A newly identified “metabolic signature” can evaluate an individual’s adherence and metabolic response to the Mediterranean diet and help predict future risk of developing cardiovascular disease (CVD), according to new research led by Harvard T.H. Chan School of Public Health with collaborators from the Broad Institute of MIT and Harvard and Spain.

The metabolic signature consists of 67 metabolites — small chemicals produced in the processes of metabolism that circulate in the bloodstream — and can be measured through a blood sample.

The findings were published online in the European Heart Journal on May 14.

For the study, researchers used a machine-learning model to analyze hundreds of metabolites in blood samples from 1,859 participants from the Spanish PREDIMED study, the largest study of the Mediterranean diet’s ability to prevent CVD. The model identified 67 metabolites that when analyzed collectively indicated whether a person had followed the Mediterranean diet and showed how the person responded to the diet, which is high in unsaturated fats and emphasizes plant-based foods, fish, and olive oil, and has shown to be effective in reducing the risk of CVD and overall mortality.

The study also showed that a higher level of the metabolic signature was associated with a lower long-term risk of CVD among PREDIMED study participants. Even after accounting for traditional CVD risk factors, the metabolic signature was effective at predicting long-term risk of CVD, the researchers said.

The researchers further tested and verified the metabolic signature in blood samples from 6,868 participants from the U.S.-based Nurses’ Health Study, Nurses’ Health Study II, and Health Professional’s Follow-Up Survey. They noted that ability for the signature to determine adherence and metabolic response to the Mediterranean diet, and to predict future CVD risk, were highly reproducible across all the study populations despite the fact that individuals living in Spain and in the U.S. have different dietary habits, lifestyles, and environmental exposures.

“This study is the first to develop a metabolic signature for the Mediterranean diet based on comprehensive metabolomic profiles. It demonstrates that the level of dietary adherence and individual’s response to diet can be objectively measured,” said Liming Liang, associate professor of epidemiology and biostatistics at Harvard Chan School and co-senior author of the paper. “The reproducibility of the findings in the U.S. and Spanish populations indicate the robustness of the approach.”

Assessing adherence to the Mediterranean diet has often relied on self-reported data obtained through questionnaires of study participants. The newly discovered metabolic signature could prove to be a potent and objective tool for the research community to further evaluate individuals’ adherence and metabolic response to the Mediterranean diet in various study populations and settings.

“The metabolic signature and metabolites included in the signature could also help researchers better understand how the Mediterranean diet can benefit people with complex metabolic diseases,” said Jun Li, research scientist of nutrition and epidemiology at Harvard Chan School and the first author of the paper. “Given that the metabolic signature is reflective of individuals’ metabolic response to diet and CVD risk, the signature has potential in the future to help facilitate personalized nutrition interventions.”

“From a public health perspective, our findings underscored the beneficial effects of the Mediterranean diet for the prevention of cardiovascular disease at a molecular level,” said Miguel A. Martinez-Gonzalez, Professor at the University of Navarra (Spain) and co-author of this study.

Other Harvard Chan School authors include Jun Li, Marta Guasch-Ferré, Wonil Chung, Shilpa Bhupathiraju, Deirdre Tobias, Fred Tabung, Tong Zhao, Constance Turman, Yen-Chen Anne Feng, Lorelei Mucci, Heather Eliassen, Alberto Ascherio, Eric Rimm, JoAnn Manson, Lu Qi, and co-senior author Frank Hu.

Researchers from the Spanish PREDIMED study group, Brigham and Women’s Hospital, and the Broad Institute of MIT and Harvard were also co-authors of the paper.

The PREDIMED metabolomics studies were funded by National Institutes of Health (NIH) grants R01 HL118264 and R01 DK102896. The PREDIMED trial was funded by the Spanish Ministry of Health (Instituto de Salud Carlos III, The PREDIMED Network grant RD 06/0045, 2006–45 13, coordinated by M.A. Martinez-Gonzalez; and a previous network grant RTIC-G03/140, 2003–05, coordinated R. Estruch). Additional grants were received from the Ministerio de Economia y Competitividad-Fondo Europeo de Desarrollo Regional (Projects CNIC-06/2007, CIBER 06/03, PI06-1326, PI07-0954, PI11/02505, SAF2009-12304, and AGL2010–22319-C03-03) and by the Generalitat Valenciana (PROMETEO17/2017, 5 ACOMP2010-181, AP111/10, AP-042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165). The NHS, NHSII, and HPFS, and their metabolomics studies were supported by NIH grants U01 HL145386, UM1 CA186107, R01 CA49449, R01 HL034594, R01 HL088521, UM1 CA176726, R01 CA67262, UM1 CA167552, R0110 HL35464, HL60712, R01 CA50385, P01 CA87969, and R01 AR049880. J.L. was supported by 9-17-CMF-011 from the American Diabetes Association (ADA), K99 DK122128 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and a pilot and feasibility grant from the NIDDK-funded Boston Nutrition Obesity Research Center (P30 DK046200). M.G.-F. was supported by 1-18-PMF-029 from ADA. F.K.T was supported by R00 CA207736 from the National Cancer Institute. D.K.T is supported by 1-18-JDF-104977 from ADA.

