Many people have been talking about the “COVID 15,” referring to gaining 15 pounds during quarantine. But did people really gain weight? This question intrigued researchers. So they examined patient data from electronic health records. Specifically, they looked at 15 million patients’ weight changes the year prior to the start of the pandemic, and then weight change for one year over the course of the pandemic.

As it turns out, 39 percent of patients gained weight during the pandemic, with weight gain defined as above the normal fluctuation of 2.5 pounds. Approximately 27 percent gained less than 12.5 pounds and about 10 percent gained more than 12.5 pounds, with 2 percent gaining over 27.5 pounds.

The role of stress in weight gain

There was a great deal of stress during the first year of the pandemic, and stress is associated with increased cortisol. Increased cortisol has been associated with increased intake of hyperpalatable foods, which are foods high in salt, fat, or both. There is also evidence that our bodies metabolize food more slowly when under stress. In addition, stress and high cortisol levels are associated with increased belly fat, which puts people at risk for diseases like heart disease and Type 2 diabetes. To add to the list of unhealthy effects of stress on the body, high cortisol levels can reduce lean muscle mass, and this in turn has an impact on your metabolic rate. The less lean muscle mass you have, the lower your metabolic rate and the fewer calories you burn at rest. All of this is a set-up for weight gain and poor health with increased stress.

Not everybody put on pounds during quarantine

Some people respond to stress by not eating. These people ignore their hunger cues, and so some lose weight during times of stress. As it turns out, the electronic health record analysis revealed that 35 percent of patients lost weight during the first year of the pandemic.

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

To read the full story

Elizabeth Pegg Frates teaches at Harvard Medical School as well as Harvard Extension School. She currently practices lifestyle medicine through her health and wellness coaching company, Wellness Synergy, LLC.

Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionized cancer treatment; however, the medications aren’t effective in a large number of patients, including those with colorectal cancer.

Now, new research led by investigators at Harvard-affiliated Massachusetts General Hospital and the University of Geneva and published in PNAS provides insights on why some types of colorectal cancer don’t respond to immune checkpoint inhibitors, and offers a strategy to overcome their resistance.

“Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide,” said senior and co–corresponding author Rakesh K. Jain, director of the E.L. Steele Laboratories for Tumor Biology at MGH and Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School. “A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver.”

Jain explained that most colorectal cancers that spread to the liver do not respond to immune checkpoint inhibitors. When the team injected colorectal cancer cells under the skin in the hind flanks of mice (the most commonly used method for studying cancer in these animals), the cells responded well to immune checkpoint inhibitors, unlike what happens in patients.

To address this discrepancy, the investigators decided to take an orthotopic approach (meaning “the normal place in the body”) by injecting the cancer cells in the relevant anatomical sites — for example, the colon, where primary colorectal cancer cells grow, and the liver, where they metastasize.

“We found that these colorectal cancer mouse models were profoundly resistant to immune checkpoint inhibitors, similar to what is seen in patients,” said co-corresponding author Dai Fukumura, deputy director of the E.L. Steele Laboratories at MGH and associate professor of radiation oncology at HMS. “Our results highlight how the environment in which cancer cells grow can influence the effectiveness of immunotherapy. Also, and most important, they indicate that these orthotopic cancer models should be used to study resistance to immune checkpoint blockade as observed in patients with colorectal cancer.”

To determine how liver metastases are resistant to immune checkpoint blockade, Jain and his colleagues investigated the composition of immune cells present in liver metastases in mice and compared it with that of colorectal cancer cells injected under the skin.

“We found that liver metastases lacked certain immune cells — called dendritic cells — that are required for the activation of other immune cells known as cytotoxic T lymphocytes, which can kill cancer cells,” said lead author William W. Ho, a research fellow at MGH. “We saw a similar situation in patients — their liver metastases showed a lack of dendritic cells and activated T lymphocytes.”

When the team augmented the number of dendritic cells within liver metastases (by giving mice a growth factor called Flt3L), the treatment led to an increase in cytotoxic T lymphocytes within the tumors and caused the tumors to become sensitive to immune checkpoint inhibitors.

“Our study highlights the importance of orthotopic tumor models in immunotherapy studies and underscores the relevance of dendritic cells for effective immune checkpoint blockade,” said co–corresponding author Mikaël J. Pittet, professor of immunology at U. Geneva. “It also points to the possibility of developing new therapies that could be effective in controlling resistant colorectal cancer. For example, the combination of Flt3L and immune checkpoint inhibitors is an interesting therapeutic option that is worth evaluating in clinical trials.”

