A novel liquid biopsy method can detect kidney cancers with high accuracy, including small, localized tumors which are often curable but for which no early detection method exists, say scientists from Dana-Farber Cancer Institute.

The report in Nature Medicine suggests that if validated in larger trials and applied widely, the noninvasive test could find more early kidney cancers when they haven’t spread, thus reducing the mortality of the disease. “Hopefully we can scale this to a much larger level and detect cancer earlier so we can act earlier,” said Toni Choueiri, director of the Lank Center for Genitourinary Oncology at Dana-Farber and a co-senior author of the study.

It is estimated that 73,750 new kidney cancer cases will be diagnosed in 2020, and about 14,830 will die of the disease. About 35 percent of cancers are diagnosed only after they have spread beyond the kidney and are more difficult to treat. Small, early kidney tumors usually cause no symptoms, and increasingly are found incidentally in scans of the abdomen performed for another purpose. However, there is no imaging or other screening test recommended for the general population to look for early kidney cancers. Initially, a test based on the method described in the new report might be used to screen people with a family history of kidney cancer, or who had a previous kidney cancer, said Choueiri. “We need to be specific first, before making it totally mainstream,” he said.

Noninvasive liquid biopsies, which search for cancer-related DNA shed by tumors into blood or other body fluids, are moving rapidly toward clinical use as a means of early detection for some kinds of tumors. “Kidney cancer is one of the hardest tumors to detect, because it doesn’t shed as much DNA as other tumors,” said Matthew Freedman, a medical oncologist at Dana-Farber and co-senior author of the report.

The test performs well because it can identify abnormal patterns in small amounts of tumor-shed DNA, Freedman added. “It’s a proof of principle that early stage disease is detectable.”

The test was nearly 100 percent accurate when used with blood samples to distinguish patients with kidney cancer from those known to be free of kidney cancer. The method achieves less accuracy in testing urine samples, but the researchers believe that performance can be improved. If the test is validated in larger trials and becomes widely applicable clinically, a urine sample would be even less invasive than a blood draw.

The testing method is known as cell-free methylated DNA immunoprecipitation and high-throughput sequencing, or cfMeDIP-seq. Where other liquid biopsy methods search for mutations in tumor-shed DNA that reveal the type and location of cancer, cfMeDIP-seq detects abnormal methylation — the addition of chemical tags to DNA, which doesn’t alter their genetic code but can affect their function.

The method was tested on samples from 99 patients with early and advanced kidney cancer, 15 patients with stage IV urothelial bladder cancer, and 28 healthy, cancer-free control subjects. In analyzing blood serum with the test, the study reported “near-perfect” classification of patients across all stages of kidney cancer. While urine-based classification was not as accurate, the study authors claimed that “performance can be improved through technical and computational optimization.”

Co-first authors of the report are Pier Vitale Nuzzo, Jacob E. Berchuck, Keegan Korthauer, and Sandor Spisak.

This study was conducted with support from Rebecca and Nathan Milikowsky, the Claudia Adams Barr Program for Innovative Cancer Research, the H.L. Snyder Medical Research Foundation, the Dana-Farber/Harvard Cancer Center Kidney SPORE and Program, the Kohlberg Chair at Harvard Medical School and the Trust Family, Michael Brigham, and Loker Pinard Funds for Kidney Cancer Research at Dana-Farber Cancer Institute.

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.

Primary care practices are projected to lose more than $65,000 in revenue per full-time physician in 2020, following drastic declines in office visits and fees for services from March to May during the COVID-19 pandemic, according to a study led by researchers in the Blavatnik Institute at Harvard Medical School (HMS).

The lost revenue adds up to a shortfall of $15 billion to primary care practices across the United States, according to the analysis to be published June 25 in Health Affairs. (DOI: 10.1377/hlthaff.2020.00794). The researchers also caution that losses would balloon substantially if there is a second viral peak later in the year or if the reimbursement rates for telehealth visits revert to pre-COVID levels.

The study was led by Sanjay Basu, a faculty affiliate in the HMS Center for Primary Care, Russell Phillips, director of the center and professor of global health and social medicine at HMS, and Bruce Landon, HMS professor of health care policy.

“For many primary care practices, particularly those serving the most vulnerable populations, these losses could be catastrophic, with many practices being forced to close,” Basu said. “This could weaken the U.S. health system dramatically at a time when we need it to be at its strongest.”

“Our prior work shows that primary care saves lives, and loss of primary care practices will translate to lives lost across the United States,” Phillips said.

To calculate the projected financial losses on operating expenses and revenues, the researchers simulated the impact of the pandemic on a variety of practices analyzing both visit volume and visit type, among other variables. They then compared the anticipated revenues, expenses and losses under several scenarios, including a second shelter-in-place order in November and December as well as reverting back to the significantly lower pre-pandemic levels of provider reimbursement for telemedicine visits.

Once the most acute threat of COVID-19 subsides and the pandemic winds down, primary care in the United States will have to absorb the brunt of long-term COVID-19 care and management, testing and vaccination, the team said. The primary care system must also be equipped to meet the piled-up needs of the population and return its attention to the major chronic medical conditions that collectively will determine the health of Americans for many years to come, they said.

“The coronavirus pandemic highlights the fragility of the primary care system,” said Landon, noting that “over half of primary care practices remain small and physician-owned and these independent practices have limited access to capital and other support that could help them weather the pandemic.”

The researchers said their findings and the looming growth in primary care use underscores the need for a financial boost to the primary care system.