When the COVID-19 pandemic prompted Harvard Medical School (HMS) to move learning online in March, faculty moved swiftly, developing new curriculum approaches, sometimes within hours, allowing educators to continue to teach classes and ensure that students are achieving learning objectives remotely.

But, among Harvard Schools, they had some unique challenges. Part of the process of teaching medical students how to fully assess their patients’ conditions requires human touch — and that can’t be done remotely.

“What is missing is the actual laying on of hands. We can use all of our other senses, but the ability to lay hands on and connect with a patient that way just can’t be replicated with virtual learning,” said John Dalrymple, associate dean for medical education quality improvement in the program in medical education.

“You can use your eyes and your ears a lot more, but just that physical connection … There’s no way to replicate that effectively,” he said.

It’s an obstacle, but not one that HMS faculty are letting hinder their teaching or the medical students’ education. In response, they have become more creative, and they’ve done it in record time.

Within weeks of moving classes online, for example, they converted objective structured clinical examination courses (OSCEs), into a virtual format. Ordinarily, students would perform OSCE’s with standardized patients — individuals trained to portray actual patients — in the School’s Clinical Skills Center, while faculty observe, coach and assess.

Now, faculty — led by OSCE Director Susan Farrell working with HMS IT teams — have developed a way to create televisits, where students can conduct standardized patient exams remotely, with faculty still able to watch and assess students’ skills.

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

With COVID-19 looming over the upcoming Memorial Day weekend, warm-weather fun is not only possible but also advisable, according to a Harvard healthy-building expert. But he nonetheless warned that, if mismanaged, unfettered gatherings could spark fresh summer outbreaks.

“This is going to be a very different summer,” said Joe Allen, assistant professor of exposure assessment science at the Harvard T.H. Chan School of Public Health and director of its Healthy Buildings Program. “We’re ready for a change, we’re all ready to get out of this. But we don’t yet have the systems in place to manage this effectively. So we should expect that things will be very different this summer. I don’t think this is going to be anything like past summers.”

Allen, who spoke Tuesday at a press briefing, expects there will be less travel — though he’s written recently that airlines are relatively safe — and that regular vacation areas will have fewer visitors. But what summer winds up looking like will vary not only by activity but also by location. The summer of 2020 will look a lot different in Montana than in Manhattan.

Allen has been a proponent of keeping parks open and getting outside, safely, even during the strict social-distancing phase now waning across the U.S. He said getting outdoors has multiple benefits, both physical and mental, and — due to the “unlimited dilution” of viral particles in a breeze and the virus’ low survival on sunny surfaces — lower risks than remaining indoors.

But even with travel, camping, and beach-going on the summer agenda, COVID and the potential to become infected or to infect others should always be taken into consideration, and steps should be taken to minimize risk. In many cases, he suggested, a phased approach to reopening outdoor spaces will allow managers and workers to ensure that the systems in place can control crowds and keep people safe before inviting in larger crowds.

The safest summer activities will occur within established personal networks, involving in many cases the people with whom you share a household. Allen said the onus will fall most heavily on individuals and their willingness to take the now-familiar steps to ensure safety. He recommended people think of access to a park or a beach not as a right but a privilege, one that not only can be revoked quickly, but that should be if laxity sparks outbreaks.

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

With nearly 5 million confirmed cases globally and more than 300,000 deaths from COVID-19, much remains unknown about SARS-CoV-2, the virus that causes the disease. Two critical questions are whether vaccines will prevent infection with COVID-19, and whether individuals who have recovered from COVID-19 are protected against re-exposure to the virus.

Now, a pair of new studies led by researchers at Harvard-affiliated Beth Israel Deaconess Medical Center (BIDMC) suggests the answer to these questions is yes, at least in animal models. Results of these studies were published today in the journal Science.

“The global COVID-19 pandemic has made the development of a vaccine a top biomedical priority, but very little is currently known about protective immunity to the SARS-CoV-2 virus,” said senior author Dan H. Barouch, director of the Center for Virology and Vaccine Research at BIDMC. “In these two studies, we demonstrate in rhesus macaques that prototype vaccines protected against SARS-CoV-2 infection and that SARS-CoV-2 infection protected against re-exposure.”

