Category: 8. Health

Over 200 viruses infect humans, and all rely on living host cells to survive. In doing so, they induce striking changes to the cell and its environment. Scientists like Ileana Cristea are investigating these changes to better understand the complex virus–host relationship.

Cristea recently shared her research on the American Society for Biochemistry and Molecular Biology webinar Breakthroughs, a series highlighting research from ASBMB journals. A professor of molecular biology and director of graduate studies at Princeton University, she also serves as editor-in-chief of Molecular & Cellular Proteomics. During her talk, sponsored by MCP, Cristea discussed how viral infections reshape organelles and cellular metabolism and how these changes relate to broader disease biology.

One key intracellular change during viral infection, Cristea said, is organelle remodeling. Organelles — such as mitochondria, which drive energy production, and the endoplasmic reticulum, or ER, which synthesizes proteins and lipids — are often disrupted by viruses.

“Diverse viruses that infect so many different types of cells (and) have different replication strategies, different genomes, they’re united by this need to induce organelle remodeling,” she said.

Cristea and colleagues observed that cells infected with human cytomegalovirus, or HCMV, a double-stranded DNA virus, exhibited mitochondrial fragmentation; but, in HCMV-infected cells, it surprisingly increased cellular respiration. The team turned to mass spectrometry-based proteomics and microscopy to investigate.

They discovered a novel organelle–organelle interaction: small mitochondrial fragments induced by HCMV infection became encased in ER pockets. They named these new structures mitochondria–ER encapsulations, or MENCs. Studies across various HCMV strains and cell types confirmed MENCs as a consistent feature of late-stage infection.

Additional work revealed that MENCs helped sustain high cellular respiration, ultimately benefiting the virus. Similar patterns of elevated metabolism despite mitochondrial fragmentation had been seen in other diseases.

“When we thought about this, we immediately thought about cancer, because HCMV is known to be also an oncomodulatory virus, and in cancer, we see mitochondrial fragmentation,” Cristea said.

In metastatic melanoma cells, the team observed the same phenomenon: fragmented mitochondria encapsulated in MENCs with high bioenergetic activity — and MENC formation correlated with greater cancer severity.

In addition to organelle remodeling, viral infection disrupts metabolism, notably increasing levels of the byproduct lactate. While lactate is known to dampen immunity in cancer, its role in viral infection was unclear.

In a recent study, Cristea’s team found that treating cells with lactate enhanced viral replication. Proteomics analysis of cells infected with HCMV, or the herpes simplex 1 virus, called HSV-1, showed lactate-modified host defense proteins. This lactylation, occurring in intrinsically disordered regions, inhibited immune signaling and promoted infection.

Cristea’s research also explores how viruses influence the space outside infected cells. Her team found that viruses can alter the surrounding microenvironment to promote infection. Using a fluorescence-based assay, they observed that infection in one cell disrupted cell division and weakened immune responses in neighboring cells. This priming helped HCMV, HSV-1 and influenza viruses spread more easily.

“We thought initially that (the neighboring cells should) be ready for defense because this cell is becoming infected, but actually they have dampened immunity,” she said.

While much of Cristea’s work has largely focused on viral infections, her lab is now exploring whether the same cellular mechanisms underlie other diseases, including cancer.

In case you missed it, you can watch the full Breakthroughs webinar here.

Influenza, and not the antiviral treatment for it, is responsible for increased neuropsychiatric risks in pediatric patients, new research suggested.

The risk for these events was about 50% lower in children treated with oseltamivir (Tamiflu), the most widely prescribed antiviral for influenza, compared to no treatment, investigators found.

Oseltamivir currently carries a warning label about increased risk for neuropsychiatric events, including seizure. However, the label is based on low-quality studies, lead investigator James W. Antoon, MD, PhD, assistant professor of pediatrics at Vanderbilt University Medical Center, Nashville, Tennessee, told Medscape Medical News.

The findings of the study, which Antoon said is the most rigorous of its kind to date, suggest that the warning label may no longer be necessary.

“Our main finding was that oseltamivir prevents neuropsychiatric events and that neuropsychiatric events during periods of influenza is really driven by influenza itself,” he said. “This influenza antiviral is safe and effective and should be used as early as possible in the course of influenza illness.”

Definitive Answer?

Oseltamivir is currently the most commonly prescribed antiviral for influenza for both children and adults and is particularly beneficial during the illness’ early stages.