“The coronavirus pandemic is a pointed reminder of the importance of primary care to our society. Primary care is critical to limiting the spread of the virus, in treating the comorbidities that can make COVID-19 so deadly and in helping people navigate the social and psychological challenges of social distancing and of living with the pandemic,” Phillips said.

While legislation proposing financial aid to hospitals has already been introduced in Congress, independent primary care practices have yet to receive significant financial help, the researchers said.

Additional collaborators on the study include colleagues from the American Board of Family Medicine.

The authors report no external funding for this study.

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.

Most American public schools will be bringing students back in the fall, a Harvard healthy buildings expert said, and districts should employ a broad risk-reduction strategy proven effective in places like hospitals — where maintaining appropriate distancing isn’t always possible — to keep them safe.

Joseph Allen, assistant professor of exposure assessment science at the Harvard T.H. Chan School of Public Health, said while the goal should be zero COVID-19 cases in schools and elsewhere, the national containment strategy has failed. That leaves school officials facing a difficult decision as to whether schools can be reopened safely in the fall despite continued community transmission of SARS-CoV-2, the virus that causes COVID-19.

Allen’s answer is a qualified yes: There will be some risk, but it can be kept relatively low as long as schools foster a culture of healthy compliance among students, employ an array of strategies designed to keep students, teachers, and staff safe, and isolate outbreaks when they occur.

“There’s certainly no such thing as zero risk in anything we do, and that is certainly the case during a pandemic,” Allen said. “[But] the U.S. has failed to put in the systems necessary to keep case counts low, and we’re forced to navigate reopening businesses, reopening society — not in a place where we want to be or should be — but facing the reality we have.”

The healthy school reopening measures are outlined in a 62-page report, “Schools for Health: Risk Reduction Strategies for Reopening Schools,” released Wednesday by the Harvard Chan School’s Healthy Buildings Program, which Allen leads.

Allen said the virtual classrooms employed in much of the country in March and April were a stopgap made necessary by the speed of the pandemics’ spread. But they also showed the importance of returning to in-person schooling. The experience in several big cities showed that substantial numbers of students did not log in regularly, risking a generation of not just virtual absentees, but virtual dropouts. In Boston, for example, 20 percent of students didn’t log in to class at all in May. In Philadelphia, only half of elementary schoolkids made daily contact with their classes.

Online learning should continue to be part of every districts’ reopening plan, Allen said, but it should be aimed at a minority of students and teachers, those ill or at high risk of suffering severe COVID-19 illness. Most kids, he said, should be in school, where they can grow not only through in-person learning, but also from the host of other benefits that schools bestow, from socialization to exercise to nutrition for students from struggling families. Reopening schools also allows parents to return to work — an important benefit as the economy struggles to regain its footing.

“There are devastating costs of keeping kids out of school,” said Allen, who outlined the report during a conference call with reporters Wednesday morning. “When we have this discussion about sending kids back to school, we have to have it in the context of the massive individual and societal costs of keeping kids at home.”

The “Schools for Health” report offers a detailed reopening plan with more than 100 suggestions in five major categories: healthy classrooms, healthy buildings, healthy policies, healthy schedules, and healthy activities. Though many schools have only recently let out for the summer, Allen said, now is the time for school officials to begin to prepare for the fall. Allen said flexibility is important in adopting the recommendations and that, as the weeks pass, school officials should be looking for changes to the science of COVID-19 or the local pandemic that might affect their plans.

The report’s 13 authors, led by Allen, warn that even if schools follow all the recommendations, infections may occur. But the guidelines recommend routine steps that will create a schoolwide system based on discrete groups, increased fresh air, distancing where possible, and the standbys of masking and handwashing that will minimize spread when cases do occur.

While Allen does not recommend that schools employ A/B days, when half of students are learning in person and half at home, he does recommend employing a flexible daily schedule that may start earlier and end later, creating leeway to stagger class times to avoid crowded hallways and facilitate pickup and drop off of students without crowding.

A key factor at hospitals, where masking, handwashing, and other infection-control measures have proven effective, is near-universal compliance. Allen acknowledged that may be difficult when dealing with children, which is why creating a schoolwide culture of compliance will be important to success. Healthy messages should be reinforced in pre-opening-day training programs, during daily morning announcements, and repeatedly through the day via school posters and other communication strategies.

“[Compliance] is going to be the biggest challenge,” Allen said. “The most important recommendation we have … is that schools have to establish and reinforce a culture of health, safety, and shared responsibility. This is really the only way we’re going to get through this. We have to move from the place where mask-wearing and handwashing is the exception to where it’s the norm.”

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 public health experts said the nation’s COVID-19 epidemic is getting “quite out of hand” and that, with cases rising rapidly in the hardest-hit states and a two-week lag between infection and hospitalization, the situation appears set to worsen quickly.

“I have this awful feeling of déjà vu, like it’s March all over again,” said William Hanage, associate professor of epidemiology at the Harvard T.H. Chan School of Public Health.

Hanage, who spoke with reporters during a conference call Thursday morning, said that hospitals are nearing capacity in Arizona and Houston and are likely to be stressed elsewhere soon. And, in contrast to the nation’s early spike in COVID-19 cases that were concentrated in a few states, the current surge is much more widespread and so has greater potential to take off.

“The increases that we’re seeing right now have the capacity to cause far more disease in the future,” Hanage said.

Barry Bloom, the Joan L. and Julius H. Jacobson Research Professor of Public Health, who also fielded reporters’ questions Thursday, said other countries have shown that the epidemic can be contained by acting swiftly when cases appear. Even Italy, once on the verge of health system collapse, has regained control of its epidemic, Bloom said. Italy on Tuesday reported just 113 new cases and 18 deaths.