In the first study, the team found that six candidate DNA vaccines — each formulation using a different variant of the key viral protein — induced neutralizing antibody responses and protected against SARS-CoV-2 in rhesus macaques.

Barouch and colleagues, who began working toward a COVID-19 vaccine in mid-January when Chinese scientists released the SARS-CoV-2 genome, developed a series of candidate DNA vaccines expressing variants of the spike protein, the part used by the virus to invade human cells and a key target for protective antibodies. The vaccines are designed to train the body’s immune system to recognize the virus swiftly upon exposure and respond quickly to disable it.

To assess the efficacy of the vaccines, the researchers immunized 25 adult rhesus macaques with the investigational vaccines. Ten animals received a sham version as a control group. Vaccinated animals developed neutralizing antibodies against the virus. Three weeks after a booster vaccination, all 35 animals were exposed to the virus. Follow-up testing revealed dramatically lower viral loads in vaccinated animals, compared with the control group. Eight of the 25 vaccinated animals demonstrated no detectable virus at any point following exposure to the virus, while the other animals showed low levels of virus. Moreover, animals that had higher antibody levels had lower levels of the virus, a finding that suggests neutralizing antibodies may be a reliable marker of protection and may prove useful as a benchmark in clinical testing of SARS-CoV-2 vaccines.

In the second study, the team demonstrated that macaques that recovered from COVID-19 developed natural protective immunity against re-infection with the virus. The results shed much-needed light on the critical question of just how much, if any, immunity does infection with SARS-CoV-2 provide against subsequent encounters with the virus.

“Individuals who recover from many viral infections typically develop antibodies that provide protection against re-exposure, but not all viruses generate this natural protective immunity,” said Barouch, who is also professor of medicine at Harvard Medical School, a co-leader of the vaccine development group of the Massachusetts Consortium on Pathogen Readiness, and a member of the Ragon Institute of MGH, MIT, and Harvard.

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

Couples who are cooped up by COVID-19 are getting the rare opportunity to spend more time together, but also discovering the downside of having too much of a good thing, said an expert in romantic relationships at a Harvard forum.

But don’t despair. There are ways to keep love alive in the time of coronavirus.

“COVID-19 has created an environment that has changed and often strained relationship dynamics,” said Joanne Davila, professor of psychology and associate director of clinical training in the Department of Psychology at Stony Brook University.

One of the biggest challenges couples face now is deciding how much closeness and how much separation they want from one another. Some people may find it hard adjusting to having their spouses in the house all day long. It’s important to carve out personal time to help preserve both partners’ mental sanity and the relationship’s strength.

“Maybe you’re used to getting up early and doing your yoga quietly, but now your partner is there, and they’re listening to the news loudly or want to have coffee with you,” said Davila, director of the Relationship Development Center at Stony Brook. “There is no private time unless you make it these days.”

Davila spoke Wednesday at the latest installment of a series of forums on COVID-19 and mental health sponsored by the Harvard T.H. Chan School of Public Health. She shared her research on how to achieve “romantic competence,” which could help people navigate relationships amid the pandemic.

According to Davila, romantic competence requires three skills: insight, mutual understanding of both partners’ needs, and emotion regulation. These skills have to be used all at once because they inform each other, but the most important thing is to remember that a couple is made of two people.

“First of all, we need to remember that both people in a relationship have needs” said Davila. “This is the core, and it’s so hard to remember this. Sometimes when we’re struggling, when there are challenges, we’re really focused on ourselves, or there are times when we’re actually really focused on the other person, and we lose sight of ourselves.”

When there is a mutual understanding of both parties’ needs, couples find it easier to put themselves in each other’s shoes, but both partners must communicate their needs to one another in a clear, direct, and calm manner, without making assumptions or expecting the other to read their minds. They should also avoid holding things in or blaming the other and instead focus on how a partner’s behaviors are affecting them.

“If we tell somebody that we’re feeling hurt, they’re going to take that a lot better than if we tell them how angry they are or what a jerk they are,” said Davila.

It’s also important that partners make an extra effort to control their emotions. Unregulated emotions can create turmoil in their love lives and their physical and mental well-being.

“We may be feeling more tense right now, more short-tempered, more anxious and afraid, or more sad,” said Davila. “These are emotions that are going to be heightened in the face of everything we’re dealing with, and it’s really important that we know how to handle them.”

Love during a pandemic is hard. Domestic-violence victims are at a higher risk as they are forced to hunker down with their abusers. According to reports, divorce and break-ups are on the rise in China, the U.K., and the U.S. Davila warns against making quick decisions during times of upheaval.