The FDA added the warning label to the drug packaging after safety concerns were raised in 2006. However, the researchers noted that “it is important to note that these warnings were placed on the basis of case reports rather than studies on associated risks for these events.”

No randomized study to date has shown a significant association between the medication and neuropsychiatric events in pediatric patients, and there have been conflicting results from observational studies, they added.

Antoon said he first became aware of the warning during his medical residency. However, upon reviewing the studies examining the link, he found that there was little high-quality research on the topic.

Once he began practicing, he noted that parents frequently expressed concerns about these risks.

“Even for children at high risk for influenza complications, who would benefit from treatment, parents would decline it. So we chose to do this study to be the definitive answer of whether oseltamivir is associated with neuropsychiatric events or is it the underlying influenza that’s really driving the alterations in children’s behavior,” Antoon said.

The retrospective cohort study assessed data from influenza seasons in 2016-2017 and 2019-2020. It included 692,295 children and adolescents aged 5-17 years (median age, 11 years; 50.3% girls) enrolled in Tennessee Medicaid.

Each person-day of follow-up was stratified into one of five exposure groups: no exposure (to influenza or oseltamivir), untreated influenza (up to 10 days after diagnosis), treated influenza, posttreatment (time between oseltamivir completion to end of influenza period), and influenza prophylaxis (oseltamivir treatment without influenza).

The primary outcome was any neuropsychiatric event that required hospitalization.

Helpful, Not Harmful

Results showed that 129,134 individuals had 151,401 influenza episodes, and 66.7% of those episodes were treated with oseltamivir. Among the participants deemed to be at high risk for influenza-related complications, 60.1% received oseltamivir treatment.

There were 898 neurologic and 332 psychiatric events during 19,688,320 person-weeks of follow-up.

The most common serious neuropsychiatric adverse events were mood disorders (36.3%) and suicidal or self-harm behaviors (34.2%), followed by seizures (13.7%). The overall incidence rate ratio (IRR) was 6.25 per 100,000 person-weeks for a serious neuropsychiatric event.

The risk for these events was significantly lower during periods where influenza was treated with oseltamivir (adjusted IRR, 0.53; 95% CI, 0.33-0.88) and during posttreatment (adjusted IRR, 0.42; 95% CI, 0.24-0.74) than during untreated influenza.

“Sensitivity analyses suggest misclassification or unmeasured confounding would not explain these findings,” the investigators wrote.

Subanalyses showed that the adjusted IRRs for neurologic and psychiatric events separately in the treated group were 0.45 (95% CI, 0.25-0.83) and 0.80 (95% CI, 0.34-1.88), respectively.

Antoon noted that neurologic events are more common than psychiatric events in young patients and that the lower number of those outcomes overall may have led to a smaller decrease in psychiatric events.

“All of the results together suggest that oseltamivir is not associated with neuropsychiatric events and, in fact, may be helpful in preventing these events in children,” Antoon said.

‘Double-Edged Sword’

Commenting for Medscape Medical News, Soonjo Hwang, MD, associate professor of psychiatry and from the Child and Adolescent Psychiatry Department at the University of Nebraska Medical Center, Omaha, Nebraska, noted that although the study provides important and reassuring information, he wouldn’t necessarily say it provides the definitive answer on this topic.

Hwang, who was not involved with the research, noted that the study was a retrospective cohort review with several confounding variables that were not controlled for, including various socioeconomic factors and how amenable the parents were to the treatment options.

Additionally, he pointed out that medication warning labels for pediatric populations are often based on case reports because of the difficulty in conducting clinical trials in an ethical way in such a young group.

“It’s kind of a double-edged sword. You want to use the medicine as safely as possible, but you also don’t want to limit the access to treatment options just because there are no sufficient data available,” Hwang said.

So what should clinicians do while waiting for additional research?

“I think, as a clinician, you need to have an informed conversation with parents of young children about the risk and benefit of any treatment option and make the best judgement you can case-by-case. But, indeed, we really need more clinical trials to make sure we’re using them in a safe way but also in an effective way,” he concluded.

The study was funded in part by the US National Institute for Allergy and Infectious Diseases and the National Institute of Child Health and Human Development. Antoon reported having received personal fees from serving on an AstraZeneca Scientific Advisory Board. A full list of relevant conflicts for the other investigators are provided in the original article. Hwang reported having no relevant financial relationships.

If it weren’t for post hoc analyses and findings from curious academic labs, the substantial list of biological differences that separates the sexes would still be relegated to the shadows. That list — including research from the fields of neurology, cardiology, immunology, oncology, endocrinology — shows that the longtime presumption of men and women reacting as one to diagnoses, disease progression, and treatment should be considered, scientifically speaking, passé.

