Researchers at Harvard Medical School have repurposed anthrax, a bacterial toxin known for its lethal effects, into a potent pain blocker that could someday serve as an alternative to drugs with addictive side effects. The work is described in a new paper in Nature Neuroscience.

Collaborating with other institutions and industry, the lab of Associate Professor of Immunology Isaac Chiu found that injecting anthrax toxin into the nervous system selectively quieted pain fibers and provided a novel way to target pain. The Gazette spoke with Chiu about the research, which has not yet been tested in human trials. The interview has been edited for clarity and length.

Q&A

Isaac Chiu

GAZETTE: It seems counterintuitive that anthrax — a toxin that causes deadly disease — might also be a painkiller. Was that what you set out to study or was it something you came upon as you were studying something else?

CHIU: Pain is a major area of research because, while acute pain can warn us of something that’s damaging, chronic pain arises in inflammatory diseases and conditions that affect the nervous system and is not necessarily good for us. Many of the conditions that cause chronic pain are very hard to treat, so we need to develop new ways of targeting pain circuits in the brain as well as in the body’s periphery. We mined gene-expression data which we and others have collected on pain fibers and many other types of neurons. My lab is focused on how microbes interact with neurons. We were looking at what microbe-related genes pain fibers expressed that other neurons don’t, and one gene stood out, which is the receptor for anthrax toxin. It was not like we were looking for anthrax receptors, but that’s the one that popped out.

GAZETTE: What diseases is this chronic pain associated with?

CHIU: Chronic inflammatory pain arises as a result of inflammation in tissues, which includes diseases like rheumatoid arthritis, osteoarthritis, cancer, and inflammatory bowel disease. The second category is neuropathic pain, meaning that it arises due to damage to the nerves. That could be a result of an injury or it could also result from things like chemotherapy-induced neuropathy. (This is a big problem for cancer patients — they often stop taking chemotherapies because they’re in so much pain.) Another cause is diabetes, which leads to nerve damage. In mouse models of inflammatory and neuropathic pain, we found that the anthrax toxin was able to block pain.

GAZETTE: You talked about the need for new painkillers — are you thinking about opioids and their impact on society?

CHIU: Not specifically, but in the field of pain research, this is very important. The opioid crisis is still a major problem and finding solutions to develop non-opioid analgesics is a top priority of the National Institutes of Health. Chronic pain affects about 50 million Americans. The numbers are sobering and there is a need for better treatments. Opioids can be effective at blocking pain, but the problem is that they also have off-target effects. The reason is that the receptors for opioids are not just in pain fibers, they also act on regions of the brain that mediate breathing and reward. That’s why there’s a problem with opioid painkillers: they’re addictive and, if they cause a blockade of breathing circuits, lethal. We need to find molecular targets that can block pain that are not going to cause addiction and not cause off-target effects.

GAZETTE: Are the receptors for anthrax toxin indeed very specific to the pain fibers?

CHIU: One of the things that we were struck by is that the high-affinity receptor for anthrax toxin, if you compare across the brain and across the nervous system, seems to be highly expressed in pain fibers, but absent in brain or spinal cord neurons. I have to qualify this — the receptors are also expressed in many non-neuronal cells. That’s why anthrax is lethal in humans: it will target blood vessels, it will target the liver. But in our study, we were able to largely limit it to pain fibers by injecting the toxin only into the nervous system, between the vertebrae in the spine.

GAZETTE: We should highlight that this research is in an early stage, and that part of the remaining work is addressing safety issues in a way that would be practical in the clinic.

CHIU: Yes, and all of the work so far is preclinical, in mouse models. To even get close to clinical application, safety is a big part of it. There are some potential ways of getting at it, though. Like I mentioned, through injection into the spine or cerebrospinal fluid, we could limit it to the nervous system. Another way is to engineer the toxin to deliver different cargoes, and if we make that cargo also more specific to neurons, that could also allow it to be safer.

GAZETTE: That was another part of your work. You used anthrax proteins to create essentially a cargo hold for botulinum toxin, and then delivered that precisely where you wanted it. How did you get that idea? And is botulinum for some reason a better analgesic than anthrax?

