An Entirely New COVID-related Syndrome

SARS-CoV-2 infecting a human cell. Credit: NIH

A rare autoimmune disease has been newly described as a COVID-related syndrome, following an investigation by the University of California San Diego School of Medicine and Leeds University.

It started when Pradipta Ghosh, MD, a professor in the Departments of Medicine and Cellular and Molecular Medicine at UC San Diego School of Medicine, received an email from Dennis McGonagle, PhD, professor of investigative rheumatology at the University of Leeds in the UK. This was the beginning of an international collaboration, one that uncovered a previously overlooked COVID-related syndrome and resulted in a paper in eBioMedicine, a journal published by The Lancet.

McGonagle asked if she was interested in collaborating on a COVID-related mystery. “He told me they were seeing mild COVID cases,” Ghosh said. “They had vaccinated around 90 percent of the Yorkshire population, but now they were seeing this very rare autoimmune disease called MDA5 – autoantibody associated dermatomyositis (DM) in patients who may or may not have contracted COVID, or even remember if they were exposed to it.”

McGonagle told of patients with severe lung scarring, some of whom presented rheumatologic symptoms – rashes, arthritis, muscle pain – that often accompany interstitial lung disease. He was curious to know if there was a connection between MDA5-positive dermatomyositis and COVID.

“DM is more common in individuals of Asian descent, particularly Japanese and Chinese,” Ghosh said. “However, Dr McGonagle was noting this explosive trend of cases in Caucasians.”

“But that’s the least of the problem,” Ghosh said. “Because he said, ‘Oh, and by the way, some of these patients are progressing rapidly to death.'”

Ghosh is the founding director of the Institute for Network Medicine at UC San Diego School of Medicine, home to the Center for Precision Computational Systems Network (PreCSN – the computational pillar within the Institute for Network Medicine). PreCSN’s signature asset is BoNE – the Boolean Network Explorer, a powerful computational framework for extracting actionable insights from any form of big-data.

“BoNE is designed to ignore factors that differentiate patients in a group while selectively identifying what is common (shared) across everybody in the group,” Ghosh explained. Previous applications of BoNE allowed Ghosh and her team to identify other COVID-related lung and heart-afflicting syndromes in adults and children, respectively.

As a rheumatologist, McGonagle specialises in inflammatory and autoimmune conditions. Ghosh said that McGonagle’s roster of patients, all within the UK’s National Health System (NHS), helped to facilitate the investigation.

“The NHS has a centralised health care database with comprehensive medical records for a large population, making it easier to access and analyse health data for research purposes,” Ghosh explained.

Ghosh and McGonagle put together a team to probe what they found was indeed an entirely new syndrome.

The study began with McGonagle lab’s detection of autoantibodies to MDA5 – an RNA-sensing enzyme whose functions include detecting COVID and other RNA viruses. A total of 25 patients from the group of 60 developed lung scarring, also known as interstitial lung disease. Ghosh noted that the lung scarring was bad enough to cause eight people in the group to die due to progressive fibrosis. She said that there are established clinical profiles of MDA5 autoimmune diseases.

“But this was different,” Ghosh said. “It was different in behaviour and rate of progression – and in the number of deaths.”

Ghosh and the UC San Diego team explored McGonagle’s data with BoNE. They found that the patients who showed the highest level of MDA5 response also showed high levels of interleukin-15.

“Interleukin-15 is a cytokine that can cause two major immune cell types,” she explained. “These can push cells to the brink of exhaustion and create an immunologic phenotype that is very, very often seen as a hallmark of progressive interstitial lung disease, or fibrosis of the lung.”

BoNE allowed the team to establish the cause of the Yorkshire syndrome – and pinpoint a specific single nucleotide polymorphism that is protective. By right of discovery, the group was able to give the condition a name: MDA5-autoimmunity and Interstitial Pneumonitis Contemporaneous with COVID. It’s MIP-C for short, “Pronounced ‘mipsy,'” Ghosh said, adding that the name was coined to make a connection with MIS-C, a separate COVID-related condition of children.