“Things are going to be worse now probably than they were, or they may get better when the stress goes down,” said Davila. “We don’t want to make impulsive decisions, but we do want to look across time and across situations to see the consistency in whether our needs are or are not getting met.”

Davila said perhaps the healthiest piece of advice for a wholesome relationship is to give up the idea that people should strive for a perfect relationship, in which one’s partner will meet all one’s needs. People should strive to have healthy relationships in which each person gets their needs met as best as they can.

“On average in the U.S. we have this idea that our romantic partner should meet our every need, and I think that that is unrealistic,” said Davila. “Romantic relationships should meet some basic core needs, but those needs that may be different depending on who you are and what relationship you’re in. We all do have needs that can get met and perhaps maybe even be better met by friends, extended family members, therapists, and other people in our lives who can really support us in different ways.”

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

Hospital officials, anticipating a surge of COVID-19 cases, urged deferring routine, nonemergency care so doctors, nurses, and other personnel could focus on pandemic patients. But a new study from Beth Israel Deaconess Medical Center suggests that too many, either to avoid straining medical resources or fearing infection at the hospital, may have put off emergency care for issues like heart attacks and strokes, at a cost of lives. Dhruv Kazi, director of Beth Israel’s Cardiac Critical Care Unit and a Harvard Medical School faculty member, and associate director of the hospital’s Smith Center for Outcomes Research in Cardiology, spoke with the Gazette about the study’s findings of a 33 percent drop in heart attack patients and 58 percent drop in stroke patients at the hospital during March and April.

Q&A

Dhruv Kazi

GAZETTE: What did you find when you looked at hospitalizations for non-COVID conditions at Beth Israel?

KAZI: Early on in the pandemic, it became clear to those of us who work in the intensive care unit and more broadly in cardiology that the number of patients seeking care for emergencies such as heart attacks or strokes had dropped precipitously. Patients were simply not showing up.

And, as we had conversations with colleagues across the country, we realized that this was a national phenomenon and, in fact, an international phenomenon. Patients are not seeking care for conditions that we would normally think of as emergent and potentially life-threatening. So we compared the rates of patients presenting with heart attacks and stroke during the course of the pandemic with an equivalent period of time earlier in the year, before the start of the pandemic.

We used last year’s data to adjust for the usual month-to-month variation you would expect over this time period. We expected to find a decline but were still surprised by the magnitude of it: a 33 percent reduction in hospitalizations for heart attacks and a 58 percent reduction in strokes. The reduction in heart attacks my co-investigators and I had seen firsthand as cardiologists, but the stroke numbers were pretty stunning.

GAZETTE: Is it possible that people are calmer because they’re home, less stressed, so fewer of these things are happening?

KAZI: The data can only tell us what’s actually happening, not why these numbers have dropped. There’s a possibility that we’re at home and, hypothetically, we’re eating better, working out more often, feeling less stressed about trying to beat Boston traffic. We also know that, to some extent, air quality has gotten better. But none of these factors, individually or collectively, can explain the magnitude of this decline. In fact, recently released census data suggest that concerns about the pandemic and the resulting economic uncertainty are increasing levels of anxiety and stress in the population.

The decline in heart attack hospitalizations has been seen across the country and the world, including places like Northern California, where the COVID-19 pandemic didn’t hit nearly as hard as it did in Boston, and Italy, where they had a public health catastrophe. So it’s clear that the messaging that this is a highly infectious disease and that people need to shelter in place, combined with images of hospitals that are overwhelmed — even far away — has encouraged patients to stay at home. The effect we saw on heart attacks and strokes I think is primarily driven by fear of contagion. And that fear has important public health implications.

It means that we, as health systems, have to do a better job convincing patients that hospitals are safe for emergencies. And, as we open up, we’ve got to do a better job convincing patients that hospitals are safe for routine care. Because if this fear lingers, people are going to continue to put off routine and even urgent care.

GAZETTE: Talking specifically about Massachusetts, aren’t guidelines for nonemergency care loosening up?

KAZI: Good point. It’s important to remember that even at the peak of the lockdown, there were no restrictions at all on emergency care. That’s why heart attacks and strokes shouldn’t, in an ideal world, have seen any drop at all. With regard to nonemergency care, the state is starting to open up slowly, but there are pretty strict requirements in terms of maintaining adequate social distancing and reducing crowding in waiting rooms. Patients should rest assured that hospitals and clinics have developed systems to safeguard their health while they’re in the hospital for care.

GAZETTE: How dangerous were ERs for people presenting without COVID? Did you have a lot of cases of people who came in for other conditions who wound up getting COVID in the hospital?