Co-authors of the study include MGH investigators Igor L. Gomes-Santos, Shuichi Aoki, Meenal Datta, Kosuke Kawaguchi, Nilesh P. Talele, Sylvie Roberge, Jun Ren, Hao Liu, Ivy X. Chen, Patrik Andersson, Sampurna Chatterjee, Ashwin S. Kumar, Zohreh Amoozgar, Qixian Zhang, Peigen Huang, Mei Rosa Ng, Vikash P. Chauhan, Lei Xu, Dan G. Duda, and Jeffrey W. Clark.

Funding for the study was provided by the National Institutes of Health, the Harvard Ludwig Center, the Advanced Medical Research Foundation, Jane’s Trust, and the ISREC Foundation.

Mortality rates after cancer surgery declined for Black as well as white patients during a recent 10-year period, although the mortality gap between the two groups did not narrow, according to new research by Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard University investigators.

The findings, published online today by JAMA Network Open, present a mixed picture for health care policymakers: While postsurgical mortality rates have fallen for patients generally, more targeted efforts are needed to reduce disparities between Black and white patients undergoing such surgery, study authors say.

“Black Americans are likely to be diagnosed with more advanced cancer than whites and, historically, have had higher mortality rates following cancer surgery,” said lead author Miranda Lam of Dana-Farber, Brigham and Women’s Hospital, Harvard T.H. Chan School of Public Health, and Harvard Medical School. “Hospitals have put a variety of policies in place to improve surgical cancer care over the past 15 years. This study provided an opportunity to gauge the effects of those measures for patients in general and for Black and white [people] specifically.”

Investigators used national Medicare data to examine the trends in mortality rates for the years 2007-2016 in Black and white patients who had undergone surgery for any of nine major types of cancer. (The racial group was determined by patients’ self-identification in Medicare documentation.) The data covered 870,929 cancer operations in all.

The researchers found that national mortality trends following cancer surgery improved for Black and white patients by 0.12 percent and 0.14 percent per year, respectively. Because mortality rates for Black patients were higher to begin with than for white patients, the equal decline in rates for both groups meant the gap between them did not shrink.

“The findings tell us that even though policies designed to improve cancer surgery outcomes are working better for all patients, none of them have been specific enough to close the gap in mortality between Black and white [people],” Lam said. “It’s possible that part of the gap may be due to upstream and/or downstream issues from the surgery itself, such as late referrals which may lead to late presentation at time of surgery, fragmented follow-up after discharge, and limited resources in the community, and that different policies and interventions may be needed to address disparities in cancer surgery.”

The senior author of the study is Jose F. Figueroa of Harvard T.H. Chan School of Public Health, Brigham and Women’s, and Harvard Medical School. Co-authors are Katherine Raphael and Jessica Phelan of Harvard T.H. Chan School of Public Health; and Winta T. Mehtsun, E. John Orav, and Ashish K. Jha of Harvard T.H. Chan School of Public Health, Brigham and Women’s, and Harvard Medical School.

Excerpted from “Letter to a Young Female Physician: Notes from a Medical Life” by Suzanne Koven, associate professor, Harvard Medical School, and primary care physician and writer in residence, Massachusetts General Hospital.

I knocked shyly on the open door of Albert Blake’s hospital room. All I knew about him was that he was 54 years old and that he had leukemia. As I watched him doze for a few long seconds before knocking again more firmly, I took in his gaunt, ashen face and withered arms and observed that Mr. Blake, as we’d been taught to record in our notes, “appeared older than his stated age.” He opened his eyes, smiled, and nodded toward the chair beside his bed, inviting me to sit down. Suddenly he seemed younger, healthier. I felt as if I were looking at one of those holograms where two images alternate, one shifting into the next, in Mr. Blake’s case: sick/well, patient/person.

I’d been assigned to interview Mr. Blake in the spring of my first year of medical school at Johns Hopkins during a course called Clinical Skills. A few weeks earlier my classmates and I sat excitedly in a lecture hall and each received, courtesy of a pharmaceutical company, a starched white coat and a monogrammed black leather doctor’s bag equipped with an otoscope, an ophthalmoscope, a stethoscope, and a reflex hammer. Once a week we’d put on the coats and carried the bags to the hospital to meet, in groups of four or five, an instructor who taught us how to record patients’ histories and how to use our tools. We walked through the hospital corridors on the way to these sessions hoping that we wouldn’t be mistaken for doctors — and also hoping that we would.