Ghosh said that it’s extremely unlikely that MIP-C is confined to the United Kingdom. Reports of MIP-C symptoms are coming from all over the world. She said she hopes the team’s identification of interleukin-15 as a causative link will jump start research into treatment.

Source: University of California – San Diego

Mental Disorders can Spread within Young People’s Social Networks

Photo by Inzmam Khan

Using population-wide registry data, researchers investigated whether mental disorders can be transmitted within social networks formed by school classes.

The study is the largest and most comprehensive so far on the spread of mental disorders in social networks, with more than 700 000 ninth-grade pupils from 860 Finnish schools participating. The adolescents were followed from the end of ninth grade for a median of 11 years.

The researchers, from the University of Helsinki, the Finnish Institute for Health and Welfare, the University of Jyväskylä and the University of Manchester, demonstrated that the number of classmates diagnosed with a mental disorder was associated with a higher risk of receiving a mental disorder diagnosis later in life.

“The observed link was the strongest during the first year of follow-up in the study. This was not explained by a number of factors related to parents, school and residential area. The link was most pronounced in the case of mood, anxiety and eating disorders,” says Associate Professor Christian Hakulinen of the University of Helsinki.

Schools well-suited to social network research

According to Hakulinen, prior studies have yielded similar results: for example, American researchers have observed indications of depressive symptoms potentially being transmitted from one individual to another in social networks.

In prior research, however, social networks have typically been chosen independently by the research subjects, which may result in bias in the data. Hakulinen points out that school classes are social networks well suited to research, as people are usually not able to choose their classmates.

“Defining the social networks and following adolescents were made possible by extensive Finnish registers. The findings significantly deepen our understanding of how mental health problems develop and affect other people in our social networks,” he says.

Hakulinen nevertheless notes that the connection observed in the study is not necessarily causal. Furthermore, the study did not investigate how mental disorders can potentially be transmitted between individuals.

“It may be possible, for instance, that the threshold for seeking help for mental health issues is lowered when there are one or more people in your social network who have already sought help for their problems. In fact, this kind of normalisation of diagnosis and treatment can be considered beneficial contagion of mental disorders,” Hakulinen says.

The study involved a total of 713 809 Finnish citizens born between 1985 and 1997. The adolescents were investigated from the end of comprehensive school until they received their first mental disorder diagnosis, relocated from the country or died. At the latest, the follow-up was discontinued at the end of 2019, resulting in a median follow-up period of 11.4 years.

More preventive measures?

Mental disorders are a significant global challenge, adversely affecting individuals, society and the economy. According to Hakulinen, anxiety and mood symptoms in particular have in recent years increased among young people.

Previous studies have shown that, in roughly half of all cases, the onset of mental disorders in adulthood occurs when people are under 18. In fact, Hakulinen emphasises the importance of preventive measures and early intervention.

“When taking preventive measures, it’s worthwhile considering that mental disorders can spread from one adolescent to another,” Hakulinen says.

Source: University of Helsinki

Most Young Breast Cancer Survivors can Still Have Children

Photo by SHVETS production

A new study by Dana-Farber Cancer Institute investigators, which tracked nearly 200 young women treated for breast cancer, found that the majority of those who tried to conceive during a median of 11 years after treatment were able to become pregnant and give birth to a child.

The findings, to be presented at the 2024 Annual Meeting of the American Society of Clinical Oncology (ASCO), are particularly noteworthy because they answer several questions left open by previous studies of pregnancy and live-birth rates among breast cancer survivors, the study authors say.

“Earlier studies were limited because they included select subgroups of patients, followed patients for a relatively short period of time, and didn’t ask participants, during the study period, if they had attempted pregnancy,” says the study’s senior author, Ann Partridge, MD, MPH, the founder and director of the Program for Young Adults with Breast Cancer at Dana-Farber. “This study was designed to address those gaps by tracking pregnancy and live birth rates among a group of breast cancer survivors and patients who indicated they’d attempted to conceive following their cancer diagnosis.”

