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Yesterday — 30 November 2021Health & Medicine – Harvard Gazette

Undergrad’s papers published in prestigious medical journals

30 November 2021 at 09:37

For Simar Singh Bajaj ’24, the key to equity begins on the page. The history of science concentrator is still a few years from his planned career in medicine, but he has already begun tackling health care disparities in prestigious journals such as The New England Journal of Medicine and The Lancet.

“I’m a big believer in the power of writing to push conversations forward,” said Bajaj, who collaborated with his mentor, Fatima Cody Stanford, an assistant professor of medicine and pediatrics at Harvard Medical School, and sociology concentrator Lucy Tu ’24 on the recent Lancet paper “Superhuman, but never enough: Black women in medicine.”

Weeks before the Lancet article, Nature Medicine published Bajaj’s “Health-based civic engagement is a professional responsibility,” co-authored with Stanford and Alister Francois Martin, an assistant professor at the Medical School. In it, the authors argue that health care providers should work to empower their patients to vote as a means of improving their own care. (The article highlights the nonprofit advocacy group Vot-ER, which was founded by Martin.)

These publications follow last February’s “Beyond Tuskegee — Vaccine Distrust and Everyday Racism,” which was accepted by NEJM within a week of being submitted. The response surprised even Bajaj’s mentor. The young researcher had just turned 19 when he told Stanford: “I’m interested in inequalities and equities, and I know you’re into policy, and I want to do this work.”

“I thought, oh, that’s really sweet,” she said. Within 12 hours, he’d written a piece of such high quality that she suggested submitting it to the NEJM, and the two began collaborating on additional research.

For Bajaj, who hopes to do a summer writing internship at a medical publication, the work stems from his early exposure to health care inequities and their real-world repercussions. While in high school in California’s Bay Area, he volunteered at a free health clinic. A lack of preventive care, financial straits that put both a healthy diet and medications out of reach, and distrust of the health care system left patients perpetually vulnerable to medical emergencies.

“There are people who, because of the lack of access to care, because of different socioeconomic barriers, were coming to the emergency department as a last-ditch effort for their severely exacerbated conditions,” he said. “We need a better socioeconomic support, we need a more comprehensive safety net.”

One of Bajaj’s teachers, Hannah Marcus, an assistant professor in the history of science, recalled a discussion about the legacy of racism in medicine that helped inspire the NEJM article. Sitting in on the class, Evelynn Hammonds, Barbara Gutmann Rosenkrantz Professor of the History of Science and a professor of African and African American Studies, told Bajaj that she thought the day-to-day racism Black patients encounter in their engagements with the medical establishment was a bigger hindrance to care than historical atrocities like Tuskegee.

“I could see Simar’s wheels turning as she responded,” said Marcus. “For Simar, knowledge once acquired is not to be hoarded, but to be generously shared where it can change lives for the better.”

Lessons of equity within his family also draw Bajaj to medicine. His uncle, a radiologist and nuclear medicine physician, served in the Air Force.

“He was deployed to Afghanistan when I was about 9 years old, and he would tell me over Skype about how he would treat U.S. Air Force and NATO personnel, but also Taliban and al-Qaida members,” said Bajaj. “I asked, ‘Why are you treating the bad guys?’ And he told me that medicine doesn’t care about who you are. It treats you because you’re human.”

Before yesterdayHealth & Medicine – Harvard Gazette

MGH expert responds to 100,000 overdose deaths

29 November 2021 at 13:33

The Centers for Disease Control and Prevention recently reported that overdose deaths exceeded 100,000 over a 12-month period for the first time in U.S. history. The grim milestone represents an almost 30 percent increase from the previous 12-month period. Fentanyl, 100 times more powerful than heroin, and other synthetic opioids have been linked to a majority of the deaths, and experts say that isolation and anxiety related to COVID have reversed pre-pandemic progress against opioid abuse.

The Gazette spoke with Sarah Wakeman, medical director of the Substance Use Disorders Initiative at Massachusetts General Hospital and an associate professor at Harvard Medical School, about what can be done to save lives. The interview was edited for clarity and length.

Q&A

Sarah Wakeman

GAZETTE: What is fueling the increase in overdose deaths?

WAKEMAN:  The crisis and its worsening are related to a number of factors. One is the ongoing unpredictability and poisoning of the illicit drug supply. Increasingly, the drug supply is contaminated with fentanyl, and there is a lot of unpredictability in what people are using.

You could compare it to alcohol, where we have a regulated supply. We of course still worry about alcohol use disorder and identify and treat it. But if you’re going to a restaurant or a bar or a store and you’re consuming alcohol, you know the alcohol level by volume content of the product you’re consuming. But imagine if you ordered a drink, and it could be 5 percent beer or it could be 80 proof liquor — that would be huge difference, and you would have no sense of how to regulate that.

GAZETTE: What about the effects of COVID?

WAKEMAN: One meta and ongoing issue, even pre-COVID, was this growing unpredictability in the drug supply and the background of decades of policy approaches which have not adequately supported or funded effective treatment or harm reduction interventions to reduce overdose death. And then COVID happened and amplified things in a number of ways. First, it’s increased trauma, social isolation, loss of economic opportunity, boredom, despair, all of these factors that we know can increase chaotic substance use. It has also made it harder to access some of the treatments and resources that keep people safe. For example, many of the harm-reduction interventions that we advise people about, like never using alone or seeking out treatment services, became much harder in the time of COVID. And fundamentally, I think we’re seeing the end result of years of failed policies and approaches toward thinking about drug use and addiction and how we should be addressing these complex public health challenges.

The other part that’s been really crucial to note are the worsening racial disparities in the overdose crisis. In Massachusetts between 2019 and 2020, there was a 75 percent increase in opioid-related overdose deaths among Black men. I think the public narrative has been that this issue is only impacting white communities. But the reality is that Black communities are being ravaged by overdose, and the health harms of racism are increasingly evident in the overdose crisis. That’s layered on top of the fact that many of these communities have already been devastated by the failed and racist war on drugs, leading to families separated through the child welfare system, people sent to prison, incarceration instead of treatment.

GAZETTE: Men between the ages of 24 and 54 have been most affected by the overdose surge. What’s your response to that statistic?

WAKEMAN: I think that these are young people with decades of life ahead of them, and I think about what has not been working: supply-side strategies. This “let’s just make it harder for people to access it” strategy — a focus on opioid prescriptions, cracking down on the borders, increasing funding to the DEA, and increasing criminal prosecution for drug-related charges — has been wholly ineffective. Yet that’s what we continue to hear about, even now in 2021, and that’s where our funding gets directed.

I find a helpful framing to be “recovery from what to what?” What is it that someone actually needs to recover from? And what is their hope for recovery for the future? If you’re unhoused, if you have no job, if you’ve been cycling in and out of the criminal legal system, if you’ve been treated terribly by systems, been harmed by racism, if you have no hope for anything, why would you ever stop using drugs? Drugs are the one thing that would allow you to cope with that reality. And if you are using drugs, what strategies can we implement that we know will reduce your likelihood of dying?

Harvard epidemiologist awaits clearer picture on Omicron

29 November 2021 at 08:41

The COVID-19 variant Omicron triggered widespread alarm over the weekend, with the U.S. and other countries moving to restrict travel from southern Africa, where the variant was first detected. On Monday, the World Health Organization, having already stamped Omicron with its most serious tracking designation, warned that the variant poses a “very high” global risk. Cases have been identified in more than a dozen nations, including Canada.

Earlier this month, Mary Bushman, a postdoctoral research fellow in the Department of Epidemiology at the Harvard T.H. Chan School, co-authored a paper that modeled the impact of hypothetical variants on populations practicing a combination of masking, distancing, vaccination, and other COVID safety measures. The research singled out Delta-like variants — which combine high transmissibility with an ability to evade immune response — as a potentially devastating threat. We talked to Bushman as the world reacted to the emergence of Omicron. The interview has been edited for clarity and length.

Q&A

Mary Bushman

GAZETTE:  The new study, published in Cell, says that variants demonstrating both greater transmissibility and an ability to escape the immune system (i.e., cause breakthrough infections), rather than either trait in isolation, are the ones we should worry about most. Do we know how Omicron fits into this framework? And, if not, when might we?

BUSHMAN: Short answer: We don’t know yet. Longer answer: The variant has a number of mutations that hint at the potential for immune escape or increased transmissibility, but that’s conjecture, based on laboratory studies that are done at the cellular level. Those results don’t always hold up in real life, which is why it’s so important to do epidemiological studies that tell us how this variant behaves in people. There is data from South Africa showing that Omicron appears to have rapidly overtaken Delta to become the dominant strain in some areas, which could be attributable to immune escape and/or enhanced transmissibility, but not necessarily. At the moment, we don’t have the necessary information to distinguish between increased transmissibility, immune escape, and other factors.

Gazette: Is it likely that the current vaccines offer significant protection against the new variant?

BUSHMAN: Still too early to say, but studies are underway to find out. One good thing about the mRNA vaccines is that, in addition to antibodies, they provide protection in the form of T cells (a type of white blood cell). T cell responses may still provide partial protection even if mutations allow the virus to escape from antibodies.

Gazette: From a public health perspective, why impose travel bans? The most anyone will say is that the measure can buy time. How much, and how will scientists use it?

BUSHMAN: Travel restrictions are almost always too little, too late. Patchy surveillance means variants can spread quite far before they’re detected, and containment measures are usually leaky, so they don’t do a good job of keeping things out. In any case, it’s not clear that additional time would do us any good. We don’t have enough information to take targeted action, and while broad measures like low-cost rapid testing could make a big difference, we don’t seem to be doing anything on that scale.

Gazette: If, a few weeks from now, Omicron starts to wane and we find that it was mostly a false alarm, what are the most important lessons we should take from the experience? What can the world do to reduce the chances of a variant that lives up to the most dire predictions?

BUSHMAN: All signs point to the need for more vaccination in low-income and lower-middle-income countries, especially Africa. Vaccines are needed first and foremost to protect the people in countries that currently have low rates of vaccination, but by limiting the spread of the virus, we also limit opportunities for new variants to evolve.

Understanding the science behind a vaccine booster

23 November 2021 at 09:45

Questions about COVID-19 vaccine boosters — like who is eligible and how to choose one — have dominated scientific discussions, news headlines, and dinner-table conversations recently, but the practice of giving our immune systems periodic “refreshers” is anything but new.

Jonathan Abraham, assistant professor of microbiology in the Blavatnik Institute at Harvard Medical School and an infectious disease specialist at Brigham and Women’s Hospital, discussed the science and history of vaccine boosters.

Q&A

Jonathan Abraham

HMS: What exactly is a booster shot, and how does it work?

Abraham: A booster shot is meant to increase levels of immune responses after these have naturally waned. A booster tricks the immune system into thinking that it is again seeing a pathogen, so antibody producing cells, and other immune cells, are recalled into gear. The quantity and quality of antibodies that are produced can increase. Through a process called antibody affinity maturation, our immune system learns to do a better job at recognizing a pathogen and making antibodies that bind more tightly to their target. For the SARS-CoV-2 virus, for example, affinity matured antibodies can be more effective at recognizing variants with multiple mutations.

HMS: This will require some degree of speculation, but given that SARS-CoV-2 has shown remarkable capacity for shape-shifting and mutation, will we require periodic boosters for the foreseeable future?

Abraham: Vaccines remain extremely effective at preventing severe infection and death, but they are not 100 percent effective at stopping acquisition and transmission of the virus.  Particularly, in areas with high-infection rates due to low vaccination uptake, vaccinated people are more likely to be exposed to the virus and get a breakthrough infection. With this in mind, I would speculate that because of highly transmissible variants, we will need periodic boosters for the next few years. During that time frame, using an updated vaccine strain may be wise because we are unlikely to ever see the original vaccine strain again — it has virtually gone extinct.

HMS:  What other types of vaccines besides COVID-19 require periodic boosters?

Abraham: An example is Tdap immunization: tetanus, diphtheria, and acellular pertussis. We usually require boosters, with Td component or Tdap, every 10 years to preserve immunity.