Long before deciding on a medical career, years before I wanted to be a journalist, I’d aspired to be an actor and my new costume and props made me feel as if I were onstage, a sensation reinforced by the scripts I’d newly memorized, long lists of questions we were supposed to ask our patients: Did they have headaches, double vision, ear pain, bloody noses? Had they been exposed to exotic birds or eaten unpasteurized cheese? Did they have chest pain, and did the pain occur when they took a deep breath, or when they ate or walked? So many questions, all of them as abstract to us as philosophy since we did not yet know which diseases could be transmitted by birds or cheese, or what the symptoms we elicited meant, much less how to treat them.

In the following three years, when we knew more, patients would be chosen for us to interview and examine based on whether they had interesting diseases or dramatic findings on their physical exams. We’d be sent to see the patient with sarcoidosis; listen to the chest of the woman with rhonchi, rattling breath sounds so loud even a novice couldn’t miss her pneumonia; introduce ourselves to the man with Wernicke’s encephalopathy, in which chronic heavy alcohol consumption obliterates short-term memory, then we’d wait five minutes, return to the room, and introduce ourselves again to the patient who would, in that short interval, have forgotten meeting us entirely. In Clinical Skills, though, patients were selected for being … patient. Those who agreed to have medical students practice on them might have dozens troop by to ask the same questions again and again. What brought you into the hospital? When did this symptom begin? Have you ever had anything like this before? What brought you into the hospital? What makes it better or worse? What brought you into the hospital?

Mr. Blake was patient. He was also a natural raconteur who said he didn’t mind passing the hours during his tedious hospitalizations by chatting with students. He’d told his story many, many times. Still, when my turn came to settle into the chair by his bed with my clipboard, Mr. Blake did not stint. What had brought him into the hospital? Well, he said, leaning back on his pillows and drawing a leisurely breath, it was like this: One afternoon about a year earlier he was coaching his 10-year-old grandson’s baseball team. He’d been spending more time with the boy since his mother, Mr. Blake’s daughter, had gotten involved with drugs and acquired a boyfriend who was, in Mr. Blake’s opinion, a stone-cold loser. Anyway, there he was, standing behind home plate, urging one of the kids to keep his eye on the ball, when suddenly he’d felt light-headed. He held on to the chain-link fence to keep from falling and as he looked at his fingers, wrapped tightly through the metal wire, he noticed how pale they were.

And on Mr. Blake went, through the arrival of the ambulance, his grandson running in crying from left field, the first and the second and the third rounds of chemo during which his wife held everyone up as she always had, including the Blakes’ daughter, who, not long after the onset of her father’s illness, had ditched the drugs and the boyfriend and would be coming by to visit shortly with his favorite cookies, though he doubted he’d have enough appetite to eat them.

I transcribed all of this information and a few days later, after my instructor had approved my report, tucked it away for sentimental reasons only, thinking I’d be unlikely ever to look at it again.

Some months afterward, though, I dug through my desk drawers looking for my note about Mr. Blake. I was now at the end of my second year and rotating on the oncology ward, where he had again been admitted. I asked if I might be assigned to help take care of him. Mr. Blake didn’t remember me, and he was sicker than when I’d last seen him, but he greeted me as he had before with a warm smile and an encouraging wave. And he again tolerated my history taking, which remained plodding, though was somewhat more efficient now that I had a better idea of what to ask and so could spare him my slavish recitation of all the questions I’d committed to memory. I asked Mr. Blake how he was feeling, got an update on his treatment, which was not going well, and left the room to copy down his medications, allergies, test results, and other data at the nurses’ station. As a new clinical student, I wasn’t expected to finish my note before leaving for the day and considered myself lucky to have waiting at home a thorough account of the onset of Mr. Blake’s illness that I could easily add to what I’d just recorded.