The patients in the study were participants in the Young Women’s Breast Cancer Study, which is tracking the health of a group of women diagnosed with breast cancer at or under age 40. Of 1213 eligible participants, 197 reported an attempt of pregnancy over a median follow-up period of 11 years. Within this latter group, the median age at the time of diagnosis was 32 years, and most were diagnosed with hormone receptor-positive breast cancer. Participants were periodically surveyed about whether they had tried to become pregnant and whether they had conceived and given birth.

Over the course of the study, 73% of women attempting to conceive achieved a pregnancy and 65% had a live birth, researchers found. Those who opted for fertility preservation by egg/embryo freezing before cancer treatment tended to have a higher live birth rate, while older participants tended to have lower pregnancy and live birth rates

Participants in the study had breast cancers ranging from stage 0, which are non-invasive and confined to the inside of the milk duct, to stage III, in which the cancer has spread to the lymph nodes. There was no statistically significant association with stage of the disease at diagnosis and achieving a pregnancy or live birth.

“For many young women with breast cancer, the ability to have children following treatment is a major concern,” says the study’s first author, Kimia Sorouri, MD, MPH, of Dana-Farber. “The findings of our study can be helpful when counselling patients about fertility issues. The finding that egg/embryo freezing before treatment was associated with a higher live birth rate underscores the need for accessibility to fertility preservation services for this population.”

Source: Dana-Farber Cancer Institute

Study Tallies Heatwave Deaths over Recent Decades

Photo by Fandy Much

Between 1990 and 2019, more than 150 000 deaths around the globe were associated with heatwaves each year, according to a new study published May 14 in PLOS Medicine by Yuming Guo of Monash University, Australia, and colleagues.

Heatwaves, periods of extremely high ambient temperature that last for a few days, can impose overwhelming thermal stress on the human body.

Studies have previously quantified the effect of individual heatwaves on excess deaths in local areas, but have not compared these statistics around the globe over such a prolonged period.

In the new study, researchers used data from the Multi-Country Multi-City (MCC) Collaborative Research Network that included daily deaths and temperatures from 750 locations across 43 countries.

With the MCC data, the researchers estimated excess heatwave deaths around the world spanning 1990 to 2019 and mapped the variance in these deaths across continents.

During the warm seasons from 1990 to 2019, heatwave-related excess deaths accounted for 153 078 deaths per year, a total of 236 deaths per 10 million residents or 1% of global deaths.

While Asia had the highest number of estimated deaths, Europe had the highest population-adjusted rate, at 655 deaths per 10 million residents.

A substantial burden of estimated deaths was seen in southern and eastern Europe as well as the area between Northern Africa, the Arabian Peninsula and Southern Asia.

At the national level, Greece, Malta, and Italy had the highest excess death ratios.

Overall, the largest estimated rates of heatwaves deaths were seen in areas with dry climates and lower-middle incomes.

Understanding the regional disparity of heatwave-related mortality is key to planning local adaptation and risk management towards climate change.

“Heatwaves are associated with substantial mortality burden that varies spatiotemporally over the globe in the past 30 years,” the authors say.

“These findings indicate the potential benefit of government actions to enhance health sector adaptation and resilience, accounting for inequalities across communities.”

The authors add, “In the context of climate change, it is crucial to address the unequal impacts of heatwaves on human health. This necessitates a comprehensive approach that not only tackles immediate health risks during heatwaves but also implements long-term strategies to minimize vulnerability and inequality. The strategies include: climate change mitigation policy, heat action plans (e.g., heat early warning system), urban planning and green structure, social support program, healthcare and public health services, education awareness, and community engagement and participation.”

Provided by PLOS

Prominent Cardiologist’s Passing a Loss to KZN Healthcare

Colleagues pay tribute to highly respected Dr Singh  

Dr Surendra Singh. Photo: supplied

Monday, 27 May 2024. The passing of esteemed cardiologist Dr Surendra Singh (11 April 1955 – 16 May 2024) at the age of 69 after a short illness is a tremendous loss to healthcare in KwaZulu-Natal, the communities he served and everyone who knew him.

“We wish to express our sincere condolences to Dr Singh’s wife, Professor Shanta, and his children Rajiv, Ameet and Rhea,” said Netcare uMhlanga Hospital general manager Wendy Beato.