HMS:  Why do we need boosters for some vaccines but not for others?

Abraham: For some pathogens, having preexisting and primed immune responses — for example, in the form of measurable antibody levels — is critical for efficacy. So, as antibody levels naturally wane over time, a booster is required. For other pathogens, like hepatitis B virus, completing the immunization three-shot series is likely to provide lifelong protection, so measurable antibody levels are not routinely checked. But, if the risk of infection is higher, for example, for health care workers, checking antibody levels at least once and providing a booster if antibodies are found to be low may be important. So, the decision to boost or not boost is multifactorial, and ultimately, it is based on studies and experience.

HMS:  Are COVID-19 boosters different in any way than other vaccine boosters?

Abraham: For now, the same SARS-CoV-2 spike protein antigen is used for the vaccine and the boosters. However, there is the chance that, over time, the SARS-CoV-2 spike protein will shape-shift or mutate enough that a booster with an updated strain antigen would be required to prime the immune system to recognize the mutant virus. This scenario would be more like what is done with the seasonal influenza virus vaccines every year, although we think more of flu vaccines as strain-matched vaccines as opposed to periodic boosters.

 

Age actively, Harvard researchers say

22 November 2021 at 12:00

Just about everyone knows that exercise is good for you. Some people can even rattle off reasons it keeps your muscles and joints strong, and how it fights off certain diseases. But how many people can tell you the story of why and how physical activity was built into human biology?

A team of evolutionary biologists and biomedical researchers from Harvard are taking a run at it (sometimes literally) in a new study published this week in PNAS. The work lays out evolutionary and biomedical evidence showing that humans, who evolved to live many decades after they stopped reproducing, also evolved to be relatively active in their later years.

The researchers say that physical activity later in life shifts energy away from processes that can compromise health and toward mechanisms in the body that extend it. They hypothesize that humans evolved to remain physically active as they age — and in doing so to allocate energy to physiological processes that slow the body’s gradual deterioration over the years. This guards against chronic illnesses such as cardiovascular disease, Type 2 diabetes, and even some cancers.

“It’s a widespread idea in Western societies that as we get older, it’s normal to slow down, do less, and retire,” said Harvard evolutionary biologist Daniel E. Lieberman, the paper’s lead author. “Our message is the reverse: As we get older, it becomes even more important to stay physically active.”

The research team, which includes Aaron Baggish and I-Min Lee from Harvard Medical School, believes the paper is the first detailed evolutionary explanation for why lack of physical activity as humans age increases disease risk and reduces longevity.

Baggish, 47, who also serves as team cardiologist for the New England Patriots and U.S. Soccer, and Lieberman, 57, are longtime running buddies and often discussed the ideas that went into the paper during 5- to 10-mile morning runs.

The study uses humans’ ape cousins as a jumping-off point. The researchers point out that apes, which usually live only about 35 to 40 years in the wild and rarely survive past menopause, are considerably less active than most humans, suggesting that there was selection in human evolution not just to live longer but also to be more physically active.

“We evolved basically from couch potatoes,” said Lieberman, who has twice observed wild chimpanzees in Tanzania and been surprised by how much of their day is spent “sitting on their butts, digesting.”

This is especially jarring when contrasted with contemporary hunter-gatherers, who average about 135 minutes of moderate to vigorous physical activity a day. That level of movement — about six to 10 times more than average Americans — is thought to be a key reason hunter-gatherers who survive childhood live about seven decades, approximately 20 years past the age at which humans stop having children, and also enjoy a longer “healthspan,” which is defined as the years of life spent in good health.

Researchers examined two pathways by which lifelong physical activity reallocates energy to improve health. The first involves steering excess energy away from potentially harmful mechanisms, like excess fat storage. The team also identified how physical activity allocates energy to repair and maintenance processes. The paper shows that besides burning calories, physical activity is physiologically stressful, causing damage to the body at the molecular, cellular, and tissue levels. The body’s response to this damage, however, is essentially to build back stronger.

This includes repairing tears in muscle fibers, repairing cartilage damage, and healing microfractures. The response also causes the release of exercise-related antioxidants and anti-inflammatories, and enhances blood flow. In the absence of physical activity, these responses are activated less. The cellular and DNA repair processes have been shown to lower the risk of diabetes, obesity, cancer, osteoporosis, Alzheimer’s, and depression.

“The key take-home point is that because we evolved to be active throughout our lives, our bodies need physical activity to age well. In the past, daily physical activity was necessary in order to survive, but today we have to choose to exercise, that is to do voluntary physical activity for the sake of health and fitness,” Lieberman said.

The research team, which includes graduate students Timothy Kistner and Daniel Richard, hope the study makes that message harder to ignore.

Physical activity levels have been decreasing worldwide as machines and technology replace human labor. A recent study from Lieberman’s lab showed that Americans are engaging in less physical activity than they did 200 years ago.

The researchers’ advice? Get out of your chair and get some exercise.

“The key is to do something, and to try to make it enjoyable so you’ll keep doing it,” Lieberman said. “The good news is that you don’t need to be as active as a hunter-gatherer. Even small amounts of physical activity — just 10 or 20 minutes a day —substantially lower your risk of mortality.”

Chan School event seeks way forward for long COVID patients

19 November 2021 at 15:02

Dismissive doctors, inconclusive tests, and an array of debilitating symptoms all too often explained away as signs of mental, rather than physical, distress. That’s been the experience for many patients suffering long COVID, a poorly-defined, long-lasting suite of symptoms affecting millions of Americans.

Patient advocates and health care experts who gathered virtually at the Harvard T.H. Chan School of Public Health Friday agreed that the first step in addressing the condition is relatively simple: Stop doubting patients who say they’re sick.

Patients and advocates recounted bad experience after bad experience: bouts of dizziness and vomiting, unrelenting pain, inability to stand up or get out of bed. They’ve lost jobs, experienced difficulties caring for children and themselves, and become suicidal and depressed. They’ve also faced skeptical medical professionals who insist that negative tests for SARS-CoV-2 mean they aren’t sick, that they should go home and wait it out, or possibly consider seeking mental health care.

Fiona Lowenstein, a journalist, long COVID sufferer, and founder of the patient group Body Politic, said the experience is both devastating and confusing, one of isolation and doubt. Chimére Smith, a patient advocate, said she was left to wait for hours for physicians who told her nothing was wrong and, when she described the cognitive impairment she experienced, was accused of drug use. Smith, who is African American, said she felt her diagnoses were affected not only by ignorance of an emerging condition but also by racism and sexism within the health care system.

“I would have doctors, usually white male doctors, who would look at me and say, ‘There’s nothing wrong. Everything is fine. Go home,’ and if something was wrong, ‘Just take the two weeks, and you’ll be fine,’” Smith said. “And I often think my two weeks have never come.”

The virtual event, “Understanding Long COVID: The Unseen Public Health Crisis,” took place Friday afternoon and featured Smith, Hannah Davis, founder of the Patient-Led Research Collaborative; Wes Ely, co-director for critical illness for Vanderbilt University’s Brain Dysfunction and Survivorship Center; Gary Gibbons, director of NIH’s National Heart, Lung, and Blood Institute; Kavita Patel, a Brookings Institution fellow, and Steven Phillips, vice president for science and strategy of the COVID Collaborative. It was moderated by Lowenstein.

“Long COVID affects millions around the globe, yet we barely understand this emerging condition,” said Harvard Chan School Dean Michelle Williams, who introduced the event. “We barely understand its devastating and long-lasting symptoms that prevent them from working, that prevent them from socializing, that prevent them from parenting, and in fact that prevents them from carrying on with any sense of normalcy. Like so many chronic disease sufferers before them, COVID long haulers face ambivalence and even outright distrust from the very health systems responsible for taking care of them.”

Even though the condition remains something of a mystery, panelists said the way forward starts with listening to — and believing —patients. From there, researchers can start cataloging symptoms — some 200 have been reported — and identify which tests have detected abnormalities, and which treatments have shown signs of helping.

Davis said despite the difficult time patients have had, it’s important that physicians and patients begin working together. It’s also important to recall that there’s a reason some never had a positive COVID test: In the pandemic’s early months, tests were scarce and unavailable to those not sick enough go to a doctor’s office or hospital. In addition, the cognitive dysfunction that many report was initially thought common only in older patients, but studies have shown it also crops up in younger ones. Davis said she finally felt heard when she visited a physician familiar with myalgic encephalomyelitis/chronic fatigue syndrome, whose symptoms overlap.

Panelists suggested an array of solutions, including extending physician visit times, since 15 minutes is often not long enough to appropriately care for a long COVID patient; developing a list of patient questions to help guide physicians unfamiliar with the condition as they try to make diagnoses; exploring other post-viral syndromes, like that associated with Lyme Disease, for clues; convening expert groups who can begin to standardize knowledge and language around the condition so medical professionals have a common body of knowledge to draw from; and encouraging patients to stay active and insist their voices be heard.

“We have to completely think about the patient voice being a central voice,” Smith said. “The truth is, we’ve been right. We were right before. We were calling it long COVID before a lot of people. We were galvanizing [action] on social media. That’s the reason why we’re having this conversation.”

Alcoholism treatment drug shows potential with COVID-19

17 November 2021 at 10:33

Every day, hundreds of thousands of new COVID-19 cases and thousands of new deaths are still being reported worldwide, creating a need for drugs that can combat the disease caused by SARS-CoV-2.

Now, new research led by investigators at Harvard Medical School and Boston Children’s Hospital points to a well-known and widely available drug called disulfiram (marketed as Antabuse) as a possible treatment for COVID-19.

In the retrospective study, published Oct. 28 in PLOS ONE, patients taking disulfiram for alcoholism were less likely to become infected with SARS-CoV-2, and those who did get infected were less likely to die from COVID-19 than those not taking the drug.

The researchers caution that since the study was observational, it cannot establish a cause-and-effect link between disulfiram and disease development. However, they say, the results are encouraging enough to warrant further study and clinical testing. The precise mechanism of the drug against SARS-CoV-2 is not yet known, but researchers have hypothesized that it may prevent the virus from taking hold by interfering with an enzyme it requires to replicate. Additionally, disulfiram may blunt the symptoms of severe COVID-19 by inhibiting a protein involved in hyperinflammation. If disulfiram’s effect against SARS-CoV-2 is confirmed, it could become a useful tool against the virus.

A pandemic pivot

In spring 2020, SARS-CoV-2 was rapidly spreading across the world, and it was quickly becoming apparent that the most severe — and deadly —symptoms of COVID-19 are caused by an intense inflammatory response to the virus. At the same time, Judy Lieberman, HMS professor of pediatrics at Boston Children’s, and Hao Wu, the Asa and Patricia Springer Professor of Structural Biology in the Blavatnik Institute at HMS, were investigating whether disulfiram, an oral medication widely prescribed for alcoholism, could be repurposed to treat inflammation. In May 2020, they published a study in mice demonstrating that disulfiram reduced inflammation caused by sepsis by blocking a key protein involved in the process.

Realizing that their research could be relevant to inflammation associated with COVID-19, the duo reached out to Chris Sander, professor in residence of cell biology at HMS.

“They approached me and asked, can you find any evidence computationally whether this drug works against COVID-19?” Sander recalled. “I just thought, the world is going to pieces here, let’s do something useful. I wanted to help them take their research one step further.”

Springing into action, Sander worked with Lieberman and Wu to assemble a team of epidemiologists and public health experts, including Nathanael Fillmore and Nhan Do at the Boston VA Cooperative Studies Program Center. The researchers used computational techniques to analyze a large database of clinical records from the national Veterans Affairs health care system.

The analysis included 944,127 veterans who had at least one SARS-CoV-2 test between February 2020 and February 2021; of these, 2,233 had been prescribed disulfiram for alcoholism. Veterans taking disulfiram had a 34 percent lower incidence of SARS-CoV-2 infection than those who weren’t. Moreover, no one on disulfiram who was infected with the virus died, compared with 3 percent of those infected and not on the drug.