Tucked into a folder containing papers I’d written in college, I found it. My florid descriptions of Mr. Blake’s pale fingers clutching the chain-link fence, his grandson’s tears, the addicted daughter and her loser boyfriend made me cringe. None of that was important. All that counted now were Mr. Blake’s daily fever charts and lab values, his IV fluids and urine output, his chemotherapy regimen. These were matters of life and death, unlike his story, which, however engagingly Mr. Blake had shared it with me, was irrelevant to his current medical care. I tossed my old note back in the folder with my essays on “Bleak House” and “Mrs. Dalloway,” having concluded that it was, like they were, useless. Then I wrote my new note as if I’d never met Mr. Blake before, as if I’d never heard his story.

Copyright 2021 by Suzanne Koven. Used with permission of the publisher, W.W. Norton & Company, Inc. All rights reserved.

Obesity has been linked to increased risk for over a dozen different types of cancer, as well as worse prognosis and survival. Over the years, scientists have identified obesity-related processes that drive tumor growth, such as metabolic changes and chronic inflammation, but a detailed understanding of the interplay between obesity and cancer has remained elusive.

Now, in a study in mice, Harvard Medical School (HMS) researchers have uncovered a new piece of this puzzle, with surprising implications for cancer immunotherapy: Obesity allows cancer cells to outcompete tumor-killing immune cells in a battle for fuel.

Reporting in Cell on Dec. 9, the research team shows that a high-fat diet reduces the numbers and antitumor activity of CD8+ T cells, a critical type of immune cell, inside tumors. This occurs because cancer cells reprogram their metabolism in response to increased fat availability to better gobble up energy-rich fat molecules, depriving T cells of fuel and accelerating tumor growth.

“Putting the same tumor in obese and nonobese settings reveals that cancer cells rewire their metabolism in response to a high fat diet,” said Marcia Haigis, professor of cell biology in the Blavatnik Institute at HMS and co-senior author of the study. “This finding suggests that a therapy that would potentially work in one setting might not be as effective in another, which needs to be better understood given the obesity epidemic in our society.”

The team found that blocking this fat-related metabolic reprogramming significantly reduced tumor volume in mice on high-fat diets. Because CD8+ T cells are the main weapon used by immunotherapies that activate the immune system against cancer, the study results suggest new strategies for improving such therapies.

“Cancer immunotherapies are making an enormous impact on patients’ lives, but they do not benefit everyone,” said co-senior author Arlene Sharpe, the HMS George Fabyan Professor of Comparative Pathology and chair of the Department of Immunology in the Blavatnik Institute.

“We now know there is a metabolic tug-of-war between T cells and tumor cells that changes with obesity,” Sharpe said. “Our study provides a roadmap to explore this interplay, which can help us to start thinking about cancer immunotherapies and combination therapies in new ways.”

Haigis, Sharpe and colleagues investigated the effects of obesity on mouse models of different types of cancer, including colorectal, breast, melanoma and lung. Led by study co-first authors Alison Ringel and Jefte Drijvers, the team gave mice normal or high-fat diets, the latter leading to increased body weight and other obesity-related changes. They then looked at different cell types and molecules inside and around tumors, together called the tumor microenvironment.

Fatty paradox

The researchers found that tumors grew much more rapidly in animals on high-fat diets compared to those on normal diets. But this occurred only in cancer types that are immunogenic, which can contain high numbers of immune cells; are more easily recognized by the immune system; and are more likely to provoke an immune response.

Experiments revealed that diet-related differences in tumor growth depended specifically on the activity of CD8+ T cells, immune cells that can target and kill cancer cells. Diet did not affect tumor growth rate if CD8+ T cells were eliminated experimentally in mice.

Strikingly, high-fat diets reduced the presence of CD8+ T cells in the tumor microenvironment, but not elsewhere in the body. Those remaining in the tumor were less robust — they divided more slowly and had markers of decreased activity. But when these cells were isolated and grown in a lab, they had normal activity, suggesting something in the tumor impaired these cells’ function.

The team also encountered an apparent paradox. In obese animals, the tumor microenvironment was depleted of key free fatty acids, a major cellular fuel source, even though the rest of the body was enriched in fats, as expected in obesity.

These clues pushed the researchers to craft a comprehensive atlas of the metabolic profiles of different cell types in tumors under normal and high-fat diet conditions.

The analyses revealed that cancer cells adapted in response to changes in fat availability. Under a high-fat diet, cancer cells were able to reprogram their metabolism to increase fat uptake and utilization, while CD8+ T cells did not. This ultimately depleted the tumor microenvironment of certain fatty acids, leaving T cells starved for this essential fuel.