KAZI: No, all of our hospitals in Boston — and the same is true nationally — have extensive experience with infection control in emergency room settings. Very quickly, for instance, we split our emergency room into a section that would care for people with respiratory complaints that might be COVID-19 and an entirely separate section that dealt with individuals who clearly did not have complaints resembling COVID-19. In the COVID-19 section of the emergency room, patients were masked immediately, and clinicians took ample precautions to ensure there was no risk of transmission from patients to clinicians or among patients. This went into place even before the first trickle of patients started showing up in our emergency rooms. So, the risk was very, very low from the get-go.

GAZETTE: Do you know whether there were any cases of infections in the emergency room?

KAZI: I don’t know of any transmission in the emergency room, and this is exactly the kind of question patients need answered. I think we did a really effective job communicating the importance of staying at home, and I’m not undervaluing what we achieved. Let’s be clear about this — staying at home and “flattening the curve” in Boston saved lives. We have the luxury in Boston of having numerous world-class hospitals, and each of the big hospitals more than doubled their critical care capacity. In hindsight, the early outbreak in the beginning of March may have pushed us all to prepare well in advance, yet, even with the flattened curve, most hospitals got pretty close to being full during the peak of the pandemic. So, I don’t interpret our findings to mean that we shouldn’t have locked down or shouldn’t have sheltered in place. Far from it. Even our hospitals with all of their spare capacity would have been completely overwhelmed if we had had the same numbers as New York. But I think we could have done a better job communicating about emergencies. And that’s a job that’s not finished.

GAZETTE: Do we know whether there were excess deaths that are attributed to non-COVID conditions and that did not occur in the hospitals?

KAZI: Based on the heart attack and stroke data that we just discussed, it’s very clear that there are patients who are having heart attacks and strokes and deciding to sit it out. They are either presenting to the hospital late — and not eligible for some of the very effective therapies for cardiovascular conditions that must be administered early on — or they may have died at home. We know from data from the Centers for Disease Control and Prevention that Massachusetts has had approximately 5,000 excess deaths since the pandemic started. Many of these are due to the pandemic itself, and some may be undiagnosed COVID-19 cases, but my hunch is that many of those deaths are from undiagnosed cardiovascular conditions, like heart attacks and strokes, where people decided to sit out the symptoms and it didn’t work out well.

GAZETTE: One of the reasons we’ve become a healthier society is that people have gotten the message, “Don’t wait; come in; get screened; get checked out.” How valuable has that “catch it early” message been and is it a potentially unrecognized casualty of COVID, from a public health messaging standpoint?

KAZI: Absolutely. That’s exactly what is happening here. Over the past two decades, organizations like the American Heart Association have done a really good job of messaging around the “golden hour,” the need to respond early, the importance of — particularly among women — recognizing that some symptoms might be atypical. When in doubt, call 911, go get checked out because in cardiology we say, “Time is muscle.” The longer you wait during a heart attack, the more heart muscle you lose. The neurologists say, “Time is brain.” The longer you wait during a stroke, the more brain tissue you lose. We’ve communicated to the public that time is essential for these conditions and we’re going to have to get that message out again. Our data suggests that we’ve taken a small but real step backward in the time of COVID.

GAZETTE: Besides heart ailments and strokes, did the tendency to avoid hospital visits have any other public health effects for non-COVID patients?

KAZI: Talking about these unintentional consequences of our response to the pandemic, the second part of our study examines cancer diagnoses. Breast cancer is most frequently diagnosed by a screening mammogram, and blood cancers are diagnosed when a patient with minor symptoms goes to their primary care doctor and has an abnormal routine blood test. Starting in March, all screening tests and most primary care visits were deferred so if you didn’t have something urgent, you just rescheduled your primary care visit for later. Screening tests like mammograms and colonoscopies were put off.

Again, the intention there was a good one. We didn’t want healthy individuals to be coming into the health care system. We wanted to preserve our protective equipment for the surge of COVID-19 patients we anticipated were coming down the pike, and it worked. It’s one thing to defer a mammogram by two weeks, but when we start talking about deferring screening tests and primary care visits over a longer period for an entire population, that’s a lot of delay in care and a high potential for harm.

We saw that, starting April 1, referrals for breast cancer and blood cancers and hematologic cancers went down more than 60 percent. Those findings are important because these findings are a real marker of health care disruption from deferred primary care and screening. And it harks back to my original point that, as a health system, we’re going to have to convince patients that, (a), the hospital is a safe place to come for emergencies. And, (b), as we start to open up again, it will be important not to defer routine care, because this is evidence-based care, tried and tested. We know that it works, and it saves lives.

JUUL and similar pod-based e-cigarettes’ efficient delivery of nicotine may foster greater dependence than other types of e-cigarettes, according to a new study by Harvard T.H. Chan School of Public Health.