“We mourn the passing of an exceptional healthcare professional and a man of stature. Dr Singh was highly respected and much loved by his colleagues, patients and the staff and management of Netcare uMhlanga Hospital, where he has practised for several years.

“Dr Singh will be deeply missed by all who had the privilege to know him,” she says.

After qualifying as a cardiologist in 1990, Dr Singh embarked on a journey during which he harnessed the power of his knowledge to heal others. Known for this brilliance both as a man and a doctor, he possessed a rare combination of exceptional expertise, humility and deep caring.

“Dr Singh’s dedication to his patients was evident throughout his career, and he continued to provide much valued service at Netcare uMhlanga Hospital until he became ill. His passing leaves a deep void for all who knew him and the countless patients whose lives he touched throughout his career.

“Dr Singh’s legacy as a caring healthcare provider and respected cardiologist will endure. Through his considerable dedication and expertise, he improved and saved lives while inspiring a new generation of healthcare professionals. His passion for healing and deep commitment to his patients will be forever remembered. Although his time with us was cut short, the impact of his life’s work will continue to be felt for many years to come,” Beato concluded.

Inflammatory Bowel Disease may Increase Risk of Heart Failure

Irritable bowel syndrome. Credit: Scientific Animations CC4.0

Inflammatory bowel disease (IBD) is associated with a slightly increased risk of heart failure up to 20 years after diagnosis, according to a comprehensive registry study from Karolinska Institutet published in the European Heart Journal.

The researchers analysed the risk of heart failure in over 80 000 patients with inflammatory bowel disease, that is, Crohn’s disease, ulcerative colitis or unclassified IBD, compared with 400 000 people from the general population, as part of the ESPRESSO study.

The results show that people with IBD have a 19% increased risk of developing heart failure up to 20 years after diagnosis. This corresponds to one extra heart failure case per 130 IBD patients in those 20 years, and the risk increase was seen regardless of the type of IBD. The highest risk of heart failure was seen in older patients, people with lower education and people with pre-existing cardiovascular-related disease at IBD diagnosis.

Contribute to new guidelines

“Both healthcare providers and patients should be aware of this increased risk, and it’s important that cardiovascular health is properly monitored,” says the study’s first author Jiangwei Sun, researcher at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. “We hope the results will raise the awareness of health workers as to the increased risk of heart failure in individuals with IBD and contribute to new guidelines for cardiovascular disease management in IBD patients.”

Comparing siblings with and without ABD, the risk increase was slightly lower, 10%, suggesting that genetics and early environmental factors shared within families may play a role. 

“We don’t know if there is a causal relationship, but we will continue to explore genetic factors and the role of IBD medications and disease activities on the risk of heart failure,” says the study’s senior author Professor Jonas F. Ludvigsson from the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.

Source: Karolinska Institutet

DNA from Ancient Viral Infections Implicated in Some Psychiatric Disorders

Photo by Sangharsh Lohakare on Unsplash

New research led by King’s College London has found that thousands of DNA sequences originating from ancient viral infections are expressed in the brain, with some contributing to susceptibility for psychiatric disorders such as schizophrenia, bipolar disorder, and depression.

Around 8% of the human genome is made up of sequences called Human Endogenous Retroviruses (HERVs), which are products of ancient viral infections that occurred hundreds of thousands of years ago. Until recently, it was assumed that these ‘fossil viruses’ were simply junk DNA, with no important function in the body. However, due to advances in genomics research, scientists have now discovered where in our DNA these fossil viruses are located, enabling us to better understand when they are expressed and what functions they may have.

This new study, published in Nature Communications, builds upon these advances and is the first to show that a set of specific HERVs expressed in the human brain contribute to psychiatric disorder susceptibility, marking a step forward in understanding the complex genetic components that contribute to these conditions.

Dr Timothy Powell, co-senior author on the study and Senior Lecturer at the Institute of Psychiatry, Psychology & Neuroscience (IoPPN), King’s College London, said: “This study uses a novel and robust approach to assess how genetic susceptibility for psychiatric disorders imparts its effects on the expression of ancient viral sequences present in the modern human genome. Our results suggest that these viral sequences probably play a more important role in the human brain than originally thought, with specific HERV expression profiles being associated with an increased susceptibility for some psychiatric disorders.”