“The paradoxical depletion of fatty acids was one of the most surprising findings of this study. It really blew us away and it was the launch pad for our analyses,” said Ringel, a postdoctoral fellow in the Haigis lab. “That obesity and whole-body metabolism can change how different cells in tumors utilize fuel was an exciting discovery, and our metabolic atlas now allows us to dissect and better understand these processes.”

Hot and cold

Through several different approaches, including single-cell gene expression analyses, large-scale protein surveys and high-resolution imaging, the team identified numerous diet-related changes to metabolic pathways of both cancer and immune cells in the tumor microenvironment.

Of particular interest was PHD3, a protein that in normal cells has been shown to act as a brake on excessive fat metabolism. Cancer cells in an obese environment had significantly lower expression of PHD3 compared to in a normal environment. When the researchers forced tumor cells to overexpress PHD, they found that this diminished a tumor’s ability to take up fat in obese mice. It also restored the availability of key free fatty acids in the tumor microenvironment.

Increased PHD3 expression largely reversed the negative effects of a high-fat diet on immune cell function in tumors. Tumors with high PHD3 grew slower in obese mice compared to tumors with low PHD3. This was a direct result of increased CD8+ T cell activity. In obese mice lacking CD8+ T cells, tumor growth was unaffected by differences in PHD3 expression.

The team also analyzed human tumor databases and found that low PHD3 expression was associated with immunologically “cold” tumors, defined by fewer numbers of immune cells. This association suggested that tumor fat metabolism plays a role in human disease, and that obesity reduces antitumor immunity in multiple cancer types, the authors said.

“CD8+ T cells are the central focus of many promising precision cancer therapies, including vaccines and cell therapies such as CAR-T,” Sharpe said. “These approaches need T cells to have sufficient energy to kill cancer cells, but at the same time we don’t want tumors to have fuel to grow. We now have amazingly comprehensive data for studying this dynamic and determining mechanisms that prevent T cells from functioning as they should.”

More broadly, the results serve as a foundation for efforts to better understand how obesity affects cancer and the impact of patient metabolism on therapeutic outcomes, the authors said. While it’s too early to tell if PHD3 is the best therapeutic target, the findings open the door for new strategies to combat cancer through its metabolic vulnerabilities, they said.

“We’re interested in identifying pathways that we could use as potential targets to prevent cancer growth and to increase immune antitumor function,” Haigis said. “Our study provides a high-resolution metabolic atlas to mine for insights into obesity, tumor immunity and the crosstalk and competition between immune and tumor cells. There are likely many other cell types involved and many more pathways to be explored.”

Additional authors on the study include Gregory Baker, Alessia Catozzi, Juan García-Cañaveras, Brandon Gassaway, Brian Miller, Vikram Juneja, Thao Nguyen, Shakchhi Joshi, Cong-Hui Yao, Haejin Yoon, Peter Sage, Martin LaFleur, Justin Trombley, Connor Jacobson, Zoltan Maliga, Steven Gygi, Peter Sorger and Joshua Rabinowitz.

This study was supported by the National Cancer Institute and National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health (grants U54-CA225088, R01CA213062, R01DK103295, P01AI56299, 5F31CA224601 and T32CA207021), the Ludwig Center at Harvard Medical School, the Evergrande Center for Immunologic Disease, the Glenn Foundation for Medical Research and the American Cancer Society.

Amid the COVID-19 pandemic, it’s been easy to forget that a number of longstanding deadly global health problems remain with us, in some cases exacerbated by the outbreak. More people are hungry this year than last; childhood vaccinations and polio eradication have taken a step back; and AIDS, malaria, and TB continue to kill millions annually. In early December, a group of public health leaders recommended an “action agenda” for the incoming Biden administration that looked at the damage done to global health programs by the pandemic and plotted a path forward. Authors of the plan, published in The Lancet, include Harvard T.H. Chan School of Public Health Dean Michelle Williams, former Chan School Dean Barry Bloom, former Health and Human Services Secretary Donna Shalala — now a U.S. representative from Florida — and experts from Georgetown University, Emory University, and the University of North Carolina at Chapel Hill. The Gazette recently talked with Williams about what needs to happen.

Q&A

Michelle Williams

GAZETTE: Your comment in The Lancet mentioned “major setbacks” in reducing poverty, hunger, and disease. What is the status of global health today, and has the intense focus on COVID-19 globally hurt efforts in other areas?