The pod-based e-cigarettes have been popular with teenagers and young adults since they came on the market in 2015, but little has been known about their health effects. A new systematic review led by researchers at the Harvard Chan School found that while the products may contain lower levels of harmful ingredients than conventional cigarettes, there is no evidence that even these lower levels are safe for youth.

This is the first paper to synthesize research findings on pod-based e-cigarettes, said first author Stella Lee, formerly a National Cancer Institute Cancer Prevention postdoctoral fellow in the Department of Social and Behavioral Sciences and currently an assistant professor at Konkuk University in South Korea.

“We found that pod-based e-cigarettes have a higher potential to get youth and young adults addicted than other devices,” she said. “To prevent this from happening, we need stronger health communication messages that alert people to these findings.”

The study will be published online June 1 in JAMA Pediatrics.

Pod-based e-cigarettes are sleekly designed and easy to conceal. Users pop in replaceable nicotine cartridges that come in appealing flavors like mango and mint. JUUL has dominated retail sales, although other pod-based products are now on the market, including Suorin, Bo, Phix, and Vuse Alto. Recent data have shown that e-cigarette use in adolescents has increased substantially since the introduction of pod-based e-cigarettes, prompting the U.S. Surgeon General to declare youth vaping an epidemic.

According to the new study, the design of pod-based e-cigarettes ensures the delivery of high doses of nicotine in a low pH form, which is less harsh compared to the higher pH nicotine found in most other e-cigarette brands, thus encouraging deeper inhalation. In one study, the level of nicotine exposure in adolescents (as measured by urinary cotinine) using JUUL or other brands of pod-based e-cigarettes was higher (245 ng/ml) than levels detected in adolescents who smoked regular cigarettes (155 ng/ml). Study findings also suggested that adolescents using pod-based e-cigarettes were more likely than other e-cigarette users to vape daily and to have more symptoms of nicotine dependence.

For this study, the researchers reviewed recent peer-reviewed scientific literature on pod-based e-cigarettes. They identified 35 English-language articles that presented primary data on pod-based e-cigarettes from June 2015 to June 2019. Studies looked at product design and biological effects, marketing and social media messaging, and population use and perception.

The researchers also found that pod-based e-cigarette social media marketing campaigns have targeted youth and young adults more than campaigns for other e-cigarette devices. Messages focused less on use of these products as smoking cessation devices and more on ease of use and lifestyle appeal.

The researchers were surprised to find that no study has yet focused on knowledge and perceptions of pod-based e-cigarette use among parents of teenagers, said senior author Andy Tan, assistant professor in the Department of Social and Behavioral Sciences. “Learning parents’ perspectives and their information needs around pod-based e-cigarettes is important to address the vaping epidemic among young people,” he said. “This is because we will then be able to empower parents with accurate information and tools to communicate with their children that pod-based e-cigarettes are extremely addictive, and to avoid using these products.”

Other Harvard Chan School authors of the study included Vaughan Rees, Noam Yossefy, and Karen Emmons.

This study was supported by a gift from Roslyn and Lisle Payne, and by awards R25CA057711 and 2T32CA057711-26 from the National Cancer Institute of the National Institutes of Health.

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

Though fever, cough, and shortness of breath are the symptoms most commonly associated with COVID-19 infection, a recent study in which 2.6 million people used a smartphone app to log their symptoms daily showed that the most oddball pair of indicators — loss of smell and taste — was also the best predictor, and one that scientists said should be included in screening guidelines.

Researchers, led by scientists at Massachusetts General Hospital (MGH) and King’s College London, began the study as a way to fill the numerous gaps in knowledge about COVID-19, several of which are the result of the lack of broad-based clinical testing. Using crowdsourcing, they were able to rapidly gather data on the disease’s spread through a large swath of the population.

“It’s clear we understand very little about COVID, and we need to try to fill in a lot of gaps with respect to understanding the disease: who is susceptible to getting infected, the symptoms people develop related to COVID, and ultimately where around the country people were getting sick,” said Andrew Chan, chief of clinical and translational epidemiology at MGH and a professor at Harvard Medical School and the Harvard T.H. Chan School of Public Health.

The scientists adapted a smartphone app that had been created by corporate partner ZOE, a health science company, for research on how to personalize diet to address chronic disease. The new program, a free download from the Apple or Google app stores, collects demographic and health background information and then asks how the participant is feeling. If they’re feeling well, that’s the end of the daily entry. If they’re not it asks further questions about symptoms.

The app went viral after its late March release. Some 2.6 million participants in the U.K. and U.S. were involved in the recent study but numbers have continued to climb, touching 3.7 million before the end of May.