But in the world of clinical trials, it has been and still is mostly a sexless, homogenous world. One reason: Stratifying by sex in a trial would not be cheap. “Doing that up front would cost millions more,” said Antonella Santuccione Chadha, MD, PhD, founder and CEO of the Women’s Brain Foundation and a former member of the EU Commission Directorate-General for Health and Food Safety.

A significant issue is under enrollment of women in randomized trials, meaning the percentage of women enrolled isn’t in line with the percentage of women with a particular disease in the real world — so signals that indicate an adverse event are not picked up. From a systems perspective, women do not clear drugs through their kidneys as quickly as men, and women maintain a higher blood concentration of the medication. “Women may be overmedicated,” Neurologist Irving Zucker and others wrote in a 2020 analysis of 86 medications.

This can lead to adverse events (AEs). And they do.

“ Women experience adverse drug reactions nearly twice as often as men, yet the role of sex as a biological factor in the generation of [these reactions] is poorly understood,” Zucker wrote in that study, published in the journal Biology of Sex Differences, which showed that pharmacokinetics “strongly linked” sex differences in adverse drug events.

Among the 86 medications was the GLP-1 receptor agonist (GLP-1 RA), liraglutide. It was found to be biased toward women with regard to headache, vomiting, nausea.

There are little stratified data in the GLP-1 RA receptor clinical trials, let alone appropriate enrollment percentages, as compared to real world disease prevalence. Considering that these medications are being used in patients with diabetes, obesity and overweight, cardiovascular problems, and likely in the future, to mitigate Alzheimer disease advancement, it likely would help to know how sex affects these drugs.

So the question is: How can general practitioners determine what treatment is right for patients, especially their female patients, when so little evidence is based on sex?

“The side effects are very real and important to track,” said Sadiya S. Khan, MD, MSc, professor of cardiovascular epidemiology, and associate professor, medicine medical social sciences, preventive medicine, at the Feinberg School of Medicine at Northwestern University, Chicago.

“The truth about GLP-1 agonists is that you have to personalize it for the patient in front of you,” said Martha Gulati, MD, MS, professor of cardiology at Cedars-Sinai Heart Institute. Efficacy has to be balanced with the potential for side effects. “Every individual will be slightly different.” 

Sex Differences of Note

In its natural state, GLP-1 is found in many areas of the body, including the brain. It has multiple purposes, including gastric emptying, food intake inhibition, and neuroprotective effects on lung and cardiovascular systems. But in its natural state, GLP-1 has a short half-life, hence the pharmaceutical drive for analogues.

As a class, these analogues, primarily the injectables, have been much ballyhooed for their ability to treat diabetes, induce weight loss, and reduce the risk for cardiovascular events. One recent study also demonstrated how the GLP-1 RAs can mitigate cognition issues.

These analyses show how the GLP-1 RAs work at the stratified population level: 

• In this study, women, who generally have a smaller stature than men, had higher concentrations (32%) of the tested medication than men; patients with diabetes had lower amounts of medication than those with normal blood glucose levels or prediabetes.
• In a new analysis of FAERS, the FDA’s adverse event reporting system, among reports of neurologic related events in GLP-1 agonists, 46.25% occurred within 30 days of the start of treatment. The report, based on complaints filed from 2004 to 2025, found that 11.58% of the 250,014 listed were neurologic in nature. Women reported 65% of the 28,953 neurologic AEs events; most came from consumers. The top AEs reported were dizziness, tremor, and dysgeusia.
• Women who had taken semaglutide, liraglutide, and tirzepatide reported 65% of the 372 psychiatric events found in the EudraVigilance database, between January 1, 2021, and May 30, 2023.
• In a new JAMA article discussing the management of GLP-1 events, neurologic issues are not mentioned, just common gastrointestinal ailments, including nausea. In the huge study published in February confirming semaglutide 2.4 mg safety in overweight, obesity, cardiovascular disease but not diabetes, the sexes were segregated in listing fractures, poisoning, and procedural events but not in serious cardiac and nervous system disorders.
• The inclusion criteria for the still-running Evoke trials, which is testing oral semaglutide’s efficacy in early-stage symptomatic Alzheimer’s disease (AD), have no breakdown of the 1840 participants by sex, either in clinicaltrials.gov or the peer-reviewed summary. AD affects women significantly more than men. Efforts to reach an investigator were not successful.

