second is a randomised controlled trial involving 787 patients (778 from India and nine from Australia) with an average age of 49 years, admitted to hospital from May 2020 to November 2021. Included patients had predominantly mild disease, although the researchers aimed to recruit patients at risk of severe covid. 

Half received angiotensin receptor blockers or ARBs (drugs widely used to treat high blood pressure and heart disease) and the other half (controls) received a placebo for 28 days.

A standard dose of the ARB drug telmisartan (starting dose 40 mg/d) was used only in India while the type and dose of ARB was at the discretion of the treating physicians in Australia. 

These particular drugs were chosen because they work by regulating the same angiotensin protein as coronavirus uses to enter the body, and in the laboratory have shown potential protectivity against severe effects of coronaviruses. 

However, after 14 days of treatment, the researchers found no meaningful difference in illness severity between the two groups. These findings should help to inform clinical practice. The lack of effect provides reassurance that it is safe to use these protective agents in people indicated, with or without covid-19.

Both studies have some important limitations. For instance, in the observational study, some misclassification about cause of death or hospital admission may have occurred, and the researchers can’t rule out the possibility that differences in initial severity of covid-19 or other unmeasured factors between treatment groups may have influenced their results.

And in the randomised controlled trial, the researchers were unable to source placebo in Australia, meaning participants and treating clinicians knew they were taking an active drug. Participants were also treated with a relatively low drug dose, so the effect of higher doses remains unknown.

Nevertheless, key strengths included the scale, level of detail and completeness of the underlying data in the observational study, and good adherence to study treatment and an adaptive design that allowed the study question to be answered most quickly in the randomised trial.

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JOURNAL

The BMJ

DOI

10.1136/bmj-2022-071932 

METHOD OF RESEARCH

Observational study

SUBJECT OF RESEARCH

People

ARTICLE TITLE

Comparative effectiveness of sotrovimab and molnupiravir for prevention of severe COVID-19 outcomes in non-hospitalised patients: observational cohort study using the OpenSAFELY platform

ARTICLE PUBLICATION DATE

16-Nov-2022

Investigation raises concerns about poor FDA oversight of clinical trials

Peer-Reviewed Publication

BMJ

Covid-19 vaccines and drugs were developed at “warp speed” and now experts are concerned about the US Food and Drug Administration’s (FDA) inadequate surveillance of clinical trial sites, reports an investigation published by The BMJ today.

Regulatory documents show that only nine out of 153 Pfizer trial sites were subject to FDA inspection prior to licensing its covid-19 mRNA vaccine. Similarly, 10 out of 99 Moderna trial sites and five of 73 remdesivir trial sites were inspected, writes investigative journalist Maryanne Demasi.  

Notably, the FDA received a complaint from whistle-blower Brook Jackson, about misconduct at three clinical trial sites that were testing Pfizer’s covid-19 vaccine, while she was employed as a regional director. Jackson observed a range of problems including falsified data, unblinded patients, and inadequately trained vaccinators who were slow to follow up on adverse events. “I thought that the FDA was going to swoop in and take care of everything,” said Jackson. The FDA did not, however, inspect the trial sites in question.

Experts have criticised the FDA’s oversight of clinical trials, describing it as “grossly inadequate.” They say the problem, which predated covid-19, is not limited to a lack of inspections, but also includes failing to proactively notify the public or scientific journals when violations are identified, effectively keeping scientific misconduct from the medical establishment.

The FDA is “endangering public health” by not being candid about violations that are uncovered during clinical trial site inspections, says David Gortler, a pharmacist and pharmacologist who worked as an FDA medical reviewer between 2007 and 2011 and then as a senior advisor to the FDA commissioner in 2019-2021.

The FDA oversees clinical research of FDA-regulated drugs and devices in the US and abroad, if the product is intended for the US market. It conducts routine visits for trials, reviews records of those sites or the institutional review boards (IRBs) that oversee trials locally and follows up on complaints of violations. The FDA does not have a target for the proportion of trial sites it inspects.

Despite the estimated hundreds of thousands of clinical trial sites in operation across the US and abroad, the FDA told The BMJ that it only has 89 inspectors for its bioresearch monitoring programme, which assures the quality and integrity of data submitted to the agency in support of new product approvals and marketing applications, but that it is recruiting more inspectors to reach its yearly average of 100.

“I don’t think that it is a sufficient number of staff to do that kind of level of oversight,” says Jill Fisher, professor of social medicine at the University of North Carolina. “The FDA must have enough of a presence to dissuade investigative sites from committing fraud,” she continues.

Between March and July 2020, at the peak of pandemic restrictions, the FDA paused its site inspections and only “mission critical” inspections were carried out. However, Gortler says this was the precise time that the FDA should have ramped up its oversight, not scaled back, especially since covid-19 products were being developed at warp speed and intended for millions of people.

The FDA told The BMJ it takes oversight of clinical trials seriously and had adapted to travel restrictions, publishing draft guidance for remote regulatory assessments, which describes virtual inspections using live streaming and video conferencing and requests to view records remotely.

The FDA has a long history of failing adequately to oversee clinical trial sites, notes Demasi. For example, a 2007 report by the Department of Health and Human Services’ Office of the Inspector General found the FDA audited less than 1% of the nation’s clinical trial sites between 2000 and 2005 and was highly critical of the agency because it did not have a database of operational clinical trial sites.

In response, the FDA said it created a dedicated task force and “developed new regulations and guidance further to improve the conduct of clinical trials and enhance the protection of people participating in clinical trials,” but denied The BMJ an interview with a member of the task force. 

Further, a 2020 investigation by the journal Science into the FDA’s enforcement of clinical research regulations between 2008 and 2019 concluded that the agency was often light handed, slow moving, and secretive. It said that the FDA rarely levelled sanctions and when it did formally warn researchers about breaking the law, it often neglected to ensure that the problems were remedied.  

Although the FDA publishes its inspection reports, they are not proactively disclosed. Nor does it typically notify journals when a site participating in a published clinical trial receives a serious warning or alert the public about the research misconduct it finds. 

Demasi points to reports of insufficient staff and low morale at the FDA. Fisher says the FDA “needs to be better funded and staffed to conduct inspections. At a minimum, the agency needs to inspect sites when complaints or concerns have been filed.”

Gortler doesn’t agree, however, that the FDA is under-resourced. With a total budget of $6.1bn in 2021, he suggests the agency needs to be leaner and more efficient, with employees interested in improving public health. “Half of its budget, about $3bn, is discretionary, which means it could have hired contractors, retirees, or repurpose existing workers. It chose not to. The FDA was just yawning its way through the pandemic. The entire agency is broken.”

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JOURNAL

The BMJ

DOI

10.1136/bmj.o2628 

METHOD OF RESEARCH

News article

SUBJECT OF RESEARCH

Not applicable

ARTICLE TITLE

Investigation: FDA oversight of clinical trials is “grossly inadequate,” say experts

ARTICLE PUBLICATION DATE

16-Nov-2022