WILLIAMS: Public health connects the dots between structural problems such as poverty and racism and a range of poor health outcomes, including increased risk of complications and death from COVID-19. The pandemic has put the spotlight squarely on the primacy of public health, so when speaking to the current status of global health, we must take into consideration the social determinants of health as well. Among the most critical areas in need of attention are education, food systems, environmental protection, economic stability, and behavioral and mental health.

GAZETTE: Clearly COVID-19 is the most pressing health concern today, both in the U.S. and globally. Are there resources available to address these more traditional health concerns and COVID at the same time, or have public health leaders been forced to choose?

WILLIAMS: We speak about the “COVID slide” in terms of the learning losses suffered by students, but the term can be applied to global health as well. The need to take an all-hands-on-deck approach to the pandemic has meant that other pressing public health efforts have been waylaid. In July, for example, the WHO released a report showing that prevention and treatment efforts for noncommunicable diseases have suffered during the pandemic.

And public health leaders are only human, after all. We are seeing exhaustion and burnout not just among frontline health care workers, but among public health experts as well. For many, there are only so many hours in a day to devote to causes other than COVID-19.

Long before the pandemic began, the U.S. public health system was severely underfunded but now the world has seen what a failure to invest in public health really means — and not just in lives lost. COVID-19 has also represented the greatest threat to value creation since World War II. Having now been brought to our knees, we need to stop making do with less and instead start investing more in public health infrastructures — not only for our collective well-being, but for our economic health as well.

GAZETTE: You and your co-authors mention a variety of steps to fight COVID-19. How, in your mind, can the U.S. most effectively help efforts abroad?

WILLIAMS: First and foremost, the U.S. should do everything it can to regain its leadership role in the world. This means leading by example, certainly, but also leading by investing in key initiatives that ensure our collective safety in a way that recognizes our interconnectedness. A threat anywhere is a threat to all of us, and this is true for viral threats as well as inattention to, say, planetary sustainability.

The incoming administration could make an immediate, meaningful impact across several areas, such as mobilizing partners to fund the U.N. COVID-19 Global Humanitarian Response Plan (GHRP) to re-engage with and strengthen WHO. WHO covers a whole range of global health threats, from maternal and child health to noncommunicable diseases and universal health care. However, WHO’s $5.8 billion biennial budget falls far short of its enormous global mandate. Of course, all of this in addition to working to ensure equitable worldwide distribution of COVID-19 vaccines.

WILLIAMS: The World Food Programme (WFP) projects a doubling of children and adults facing acute hunger globally by the end of 2020. Beyond illness and death, this virus has had a tremendous impact on the global economy, supply chains, food supplies, and access to humanitarian aid. COVID-19 has created a pandemic on top of a pandemic — food insecurity is a real and present threat all over the world. To address this crisis, we need long-term policy solutions to hunger, food waste, and climate change. Food donation is only one piece of the puzzle. Countries must bridge the gap between surplus food and the growing need for food for the most vulnerable. (One-third of all food produced for human consumption goes to waste, according to the Food and Agriculture Organization of the United Nations.)

By studying 110 children aged two weeks to 21 years who tested positive for COVID-19 at Massachusetts General Hospital (MGH) or urgent care clinics, researchers confirmed earlier findings that infants, children and adolescents are equally capable of carrying high levels of live, replicating SARS-CoV-2 in their respiratory secretions.

The researchers at Harvard-affiliated MGH and colleagues from Brigham and Women’s Hospital and the Ragon Institute of MGH, MIT and Harvard then showed that these high levels of virus correspond with live, infectious virus, and that levels are highest early in the illness in both symptomatic and asymptomatic children. They found no correlation between the age of the children and the amount of their viral load.

The researchers published additional data on several features of the SARS-CoV-2 virus in children in the Journal of Infectious Diseases.

“There had been the question about whether the high viral load in children correlated with the live virus. We’ve been able to provide a definitive answer that these high viral loads are infectious,” says Lael Yonker, pediatric pulmonologist at MGH and co-first author with Julie Boucau, senior research scientist at MGH and the Ragon Institute.

Reassuringly, they also found that viral load had no correlation to severity of disease in the kids themselves, but concerns remain for them and those around them: “Children can carry the virus and infect other people,” says Yonker.