“There’s evidence that disulfiram not only reduces the incidence of SARS-CoV-2 infection, but it may actually reduce the number of deaths,” Sander said. He noted, however, that the study, being retrospective, can only establish an association between disulfiram and SARS-CoV-2 — and thus the findings must be confirmed in randomized clinical trials.

A small randomized phase 2 clinical trial of disulfiram in patients with moderate COVID-19 is nearing completion, and another is underway. The authors hope that the study will motivate large international phase 3 trials of the drug. Noting that it would be unrealistic to give the drug as a preventative measure, they are especially interested in how patients hospitalized with severe COVID-19 fare on disulfiram.

The researchers are also eager for further research on the mechanism underlying disulfiram’s effect against SARS-CoV-2. One possibility is that the drug inhibits a key protease that SARS-CoV-2 needs in order to replicate, thus preventing the virus from proliferating inside cells. “That’s a plausible mechanism, but it must be confirmed with further research. It’s a work in progress,” Sander said. Disulfiram may also tamp down hyperinflammation — which can cause respiratory issues in patients with severe COVID-19 — by inhibiting a protein called gasdermin D that is needed for this inflammatory response.

If disulfiram does indeed reduce infection with SARS-CoV-2 and death from COVID-19, it could become part of a growing arsenal in the global fight against the disease.

The drug is FDA-approved and has been prescribed for over 60 years as a treatment for alcoholism. It is safe, inexpensive, familiar to physicians, and widely used in many countries.

“This is a great candidate for a repurposed drug,” Sander said. “It could easily be made available worldwide if we can prove it has a positive effect on patients with COVID-19.”

The work was supported by the British Heart Foundation (RG/4/32218), the VA Cooperative Studies Program, the VA Boston Healthcare System, the National Institute of Arthritis and Musculoskeletal and Skin Disease (K23AR069127), Dana-Farber Cancer Institute, Harvard Medical School, and the National Institutes of Health.

Scientists identify HIV patient whose body rids itself of virus

16 November 2021 at 08:00

During infection, HIV places copies of its genome into the DNA of cells, creating what is known as a viral reservoir. In this state, the virus effectively hides from anti-HIV drugs and the body’s immune response. In most people, new viral particles are constantly made from this reservoir. Anti-retroviral therapy (ART) can prevent the new viruses from being made but cannot eliminate the reservoir, necessitating daily treatment to suppress the virus.

Some people, known as elite controllers, have immune systems that are able to suppress HIV without the need for medication. Though they still have viral reservoirs that can produce more HIV virus, a type of immune cell called a killer T cell keeps the virus suppressed without the need for medication.

Xu Yu, a member of the Ragon Institute of MGH, MIT and Harvard, has been studying the HIV reservoirs of elite controllers. Her research group identified one patient who had no intact HIV viral sequence in her genome, indicating that her immune system may have eliminated the HIV reservoir — what scientists call a sterilizing cure. Yu’s team sequenced billions of cells from this patient, known as the San Francisco Patient, searching for any HIV sequence that could be used to create new virus, and found none. This extraordinary finding, the first known incidence of a sterilizing cure without a stem cell transplant, was reported in Nature in 2020 (and Yu discusses in this video).

Yu’s group now reports a second untreated HIV-infected patient, known as the Esperanza Patient, who, like the San Francisco Patient, has no intact HIV genomes found in more than 1.19 billion blood cells and 500 million tissue cells sequenced. This report, published in the Annals of Internal Medicine, may represent a second instance of a sterilizing cure.

“These findings, especially with the identification of a second case, indicate there may be an actionable path to a sterilizing cure for people who are not able to do this on their own,” says Yu, who is also a physician investigator at Harvard-affiliated Massachusetts General Hospital.

She further explains that these findings may suggest a specific killer T cell response common to both patients driving this response, with the possibility that other people with HIV have also achieved a sterilizing cure. If the immune mechanisms underlying this response can be understood by researchers, they may be able to develop treatments that teach others’ immune systems to mimic these responses in cases of HIV infection.

Yu adds: “We are now looking toward the possibility of inducing this kind of immunity in persons on ART through vaccination, with the goal of educating their immune systems to be able to control the virus without ART.”

Additional co-authors on this study include: Gabriela Turk, Kyra Seiger, Xiaodong Lian, Weiwei Sun, Elizabeth M. Parsons, Ce Gao, Yelizaveta Rassadkina, Maria Laura Polo, Alejandro Czernikier, Yanina Ghiglione, Alejandra Vellicce, Joseph Varriale, Jun Lai, Yuko Yuki, Maureen Martin, Ajantha Rhodes, Sharon R. Lewin, Bruce D. Walker, Mary Carrington, Robert Siliciano, Janet Siliciano, Mathias Lichterfeld, and Natalia Laufer.

Funding for this study comes from National Institutes of Health (NIH) grants HL134539, AI116228, AI078799, DA047034, AI155171, and AI150396 and by the Bill & Melinda Gates Foundation (INV-002703); NIH grants AI135940, AI114235, AI117841, AI120008, AI152979, AI130005, DK120387, and AI155233 and by amfAR (110181-69-RGCV). Lichterfeld and Yu are Associated Members of the BEAT-HIV Martin Delaney Collaboratory (UM1 AI126620). This project was funded in whole or in part by federal funds from the Frederick National Laboratory for Cancer Research under contract no. HHSN261200800001E. This research was supported in part by the Intramural Research Program of the NIH, Frederick National Laboratory, Center for Cancer Research.

AI-based method predicts risk of atrial fibrillation

15 November 2021 at 09:04

An artificial intelligence-based method for identifying patients who are at risk for atrial fibrillation has been developed by a team led by researchers at Harvard-affiliated Massachusetts General Hospital and the Broad Institute of MIT and Harvard

Atrial fibrillation — an irregular and often rapid heart rate — is a common condition that often leads to the formation of clots in the heart that can travel to the brain to cause a stroke. The study was published in Circulation.

The investigators developed the artificial intelligence-based method to predict the risk of atrial fibrillation within the next five years based on results from electrocardiograms (noninvasive tests that record the electrical signals of the heart) in 45,770 patients receiving primary care at MGH.

Next, the scientists applied their method to three large data sets from studies including a total of 83,162 individuals. The AI-based method predicted atrial fibrillation risk on its own and was synergistic when combined with known clinical risk factors for predicting atrial fibrillation. The method was also highly predictive in subsets of individuals such as those with prior heart failure or stroke.

“We see a role for electrocardiogram-based artificial intelligence algorithms to assist with the identification of individuals at greatest risk for atrial fibrillation,” says senior author Steven A. Lubitz, a cardiac electrophysiologist at MGH, an associate member at the Broad Institute, and associate professor of medicine at Harvard Medical School.

The algorithm could serve as a form of pre-screening tool for patients who may currently be experiencing undetected atrial fibrillation, prompting clinicians to search for atrial fibrillation using longer-term cardiac rhythm monitors, which could in turn lead to stroke prevention measures, explains Lubitz.

The study’s findings also demonstrate the potential power of AI — which in this case involve a specific type called machine learning — to advance medicine. “With the explosion of data science technologies and the vast amounts of clinical data now available, machine learning is poised to help clinicians and researchers make great strides in enhancing cardiology care,” says co-author Anthony Philippakis, chief data officer at the Broad and co-director of the institute’s Eric and Wendy Schmidt Center. “As a data scientist and former cardiologist, I’m excited to see how machine learning–based methods can work with the tests and clinical approaches we use every day to help us improve risk prediction and take care of patients with atrial fibrillation.”

Adds co–lead author Shaan Khurshid, an electrophysiology clinical and research fellow at MGH: “The application of such algorithms could prompt clinicians to modify important risk factors for atrial fibrillation that may reduce the risk of developing the disease altogether.”

Co–lead author is Shaan Khurshid, an electrophysiology clinical and research fellow at MGH; co-authors include Samuel Friedman, Christopher Reeder, Paolo Di Achille, Nathaniel Diamant, Pulkit Singh, Lia X. Harrington, Xin Wang, Mostafa A. Al-Alusi, Gopal Sarma, Andrea S. Foulkes, Patrick T. Ellinor, Christopher D. Anderson, Jennifer E. Ho, and Puneet Batra.

This work was supported by the National Institutes of Health, the American Heart Association, the Doris Duke Foundation, and the Leducq Foundation.

Less sodium, more potassium lowers risk of cardiovascular disease

13 November 2021 at 05:00

Lower sodium consumption and higher potassium intake is linked with a reduced risk of cardiovascular disease (CVD) in most people, according to a study led by Harvard T.H. Chan School of Public Health researchers.

“Methodological limitations in prior observational studies have led to confusion about whether reducing current levels of sodium in the diet increases CVD risk,” said first author Yuan Ma, a research scientist in the Department of Epidemiology at Harvard Chan School. “Our study combined high-quality individual participant data from six cohort studies where sodium was measured by the currently most reliable method, namely, multiple 24-hour urine samples. Our results should help clarify sodium’s role in CVD — that lower consumption is associated with lower risk of CVD in most populations, including in the U.S.”

The study was published online Saturday in the New England Journal of Medicine.

Sodium, one of the components of table salt, is naturally found in some foods, but high amounts of sodium are frequently added to commercially processed, packaged, and prepared foods. The U.S. Food and Drug Administration recently released new voluntary guidance encouraging the food industry to gradually reduce sodium — linked in previous research with increased blood pressure  —in commercially produced foods over the next two and a half years.

Potassium has an opposite effect in the body — it can help relax blood vessels and increase sodium excretion while decreasing blood pressure. Rich sources of potassium include fruits, leafy greens, beans, nuts, dairy foods, and starchy vegetables like winter squash.

The relationship between sodium consumption and the risk of CVD has been controversial, according to the study authors. Comprehensive data, including those from randomized trials, have consistently shown that as daily sodium intake increases, so does blood pressure, and as blood pressure increases, so does the risk of CVD. A few cohort studies suggested that lower sodium intake is associated with increased risk of CVD. However, those studies assessed sodium intake using methods prone to measurement errors, such as spot urine or single 24-hour samples that are unreliable for estimating individual usual sodium intake.

In the new study, the researchers conducted a pooled analysis of six prospective cohort studies: the Health Professionals Follow-up Study, the Nurses’ Health Study, the Nurses’ Health Study II, the Prevention of REnal and Vascular ENd-stage Disease study, and the Trials of Hypertension Prevention Follow-up studies. The researchers analyzed the individual sodium and potassium excretion data and the incidence of CVD — which includes coronary heart disease or stroke. The data came from multiple 24-hour urine samples — the most reliable method for assessing sodium intake — that were taken from more than 10,000 generally healthy adults with a study follow-up of CVD events for an average of nearly nine years. A total of 571 cardiovascular events were documented during the cohort studies.

After accounting for a wide range of cardiovascular risk factors, the researchers determined that higher sodium intake, as measured by multiple 24-hour urine samples, was significantly associated with higher cardiovascular risk in a dose-response manner with a daily sodium intake of approximately 2,000 to 6,000 mg. Every 1,000 mg per day increase in sodium excretion was associated with an 18 percent increased risk of CVD. For every 1,000 mg per day increase in potassium excretion, the risk of cardiovascular disease was 18 percent lower. In addition, higher sodium to potassium ratio was significantly associated with increased cardiovascular risk. These associations were consistent across subgroups defined according to age, sex, baseline hypertension, weight status, and years of follow-up.

“This study underscores the importance of using a reliable biomarker to measure habitual sodium intake and assess its relationship with cardiovascular risk,” said Frank Hu, Fredrick J. Stare Professor of Nutrition and Epidemiology, chair of Department of Nutrition at Harvard Chan School and senior author of the paper. “The findings provide further support for public health strategies including regulations, food labeling, and promoting healthy dietary patterns to reduce sodium intake and increase potassium intake.”

Other institutions involved in this research included the Wolfson Institute of Population Health at Queen Mary University of London, Brigham and Women’s Hospital, University Medical Center Groningen, and O’Brien Institute of Public Health and Libin Cardiovascular Institute of Alberta at the University of Calgary, Canada.