“When political leaders wait until it gets really bad, that’s where we are now,” Bloom said. “If you only look at what you see today, you’re three weeks behind the curve. … It’s trying to imagine what will be three weeks from now — rather than what you see today — that should be determining policy.”

Hanage said he understands political leaders’ reluctance to reimpose lockdowns, but with few tools to fight the coronavirus and more moderate steps like masking and hand-washing most effective when numbers are also more moderate, a shutdown may turn out to be what’s needed.

“Let me be clear: I do not like shutdowns. But if they’re the only thing to prevent a worse catastrophe, you have to use them,” Hanage said.

A bright spot in the current epidemic is that the age of those contracting COVID-19 appears to be declining. Hanage said that he didn’t view it as a sign of the epidemic evolving, but rather a marker of testing being more widespread and catching more cases than during the March-April spike. Though younger people have better survival rates, that good news is tempered by the fact that we’ve been largely ineffective at keeping the virus away from those most susceptible for severe illness: the elderly and people with pre-existing conditions. But that may nonetheless mean there is a window of opportunity to suppress the epidemic before it takes hold among those more vulnerable populations.

“If there is a window of action, it’s now,” Hanage said.

Hanage struck a similar note on lower death rates in the current spike, saying deaths lag behind cases, so we should wait for a few weeks before concluding that anything different is going on.

Bloom said the difference between the U.S. and nations where the pandemic appears to be controlled is that those countries had uniform national policies and didn’t lift lockdowns until case numbers were very low. The fact that some of them have experienced new outbreaks — like the recent spate of cases in Beijing — is to be expected. Once the local epidemic is controlled, easing the lockdown will inevitably lead to new cases. The strategy then is to use testing to quickly identify cases and use contact tracing and isolation to contain outbreaks before they become widespread. In a state like California, with 7,000 new cases reported Tuesday, tracing the contacts of each positive test becomes a monumental task.

Rather than flinging the doors wide, the two said reopening should more closely resemble refining the shutdown, letting some things resume with safeguards in place that can be tightened should cases rise. Leaders should consider risk versus value to society in deciding what to reopen and when. For instance, bars, casinos, and churches, where people are crammed together and which have been shown to be hotspots of infection in some instances, may need to stay closed in order to keep the overall infection rate in the community low enough that we can safely reopen places with broad societal benefit, Bloom and Hanage said.

“We should be wanting to be able to open schools, and schools should have a higher priority, arguably, than other parts of the economy,” Hanage said. “What those [other parts of the economy to reopen] are, ought to be debated. … What we should be thinking about in reopening is not reopening everything in a safe way, but which things we want to reopen and being able to do that without enhancing community transmission.”

Even well-honed strategies will fail if citizens are noncompliant, however, Bloom said. In New York City, contact tracing programs have run into people not answering phones or refusing to isolate after hearing they’ve been exposed to infection.

“If people are ignoring the epidemic, it’s going to be very hard to control,” Bloom said, “and leadership should be inspiring people to be more cautions.”

The premiere of the movie “Scent of Mystery” in 1960 marked a singular event in the annals of cinema: the first, and last, motion picture debut “in glorious Smell-O-Vision.”

Hoping to wow moviegoers with a dynamic olfactory experience alongside the familiar spectacles of sight and sound, select theaters were outfitted with a Rube Goldberg-esque device that piped different scents directly to seats.

Audiences and critics quickly concluded that the experience stunk. Fraught with technical issues, Smell-O-Vision was panned and became a running gag that holds a unique place in entertainment history.

The flop of Smell-O-Vision, however, failed to deter entrepreneurs from continuing to chase the dream of delivering smells to consumers, particularly in recent years, through digital scent technologies.

Such efforts have generated news headlines but scant success, due in part to a limited understanding of how the brain translates odor chemistry into perceptions of smell — a phenomenon that in many ways remains opaque to scientists.

A study by neurobiologists at Harvard Medical School (HMS) now provides new insights into the mystery of scent. Reporting in Nature on July 1, researchers describe for the first time how relationships between different odors are encoded in the olfactory cortex, the region of brain responsible for processing smell.

By delivering odors with carefully selected molecular structures and analyzing neural activity in awake mice, the team showed that neuronal representations of smell in the cortex reflect chemical similarities between odors, thus enabling scents to be placed into categories by the brain. Moreover, these representations can be rewired by sensory experiences.

The findings suggest a neurobiological mechanism that may explain why individuals have common but highly personalized experiences with smell.

“All of us share a common frame of reference with smells. You and I both think lemon and lime smell similar and agree that they smell different from pizza, but until now, we didn’t know how the brain organizes that kind of information,” said senior study author Sandeep Robert Datta, associate professor of neurobiology in the Blavatnik Institute at HMS.

The results open new avenues of study to better understand how the brain transforms information about odor chemistry into the perception of smell.

“This is the first demonstration of how the olfactory cortex encodes information about the very thing that it’s responsible for, which is odor chemistry, the fundamental sensory cues of olfaction,” Datta said.

Computing odor

The sense of smell allows animals to identify the chemical nature of the world around them. Sensory neurons in the nose detect odor molecules and relay signals to the olfactory bulb, a structure in the forebrain where initial odor processing occurs. The olfactory bulb primarily transmits information to the piriform cortex, the main structure of the olfactory cortex, for more comprehensive processing.

Unlike light or sound, stimuli easily controlled by tweaking characteristics such as frequency and wavelength, it is difficult to probe how the brain builds neural representations of the small molecules that transmit odor. Often, subtle chemical changes — a few carbon atoms here or oxygen atoms there — can lead to significant differences in smell perception.