Students and teachers have returned to classrooms, but many questions remain about the impact of the COVID-19 pandemic on children. Most children are asymptomatic or only mildly symptomatic when they develop COVID-19, giving the misconception that children are less infectious. Studying the virologic features of SARS-CoV-2 in children with COVID-19, and how SARS-CoV-2 infection differs between children and adults, is an essential component for establishing effective public health policies, not only to ensure safety within the school but also for controlling the pandemic, says Yonker.

As COVID-19 variants continue to emerge, infected children are potential “reservoirs” for the evolution of new variants as well as potential spreaders of current variants, she says. “Kids with COVID-19, even if asymptomatic, are infectious and can harbor SARS-CoV-2 variants. Variants could potentially impact both the severity of the disease and the efficacy of vaccines, as we are seeing with the Delta variant. When we cultured the live virus, we found a wide variety of genetic variants,” adds Yonker. “New variants have the potential to be more contagious and also make kids sicker.”

Yonker emphasizes that the group’s findings reinforce the importance of masking for children: “The implications of this study show that masking and other public health measures are needed for everyone — children, adolescents, and adults — to get us out of this pandemic.”

The viral loads of kids in the hospital were no different from those found in hospitalized adults, according to the study. Evidence cited by the Centers for Disease Control and Prevention (CDC) suggests that when compared to adults, children “likely have similar viral loads in their nasopharynx, similar secondary infection rates, and can spread the virus to others.”

Increasing awareness of pediatric COVID-19 and implementing broader testing programs for children are two of Yonker’s aspirations. According to the CDC, the “true incidence of SARS-CoV-2 infection in children is not known due to lack of widespread testing and the prioritization of testing for adults and those with severe illness.”

Yonker adds: “To develop effective public health policies, we need data-driven public health guidance. Kids are an essential component of beating the COVID-19 pandemic, and we must learn more about how they are affected and interact with others.”

Co-senior authors are Jonathan Li, director of the Harvard/Brigham Specialty Virology Laboratory and Amy Barczak, infectious disease specialist at MGH and the Ragon Institute.

We all know that exercise is good for us and that being fit can lower our risk of heart disease and possibly help us to live longer, but what amount and type of physical activity can change a person’s fitness level? New research led by investigators at Harvard-affiliated Massachusetts General Hospital (MGH) and Boston University and published in the European Heart Journal provides some specifics.

The research looked at cardiorespiratory fitness, or the capacity of the heart and lungs to supply oxygen to the body’s muscles during physical activity, in 2,070 participants from the Framingham Heart Study, a long-running multigenerational study designed to identify factors that contribute to cardiovascular disease. Participants underwent tests of physiologic parameters during exercise and wore physical activity trackers for a week at one point, then again nearly eight years later.

In this analysis, investigators found that people who increased their steps per day, participated in a greater amount of moderate-to-vigorous physical activity, or reduced their sedentary time between the two exams showed improvements in distinct aspects of cardiorespiratory fitness throughout exercise sessions, from warm-up to peak exercise to recovery. These findings were largely consistent regardless of participants’ baseline activity level, age, sex, weight, and risk of heart disease.

For each minute of increase in average moderate-to-vigorous physical activity, more than 3 minutes of intermediate cadence walking or 14.6 fewer minutes of sedentary time would be required for the equivalent changes in fitness. Increasing moderate-to-vigorous physical activity by 17 minutes per day, taking an additional 4,312 steps per day (approximately 54 minutes at 80 steps per minute), or reducing 249 minutes of sedentary time per day between the two exams corresponded to a 5 percent higher peak VO₂, or peak oxygen uptake.

Researchers also found that individuals with higher than the average number of steps or higher than the average amount of moderate-to-vigorous physical activity among the study participants also had above average peak VO₂ values regardless of how much sedentary time they had during the day.

“We conducted this analysis to understand relative effects of changing sedentary activity, low-level physical activity, and moderate-to-vigorous activity on multiple domains of exercise capacity as objectively measured by cardiopulmonary exercise testing,” says senior author Gregory D. Lewis, who is director of the Cardiopulmonary Exercise Testing Laboratory at MGH and medical director of MGH’s Heart Failure and Cardiac Transplantation Program. “The results offer adults equivalents of how much reduction in sedentary time, walking, or moderate-to-vigorous exercise will translate to changes in exercise capacity, which in turn are known to strongly predict long-term health status.”