Other Harvard Chan School co-authors of the study included Qi Sun, Changzheng Yuan, Gary Curhan, Molin Wang, Eric Rimm, JoAnn Manson, Walter Willett, Albert Hofman, and Nancy Cook.

Funding for the study came from the American Heart Association (20POST35120057 and 14GRNT18440013), the National Institutes of Health (K99AG071742, CA186107, CA176726, CA167552, CA055075, CA071789, DK082486, DK091417, DK059583, ES021372, HL35464, HL60712, HL34594, HL145386, HL37849, HL37852, HL37853, HL37854, HL37872, HL37884, HL37899, HL37904, HL37906, HL37907, HL37924, and HL57915), the Dutch Kidney Foundation, the Dutch Ministry of Health, and University Hospital Groningen. 

 

Harvard researcher turns to chess for insights on brain health

12 November 2021 at 13:35

As the U.S. population ages, concerns about dementia grow larger. David Canning, the Richard Saltonstall Professor of Population Sciences and of Economics and International Health at the Harvard T.H. Chan School of Public Health, is studying aging among chess players, reasoning that the centuries-old game serves as a type of cognitive test. The research involves analysis of a massive database of games from the U.S. Chess Federation and a second pilot study that will follow 200 players over time. Canning spoke to the Gazette about what he hopes to find. The interview was edited for clarity and length.

Q&A

David Canning

GAZETTE: Why study chess and cognitive decline?

CANNING:  There’s a big concern about population aging, and dementia in particular: what it’s going to do to the economy, what it’s going to do to the healthcare system. There are a lot of people living longer and we had this compression of morbidity over the last century — the period of ill health at the end of life getting shorter. But now there’s some evidence in the U.S. over the last 20 years that morbidity is expanding, so people are living longer but they’re not healthy years. One of the big burdens is dementia.

The reason for chess is that I play chess. One of the problems in studying dementia is our data sets are small because it’s hard to get people to do surveys, and it takes an hour to do full cognitive testing on people. Then I realized that we have all these people playing chess. They’re essentially doing cognitive tests many times a year. It’s a huge data set that spans the whole age range — very few data sets do. We have children playing chess, we have old people playing chess. It has been used in other countries — some people have looked at world champions, and elite players have been looked at — but no one has ever used the U.S. chess database before.

GAZETTE: So the idea is to use chess as a cognitive survey?

CANNING: Yes, we can get insights into cognition by looking at chess performance. There is a potential complication, in that mental activity may improve your cognitive performance, so the players may do better because they’re playing. We want to study that as well, though the main evidence is that it is physical activity that really helps amend your cognition. The evidence for mental activity helping is mixed. But it is possible that playing chess prevents cognitive decline.

GAZETTE: What does the existing literature on chess and cognition show?

CANNING: There’s a literature on world champions, which shows only slow decline with age. We also have standard cognitive tests of chess players. There is a correlation with chess performance and general cognitive abilities, but it’s not incredibly high. There’s quite a lot of work on age effects and cohort effects, looking at life cycle patterns of chess ability, but usually focused on elite players. And then there is some literature on whether playing chess is good for cognition, particularly in children.

One thing I’m particularly interested in is air pollution and cognition. There’s a study actually measuring air pollution in a chess tournament hall and its effect on move quality. You can measure the quality of each move versus a computer program and basically people’s move quality goes down when there’s air pollution. I’m interested in looking at that, and whether that affects performance.

GAZETTE: How big is the effect?

CANNING: I just got results. I was excited because I linked the air pollution and the chess data set for the first time. The finding we have is fine particulate matter, PM 2.5, varies between about 0 and 20 micrograms per cubic meter in the U.S. and it goes up to over 100 in developing countries. In India rates of 70 or 80 are quite common. A 10 point change in air pollution —10 points higher on your average annual exposure — reduces your chance of winning a game by about 30 percent.

GAZETTE: I think people tend to think of these effects as being durable: You live in a polluted place and the effects are constant. But pollution can affect you differently on different days?

CANNING: There is the literature on long-term effects on mortality, but there’s also literature on daily effects, these acute effects, with higher death rates on days with high pollution. The evidence on cognition is similar, with both long-term chronic effects and a short-run acute effect. There’s also a lot of evidence linking general cognitive abilities to chess ability, but no one’s really looked at that over time. What we want to do in the long-run study is look at a group of chess players over time, hopefully three to five years, and see how their cognitive ability changes and their chess-playing ability changes. Changes over time are more interesting than what the levels are. We can also get at this issue of if people stop playing, does that affect cognition? It’s a really good data set, but quite a lot of people drop out so there’s a lot of loss to follow up, attrition. People stop playing chess after a few years.

GAZETTE: Was that a surprise? I always thought it was a lifelong game.

CANNING: I thought so too, but what we see is a lot of dropout and turnover over time. Most chess players are under 18 because a lot of people play in school and then they quit when they leave school. People play as adults, but even among adults we are finding in any year about 30 percent of players are dropping out. There’s more turnover of players than I was expecting. I thought that once people were playing and they were older, they would be very long term. There are some, but actually the attrition rate is quite high.

GAZETTE: You’re still recruiting for this study, is that right?

CANNING: We have this big data set with millions of observations from the U.S. Chess Federation for all of the chess players in the U.S. For our pilot study, we have about 150 out of a target of 200 people recruited. What we want to do with the pilot is get some baseline and show that we can do it. And then do a bigger study where we have a big cohort of chess players that we follow.

GAZETTE: So the first study, with the big data set, looks back in time at games and scores and environmental conditions that have already occurred. And the pilot will move ahead in time, following this group longitudinally?

CANNING: Yes. For the pilot, we want to use the cohort of chess players to harmonize the chess-playing data with standard cognitive testing to understand really what we’re getting out here. That cohort will allow us to do that and also look at changes over time. I would also love to do an intervention study encouraging people to keep playing chess and see what effect that has. That would be very exciting.

 

Pills could prove COVID game changer

10 November 2021 at 12:09

Harvard experts in medical therapeutics say the recent development of pills to treat COVID-19 may turn out to be a pandemic game changer for a simple reason: When it comes to treating the ailment, the earlier the better.

Mark Namchuk, executive director of Harvard Medical School’s Therapeutics Initiative, said pills have some clear advantages over existing treatments — the drug remdesivir and a handful of antibody therapies — because they are by comparison easy to transport, store, and administer. The other treatments must be given intravenously and have largely been reserved for use by the sickest patients confined to medical facilities late in their illness’ course.

Namchuk said that assuming the pills are made widely available, they can be prescribed soon after symptoms start at home, with nothing else required to administer them beyond possibly a glass of water.

“They’re both oral, so much easier to get them distributed to folks early in their illness and make them more broadly available,” said Namchuk, professor of the practice of biological chemistry and molecular pharmacology. “The efficacy is very encouraging, but the route of administration opens up the possibility of using it more broadly.”

The assessment comes after reports by Merck and Ridgeback Biotherapeutics that their COVID-19 pill — currently being reviewed by federal regulators — lowers risk of hospitalization and death by 50 percent, and on the heels of last week’s promising results by Pfizer Inc., which said a Phase 2/3 study of its pill showed that it cuts risk of hospitalization and death by 89 percent. The Pfizer results were so promising the study was halted early, the company said. About 1 percent of study participants (6 out of 607) were hospitalized, and none died after 28 days. That compared with 6.7 percent (41 out of 612) hospitalized in the control group, with 10 subsequently dying. The company also plans to seek FDA emergency use authorization to market the pill.

Jonathan Abraham, assistant professor of microbiology and, with Namchuk, co-leader of the Massachusetts Consortium on Pathogen Readiness’ Therapeutics Working Group, said the ability to mass-produce a stable, long-lasting pill will likely mean far fewer people wind up needing hospitalization. That will enhance protection of society’s most vulnerable and ease the strain the pandemic continues to exert on the nation’s health care system.

“This is a game changer from the standpoint of being able to get a direct-acting antiviral in a person’s system as quickly as possible,” Abraham said. “There was a lot of excitement about monoclonal antibodies — and there still is — but the big issue there has been the rapidity at which those can actually be administered. I think the biology of these viruses teaches us we just need to be able to treat these types of infections as early as possible.”

Abraham said vaccination will remain an important tool to fight the virus, as will public health measures that are likely to remain useful against any new variant that might emerge. He added, though, that an effective treatment will be an important boon for vulnerable people, particularly if it both eases symptoms and reduces transmission.

“The key to me in terms of the bigger question of how this changes the landscape of the pandemic is really one of how do we prevent transmission?” Abraham said. “And the biggest question is, how are we doing at protecting our most vulnerable populations, including the elderly?”

Namchuck said the pill form also means that, once production ramps up, it can make a big impact in parts of the world struggling to acquire vaccine doses or whose lack of infrastructure hampers the distribution of vaccines that need deep refrigeration to retain effectiveness.

“The ability to be able to get something as a tablet or a pill that you can ship everywhere, that’s room-temperature stable, doesn’t require any complicated intervention, is a really important next step for the current pandemic,” Namchuk said.

The two companies’ pills operate by different mechanisms. The Merck drug, called molnupiravir, inserts errors into the virus’ genetic code to disrupt replication. The Pfizer drug, Paxlovid, is a protease inhibitor, a class of drugs developed in the fight against HIV and Hepatitis C with which there are decades of experience. Paxlovid also attacks SARS-CoV-2’s ability to replicate, but by interfering with the process by which proteins important in reproduction are “cut” from precursor molecules, rendering them unusable by the virus. Abraham speculated that the drugs will likely need to be administered with a second drug that in combination reduces the chances of the virus becoming drug resistant.

Namchuk said the development of pills has been fairly swift, though it has lagged that of vaccines. The Merck drug had been tested earlier for flu, and Pfizer leveraged its past experience seeking treatments for the original SARS virus.

Both companies tested their drugs on high-risk adults, but Namchuk said that if the pills become widely available, they could potentially also be used in conjunction with vaccines to fight breakthrough infections and even, if their safety profiles are robust enough for wide use, as a precaution before symptoms develop among those exposed to COVID.

“When you think about the impact of a drug like that, being able to be broadly distributed and using it even in patients where they’ve been exposed but are not showing symptoms, that could be really beneficial,” he said.

Blocking tau, an Alzheimer’s hallmark, may help ALS patients

10 November 2021 at 11:59

New research may have identified a potential treatment for amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease.

The study, published in the journal Molecular Neurobiology, was led by investigators at the Healey Center for ALS at Massachusetts General Hospital.

ALS, a degenerative condition without a cure, attacks brain and spinal cord nerve cells and progressively eats away at individuals’ ability to move, speak, eat, and even breathe. Previous studies have implicated dysfunction within mitochondria, which generate energy within cells, as playing an important role in the development of ALS. Studies of Alzheimer’s disease also have linked changes in mitochondrial function to interactions between an abnormal form of tau, which accumulates in the brains of Alzheimer’s patients, and a mitochondrial protein called dynamin-related protein 1. Piecing these bits of information together, Ghazaleh Sadri-Vakili, director of the NeuroEpigenetics Laboratory at MGH’s Institute for Neurodegenerative Disease and the Healey Center, and her colleagues examined whether these interactions might also promote mitochondrial dysfunction in ALS, and whether reducing tau could be a novel and promising therapeutic approach to fight the disease.

Using brain tissue from dead ALS patients, the team found the abnormal form of tau in brain in places where tau is not normally found. When cells were grown in contact with deceased ALS patients’ brain tissue that contained abnormal tau, the cells’ mitochondria fragmented and oxidative stress increased. Importantly, reducing tau with a specific degrader reversed these effects, reducing mitochondrial fragmentation and lowering oxidative stress.

“We demonstrated for the first time that targeting tau with a new class of small molecules that selectively degrade it can reverse the ALS-induced changes in mitochondria’s shape and function, highlighting tau as a potential therapeutic target,” said Sadri-Vakili.