Datta, along with study first author Stan Pashkovski, research fellow in neurobiology at HMS, and colleagues approached this challenge by focusing on the question of how the brain identifies related but distinct odors.

“The fact that we all think a lemon and lime smell similar means that their chemical makeup must somehow evoke similar or related neural representations in our brains,” Datta said.
To investigate, the researchers developed an approach to quantitatively compare odor chemicals analogous to how differences in wavelength, for example, can be used to quantitatively compare colors of light.

They used machine learning to look at thousands of chemical structures known to have odors and analyzed thousands of different features for each structure, such as the number of atoms, molecular weight, electrochemical properties and more. Together, these data allowed the researchers to systematically compute how similar or different any odor was relative to another.

From this library, the team designed three sets of odors: a set with high diversity; one with intermediate diversity, with odors divided into related clusters; and one of low diversity, where structures varied only by incremental increases in carbon-chain length.

They then exposed mice to various combinations of odors from the different sets and used multiphoton microscopy to image patterns of neural activity in the piriform cortex and olfactory bulb.

Smell prediction

The experiments revealed that similarities in odor chemistry were mirrored by similarities in neural activity. Related odors produced correlated neuronal patterns in both the piriform cortex and olfactory bulb, as measured by overlaps in neuron activity. Weakly related odors, by contrast, produced weakly related activity patterns.

In the cortex, related odors led to more strongly clustered patterns of neural activity compared with patterns in the olfactory bulb. This observation held true across individual mice. Cortical representations of odor relationships were so well-correlated that they could be used to predict the identity of a held-out odor in one mouse based on measurements made in a different mouse.

Additional analyses identified a diverse array of chemical features, such as molecular weight and certain electrochemical properties, that were linked to patterns of neural activity. Information gleaned from these features was robust enough to predict cortical responses to an odor in one animal based on experiments with a separate set of odors in a different animal.

The researchers also found that these neural representations were flexible. Mice were repeatedly given a mixture of two odors, and over time, the corresponding neural patterns of these odors in the cortex became more strongly correlated. This occurred even when the two odors had dissimilar chemical structures.

The ability of the cortex to adapt was generated in part by networks of neurons that selectively reshape odor relationships. When the normal activity of these networks was blocked, the cortex encoded smells more like the olfactory bulb.

“We presented two odors as if they’re from the same source and observed that the brain can rearrange itself to reflect passive olfactory experiences,” Datta said.

Part of the reason why things like lemon and lime smell alike, he added, is likely because animals of the same species have similar genomes and therefore similarities in smell perception. But each individual has personalized perceptions as well.

“The plasticity of the cortex may help explain why smell is on one hand invariant between individuals, and yet customizable depending on our unique experiences,” Datta said.

Together, the results of the study demonstrate for the first time how the brain encodes relationships between odors. In comparison to the relatively well-understood visual and auditory cortices, it is still unclear how the olfactory cortex converts information about odor chemistry into the perception of smell.

Identifying how the olfactory cortex maps similar odors now provides new insights that inform efforts to understand and potentially control the sense of smell, according to the authors.

“We don’t fully understand how chemistries translate to perception yet,” Datta said. “There’s no computer algorithm or machine that will take a chemical structure and tell us what that chemical will smell like.”

“To actually build that machine and to be able to someday create a controllable, virtual olfactory world for a person, we need to understand how the brain encodes information about smells,” Datta said. “We hope our findings are a step down that path.”

Additional authors on the study include Giuliano Iurilli, David Brann, Daniel Chicharro, Kristen Drummey, Kevin Franks, and Stefano Panzeri.

The study was supported by the Vallee Foundation, the National Institutes of Health (RO11DC016222, U19NS112953) and the Simons Collaboration on the Global Brain.

Study after study has shown that statins can prevent heart attacks, strokes and death in middle-aged adults. But in 28 major clinical trials of statins, only 2 percent of participants have been 75 years or older. This means that even though older adults are at greater risk of heart disease and death, there is scant data on whether statins should be prescribed for them.

A new study sheds light on the role statins may play for older adults who have not yet experienced a heart attack, stroke or other cardiovascular event.

In their retrospective analysis, a team of investigators from Harvard-affiliated Brigham and Women’s Hospital and the VA Boston Healthcare System leverages national data from the U.S. Veterans Health Administration Services and Centers for Medicare & Medicaid Services found that the risk of dying from any cause was lower by 25 percent among veterans who were using statins compared to those who were not treated with statins. The risk of dying from a cardiovascular event, such as a heart attack or stroke, was lower by 20 percent. The team’s results are published in JAMA.

“Based on these data, age is not a reason to not prescribe statins,” said lead and corresponding author Ariela Orkaby, a physician scientist at the VA Boston Health Care System and in the Division of Aging at the Brigham. “Statins are commonly studied and prescribed for middle-aged adults but understudied in people over age 75. One of the most remarkable things about our results is that we found the benefit of statins held true regardless of whether a person was older or younger or had a condition such as dementia.”

Orkaby and colleagues looked at data on veterans who used VA services between 2002 and 2012, were 75 years or older, and had not previously had a heart attack, stroke or other cardiovascular event. Of the more than 300,000 eligible veterans, the team identified more than 57,000 who began taking statins during this time. Using propensity scoring, the authors compared individuals who began taking statins to those who had the same likelihood of being prescribed a statin based on clinical characteristics but did not receive a prescription for the drug.