The study analysed data from large genetic studies involving tens of thousands of people, both with and without mental health conditions, as well as information from autopsy brain samples from 800 individuals, to explore how DNA variations linked to psychiatric disorders affect the expression of HERVs.

Although most genetic risk variants linked to psychiatric diagnoses impacted genes with well-known biological functions, the researchers found that some genetic risk variants preferentially affected the expression of HERVs. The researchers reported five robust HERV expression signatures associated with psychiatric disorders, including two HERVs that are associated with risk for schizophrenia, one associated with risk for both bipolar disorder and schizophrenia, and one associated with risk for depression.

Dr Rodrigo Duarte, first author and Research Fellow at the IoPPN, King’s College London, said: “We know that psychiatric disorders have a substantial genetic component, with many parts of the genome incrementally contributing to susceptibility. In our study, we were able to investigate parts of the genome corresponding to HERVs, which led to the identification of five sequences that are relevant to psychiatric disorders. Whilst it is not clear yet how these HERVs affect brain cells to confer this increase in risk, our findings suggest that their expression regulation is important for brain function.”

Dr Douglas Nixon, co-senior author on the study and and researcher at the Feinstein Institutes for Medical Research at Northwell Health, in the US, said: “Further research is needed to understand the exact function of most HERVs, including those identified in our study. We think that a better understanding of these ancient viruses, and the known genes implicated in psychiatric disorders, have the potential to revolutionise mental health research and lead to novel ways to treat or diagnose these conditions.”

Source: King’s College London

How Zebrafish Heal from Spinal Cord Injury could Help Humans

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Zebrafish have a remarkable ability to heal their spinal cord after injury. Now, researchers at Karolinska Institutet have uncovered an important mechanism behind this phenomenon – a finding that could have implications for the treatment of spinal cord injury in humans.

In a new study published in Nature Communications, researchers show that the neurons of adult zebrafish immediately start to cooperate after a spinal cord injury, keeping the cells alive and stimulating the healing process.

“We have shown that the neurons form small channels called gap junctions, which create a direct connection between the neurons and enable the exchange of important biochemical molecules, allowing the cells to communicate and protect each other,” explains Konstantinos Ampatzis, a researcher in the Department of Neuroscience at Karolinska Institutet, who led the study.

The researchers will further investigate the exact mechanisms behind this protective strategy in zebrafish and hope this knowledge will lead to new ways of treating spinal cord injury in humans.

“Spinal cord injuries are a major burden for sufferers and their families,” says Konstantinos Ampatzis. “What if we could get human neurons to adopt the same survival strategy and behave like zebrafish neurons after an injury? This could be the key to developing new effective treatments.”

Source: Karolinka Institutet

Milk Samples From the 1940s Reveal Antibiotic Resistance in the Pre-antibiotic Era

Photo by Robin Worrall on Unsplash

Using stored milk samples as a kind of time capsule, veterinary researchers at the University of Connecticut have uncovered insights about the presence of antibiotic resistance even in the pre-antibiotic era.

Sometime in the 1940s or so, someone in what is now the Department of Pathobiology and Veterinary Science got a lyophiliser, a piece of equipment that freeze-dries samples, says Director of the Connecticut Veterinary Medical Diagnostic Laboratory (CVMDL) Dr Guillermo Risatti. Risatti explains that at that time, the microbiology lab was very active in testing milk for the dairy farms in the region. With an exciting new piece of equipment, it seems they started lyophilising hundreds of samples.

The samples have been in storage ever since. Beyond the scant details that these are milk samples containing Streptococcus bacteria from the 1940s, Risatti explains that he and his colleagues – CVMDL Research Associate Dr. Zeinab Helal, Ji-Yeon Hyeon and Dong-Hun Lee – were interested in exploring their microbial history.

Risatti says that over the years, the data was lost, so researchers don’t have precise details of the provenance of the samples. But knowing a bit of history about the department, they can deduce some information.