Co-authors include Tiziana Petrozziello, Evan A. Bordt, Alexandra N. Mills, Spencer E. Kim, Ellen Sapp, Benjamin A. Devlin, Abigail A. Obeng-Marnu, Sali M.K. Farhan, Ana C. Amaral, Simon Dujardin, Patrick M. Dooley, Christopher Henstridge, Derek H. Oakley, Andreas Neueder, Bradley T. Hyman, Tara L. Spires-Jones, Staci D. Bilbo, Khashayar Vakili, Merit E. Cudkowicz, James D. Berry, Marian DiFiglia, M. Catarina Silva, and Stephen J. Haggarty.

 Funding for the study was provided by the Judith and Jean Pape Adams Charitable Foundation; the Byrne Family Endowed Fellowship in ALS Research; the ALS Canada Tim E. Noël Postdoctoral Fellowship; the Alzheimer’s Association; the Jack Satter Foundation; the Dr. and Mrs. E. P. Richardson, Jr Fund for Neuropathology at MGH; the Alzheimer’s Association/Rainwater Foundation Tau Pipeline Enabling Program; and the Stuart & Suzanne Steele MGH Research Scholars Program.

 

Harvard diabetes researcher details science behind potential breakthrough

9 November 2021 at 12:20

When Vertex Pharmaceuticals announced last month that its investigational stem-cell-derived replacement therapy was, in conjunction with immunosuppressive therapy, helping the first patient in a Phase 1/2 clinical trial robustly reproduce his or her own fully differentiated pancreatic islet cells, the cells that produce insulin, the news was hailed as a potential breakthrough for the treatment of Type 1 diabetes. For Harvard Stem Cell Institute Co-Director and Xander University Professor Douglas Melton, whose lab pioneered the science behind the therapy, the trial marked the most recent turning point in a decades-long effort to understand and treat the disease. In a conversation with the Gazette, Melton discussed the science behind the advance, the challenges ahead, and the personal side of his research. The interview was edited for clarity and length.

Q&A

Douglas Melton

GAZETTE: What is the significance of the Vertex trial?

MELTON: The first major change in the treatment of Type 1 diabetes was probably the discovery of insulin in 1920. Now it’s 100 years later and if this works, it’s going to change the medical treatment for people with diabetes. Instead of injecting insulin, patients will get cells that will be their own insulin factories. It’s a new kind of medicine.

GAZETTE: Would you walk us through the approach?

MELTON: Nearly two decades ago we had the idea that we could use embryonic stem cells to make functional pancreatic islets for diabetics. When we first started, we had to try to figure out how the islets in a person’s pancreas replenished. Blood, for example, is replenished routinely by a blood stem cell. So, if you go give blood at a blood drive, your body makes more blood. But we showed in mice that that is not true for the pancreatic islets. Once they’re removed or killed, the adult body has no capacity to make new ones.

So the first important “a-ha” moment was to demonstrate that there was no capacity in an adult to make new islets. That moved us to another source of new material: stem cells. The next important thing, after we overcame the political issues surrounding the use of embryonic stem cells, was to ask: Can we direct the differentiation of stem cells and make them become beta cells? That problem took much longer than I expected — I told my wife it would take five years, but it took closer to 15. The project benefited enormously from undergraduates, graduate students, and postdocs. None of them were here for 15 years of course, but they all worked on different steps.

GAZETTE: What role did the Harvard Stem Cell Institute play?

MELTON: This work absolutely could not have been done using conventional support from the National Institutes of Health. First of all, NIH grants came with severe restrictions and secondly, a long-term project like this doesn’t easily map to the initial grant support they give for a one- to three-year project. I am forever grateful and feel fortunate to have been at a private institution where philanthropy, through the HSCI, wasn’t just helpful, it made all the difference.

I am exceptionally grateful as well to former Harvard President Larry Summers and Steve Hyman, director of the Stanley Center for Psychiatric Research at the Broad Institute, who supported the creation of the HSCI, which was formed specifically with the idea to explore the potential of pluripotency stem cells for discovering questions about how development works, how cells are made in our body, and hopefully for finding new treatments or cures for disease. This may be one of the first examples where it’s come to fruition. At the time, the use of embryonic stem cells was quite controversial, and Steve and Larry said that this was precisely the kind of science they wanted to support.

GAZETTE: You were fundamental in starting the Department of Stem Cell and Regenerative Biology. Can you tell us about that?

MELTON: David Scadden and I helped start the department, which lives in two Schools: Harvard Medical School and the Faculty of Arts and Science. This speaks to the unusual formation and intention of the department. I’ve talked a lot about diabetes and islets, but think about all the other tissues and diseases that people suffer from. There are faculty and students in the department working on the heart, nerves, muscle, brain, and other tissues — on all aspects of how the development of a cell and a tissue affects who we are and the course of disease. The department is an exciting one because it’s exploring experimental questions such as: How do you regenerate a limb? The department was founded with the idea that not only should you ask and answer questions about nature, but that one can do so with the intention that the results lead to new treatments for disease. It is a kind of applied biology department.

GAZETTE: This pancreatic islet work was patented by Harvard and then licensed to your biotech company, Semma, which was acquired by Vertex. Can you explain how this reflects your personal connection to the research?

MELTON: Semma is named for my two children, Sam and Emma. Both are now adults, and both have Type 1 diabetes. My son was 6 months old when he was diagnosed. And that’s when I changed my research plan. And my daughter, who’s four years older than my son, became diabetic about 10 years later, when she was 14.

When my son was diagnosed, I knew nothing about diabetes and had been working on how frogs develop. I changed my research focus, thinking, as any parent would, “What am I going to do about this?” Again, I come back to the flexibility of Harvard. Nobody said, “Why are you changing your research plan?”

GAZETTE: What’s next?

MELTON: The stem-cell-derived replacement therapy cells that have been put into this first patient were provided with a class of drugs called immunosuppressants, which depress the patient’s immune system. They have to do this because these cells were not taken from that patient, and so they are not recognized as “self.” Without immunosuppressants, they would be rejected. We want to find a way to make cells by genetic engineering that are not recognized as foreign.

I think this is a solvable problem. Why? When a woman has a baby, that baby has two sets of genes. It has genes from the egg, from the mother, which would be recognized as “self,” but it also has genes from the father, which would be “non-self.” Why does the mother’s body not reject the fetus? If we can figure that out, it will help inform our thinking about what genes to change in our stem cell-derived islets so that they could go into any person. This would be relevant not just to diabetes, but to any cells you wanted to transplant for liver or even heart transplants. It could mean no longer having to worry about immunosuppression.

Baby teeth may help identify kids at risk for mental disorders

9 November 2021 at 10:57

The thickness of growth marks in primary (or “baby”) teeth may help identify children at risk for depression and other mental health disorders later in life, according to researchers at Harvard-affiliated Massachusetts General Hospital.

The results of this study were published in JAMA Network Open.

The researchers believe the findings could lead to the development of a much-needed tool for identifying children who have been exposed to early-life adversity, which is a risk factor for psychological problems.

The origin of this study traces back several years with senior author Erin C. Dunn, a social and psychiatric epidemiologist and an investigator in MGH’s Psychiatric and Neurodevelopmental Genetics Unit. Dunn studies the effects of childhood adversity, which research suggests is responsible for up to one-third of all mental health disorders. She is particularly interested in the timing of these adverse events and in uncovering whether there are sensitive periods during child development when exposure to adversity is particularly harmful. Yet Dunn notes that she and other scientists lack effective tools for measuring exposure to childhood adversity. Asking people (or their parents) about painful experiences in their early years is one method, but that’s vulnerable to poor recall or reluctance to share difficult memories. “That’s a hindrance for this field,” says Dunn.

However, Dunn was intrigued to learn that anthropologists have long studied the teeth of people from past eras to learn about their lives.

“Teeth create a permanent record of different kinds of life experiences,” she says. Exposure to sources of physical stress, such as poor nutrition or disease, can affect the formation of dental enamel and result in pronounced growth lines within teeth, called stress lines, which are similar to the rings in a tree that mark its age. Just as the thickness of tree growth rings can vary based on the climate surrounding the tree as it forms, tooth growth lines can also vary based on the environment and experiences a child has in utero and shortly thereafter, the time when teeth are forming. Thicker stress lines are thought to indicate more stressful life conditions.

Dunn developed a hypothesis that the width of one variety in particular, called the neonatal line (NNL), might serve as an indicator of whether an infant’s mother experienced high levels of psychological stress during pregnancy (when teeth are already forming) and in the early period following birth.

To test this hypothesis, Dunn and two co-lead authors — postdoctoral research fellow Rebecca V. Mountain and data analyst Yiwen Zhu, who were both in the Psychiatric and Neurodevelopmental Genetics Unit at the time of the study — led a team that analyzed 70 primary teeth collected from 70 children enrolled in the Avon Longitudinal Study of Parents and Children in the United Kingdom. In ALSPAC, parents donated primary teeth (specifically, the pointed teeth known as canines) that naturally fell out of the mouths of children aged 5 to 7. The width of the NNL was measured using microscopes. Mothers completed questionnaires during and shortly after pregnancy that asked about four factors that are known to affect child development: stressful events in the prenatal period, maternal history of psychological problems, neighborhood quality (whether the poverty level was high or it was unsafe, for instance), and level of social support.

Several clear patterns emerged. Children whose mothers had lifetime histories of severe depression or other psychiatric problems, as well as mothers who experienced depression or anxiety at 32 weeks of pregnancy, were more likely than other kids to have thicker NNLs. Meanwhile, children of mothers who received significant social support shortly after pregnancy tended to have thinner NNLs. These trends remained intact after the researchers controlled for other factors that are known to influence NNL width, including iron supplementation during pregnancy, gestational age (the time between conception and birth) and maternal obesity.

No one is certain what causes the NNL to form, says Dunn, but it’s possible that a mother experiencing anxiety or depression may produce more cortisol, the “stress hormone,” which interferes with the cells that create enamel. Systemic inflammation is another candidate, says Dunn, who hopes to study how the NNL forms. And if the findings of this research can be replicated in a larger study, she believes that the NNL and other tooth growth marks could be used in the future to identify children who have been exposed to early life adversity.

“Then we can connect those kids to interventions,” says Dunn, “so we can prevent the onset of mental health disorders, and do that as early on in the lifespan as we possibly can.”

Dunn is also an associate professor of psychiatry at Harvard Medical School. Mountain is now a postdoctoral research fellow at Maine Medical Center Research Institute. Zhu is now a doctoral student at the Harvard T.H. Chan School of Public Health.

This research was supported by a grant from the Bezos Foundation. Dunn is also supported by the National Institute of Mental Health.

Potential treatment found for COVID-related GI issues

8 November 2021 at 11:58

Most of us are familiar with COVID-19’s hallmark symptoms of a loss of taste or smell and difficulty breathing, but a full 60 percent of patients infected with SARS-CoV-2 also report gastrointestinal symptoms such as nausea, diarrhea, and stomach pain.

Infection of the gut, which expresses high levels of the ACE2 receptor protein that SARS-CoV-2 uses to enter cells, is correlated with more severe cases of COVID-19, but the exact interactions between the virus and intestinal tissue is difficult to study in human patients. Animal models, while useful, do not fully reflect how human organs react to infection by pathogens.

To solve that problem, a team of scientists at the Wyss Institute for Biologically Inspired Engineering at Harvard University and several other Wyss partner organizations in Boston used a human Intestine Chip previously developed at the institute to study coronavirus infection and potential treatments in an environment that mimics the human intestine more effectively than cells grown in a dish.

They infected the Intestine Chip with a coronavirus called NL63 that causes the common cold and, like SARS-CoV-2, uses the ACE2 receptor to enter cells, and then tested the effects of various drugs that have been proposed for treating SARS-CoV-2 infection.

The scientists found that a drug called nafamostat reduced infection while the drug remdesivir, which has been used to treat COVID-19 patients, did not reduce infection and actually damaged the intestinal tissue. This new preclinical model, which could be used to identify drugs that can target GI symptoms associated with both the common cold and SARS-CoV-2 virus infections in the future, is described in Frontiers in Pharmacology.