Overall, taking statins was significantly associated with lower risk of death from a cardiovascular event or death from any cause. And the benefits remained for veterans at advanced age, including those who were 90 years or older. Lower death rates extended to those with other conditions such as dementia — individuals who have been excluded from previous studies. In secondary analyses, the team found that starting a statin was also significantly associated with a lower risk of cardiovascular events such as heart attacks and strokes. Orkaby notes that it was particularly intriguing to see a marked decline in rate of strokes among the study’s Black participants.

“There are many interesting leads to follow up on,” said Orkaby, “but it’s important to keep in mind that this is not a randomized, clinical trial. Instead, it’s a retrospective analysis using real world data that helps us explore where the truth lies.”

The study focused only on veterans, a predominantly white and male population, which may limit its generalizability, but the study’s size made it possible to glean statistically meaningful information on underrepresented groups. During the study’s timeframe, the most commonly prescribed statin was simvastatin, but currently, higher-dose and higher-intensity statins have become more frequently prescribed. While statins are generally well tolerated, many people report aches and pains as a side effect, which may lead some to stop taking the drug. The current study did not evaluate whether patients discontinued statin use.

Two randomized, clinical trials of statins among older adults are now underway with results from one of the studies expected later this year. Orkaby and colleagues plan to follow up on their study by exploring the effects of statin dosing and examining outcomes for sub-populations included in their analysis.

This research was supported by the VA (CSR&D CDA-2 award IK2-CX001800), National Institute on Aging (R03-AG060169), and VA Merit Award I01 CX001025. Support for VA/Centers for Medicare & Medicaid Services data is provided by the Department of Veterans Affairs, VA Health Services Research and Development Service, VA Information Resource Center (project numbers SDR 02-237 and 98-004). Coauthor Luc Djousse, reported receiving grants from Merck.

In this time of profound uncertainty, society can be sure of one thing: more uncertainty. The seemingly opaque path forward for us, individually and collectively, was the Gazette’s topic with three Harvard professors who shared insights into how uncertainty is viewed in their fields, and the surprising ways in which it’s not necessarily a bad thing.

In the beginning was the word

“The word ‘uncertainty’ derives from the [Latin] verb cernere, which means ‘to distinguish, to mark out, to separate one thing from the rest, to discern,’’’ said John Hamilton, William R. Kenan Professor of German and Comparative Literature. “When faced with a vast onslaught of data or with an overwhelming flood of disparate information, cernere denotes the capacity to make distinctions, to discover identities and understand the links between them. It is the first step toward knowledge, to single out one phenomenon from the field of manifold experience.

“Uncertainty is an ability to draw the lines that define one thing in distinction from something else, [and] combats the urge to be so certain about things and people that you feel you never need to think about them further.”

For a literary example, Hamilton pointed to Franz Kafka’s short story “The Burrow” (“Der Bau”). A mole-like creature constructs a shelter for himself and spends his life trying to build a home that will protect him from all kinds of unforeseeable dangers. The shelter is very secure except for the hole that serves as an entranceway. The creature could cover it, but that would mean sealing off his only exit. Referring to this hole, he says, “There I am mortal.” The hole threatens his life, but it also keeps him vigilant and ready.

“If the burrow were perfectly secure, he would waste away in idleness and complacency, and therefore put himself at an even greater risk. It is the possibility of being killed and the uncertainty of the threat that keep him alert. His mortality, so to speak, saves his life,” said Hamilton.

“Our vulnerability and our uncertainty are painful but can also have a beneficial effect insofar as we remain open and ready for what is ultimately unknowable and uncertain, namely, the future. Keeping things open, rather than making all-too-quick judgments and discernments, helps to remind us that certainty is useful as long as it remains provisional and open to reform or even complete reversal.”

Taking measure of what we don’t know

For many people, measuring uncertainty seems impossible. For astronomer Alyssa A. Goodman, the variable is integral to the study of the universe.

“In astronomy … estimating uncertainty is just about as important as making the measurement itself. We’re talking calculations where a part in a million makes a completely gigantic difference in the story of the universe, so we have to be very careful about the answers,” said the Robert Wheeler Willson Professor of Applied Astronomy, co-director for science at the Radcliffe Institute for Advanced Study, and research associate at the Smithsonian Institution.

Being comfortable with uncertainty is essential to astronomers who often can’t conduct experiments in controlled environments like other scientists, Goodman said. She even thinks astronomers can teach the rest of us how to understand and accept uncertainty as a necessary and useful part of life.

“Astronomers have to deal with uncertainty every day in our work. [We] can’t move a star or get a different angle … we have to be very serious about clever ways to estimate uncertainty in the absence of more information,” she said. “In the case of COVID-19, right now what we suffer from is a tremendous lack of reliable data, and to make predictions in the absence of reliable data is extraordinarily difficult. [But] it’s not impossible, and I think it’s important that people appreciate that.”

Hard-wired to dislike ambiguity

According to Pershing Square Professor of Human Neuroscience in the Department of Psychology Elizabeth A. Phelps, resolving uncertainty is a major challenge of the brain, whether it is determining what we are seeing or hearing from visual or auditory signals, or deciding the accuracy of a memory. When making decisions, said Phelps, economists have examined how different types of uncertainty influence our choices. They’ve found that although people tend to dislike risk, such as a 50/50 coin toss, we are particularly averse to ambiguity, when the risk is unknown. In ambiguous risky decisions, uncertainty can be seen in the region of the temporal lobe that helps process emotions.

“When you see a lot of ambiguity in [a] situation, you see more activity in the amygdala, [which] is thought to be the brain’s threat detector,” Phelps said. “This is a region that we know is important in telling you that there’s something in the environment you should pay attention to because it could potentially be threatening.