“The most surprising finding of our study was that individuals with higher-than-average steps per day or moderate-to-vigorous physical activity had higher-than-average fitness levels regardless of how much time they spent sedentary. This would indicate that much of the negative effect that being sedentary has on fitness may be offset by also having higher levels of activity and exercise,” says the study’s first author, Matthew Nayor, the Aram Chobanian Assistant Professor of Medicine in the Sections of Cardiovascular Medicine and Preventive Medicine and Epidemiology at Boston University Medical Center.

“Physical activity is a cornerstone for modern cardiovascular disease prevention,” says study co-senior author Ravi Shah, director of Clinical and Translational Research in Cardiology at Vanderbilt. “These results support ongoing efforts to improve activity as a means to improve overall cardiometabolic health.”

Co-authors of the study include Ariel Chernofsky, Nicole L. Spartano, Melissa Tanguay, Jasmine B. Blodgett, Venkatesh L. Murthy, Rajeev Malhotra, Nicholas E. Houstis, Raghava S. Velagaleti, Joanne M. Murabito, Martin G. Larson, and Ramachandran S. Vasan.

The Framingham Heart Study is affiliated with Boston University and supported by the National Heart, Lung and Blood Institute. This work was supported by the National Institutes of Health and the American Heart Association.

In pregnant women who tested positive for SARS-CoV-2, the virus that causes COVID-19, male placentas showed increased immune activation compared with female placentas, according to a new study published in Science Translational Medicine.

The significantly higher levels of certain genes and proteins associated with increased immune activation may help protect male fetuses from becoming infected with SARS-CoV-2 in utero, but the resulting inflammation could pose risks to the fetus and child, notes Andrea Edlow, senior author of the study and maternal-fetal medicine specialist at Harvard-affiliated Massachusetts General Hospital (MGH).

Moreover, pregnant women with COVID-19 transferred significantly less immunity to the virus to male fetuses than to female fetuses, which could affect an infant’s risk for becoming infected with SARS-CoV-2. “The sex of the fetus influenced both the mom’s ability to generate antibodies to COVID-19 and to transfer them to her baby,” says Edlow.

This is the first study to look at sex differences in the transfer of a mother’s antibodies from COVID infection to her fetus, and the first to examine sex differences in the placental response to maternal infection.

Epidemiological studies have shown that male adults, children, and infants have a higher prevalence of COVID-19 infection and develop more severe disease than females. Male fetuses and infants are also more vulnerable to a host of pre- and perinatal exposures compared to female babies, so Edlow and her team sought to examine placentas, maternal blood and cord blood from pregnancies affected by maternal SARS-CoV-2 infection.

The study included 68 pregnant women, of whom 38 became infected with SARS-CoV-2 during their third trimester prior to the development of the COVID vaccine. The remaining 30 subjects were healthy pregnant women who tested negative for SARS-CoV-2 in pregnancy. In both groups, half the fetuses were male and half were female.

In a novel discovery, Edlow and her colleagues showed that, compared with female fetuses, the placentas of male fetuses carried by women with COVID-19 had much higher expression of interferon-stimulated genes (ISGs), which play a key role in shielding fetuses from viral invaders in utero. However, the increased expression of ISGs and downstream production of immune cells called cytokines can also result in an inflammatory intrauterine environment, which has been associated with an increased risk for neurodevelopmental or metabolic disease later in life. “While our study didn’t assess those risks specifically, it raises the importance of following these children and looking at male and female fetuses differently,” says Edlow.

In a second significant finding, Edlow’s team showed that mothers with COVID-19 who have male fetuses make lower levels of antibodies against the virus than mothers with female fetuses; they also transfer fewer antibodies to a male fetus. That suggests that males may be more vulnerable to becoming infected with SARS-CoV-2 in infancy and demonstrates that the sex of the fetus can influence the maternal immune response to the virus, notes Edlow.

Next, Edlow and her co-investigators plan to examine the character of antibodies induced by the COVID-19 vaccine and how those are affected by the timing of the vaccine during pregnancy and of course, fetal sex. “We want to know what happens to the placenta when moms are vaccinated against COVID-19 in each of the three trimesters and how fetal sex affects that response,” says Edlow.

Edlow is an assistant professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School and principal investigator at the Vincent Center for Reproductive Biology at MGH.

Major funding for this study was provided by the National Institutes of Health and the March of Dimes.