“We believe that most of them came from Connecticut or perhaps from cases from the region, but we cannot say which parts,” Risatti says. “Most likely, this lab provided a testing service to locals, as this was mainly a pathology lab. Now it’s more like a diagnostic lab, and we receive samples from all over the region, including New York and New Jersey.”

Learning about what these historical samples hold could help with research in unexpected ways, but the first step is piecing together the lost details. To do this, Risatti explains that the team established a workflow using standard techniques to streamline processes to analyse the visual characteristics, called phenotype, and to analyse their genotype with genomic sequencing.

Different species of Streptococcus use different strategies to inflict disease in the organisms they infect. These virulence factors are used to differentiate one species of Streptococcus from another and are one way to distinguish samples through phenotypic analysis. Another phenotypic analysis includes testing bacteria for their susceptibility to antibiotics.

The researchers started with 50 samples collected from 1941 to 1947, and they found that the samples contained seven different Streptococcus species, including two subspecies of S. dysgalactiae. Interestingly, the researchers found some of the samples were resistant to the antibiotic tetracycline and did not carry antibiotic resistance genes typically seen in today’s antibiotic-resistant bacterial strains. Since these samples were collected prior to the antibiotic era, the results add to a growing body of literature showing that antibiotic resistance occurred naturally before humans discovered and began to use antibiotics.

“Antibiotic resistance is a very big area of research, and it has been for many years,” says Risatti. “We did not go any further with our analysis because we don’t have the tools here, but we hope to bring this information to the public. I think it could be the jumpstart for somebody to study further.”

Risatti explains the hope is to partner with large agencies like the CDC and the Department of Public Health to help bolster antibiotic resistance research.

Concussion is Associated with Iron Accumulation in Certain Brain Areas

Photo by Anna Shvets

People who suffer from headaches after experiencing concussions may also be more likely to have higher levels of iron in areas of the brain – a sign of injury to brain cells, according to a preliminary study presented at the American Academy of Neurology’s 76th Annual Meeting.

“These results suggest that iron accumulation in the brain can be used as a biomarker for concussion and post-traumatic headache, which could potentially help us understand the underlying processes that occur with these conditions,” said study author Simona Nikolova, PhD, of the Mayo Clinic in Phoenix, Arizona, and a member of the American Academy of Neurology.

The study involved 120 participants, 60 of whom who had post-traumatic headache (PTH) due to mild traumatic brain injury (mTBI), and 60 healthy controls. The injuries were due to a fall for 45% of the people, 30% were due to a motor vehicle accident and 12% were due to a fight. Other causes were the head hitting against or by an object and sports injuries. A total of 46% of the people had one mild traumatic brain injury in their lifetime, 17% had two, 16% had three, 5% had four and 16% had five or more mild traumatic brain injuries.

Participants underwent 3T brain magnetic resonance imaging (T2* maps). T2* differences were determined using age-matched paired t-tests. For the PTH group, scans were done an average of 25 days after injury. T2* correlations with headache frequency, number of lifetime mTBIs, time since most recent mTBI, and Sport Concussion Assessment Tool (SCAT) severity scale scores,

The researchers observed lower T2* values in PTH participants relative to HC in the right supramarginal area, left occipital, bilateral precuneus, right cuneus, right cerebellum, right temporal, bilateral caudate, genu of the corpus callosum, right anterior cingulate cortex and right rolandic operculum (p < 0.001).

Within PTH subjects, there were positive correlations with iron accumulation between lifetime mTBIs, the time since most recent mTBI and headache frequency in certain areas of the brain. For example, T2* levels in headache frequency with T2* in the posterior corona radiata, bilateral temporal, right frontal, bilateral supplemental motor area, left fusiform, right hippocampus, sagittal striatum, and left cerebellum were associated with headache frequency.

“Previous studies have shown that iron accumulation can affect how areas of the brain interact with each other,” Nikolova said. “This research may help us better understand how the brain responds and recovers from concussion.”

Nikolova said that using the indirect measure of iron burden also means that the change in that measure could be due to other factors such as haemorrhage or changes in tissue water rather than iron accumulation.

Source: American Academy of Neurology