“Ambiguity is one type of uncertainty [that] is more aversive to people than just knowing that there are some risks [in a situation]. When there’s a lot of ambiguity, meaning we don’t actually know what the probabilities are, [we’ll] make decisions that will pull us away from ambiguity. So we might be more likely to do nothing than have to deal with the ambiguity that’s out there in the world,” she said.

Phelps has found through research that uncertainty can, therefore, change our learning about the world, our ability to deal with negative emotions, our decisions, and even our memories. People vary in how easily they can tolerate uncertainty, and those who are more intolerant are generally more likely to be depressed or anxious.

With the pandemic, people also vary in their reactions to not knowing when they can return to workplaces, or see elderly family, and in how much uncertainty they can deal with emotionally.

“We’re going to see — and we already know that there have been — a lot of mental health consequences,” Phelps said.

Life expectancy in the U.S. varies widely when analyzed at the census-tract level, and the method may provide a more detailed picture of health disparities in the U.S. than other widely used analyses of life expectancy, according to new research led by Harvard T.H. Chan School of Public Health. The study is the first to analyze life expectancy data at the local level across the contiguous U.S., as well as at the state and county level.

The method may also provide a more detailed picture of health disparities in the U.S. than other widely used analyses. According to Census.gov, census tracts are small, relatively permanent statistical subdivisions of a geographical area, averaging at about 4,000 inhabitants.

“Our study shows that as far as geographic variation in life expectancy is concerned, it’s a pretty local phenomenon,” said S.V. Subramanian, professor of population health and geography and co-author of the study. “States are also quite important, but counties are not.”

In Allegheny County in Pennsylvania, the life expectancy is 77.4 years. Within that county, the researchers found a census tract with a life expectancy of 62 years and another census tract with a life expectancy of 86 years — a 24-year difference. Similarly, at the county level, Chatham County, North Carolina, has a life expectancy of 80.4 years, but it contained a census tract with a life expectancy of 76.2 years and a census tract with a life expectancy of 97.5 years — a 21-year difference.

Data on many public health indicators, including life expectancy, is often gathered and analyzed at the county or state level. Legislation, policies, and programs that provide health care, economic assistance, and social services are administered and implemented at both levels, but focusing on counties or states may fail to highlight significant health disparities at the local level.

For this study, the research team analyzed life expectancy data in 65,662 census tracts that were nested in 3,020 counties across 48 states.

The analysis identified significant disparities in life expectancy at the census-tract level within counties and states. The researchers also found that socioeconomic and demographic variables, especially education, income, and race, were strongly associated with life expectancy at the census-tract level.

Analyzing life expectancy and other public health data at the census-tract level can help illuminate significant local health disparities and aid in the development of better and more targeted public health interventions and policies, according to the researchers.

“By looking at the census-tract level we found large disparities within counties in the U.S.,” said Antonio Fernando Boing, research fellow of the Department of Social and Behavioral Sciences and co-author of the study. “In addition, we observed that socioeconomic conditions explain an important proportion of the between-census tracts variation. These findings reinforce the importance of small geographic units when allocating resources and implementing policies that aim to increase life expectancy in the U.S.”

Other Harvard Chan School researchers who contributed to the study are Alexandra Crispim Boing, Jack Cordes, and Rockli Kim.

A modeling study looking at more than 32,000 confirmed coronavirus cases in Wuhan, China, offers fresh insights into features of the virus, including ease of transmission, effectiveness of nonpharmaceutical interventions such as social distancing and face masks, and the impact that undetected cases have on the spread of the disease.

The analysis, published in the journal Nature, underscores the stealthy nature of the virus and adds to a growing body of research that suggests people infected with COVID-19 who went undetected or were asymptomatic, presymptomatic, or had only mild symptoms have been significant spreaders of the disease.

Using statistical and epidemiological modeling to reconstruct the outbreak in Wuhan from Jan. 1 to March 8, researchers found that up to 87 percent of cases in the city during that time may have gone undetected and transmission rates during some of the earliest days could have been as high as 3.54 infections per single case. (A rate above 1 signifies rising spread.) It’s a figure that was only controlled because of widespread and strict containment measures and lockdowns, hammering home the importance of interventions like face masks even in curtailing undetected infections, according to the paper.

The researchers, including Harvard Professor Xihong Lin and a team of scientists from Huazhong Science and Technology University in Wuhan, believe that undetected infections — from sources including people who were asymptomatic, presymptomatic, or had only mild symptoms — likely played a substantial role in the fast spread of the disease and could become one of the leading factors for a possible second wave of infections if restrictions are lifted too early.

“There are important consequences to those undetected cases,” said Lin, a professor of biostatistics at the Harvard T.H. Chan School of Public Health and a professor of statistics at the Faculty of Arts and Sciences. Put simply: “Even though they are undetected, they are still infectious. It’s important to avoid reopening too early without vigilant control measures, because when the number of detected cases is not low, the numbers of undetected cases, or unascertained cases, are not low either. They are even bigger.”

The study comes as nations around the world battle to control their outbreaks. Some have been sliding backward. Many states in the U.S., for instance, have seen record surges after reopening before the outbreak was reined in. California on Monday announced major rollbacks, closing gyms and museums and halting indoor dining at restaurants.

The initial surge of COVID-19 patients in Boston-area hospitals has passed, but the memories of caring for them will forever remain with physicians involved in that care. We asked seven physician-scientists from the Broad Institute, who are also Harvard Medical School instructors, to talk about what they learned from their time helping COVID-19 patients, and how their experiences have informed their research.