Toxic treatment

The Intestine Chip is about the size of a USB memory stick made of a clear, flexible polymer through which run two parallel channels: one lined with human blood vessel cells, the other with human intestinal lining cells. A permeable membrane between the two channels ensures that the cells can exchange molecular messengers, and that substances can be delivered into the blood via the gut, mimicking digestion. The tissues in the Intestine Chip are repeatedly stretched and released to recreate the rhythmic movements caused by muscle contractions in the GI tract.

Researchers’ tool discerns COVID symptoms from vaccine reaction

5 November 2021 at 07:01

A decision-support tool helped health care workers distinguish symptoms associated with COVID-19 vaccinations from symptoms of the virus itself, found a study by investigators from Harvard-affiliated hospitals in the Massachusetts General Brigham system.

The study, published in Infection Control & Hospital Epidemiology, suggests that providing this guidance may keep employees from needlessly missing work during a critical time and help curb the spread of COVID-19 in health care settings. The study assessed employees vaccinated from Dec. 16, 2020 to March 14, 2021, in the midst of a sharp increase of COVID-19 cases in the United States, including Massachusetts.

“That’s also when we were vaccinating tens of thousands of employees, all in a very short period of time,” says the study’s co-lead author, infectious diseases specialist and health care epidemiologist Erica S. Shenoy, associate chief of the Infection Control Unit at Massachusetts General Hospital and associate professor of medicine at Harvard Medical School.

Shenoy and her colleagues recognized a potential problem with the massive number of MGB employees getting the vaccines over a short period. In keeping with public health requirements, employees at all MGB facilities must attest that they are not experiencing any symptoms of COVID-19 before reporting to work each day. However, receiving a COVID-19 vaccination can trigger a variety of symptoms, and some overlap with those caused by the virus itself, including fever, fatigue, and muscle or joint pain. That meant that a large number of MGB employees could fail attestation in the first few days after getting vaccinated and miss work, even though the symptoms that kept them home were more likely related to receiving the vaccine than to COVID-19.

“Workforce preservation was critically important,” says Shenoy. “We were in the middle of another surge and we had to make sure everyone who could be at work could do so safely.”

Shenoy and her colleagues developed an electronic decision-support tool for smartphone or computer that MGB employees were asked to use during the three days after vaccination. The tool presented a list of symptoms, some associated with allergic reactions (such as a rash or wheezing), others with COVID-19 (such as cough, nasal congestion, and loss of taste or smell), and still other symptoms that overlapped between the two. The user checked off any they were experiencing and was asked to rate the symptoms’ severity (severe or mild/moderate). Based on their answers, users were advised whether they could report to work or should stay home and get tested for COVID-19. Those who reported mild vaccine-related symptoms were advised on how to treat them.

Participation by MGB employees was exceptional, with 83 percent responding after getting their first dose of either the Pfizer-BioNTech or Moderna vaccine, while 77 percent responded after their second dose. (The Johnson & Johnson/Janssen vaccine was excluded from the study because it wasn’t introduced in the United States until early March.) The portion of participants who tested positive for COVID-19 was very low. Positive cases were more likely to be detected in participants who had three or more low-severity overlap symptoms, one or more high-severity overlap symptoms, or at least one typical COVID-19 symptom such as cough or runny nose. Interestingly, employees who had a COVID-19 infection prior to getting vaccinated were significantly more likely to report severe overlap symptoms after their first dose, though it’s not clear why.

“This paper speaks to the importance of having a system in place that provides guidance to a workforce being vaccinated around the confusing questions of when to come to work, when to pursue testing, and how to treat milder symptoms,” says co-first author Paige Wickner, who serves on the faculty in the Division of Allergy and Clinical Immunology at Brigham and Women’s Hospital and is an assistant professor at HMS. Without offering vaccinated employees a framework for making these decisions, says Wickner, “you risk losing a lot of staff at a critical time. This study is an exciting first step toward providing that guidance, which will be critical in the coming months and years.” To wit: Shenoy, Wickner, and their colleagues are currently collecting similar data from MGB employees who are receiving COVID-19 booster shots.

This work was supported by the Roger I. and Ruth B. MacFarlane Foundation, Harvard Catalyst, the Harvard Clinical and Translational Science Center, and financial contributions from Harvard University and its affiliated academic health care centers.

Pediatrician weighs in on COVID vaccines for kids 5-11

4 November 2021 at 08:59

Last week, the FDA authorized the Pfizer/BioNTech COVID vaccine for children ages 5 to 11. After conducting their own review, the CDC now recommends this vaccine for children in this age range, who can begin receiving their first dose within the week.

While many families have been eagerly awaiting the opportunity for their children to be immunized, others are hesitant. And most parents have questions about how COVID-19 affects younger children, vaccine safety in this age range, and whether the benefits outweigh potential risks. As a pediatric infectious disease specialist, I hear certain questions crop up repeatedly. Here’s what we know so far.

Which COVID vaccines and doses are authorized for children ages 5 to 11?

Pfizer/BioNTech is the first COVID vaccine authorized by the FDA for this age group, based on results from a randomized controlled trial evaluating safety and immune responses. A separate trial launched by Moderna is being considered separately.

In a small number of children, the Pfizer/BioNTech trial compared three doses:

  • 30 micrograms (the dose adults receive)
  • 20 micrograms
  • 10 micrograms

This part of the trial showed that 10 micrograms, the smallest dose, resulted in fewer side effects while still generating robust immune responses similar to responses achieved with higher doses.

In the next part of the trial, more than 2,200 children ages 5 to 11 were randomly assigned to receive either a 10-microgram dose of the vaccine (two-thirds of participants) or a placebo dose (one-third of participants). All received two shots, spaced three weeks apart.

Those given the vaccine had similar immune responses as 16-to-25-year-olds who had received the full-dose series of two shots.

When Pfizer/BioNTech submitted data to the FDA, there were not many cases of symptomatic COVID-19 infections in trial participants. Out of 19 documented cases, most had received the placebo shots. Estimates suggest the efficacy rate of the vaccine is 90 percent. (Efficacy measures how much a vaccine reduces infection in a controlled trial.) Tests confirmed that the Delta viral strain had caused the infections.

What do we know about side effects for children this age?

Most children had no side effects other than pain at the injection site. Those who did have side effects most commonly experienced fatigue, headaches, and/or muscle aches after the second dose rather than the first dose. For example, only 6 percent of children had fever after the second vaccine dose. There were no cases of severe allergic reaction to the vaccine.

What is not yet known?

In very rare instances, the Pfizer/BioNTech COVID-19 vaccine is linked to myocarditis, which is an inflammation of the heart. When this occurs, it is mostly seen in young males following their second dose of an mRNA vaccine (Pfizer/BioNTech or Moderna). Most cases are mild, and children show no signs of long-term injury to the heart.

Among the 5- to-11-year-olds who received the Pfizer vaccine during the trial, there were no cases of myocarditis. However, this side effect is very rare and might not be noted until the number of children receiving the vaccine is much higher. The FDA and Pfizer/BioNTech will continue to closely monitor this age group for any occurrence of this rare side effect.

This is an excerpt from an article that appears on the Harvard Health Publishing website.

To read the full story

Kristin Moffitt is a pediatric infectious diseases doctor and researcher at Boston Children’s Hospital, and an assistant professor of pediatrics at Harvard Medical School. 

Researchers pinpoint how acupuncture targets inflammation

3 November 2021 at 08:21

Acupuncture is a traditional Chinese technique that has been used for millennia to treat chronic pain and other health problems associated with inflammation, yet the scientific basis of the technique remains poorly understood.

Now, a team of researchers led by neuroscientists at Harvard Medical School has elucidated the underlying neuroanatomy of acupuncture that activates a specific signaling pathway.

In a study conducted in mice and published Oct. 13 in Nature, the team identified a subset of neurons that must be present for acupuncture to trigger an anti-inflammatory response via this signaling pathway.

The scientists determined that these neurons occur only in a specific area of the hindlimb region — thus explaining why acupuncture in the hindlimb works, while acupuncture in the abdomen does not.

“This study touches on one of the most fundamental questions in the acupuncture field: What is the neuroanatomical basis for body region, or acupoint, selectivity?” said lead investigator Qiufu Ma, HMS professor of neurobiology at Dana-Farber Cancer Institute.

One area of particular interest to the research team is the so-called cytokine storm  — the rapid release of large quantities of cytokines that frequently drives severe, systemic inflammation, and can be triggered by many things, including COVID-19, cancer treatment, or sepsis.

“This exuberant immune response is a major medical problem with a very high fatality rate of 15 percent to 30 percent,” Ma said. Even so, drugs to treat cytokine storm are lacking.

Adapting an ancient technique to treat aberrant inflammation

In recent decades, acupuncture has been increasingly embraced in Western medicine as a potential treatment for inflammation.

In this technique, acupoints on the body’s surface are mechanically stimulated, triggering nerve signaling that affects the function of other parts of the body, including organs.

In a 2014 study, researchers reported that electroacupuncture, a modern version of traditional acupuncture that uses electrical stimulation, could reduce cytokine storm in mice by activating the vagal-adrenal axis — a pathway wherein the vagus nerve signals the adrenal glands to release dopamine.

In a study published in 2020, Ma and his team discovered that this electroacupuncture effect was region specific: It was effective when given in the hindlimb region, but did not have an effect when administered in the abdominal region. The team hypothesized that there may be sensory neurons unique to the hindlimb region responsible for this difference in response.

In their new study, the researchers conducted a series of experiments in mice to investigate this hypothesis. First, they identified a small subset of sensory neurons marked by expression of the PROKR2Cre receptor. They determined that these neurons were three to four times more numerous in the deep fascia tissue of the hindlimb than in the fascia of the abdomen.

Then the team created mice that were missing these sensory neurons. They found that electroacupuncture in the hindlimb did not activate the vagal-adrenal axis in these mice. In another experiment, the team used light-based stimulation to directly target these sensory neurons in the deep fascia of the hindlimb.

This stimulation activated the vagal-adrenal axis in a manner similar to electroacupuncture. “Basically, the activation of these neurons is both necessary and sufficient to activate this vagal-adrenal axis,” Ma said.

In a final experiment, the scientists explored the distribution of the neurons in the hindlimb. They discovered that there are considerably more neurons in the anterior muscles of the hindlimb than in the posterior muscles, resulting in a stronger response to electroacupuncture in the anterior region.

“Based on this nerve fiber distribution, we can almost precisely predict where electrical stimulation will be effective and where it will not be effective,” Ma explained.

Together, these results provide “the first concrete, neuroanatomic explanation for acupoint selectivity and specificity,” Ma added. “They tell us the acupuncture parameters, so where to go, how deep to go, how strong the intensity should be.”

He noted that while the study was done in mice, the basic organization of neurons is likely evolutionarily conserved across mammals, including humans.

However, an important next step will be clinical testing of electroacupuncture in humans with inflammation caused by real-world infections such as COVID-19. Ma is also interested in exploring other signaling pathways that could be stimulated by acupuncture to treat conditions that cause excessive inflammation.

“We have a lot of tough chronic diseases that still need better treatments,” he said, such as inflammatory bowel syndrome and arthritis. Another area of need, he added, is excessive immune reactions that can be a side effect of cancer immunotherapy.

Ma hopes that his research will ultimately advance scientific understanding of acupuncture and provide practical information that can be used to improve and refine the technique.

The work was primarily supported by the National Institutes of Health (grant R01AT010629), and partially supported by Harvard/MIT Joint Research Grants Program in Basic Neuroscience and the Wellcome Trust (grant 200183/Z/15/Z). For further information on salary support for the researchers, please refer to the paper.

14 nurses on life and work during COVID

2 November 2021 at 10:45

Since early 2020, when the pandemic exploded around the world, Massachusetts has seen nearly 19,000 COVID deaths and more than 840,000 cases. If a line graph of hospital admissions over the past 20 months looks like a series of peaks and valleys, the initial surge was Mount Everest for the state’s medical facilities, with patient loads and death rates that have not been matched since. To understand how the crisis has felt for frontline workers caring for the sick and dying, the Gazette reached out to 14 nurses at four Harvard-affiliated hospitals, many of whom work in intensive-care units. When the pandemic began, some had just started their careers, while others had been on the job for years. They risked their lives to stand by their patients, and their stories are marked by hope, heartbreak, and resilience.