With regard to diabetes, it seems the sexes have more differences than commonalities, according to a 2023 study in Diabetologia, the journal of the European Association for the study of diabetes. One review found men: are younger at diagnosis; have a lower BMI and a lower risk factor burden, including hypertension and more weight gain; have a lower relative risk for cardiovascular complications and death; and get guideline recommended care more than women.

“Across their lifetime, changes in sex hormones mean that women experience greater variations in the risk of cardiometabolic disease, including type 2 diabetes,” the Austria-based authors wrote. A Danish study reviewing more than 200,000 cases in the country’s national registry reached similar conclusions.

A cause for concern: Population trends show that more women are obese or severely obese, particularly among those older than 60 years.

Clinical Discussion

Prescribing women GLP-1 RAs takes some planning, Gulati and Khan said. Conversations about what to expect are critical, especially about potential AEs.

Gulati said women respond better to these medications, especially if they are premenopausal. These physicians, both preventive cardiologists, discuss the benefits, including lower hypertension, weight reduction, and better glycemic control. Advice includes eating small meals, avoiding greasy food, and eating lots of fiber because constipation is no fun. And patients have to be prepared for the side effects.

“I have this oatmeal spiel,” Gulati said. One patient, she said, insisted on eating greasy food until the AEs won out. “She started improving her diet and she got the results she wanted…If they get something you told them about, they know more.”

Gulati, president-elect of the American Society for Preventive Cardiology, said some women won’t be able to go up to the highest dosage because of the AEs.

Khan said the AEs increase as the GLP-1 RA dosage increases. She said that in real life, 80% of people taking a GLP-1 RA stop because of the side effects. “It’s about going slow and seeing if people can benefit.”

At least one premarketing clinical study claimed that dose adjustment by sex wasn’t necessary.

Robert Kushner, MD, the lead investigator on the semaglutide obesity study, said in a JAMA podcast that more than 30% of patients, at least in the phase 3 trials, stopped using semaglutide because of nausea, constipation, diarrhea, and vomiting. His advice paired with that of Khan and Gulati.

Most, if not all, of this conversation could be avoided if sex-based evidence was generated in preclinical research and then used to shape the trial, said Santuccione Chadha.

By investing more money in the beginning of the trial to determine sex-based differences, there would be a “higher return on investment across the chain.” There would be fewer side effects and more adherence to drugs, the GLP-1s included. But with the current method of research, “What happens is that there are unexpected side effects, more adverse events in the female population, who also get more serious events.”

Gulati agreed more planning is needed prior to trial enrollment. “Honestly? I think it is because of a lack of prestudy planning. Who do we want, and where will we get them?” If the trial is underpowered, “you can’t look at sex differences.”

The fact that the GLP-1 RAs have proven effective in so many body systems now has more specialists prescribing these medicines. Khan said interdisciplinary care is critical, so it’s necessary to have a point person. “We are realizing this, who is owning responsibility, who is comfortable with it.”

New drug helps chemo beat resistant tumors

A new cancer drug developed at King’s College London boosts the power of chemotherapy — even against tumors that previously resisted treatment. The pill, called KCL-HO-1i, disables a key protein made by immune cells that normally shield tumors from chemo. In preclinical models, it made resistant cancers respond to standard chemo drugs, raising hopes for broader, more effective treatment. Human trials could begin within two years.

Ancient conch shell blowing shows promise for treating sleep apnea

A small clinical trial suggests that shankh blowing — an ancient Hindu practice of exhaling through a conch shell — may ease symptoms of obstructive sleep apnea. Published in ERJ Open Research, the study found that patients who practiced the technique for six months had fewer breathing interruptions at night, improved sleep and reduced daytime drowsiness. Researchers say the low-cost, noninvasive practice could offer an alternative for patients who struggle with CPAP therapy. A larger trial is now planned.

AI predicts hospital admissions in the ED hours in advance

Mount Sinai researchers have developed an AI tool that can predict hospital admissions early in an emergency department visit — often before an order is placed. Tested across nearly 50,000 patient visits, the model matched or outperformed nurse triage assessments and could help reduce overcrowding, streamline care and improve outcomes.

Loneliness has been a constant feature of Macyleen’s life since she was nine years old and her mother died in their home town in Zimbabwe. She was sent to live with her father, but he worked away from home a lot. His new wife resented his other children and was emotionally abusive.

Macyleen lived with three half-siblings, but they were much older. “We were there to survive and just get to the next day. I knew I was alone,” she recalls.