Deb Hung

Core faculty member, co-director of the Infectious Disease and Microbiome Program at Broad, infectious disease physician and attending critical care physician at Brigham and Women’s Hospital, professor of genetics and associate professor at Harvard Medical School

The thing that struck me the most, from the experience of treating COVID-19 patients, was how heartbreakingly dehumanizing it was. Patients weren’t allowed to have visitors, and those intubated and sedated in the ICUs couldn’t talk to you. As a physician, I only knew a name and the medical parameters associated with the individual. During usual times, we get to know a little more about the patient — the personal and human side, with families and friends visiting. But with COVID, it was heartbreaking to see people dying alone, and their families couldn’t come in.

On top of that, we, as physicians and healthcare workers wearing protective equipment and face masks, feel like there is another kind of barrier between our patients and us. Quite frankly, because everyone is wearing a mask in the hospital, even that’s dehumanizing among the people you know and your colleagues — you can’t even exchange a smile.

What was challenging, from the scientific side, is that everyone was so desperate to do something, to try anything to help the patients. It was crazy and frustrating, but everyone felt this acute sense of desperation.

As things have calmed down a bit, there is now more time to evaluate a lot of data that has been collected to better assess what interventions are actually effective. But there is still a lot of work to do and we still have a lot to learn.

Michael Gillette

Senior group leader in the Proteomics Platform at Broad, attending physician in pulmonary and critical care medicine at Massachusetts General Hospital (MGH), assistant professor at Harvard Medical School

One thing that was striking during the first surge of the pandemic was the number of critically ill patients relative to hospital capacity. At MGH, we got up to about 180 patients requiring ICU-level care. To put that number into perspective, our main medical intensive care unit, where I spent most of my time during the last couple of months, is an 18-bed unit.

To accommodate the influx, our medical-surgical intensive care, surgical intensive care, cardiac intensive care, neurointensive care, pediatric intensive care, and burn units all were converted to adult COVID-19 intensive care units. There were two general medicine floors in one of our buildings that had the necessary physical infrastructure and also got turned into COVID-19 intensive care units.

Our conventional ICU ventilators were in short supply, and other equipment was pressed into service: travel ventilators, operating room ventilators, and the like. Dialysis machines used for renal replacement had to be circulated between patients. Even ECMO (extracorporeal membrane oxygenation) circuits that oxygenate and scrub CO2 from the blood outside the body to allow the lungs to rest were in full utilization.

With that sort of patient census, we didn’t have the number of pulmonary or anaesthesia critical care doctors we needed. It was extraordinary to watch all kinds of care providers stepping forward to provide care for COVID-19 patients outside their usual roles. The number of people who worked extraordinary hours under very stressful circumstances, dealing with a disease that nobody understood very well, in many cases operating outside of their area of domain expertise, and did it with a positive attitude, was remarkable and heartwarming.

The biggest takeaway was probably the degree to which the pandemic highlighted all sorts of fundamental inequities in our healthcare system and our social structure. Not that one isn’t aware of them, but there hasn’t ever been anything in my lifetime that has made it this impossible to ignore.

After working 90- or 100-hour weeks in the hospital, it wasn’t easy to focus on research, which during other times of the year is my principal occupation. My proteomics group at the Broad has a translational research focus where I help scientists understand the ramifications of their work for clinical applications. We make sure that we are focusing our questions in the most meaningful way and serve the patients that the research ultimately is intended to serve.

Pradeep Natarajan

Associate member of the Program in Medical and Population Genetics at Broad, director of preventive cardiology at MGH, clinical cardiologist at the MGH Cardiovascular Disease Prevention Center, assistant professor at Harvard Medical School

During the first COVID-19 surge in Massachusetts, we converted one of our inpatient cardiology units at MGH to a COVID-19-specific cardiology unit. During this time, I was on clinical service, supervising that unit during this first surge of COVID-19.

The overwhelmingly large knowledge gap that physicians were dealing with in the face of this public health emergency was immediately apparent as I began treating patients with COVID-19. We don’t have multiple high-quality randomized controlled trials to go back and immediately reference in order to figure what’s the right thing to do for our patients. We are depending a lot on clinical intuition from experience with other acute respiratory processes, rapidly gaining experience, synthesizing and vetting scientific literature in real-time, and then immediately applying it to patients with COVID-19. None of us learned about COVID-19 in medical school. There are commonalities with other respiratory illnesses, but there are a lot of unique features as well.

It has been remarkable to see the resiliency and the adaptability of our local health systems to deal with this once-in-a-century pandemic. I certainly can’t be prouder of my colleagues — the nurses, physicians, technicians, and administrative staff — rallying together to address these needs.

Marcia Goldberg

Associate member of the Infectious Disease and Microbiome Program at Broad, infectious disease physician and professor of medicine and of microbiology at MGH and Harvard Medical School

I participate in remote analysis of hospitalized patients in two capacities: First, I provide advice to the primary caretakers caring for COVID-19 infected patients. In essence, I respond to specific questions from primary caretakers that may relate to the management, diagnosis, and/or treatment of these patients. Second, I am part of an infectious diseases team that interprets the testing of inpatients who could be infected with COVID-19, including whether an individual is infected and, for infected individuals, when it is safe for them to come out of isolation.

What struck me the most with the patients was the rapidity with which they might go from having relatively mild illness to severe and life-threatening illness.

There are two things that stay with me from this experience: when we work together, we can transform healthcare in response to any threat; and how unpredictable and fragile life is.

My indirect interactions with patients have afforded me a small window into the enormity of their suffering and isolation, which highlight the importance of identifying new therapeutics. I believe the best way to achieve this goal is to improve our understanding of the underlying mechanisms of the disease. This is what drives me to work harder and harder on our research into the immune response to COVID-19.