***

“It’s never easy to witness my patients suffering, but I never gave up on any of them. I held out hope and prayed that each would survive.”

How death shapes life, according to a Harvard philosopher

1 November 2021 at 11:50

Does the understanding that our final breath could come tomorrow affect the way we choose to live? And how do we make sense of a life cut short by a random accident, or a collective existence in which the loss of 5 million lives to a pandemic often seems eclipsed by other headlines? For answers, the Gazette turned to Susanna Siegel, Harvard’s Edgar Pierce Professor of Philosophy. Interview has been edited for length and clarity.

Q&A

Susanna Siegel

GAZETTE: How do we get through the day with death all around us?

SIEGEL: This question arises because we can be made to feel uneasy, distracted, or derailed by death in any form: mass death, or the prospect of our own; deaths of people unknown to us that we only hear or read about; or deaths of people who tear the fabric of our lives when they go. Both in politics and in everyday life, one of the worst things we could do is get used to death, treat it as unremarkable or as anything other than a loss. This fact has profound consequences for every facet of life: politics and governance, interpersonal relationships, and all forms of human consciousness.

When things go well, death stays in the background, and from there, covertly, it shapes our awareness of everything else. Even when we get through the day with ease, the prospect of death is still in some way all around us.

GAZETTE: Can philosophy help illuminate how death impacts consciousness?

SIEGEL: The philosophers Soren Kierkegaard and Martin Heidegger each discuss death, in their own ways, as a horizon that implicitly shapes our consciousness. It’s what gives future times the pressure they exert on us. A horizon is the kind of thing that is normally in the background — something that limits, partly defines, and sets the stage for what you focus on. These two philosophers help us see the ways that death occupies the background of consciousness — and that the background is where it belongs.

Rapid rollout of COVID vaccine as important as its efficacy

29 October 2021 at 09:30

For low- and middle-income countries, a COVID-19 vaccination program built on prompt procurement, effective on-the-ground distribution, and a rapid pace of vaccination is likely to have a greater public health impact than one focused on relatively small differences in vaccine efficacy, according to a study led by researchers at Massachusetts General Hospital.

Scientists evaluating clinical outcomes and cost-effectiveness of a COVID-19 vaccination program in South Africa found that an emphasis on these implementation factors in countries with limited resources is likely to dramatically reduce infections, save lives, and curtail overall health care costs through fewer hospitalizations. The study appears in Nature Communications.

“What’s critically important is getting shots into the arms of individuals as quickly as possible,” says lead author Krishna Reddy, a pulmonary and critical care physician at Harvard-affiliated MGH. “Our study shows that increasing the pace of vaccination as well as vaccine acceptance among populations is likely to be more important than focusing on relatively small differences in vaccine efficacy in terms of getting ahead of the spread of the virus and protecting more people.”

Most low- and middle-income countries do not have access to sufficient supplies of COVID-19 vaccines due to cost, limitations on available doses, and logistical challenges of vaccine production, distribution, and storage. Using a validated computer simulation model of COVID-19, the MGH team found that meeting the South African government’s goal of vaccinating 67 percent of its population within a year would make an enormous impact on infections and deaths while actually reducing health care costs compared with low levels of population coverage. Increasing vaccinations to 80 percent of the population would save even more lives while only modestly increasing costs.

“Achieving the Department of Health’s goal of vaccinating the majority of its population in South Africa, and in similar low- and middle-income countries, will require global policymakers to better fund and facilitate vaccine distribution,” says senior author Mark Siedner, an infectious diseases clinician and researcher at MGH. “These leaders must also work diligently to remove restrictive patent barriers, liberalize distribution, and achieve affordable pricing for resource-constrained countries by negotiating with vaccine suppliers, similar to what’s been done for HIV drugs over the last two decades.” At the local level, he adds, an urgent need exists for investment in well-run vaccine distribution and administration systems and community outreach to get shots into arms as quickly and efficiently as possible.

The researchers also pointed out that practices like mask-wearing and physical distancing remain crucial to reducing the spread of the global pandemic while vaccination programs are being rolled out. Underscoring the need for a multi-pronged effort is the fact that currently only 20 percent of South Africans are fully vaccinated.

“Our hope is that findings from our study will motivate international political leaders to recognize the importance of getting vaccines quickly distributed to countries that don’t have the resources of the United States and other high-income countries,” emphasizes Reddy. “It’s a sound investment for every country since the fastest and most equitable way to get out of this global pandemic emergency is to ensure that people everywhere have ready access to affordable vaccines.”

Reddy is an assistant professor of medicine at Harvard Medical School. Siedner is an associate professor of medicine at HMS. Co-authors include Kenneth Freedberg of MGH and HMS, and Richard Lessells of the University of KwaZulu-Natal in South Africa.

The study was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and by the Wellcome Trust.

 

Doctor draws on cartoons for persuasive public health messaging

29 October 2021 at 07:00

The cartoon showed a COVID vaccine syringe in the form of a gun held against a recipient’s head. It listed those not responsible if the vaccine — hastily researched and manufactured — went awry: drugmakers, doctors, the government. Then it asked who’s “irresponsible” if they don’t get the shot: You.

Joe Betancourt thought: What a great cartoon.

Betancourt is no antivaxxer. In fact, he’s pretty much the opposite. He’s an associate professor of medicine at Harvard Medical School, senior vice president for equity and community health at Massachusetts General Hospital, and founder of MGH’s Disparities Solutions Center. But he knows an effective post when he sees one, even if he disagrees with its message, and thinks it’s time for more persuasive public health communications.

“This is an example of a simple message,” Betancourt said. “Nobody can guarantee anything. Nobody assumes responsibility for what’s going to happen with the vaccine, but if you don’t get it, you’re responsible. That’s a very powerful message, the creativity makes the message.”

The post catches viewers’ attention. It provokes emotion, anger even, at a perceived injustice. That kind of visceral reaction and mobilizing impact is all too rare a result of health communications today, Betancourt says, and the shortcoming has been apparent as coordinated efforts to deal with the global pandemic rolled out in real time.

And he is not alone in this opinion.

Thomas Deisboeck, an HMS associate professor of radiology and associate in neuroscience at MGH’s Athinoula A. Martinos Center for Biomedical Imaging, helped organize a virtual exploratory seminar last spring at the Radcliffe Institute for Advanced Study to jump-start a conversation around innovating in health communications. The gathering drew about two dozen experts in health care, art, and technology, including Betancourt.

“Anything that improves the information transfer, that makes it bidirectional and not just a download from a doctor to a patient, is worth exploring,” Deisboeck said. “Let’s think of visual communication strategies that are beyond the ‘Let’s come up with a cooler Powerpoint template.’ What can we learn from illustration? From visual narratives and animation? From the methods and techniques in comics, from illustrations in children’s books?”

Years after cancer treatment, sleepless nights linger

27 October 2021 at 08:41

Once the stress of a cancer diagnosis and its intensive treatments have passed, the hope is that life can return to normal. But we know that this is not true for many people who have had treatments for cancer, and sleep is often impacted for a long time after treatment.

Researchers at the American Cancer Society studied responses from 1,903 cancer survivors from across the U.S. These survivors were diagnosed with cancers such as breast cancer or prostate cancer about nine years before the study. As part of the research, these cancer survivors were asked questions about their sleep and cancer history, and their overall physical, mental, and social health. Even though these men and women had been diagnosed with cancer almost a decade ago, a staggering 51 percent reported that their sleep had been disturbed over the prior month.

Why do sleep problems continue after cancer?

Findings suggest that the residual effects of cancer may continue to negatively affect a survivor’s sleep. Not surprisingly, poor sleepers were more likely to report that they had more physical and emotional distress. Perhaps more unexpected were results that showed survivors who were sleeping poorly were also more likely to be having some economic hardship, and expressed worries about money and a fear of cancer recurrence.

These are common burdens for cancer survivors. Financially, cancer survivors not only have to shoulder the medical costs associated with their initial treatments, but also ongoing bills from managing the lasting effects of those treatments. Additionally, survivors may have had to change their work situation, or leave their job entirely, in order to manage their health.

Other research has shown that fear of cancer recurrence is common among survivors. Despite having completed their treatments many years prior, people struggle with chronic distress regarding their health and well-being, often at levels equal to that experienced when they were initially diagnosed with cancer.

This is an excerpt from an article that appears on the Harvard Health Publishing website.

To read the full story

Eric Zhou is an assistant professor at Harvard Medical School. His research focuses on how we can better understand and treat sleep disorders in both pediatric and adult populations, including those with chronic illnesses. 

In war zone, COVID isn’t only health problem

26 October 2021 at 13:46

COVID-19 isn’t necessarily their worst problem. That was the message from experts in humanitarian relief at a virtual Harvard T.H. Chan School of Public Health Forum on Monday to those designing vaccination campaigns in areas of conflict, war, and unrest.

That doesn’t mean throwing up one’s hands and giving up the fight against the pandemic in these remote and hazardous areas, but it does mean thinking hard about what such a campaign should look like: potentially just a part of a bundle of health services and assistance. Displaced people can be more desperately in need of food, water, shelter, and safety than they are a COVID vaccine. For those not displaced but living in an area controlled by militia or other non-state actors, a suite of childhood immunizations may be needed in addition to COVID-19 shots for adults. In fact, depending on the level of information and misinformation in a region, parents may be more eager for inoculation against a long-feared disease like polio than for one they may never have heard of or whose relative danger they may doubt.

“You cannot do COVID-19 vaccines in isolation,” said Esperanza Martinez, head of the COVID-19 Crisis Team for the International Committee of the Red Cross. “In conflict zones you have drops of vaccination in polio and measles and mumps and rubella from 60 to 90 percent, depending on the countries you’re talking about. So when we look at mortality in the future or disability in the future, those are diseases that we need to prevent today.”

Martinez was part of the Chan School panel discussion, “Calling a Pandemic Ceasefire: Vaccinating in Conflict Zones.” The hourlong event also featured Jennifer Leaning, senior research fellow at the FXB Center for Health and Human Rights and associate professor of medicine at Harvard Medical School and Brigham and Women’s Hospital; Claude Bruderlein, director of the Centre of Competence on Humanitarian Negotiation and an adjunct lecturer on global health at the Chan School; and Madeline Drexler, a journalist and visiting scientist at the Chan School.

Harvard event outlines steps for helping children reconnect

26 October 2021 at 11:58

After the pandemic closed schools last year, hospitals saw a surge in mental health-related emergency visits among children 18 and under. The statistics have been grim enough that a large cohort of the nation’s top pediatricians recently declared a “national emergency” in child and adolescent mental health.

COVID disrupted connections for everyone, but especially children. Cut off from social networks — sometimes even the internet — young people had few opportunities to forge relationships outside the home, said Jenlei Li, the host of a Harvard Graduate School of Education webinar called “The Healing Power of Friendships and Relationships.” Stuck at home, they lost chances to connect with peers, teachers, coaches, and guidance counselors.

With schools back to a semblance of normal, Traci Baxley and Jean Rhodes joined Li, the Saul Zaentz Senior Lecturer in Early Childhood Education and co-chair of the Human Development and Education Program, to discuss how teachers and parents can encourage kids to rebuild these critical relationships, which are integral to both learning and mental health.

“Young people are suffering,” said Rhodes, a professor of psychology and director of the Center for Evidence-Based Mentoring at the University of Massachusetts, Boston. In her research, Rhodes has found that strong relationships between children and caring adults can have positive effects for decades, extending through middle age. Many of those relationships are built at school.

But schools alone cannot solve mental health issues, she said. Most can only afford to employ one counselor to serve hundreds of children. “It’s a systemic problem,” she said. Rhodes advocates for “stocking the pond with caring adults,” including volunteer mentors and paraprofessionals, and teaching kids to fish. “Learning occurs in relationships,” she said.

Baxley, an associate professor at Florida Atlantic University and author of “Social Justice Parenting: How to Raise Compassionate, Anti-Racist, Justice-Minded Kids in an Unjust World,” witnessed firsthand how the pandemic isolation affected learning. Her five children include a teenage son with attention deficit hyperactivity disorder, or ADHD, who struggled with virtual education.