Testing for the virus has increased dramatically as the pandemic has worn on, but experts say the current rate in the U.S. — at least 1.1 million in the week of May 10, according to the U.S. Centers for Disease Control and Prevention — represents a fraction of what is needed.

The app is among several strategies being employed worldwide to illuminate the overall COVID picture. The recent rush to develop and distribute antibody or serologic tests, which can tell whether someone has had COVID-19 in the past, is one, as is the examination of sewage for COVID-19 DNA, which can be traced to particular neighborhoods undergoing an outbreak. Understanding the disease’s path through a population is essential to design effective responses and — in the absence of a vaccine — to gauge progress toward so-called “herd immunity,” where enough people have been infected that it interferes with the virus’ spread.

Chan said his collaborators in London have worked with the public health service there and shown that data from the smartphone app can identify the onset of symptoms in an area about five days before requests for COVID tests spike.

“It gives people really critical planning time they otherwise wouldn’t have had,” Chan said.

In the work, published recently in the journal Nature Medicine, researchers used data from about 18,000 participants who had been tested for SARS-CoV-2 to understand which symptoms were most common in those who had tested positive. They found that loss of taste and smell were reported by most of those tested, about 65 percent, and that the most predictive group of symptoms was loss of smell and taste, fatigue, persistent cough, and loss of appetite.

They then applied their model to more than 800,000 study participants who had not been tested and determined that about 140,000 of them were likely infected with the virus, just over 5 percent of the entire 2.6 million study population. Researchers said the study is limited by the fact that the app volunteers are self-selected and likely don’t represent the general population. They also said the results don’t indicate when loss of smell and taste occur in the illness’ course, though that may become apparent as more results are collected over time.

Chan said the crowdsourced data includes numerous mild cases — thought to be about a quarter of those infected overall — and one of the ways the app may do the most good is by increasing understanding of them.

“They are a group most at risk of spreading it because they don’t know they have it,” Chan said.

Another such group would be those who are completely asymptomatic, and the app data wouldn’t capture them since the information is self-reported. Those numbers would only be discovered through actual testing.

Future work is focusing on other unanswered questions, such as the impact of COVID on cancer patients and the effect of past infections on developing immunity. Discussions are also ongoing as to how the app can help governments direct limited resources, such as a county deploying testing or contact tracing to places where need is highest. It can also be used by managers of smaller groups — students at a particular college or workers at a large factory — to guide decisions about how best to guard students’ and workers’ health as society reopens more fully.

“I think we’re all very nervous about that [reopening], and this will be an opportunity to see if this kind of crowdsourcing information can help,” Chan said. “Ultimately it can be a tool people use at the level of public health to predict whether we can loosen restrictions. The more planning we can do the better.”

In a new report published by the Brookings Institution, Matthew Fiedler, Ph.D. ’13 , a fellow in economic studies at the USC-Brookings Schaeffer Initiative for Health Policy, and Zirui Song, M.D. ’10, Ph.D. ’12, assistant professor of health care policy in the Blavatnik Institute at Harvard Medical School, estimate national health care spending for COVID-19 care and discuss its policy implications.

The implications of the COVID-19 pandemic on health care spending are important for providers, payers, and policymakers, the researchers said. As a nation, direct health care spending on the pandemic critically depends on infection and hospitalization rates, in addition to the prices and quantities of health care services, they said, adding that the magnitude of this spending has implications for federal policy and state budgets.

Projecting COVID-19 spending can be challenging, as the dynamics of disease transmission and population behavior remain uncertain. Thus, Fiedler and Song consider multiple scenarios, including one in which infections are driven to a low level in the near future, and another in which further spread of the virus is poorly contained. Estimates are made at the national level and separately for Medicare, Medicaid and privately insured populations.

Under several potential hospitalization rate scenarios, a cumulative national infection rate of 5 percent would lead to a modest level of direct spending on COVID-19, amounting to roughly 1 percent of baseline health care spending. A cumulative national infection rate of 60 percent would lead to COVID-19 care comprising almost 6 percent of baseline health care spending, with the range of hospitalization rates widening this estimate to about 4 percent to 10 percent of baseline health care spending.

Recent data suggest that insurers have seen a decrease of over 30 percent in overall claims spending as nonemergent care is delayed or canceled during the pandemic. Hospitals have seen similar declines in their inpatient admissions, as well as in emergency room visits (50 percent) and outpatient surgeries (70 percent) compared to the same time last year. Fiedler and Song estimate that even moderate declines in non-COVID-19 spending would in large part offset direct spending for COVID-19.