Anna Greka

Institute member at Broad, director of the Broad’s Kidney Disease Initiative, associate physician in the Renal Division in the Department of Medicine at Brigham and Women’s Hospital, associate professor at Harvard Medical School

I was not scheduled to be on service during the time of COVID-19, but I decided to volunteer in case they needed my help, as either a general physician or kidney expert. It turns out I was needed as a kidney specialist because, in addition to the obviously horrific lung disease, we started seeing an influx in COVID-19 patients facing kidney failure and in need of dialysis machines.

The most difficult thing in caring for patients with COVID-19 was the inability to spend a lot of time with them. It was really strange not to be able to touch and communicate with them. I would say the real unsung heroes in this case are the nurses, and in particular, the dialysis nurses, who had to be in the room in full PPE for the entire time that the dialysis procedure is taking place. Anybody who’s been in PPE knows, it’s extremely hot and very uncomfortable to be in that for hours. Because there were no guests allowed, the nurses were the only source of comfort for many patients. The nurses really went above and beyond, and I think it’s important that they’re recognized for their sacrifices.

The other thing that was very poignant from my time on service was having to think about what I might bring home to my family, which isn’t something that I’ve had to think about often in my career. But so many things were unknown at the time. We were all doing these elaborate decontamination procedures when we got home, every single day, to make sure that we didn’t expose our family to anything. I think that also added to people’s stress.

On a more positive side, there was an immense sense of camaraderie among physicians and nurses and respiratory technicians and other hospital staff, like our valet staff and the service staff who were manning the stations for dispensing the masks and the shields. People were really trying to be there for each other, and that helped everybody push through and feel not alone.

My time on service also stimulated me to think outside the box about ways that I could help as a scientist. I think the main thing that we learned from this is that science is the only way forward. We can overcome any difficulty that humanity faces using science and technology, and I think there’s a renewed understanding that that’s humanity’s best hope.

Benjamin Gewurz

Associate member of the Genetic Perturbation Platform at Broad, infectious disease physician at Brigham and Women’s Hospital and Dana-Farber Cancer Institute, assistant professor and associate director, virology program, Harvard Medical School

During the March through April peak, I volunteered for 10 very busy daytime and overnight shifts on the hospital COVID-19 beeper.

These were interesting and challenging shifts, with as many as 80 calls per day coming in from worried nurses, residents, and attending physicians. As testing capabilities and policies on testing and PPE were rapidly developing, many questions came in from all areas of the hospital. For instance, how many tests need to be done and how far apart should they be to clear a patient for surgery that requires general anaesthesia? What to do with a patient admitted from a rehab facility whose roommate was rumored to have COVID-19?

Early on, a major role was to work with physicians to decide how to deploy limited COVID-19 RT-PCR testing resources, ration precious PPE, and interpret test results as assays were still being optimized. We also had to help decide how best to allocate negative pressure rooms and whom to triage to rapidly expanding COVID-19 wards.

We need to be more prepared for the next pandemic. With increased air travel, population growth, climate change, and high-risk agricultural practices, we are clearly susceptible to another pandemic in the near future, perhaps even with another type of coronavirus. Not only do we need to be better prepared to test and trace earlier the next time, but also to have adequate PPE stockpiles. We should also be thinking about developing compounds against host and viral targets that can be rapidly deployed.

My experience with patient care has highlighted things that we can do to be better prepared for the next pandemic, in terms of staying ahead of the curve to develop diagnostics, small molecule and antibody therapeutics, and vaccines that can be more rapidly deployed. Seeing how frightening, dangerous and disruptive to society a pandemic virus is — and realizing how helpless we were early on, without evidence to guide treatment strategies or resources to adequately test—has been quite motivating for me in my research on the virus.

Roby Bhattacharyya

Associated scientist in the Infectious Disease and Microbiome Program at Broad, attending infectious disease physician at MGH, and instructor in medicine, Harvard Medical School

During the two weeks in April that I was on service, the surge was really building in Massachusetts, and by the end, half of our thousand-bed hospital was COVID-19 patients. Which is crazy — that this thing that had infected its first human less than six months earlier was suddenly the majority of what we were caring for.

At MGH, we had to create five new ICUs from floors that were normally regular medical wards or perioperative care areas. This was incredible. I don’t think anybody at MGH had seen the need for surge capacity like this before. The hospital had spent months planning for it, and it went off without a hitch from my perspective as a consultant, thanks to the hard work and planning of a lot of people.

The other thing I remember about the time leading up to my two weeks on service in April was how eerie it was to hear from doctors in Italy and Spain, then Washington, then New York City about how slammed they were, when our hospital was actually quieter than usual because we had cancelled elective surgeries in anticipation of the surge. People were using the analogy of when the ocean is sucked out away from the beach before a tsunami hits — eerie calm in the moment with a strong sense of foreboding. And sure enough, the surge came. Fortunately, with the preparation measures the Boston area and MGH took, it stretched us to the limits of our capacity but not past.

I’ve reflected since being on service about how much we’ve benefitted from real-time science compared to the original SARS in 2003. I was in grad school when SARS hit, and had forgotten that we didn’t even learn that it was a virus until after it had been controlled. (There was speculation at the time that it was caused by a specific kind of intracellular, unculturable bacteria.) Which meant that there was no diagnostic test possible in real-time, so diagnoses had to be phenomenological.

There have been many challenges with the real-time science around COVID playing out in the news and public sphere, and diagnostics were initially delayed and remain more limited than anyone would like, but there has been a lot of progress too. It’s easy to lose sight of how different this pandemic would have been if it had hit 15 to 20 years ago.