“Now that he’s back in school,” she said, “he’s a different kid.”

Rhodes and Baxley stressed the educational component of their message — that learning happens through relationships with teachers. And teachers, said Baxley, have the power to create community — or not. Children must feel heard and seen; teachers can build democratic classrooms, talk through stressors, and develop plans to face them. Teaching children how to handle stress, talk about emotions, and develop relationships shouldn’t be an extra, Baxley said; it should be embedded in classroom culture.

Outside school, sports teams, after-school programs, and religious institutions provide critical opportunities for kids to learn social-emotional skills and build strong connections, said Rhodes.

“We need the village,” said Baxley, punctuating her argument by noting her work in Florida’s Palm Beach County schools: “Right now, they have over 800 students that are unaccounted for since the pandemic. They shouldn’t be lost, wherever they are.”

Community organizations can help keep children safe and engaged, especially now, when adults are also struggling with increased mental health issues. The pandemic, Baxley said, is a chance to “care more and to reset how we treat people around us, including other adults.”

At home, parents can model coping skills, said Baxley, like going for a walk or talking through difficult emotions. They should also provide space for children to articulate their feelings. “A lot of the time as parents, we need to stop knowing and start listening,” she said.

Baxley taught her son with ADHD to understand his needs — academic, dietary, and physical — as well as what he can control and whom he can ask for help. “You want your kids to be independent, but part of that independence is asking for the things you need.”

Marginalized children, Rhodes added, are often the least able and least likely to speak up for themselves. Their schools tend to have fewer adult mentors and counselors to serve each child. Helping these students make connections is an urgent matter.

“The more relationships we can put in the path of children, the better,” said Rhodes.

“Amen to that,” said Baxley.

 

Putting the lid on raising your voice

25 October 2021 at 09:14

You’ve been trying to get your point across, but it’s not getting through. It’s getting you frustrated, maybe a little offended, so you go for a different approach.

You yell.

Now, concert-level volume has its place, like for saying, “There’s a bear behind you” or “Power line down.” But the big question is, how often do those situations come up? The answer is, rarely.

Next question: How often do you reach that intensity? “Too often” is that answer. You know that it doesn’t work. It never feels good. It never makes the situation better. You would just like to stop doing it.

It’s good to have that desire, but you need more to make it happen. What helps is to play detective to uncover your triggers, then set reasonable expectations, because underlying the yelling is stress, something that isn’t disappearing. The question, as Antonia Chronopoulos, clinical psychologist at Massachusetts General Hospital, asks, is “How do you regulate yourself in a tense situation?”

Start with the basics

Before you can stop, it helps to understand why we yell in the first place.

We could be in a debate and feel like we’re not being heard. We take it as an insult, get frustrated, and the brain’s limbic system sees it as a threat and sets off the fight-or-flight response.

Our blood pressure rises, breathing becomes shallow, and muscles tense up. Since our history factors in, we can start making assumptions. Adrenaline makes everything go faster, and our attention narrows. “When we’re in survival mode, we’re not thinking about creative solutions as effectively,” she says. “The prime directive is to defend, escape, or fight.”

It’s also not a solo act. We’re yelling at someone, and our attempt to control the situation triggers that person, setting off the aforementioned emotional and physiological reactions, and possibly creating a shoutfest (which is anything but festive).

And there’s one more part, which gets overlooked: the flight element. If we decide to not yell and end up holding anger in, the same process is still taking place: the tense muscles, shallow breathing, narrow focus. We might not be making a lot of noise, but we’re far from calm or looking to improve the situation. “It’s almost like a freeze response,” Chronopoulos says.

The goal is to find the middle ground: not fighting, not flighting, and where you can be more in tune with the other person.

This is an excerpt from an article that appears on the Harvard Health Publishing website.

To read the full story

Steve Calechman is a contributing editor for Men’s Health, a writer for MIT’s Industrial Liaison Program, and his work has appeared in The Boston Globe Magazine, Greentech Media, Fatherly, and BabyCenter.

New thinking on aspirin and cancer needs dose of nuance, Harvard expert says

22 October 2021 at 10:27

The U.S. Preventive Services Task Force is re-evaluating recommendations on the use of aspirin to prevent colorectal cancer. According to media reports and a review by the agency — charged since 1984 with issuing guidelines on steps that might prevent disease — recent studies have clouded evidence of aspirin’s anticancer benefits.

The Gazette spoke with Andrew Chan, director of cancer epidemiology at the Mass. General Cancer Center and a professor at Harvard Medical School, about the new thinking around aspirin. Chan says that the evidence for the medicine’s effectiveness in preventing colorectal cancer remains compelling, and called for a nuanced approach to any revision of recommendations. The interview was edited for clarity and length.

Q&A

Andrew Chan

GAZETTE: What do you think of reports that the U.S. Preventive Services Task Force is considering backing away from routine use of aspirin for colorectal cancer prevention?

CHAN: What I disagree with is their opinion that the benefit with respect to colorectal cancer is inconclusive. I think the data are actually pretty compelling. The recent studies that have been less supportive are clinical trials that have been done within selected populations over a short period of time. But if you look at the overall compendium of data, the aspirin link to lower colorectal cancer rates is quite convincing. Nonetheless, we’re at a point now where a clinical trial of aspirin, perhaps in a younger population, with longer-term cancer outcomes, would be really important for the field to cut through some of the confusion.

GAZETTE: You reported results in January that seem to confirm aspirin’s effectiveness among older adults. Can you tell us about the study?

CHAN: One reason we conducted our study is that we wanted to understand why, in a recent clinical trial of aspirin started in adults over the age of 70, there was no benefit in terms of cancer — and possibly an increased risk of cancer deaths.

This was a head-scratcher because so much prior data had shown that taking aspirin reduces your risk of cancer, especially colorectal cancer. But we know in the real world that it is not common for people to first start taking aspirin after the age of 70. Many of the molecular changes in our bodies that might influence risk of developing cancer may have already happened by then — in other words, the horse may be out of the barn. So we should not be surprised that the result of a trial of aspirin started at an older age would be disappointing, and that if you start aspirin very late in your life, you may not enjoy the same benefits.

We found that if you had started taking aspirin at a younger age, you could still potentially benefit after age 70 in terms of colorectal cancer risk. This illustrates that it may be a challenge to make blanket statements about whether you should or shouldn’t take aspirin at a certain age without taking into account when you first start and how long you take it for. Of course, it’s difficult for a group like the U.S. Preventive Services Task Force to account for this nuance in the data because their goal is to provide a simplified recommendation. But it is an important detail. If you simplify the recommendations too much, there is the risk that people get confused and disregard a potentially life-saving intervention as being ineffective in all situations.

GAZETTE: So is prevention becoming like other areas in medicine, where everyone may not benefit from any particular treatment but some may benefit a lot?

CHAN: That’s exactly right. In cancer treatment, we’ve moved toward a more targeted approach, where we base treatments on a patient’s particular cancer type and their molecular profile. What we need for the field of prevention is “precision prevention.” Aspirin is one of those drugs where targeted treatment is particularly important, because it is a low-cost, familiar, and easily taken drug which can substantially reduce someone’s individual cancer risk, though with trade-offs.

Going forward, it will be really important for precision prevention to become the focus. I think that’s going to be the new paradigm for cancer prevention. We’ve seen too many examples where a one-size-fits-all approach fails. The clinical trials don’t produce the results we thought they would because we’re trying to apply something to a too-broad population. Cancer is complicated. Not everybody develops the same cancer through the same biological pathways. It’s kind of naive to think that a one-size-fits-all prescription to cancer prevention will be successful.

GAZETTE: What are the mechanisms at work for aspirin use to prevent colorectal cancer? Are they the same as with heart attack and stroke, where there’s a blood-thinning effect?

CHAN: The mode of action in cancer is less clear. I think there are many mechanisms that could be potentially at play, some of which have been fairly well-corroborated by experimental and human studies. In the end, I think it’s probably not a single mechanism. That’s also what makes aspirin uniquely beneficial: It has so many mechanisms that could have an anticancer effect. At the same time, the difficulty in pinpointing a single mechanism has made some people uncomfortable. Nonetheless, we need to continue working to better understand all of the potential anticancer mechanisms of aspirin to better identify those people who are more likely to benefit from the drug.

GAZETTE: Could studies also identify who might be at risk for undue bleeding, one of the concerns about aspirin use? That must vary person by person as well.

CHAN: Correct. Understanding more about who potentially could be harmed from aspirin in terms of bleeding will be important. And I think understanding both clinical risk factors and biological factors to predict bleeding risk will be critical.

GAZETTE: In the end, “Oh, I better stay away from aspirin,” would be the wrong takeaway for an individual reading about the task force’s deliberations, correct?

CHAN: It would be a mistake to jump to the automatic conclusion that it’s not going to be beneficial. It’s still worth discussing with your doctor and for the scientific community to pursue further research. This speaks to the need for doing additional studies in the right populations. For example, we might expect an important benefit for people with specific risk factors who start taking it at a younger age. Doing those trials will be important. At the same time, we should be pursuing studies where we try to identify particular biomarkers or other molecular factors which could better predict benefit and harm. Ultimately, that’s where the field of preventive medicine needs to head.

Viewing climate change as a human health problem

21 October 2021 at 14:12

This week, the medical journal The Lancet released its annual “Report of the Lancet Countdown on Health and Climate Change” and a companion brief focused on conditions in the United States. The brief urges action to curb global-warming emissions, arguing that the health impacts of a shifting climate are already being seen in the U.S. and rapidly growing severe. Those include direct effects, such as illness from extreme heat or drowning from floods, as well as indirect and less-obvious ones, like shifting infectious-disease patterns or worsening allergies and asthma from more-intense pollen levels. Renee N. Salas, assistant professor of emergency medicine at Harvard Medical School, ER physician at Massachusetts General Hospital, climate and health expert at the Harvard Global Health Institute, and Yerby Fellow at the Harvard T.H. Chan School of Public Health’s Center for Climate, Health, and the Global Environment, was the lead author of the U.S. brief and an author on the global report. She spoke with the Gazette about the findings.

Q&A

Renee N. Salas

GAZETTE: Were there examples this year of weather extreme enough to affect people’s health that could be at least partly related to climate change?

SALAS: Yes. Climate change makes it more likely for these events to be more intense. This often translates to worse health outcomes and increased health-system disruption. One way to think about it is that climate change loads the dice. Overall, recent research found more than a third of heat-related deaths in U.S. cities can be attributed directly to climate change. The Pacific Northwest heat wave in June of 2021 was found by climate scientists to be virtually impossible without climate change. It was a catastrophic mass-casualty event estimated to have led to over 600 excess deaths in Washington and Oregon in a week. And there were more than 70 times the number of heat-related emergency department visits when compared to that same time period in 2019. We have an enormous opportunity to limit these harms by acting swiftly and decisively on climate change to protect health and advance equity.

GAZETTE: So we can expect more events that are completely out of the range of normal weather for a region?

SALAS: Climate change is worsening heat waves, making them more frequent, longer, and hotter. It’s amplifying drought and intensifying wildfires. It is supercharging hurricanes, which are slower, wetter, and stronger because of climate change. Climate change is fueling flood risks with increased heavy-rainfall events. It is raising sea levels that contribute to coastal flooding, which is especially of concern here in the Northeast because we are experiencing some of the highest rates of sea-level rise in the country. At the same time, there’s an increased risk that we’re going to have more very extreme events.

The Intergovernmental Panel on Climate Change shows that it’s imperative to urgently transition to a very low carbon-emission pathway if we want to keep temperature rise to below 1.5 degrees Celsius. Even though a 10th of a degree can seem small and insignificant, every fraction has significant implications for health and equity. So an extreme heat event that used to happen once every 10 years in the second half of the 19th century is today three times more likely. When we look at a 1.5 degree versus a 2 degree Celsius temperature rise, this half a degree means the difference between those events being nearly four times versus six times more likely, with an increased chance of even hotter temperatures. This translates to increased illness, suffering, and death.

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