That feeling has never really left Macyleen, who is now 33, building a childminding business and bringing up four children on her own in Gqeberha (formerly Port Elizabeth), South Africa.

There are many people in Africa experiencing loneliness, like Macyleen. According to a report in June by the World Health Organization, Africa is the loneliest continent on Earth.

Almost a quarter (24%) of people there reported feeling lonely, and adolescents aged 13 to 17 are the worst affected, the WHO says. The next highest rates of loneliness are in the eastern Mediterranean (21%), followed by south-east Asia (18%). Europe has the lowest rate, at about 10%.

The report comes after the WHO declared loneliness a pressing “global public health concern” and launched an international commission on social connection to examine the problem.

Africa is traditionally viewed as having a collectivist culture that prioritises the needs and goals of the group as a whole over individuals. But this is changing.

Dr Cleopa Mailu, a member of the commission and a former Kenyan health minister, says: “My initial reaction [to the findings] was one of rejection.

“I live in Africa and tend to think the society we are today is the one of the 1950s or 60s, and that there’s more loneliness in the western hemisphere. I came to realise that feeling I had was just an internalisation of our past.”

Loneliness is not recognised as a problem in Africa, says Mailu, and people do not want to discuss it. Instead, social wellbeing has been neglected in health policies in favour of focusing on communicable and non-communicable diseases.

Meanwhile, cities on the continent are rapidly expanding; over the next three decades, Africa’s urban population will double, increasing from 700 million to 1.4 billion by 2050.

“We never came alive to the fact that we have been globalising ourselves – living in conditions which are not traditional to the African people,” adds Mailu. “In a way, we rejected the notion that there’s loneliness and isolation in the continent.”

Mailu attributes higher levels of loneliness to a changing society, and growing urbanisation and globalisation, as well as new governance structures, migration, poverty and changing views of wealth and success.

“In traditional settings, wealth was defined differently,” says Mailu. “You just needed to have a cow and a farm or somewhere to cultivate. Everybody was the same level.

“Now there are different levels of poverty,” he says. “There is a lot of pressure and you find people are not together.”

Macyleen can identify with this. She says the Africa she grew up in is very different from the one she lives in today.

People are copying western culture, she says: “It’s all about me or my immediate people. Maybe that’s one of the reasons people are becoming more selfish.”

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Macyleen finds it hard to open up to people, fearing judgment over being a single mother to children with different fathers, all of whom abandoned her. She also has little opportunity to socialise, given that she is trying to build her own business and bring up four children with no financial help.

“I struggle with stress and things are getting hard in South Africa. There’s a lot of xenophobia and I have this heavy feeling that I don’t belong here any more,” she says.

“If something happens, I have to be the mother and the father [to my children]. It gets really lonely, especially because I’m scared of dating. Who can I find to trust?

“The world is changing so fast,” she adds. “And there’s too much pressure to do well, but we are in an environment that is not helping us.”

Lateefat Odunuga, a psychologist and global adviser for the African Network of Youth Policy Experts, agrees that Africa is changing from a continent with many people in close-knit communities to one where that traditional way of life is being erased by urbanisation.

She says loneliness is a pressing issue for young people across the continent. “Young people are frustrated,” she says. “There’s a lot of unemployment, drug abuse, mental health issues. We’re seeing a lot of young people dying [by] suicide.”

The increased cost of living, she adds, means people would rather stay at home than spend money on cultural events, for example.

She blames technology for contributing to the problem. More people are using apps such as TikTok for entertainment and, through her practice in Nigeria, she has heard of individuals turning to ChatGPT to check if they are depressed, instead of talking to a family member, for example.

While loneliness might not be recognised on a widespread basis in Africa, there are organisations dedicated to tackling it, she says. She cites Friendship Bench, an approach first developed in Zimbabwe that trains community health workers to provide basic cognitive behavioural therapy with an emphasis on activity scheduling and group support. The model has been replicated in countries throughout the world.

The WHO report highlighted the AgeWell peer-to-peer support programme in Cape Town. Older volunteers were trained to provide friendship and company to less able older residents in their community through regular home visits. South African participants reported less loneliness, and there was a significant increase in social participation.

“Depending on how committed we are to this work,” says Odunuga, “there might be a future for us to tackle social isolation and loneliness.

“But if we don’t bring people together,” she warns, “we are doomed. We’re going to have a lot of problems beyond mental health. It will be a disaster and a total shame to humanity.”