This study also suggests that policymakers should more closely critique the case for offering stimulus aid to insurers for the 2020 plan year. Even if most of the delayed care rebounds later in 2020, most insurers will likely not face very large losses during this plan year. In future years, Fiedler and Song propose a rationale for a risk corridor policy to help protect vulnerable payers and lower premiums for enrollees.

This report was produced by the USC-Brookings Schaeffer Initiative for Health Policy.

This is part of our Coronavirus Update series in which Harvard specialists in epidemiology, infectious disease, economics, politics, and other disciplines offer insights into what the latest developments in the COVID-19 outbreak may bring.

Harvard economist and former U.S. Treasury Secretary Lawrence Summers panned America’s COVID-19 response this week, decrying misplaced priorities and missed opportunities even when viewed through an economic, rather than public health, lens.

“I think the risks that we will look back at this moment and say, ‘We didn’t try enough. We weren’t aggressive enough. We didn’t do enough,’ are an order of magnitude greater than the risks that people will say, ‘They spent too much money. They were too ambitious. If they just let things go, it would have been OK,’” said Summers, who served as Harvard’s president from 2001 to 2006 and is currently the Charles W. Eliot University Professor.

Summers was Treasury secretary during the Clinton administration, director of the National Economic Council under Obama, and served as chief economist at the World Bank in the 1990s. He said the pandemic is costing the U.S. $10 billion — and the world $200 billion — a day. With that cost in mind, he said, it makes sense to provide additional incentives and guarantees against losses to boost private efforts — which are both expensive and risky — to develop and distribute tests, treatments, and vaccines.

“I think we’re neither providing enough insurance against failure nor enough reward for success,” Summers said. “And therefore, we’re getting insufficient effort on testing in particular, but also on vaccines and therapeutics.”

Summers said companies that could be producing billions of tests are sitting on the sidelines, discouraged by the prospect of a quick vaccine that will render tests unsellable. That is an area where the government can step in, he said.

“If we buy $5 billion worth of tests we don’t need, it doesn’t matter, it’s not an important error,” Summers said, “whereas if we slow things up for an extra several weeks, it’s an enormously consequential error.

Summers fielded questions on Wednesday during a webcast event on business and public health sponsored by the Harvard T.H. Chan School of Public Health and the New England Journal of Medicine. “When Public Health Means Business: A Virtual Fireside Chat with Lawrence H. Summers and Ali Velshi” was introduced by Chan School Dean Michelle Williams and moderated by Velshi, an NBC journalist and MSNBC host.

Summers also criticized government spending on economic stimulus and helping corporations while skimping on expanding COVID-19 testing and hiring workers for contact tracing efforts that could help curb the pandemic.

“It is insane that we spent more than $3 trillion on economic stimulus but we haven’t been able to spend $30 billion on putting testing in place. It is crazy that we are investing as much money as we are in bailing out the largest corporations in the country and investing so little money in providing jobs as contract tracers to those who are unemployed,” he said. “There are aspects of this that are the biological equivalent of rocket science. But there are aspects of this that are entirely straightforward, that are entirely a matter of will and competence, and we are not doing them.”

Summers laid a large share of the blame for America’s halting pandemic response at the feet of the Trump administration, saying stable leadership that engenders trust and confidence in strategies like mask-wearing, widespread testing, and other steps is crucial during crises. He didn’t let previous administrations off the hook, however, saying they were warned about the likelihood of future pandemics, but took few steps to prepare.

“We have lost tens of thousands of lives because of mistakes we made in the past, and we are in the process of making more mistakes that will cost thousands — probably tens of thousands — more lives in the future,” Summers said. “We can do better as a country … but it requires a stable, steady commitment to truth-telling.”

Summers said the focus now should be on defining the steps to move forward, and warned that government incentives for developing a vaccine should not amount to control. Market systems and democratic societies are messy, but have been responsible for many advances in public health, pharmaceutical innovations, and benefits like the environmental movement, he said. Market mechanisms will also likely be the best way to distribute an eventual vaccine because a company that stands to make a profit will ensure its product gets produced, marketed, and distributed.

“We have to be very careful about letting easy moralisms trump what we know works,” he said. “We have to find a balance here, it’s a balance that respects stakeholders, but it’s also a balance that reflects that market incentives are very, very strong. …

“The worst thing you can do, if you want this pharmaceutical intellectual property to find widespread application, is to just toss it over and make it completely available to everybody for free.”

Summers said that statistics about health care disparities are startling, but that messages speak louder when they come from unexpected sources. The voices of community organizers complaining about inequality are expected and too often ignored, he said. If, however, for the next two years every leader of a Fortune 500 company spoke as much about health care disparities as they do about rising health care costs, it would change the national discussion on the subject.