CHIU: Botulinum toxin is also a bacterial toxin that targets neurons. Botulism, which is caused by C. botulinum, is due to botulinum toxins binding to nerve terminals and silencing the neurotransmission of the nerves to the muscles. Botulinum toxins are already used widely for cosmetic use and treatment of diseases, but practitioners are very careful to inject it locally so it doesn’t have safety issues. Now, the cargo idea — we’re not the first, and in fact, we were building off many other labs’ work, including some of our collaborators: Steve Leppla’s lab at NIH and Brad Pentelute’s lab at MIT, where they decided to use the anthrax system to target tumors.

In that case, they took advantage of the fact that the anthrax system is a two-component system. There’s an A part and a B part, and the A part targets the receptor, while the B part is what the A part delivers into the cell. They’ve engineered the B part to deliver things to kill the tumor. In our case, we thought, “Can we engineer the B part to deliver something that can silence neurons?” Botulinum toxin came to mind. So we take advantage of two different bacterial toxins and combine them into one system.

GAZETTE: So it shuts off signaling after the point of injection?

CHIU: That’s right. The pain fiber can no longer transmit signals to the next neuron in the spinal cord. Now, botulinum toxin itself can block pain; the only thing is that it’s not specific for pain fibers. That same toxin will actually bind to motor neurons and paralyze your face. Here, we’re making it so that it is more specific to pain fibers. We actually show in our paper that our combination toxin does not affect neuromuscular junction signaling. What we’re excited about is that, with protein engineering, we can think about other molecules besides botulinum toxin to put into pain fibers with the same system.

GAZETTE: Why would a microbe that we view as being disease-causing have these abilities?

CHIU: There are advantages for microbes sometimes to exploit or hijack pathways in hosts. This is all very speculative, but one potential thing would be by blocking pain, they’re going to spread more efficiently. Anthrax is an environmental microbe and when livestock get infected with cutaneous anthrax, they form these coal-like lesions that are painless. Maybe this helps the bacteria get from one host to the next host. Our lab has been interested in these sorts of interactions of microbes and hosts. Tuberculosis, for example, has a molecule that can activate neurons to induce cough that could allow its spread. We don’t know for sure why the anthrax bacteria blocks pain, but it could be advantageous for its survival on the host or its spread to the next host.

GAZETTE: What happens next?

CHIU: There are a few outstanding questions. On the basic side, we know that one of the specific anthrax toxins, the edema toxin, seems to block pain when given to mice, and part of that mechanism is that it seems to silence neurotransmission from pain fibers. We still need to figure out what’s happening at a molecular level in the neuron that leads to the very potent pain block. Next we need to optimize safety and maybe go to other animal models, and then potentially bring this forward into humans. We can also optimize the cargo. Is botulinum toxin the cargo that will go forward? Are there other ones that are even more efficacious to target neurons? Another thing that I’m interested in is whether we can engineer the system so that it targets other neurons. Right now, it’s very specific for pain fibers, but can we engineer it to go after neurons in the brain that degenerate, like in Alzheimer’s or Parkinson’s?

People of color in the U.S. and UK were up to three times likelier than white people to report being unsure or unwilling to get a COVID-19 shot during the initial vaccine rollout, found a study published in Nature Communications. But among those who wanted the vaccine, Black people in the U.S. were less likely to receive it than white people, a disparity that wasn’t present in the UK.

“Our study suggests that lack of access to the COVID-19 vaccine among minority populations in the U.S., rather than lower willingness to receive the vaccine, may have played a greater role in the racial-ethnic disparities we experienced in the early phases of the U.S. vaccination campaign,” said senior author Andrew T. Chan, director of epidemiology at Mass General Cancer Center.

Chan and his team at Massachusetts General Hospital, along with research collaborators at King’s College London and the health science company Zoe Ltd., launched the study, which was designed to capture real-time data on COVID-19, in March 2020. Approximately 4.7 million participants in the U.S., UK, and Sweden reported daily information about their experiences with COVID-19 via a smartphone application. The data gave researchers insight on COVID-19 symptoms and risk factors as well as willingness to receive the vaccine.

This study assessed vaccine hesitancy and receipt from 1,254,294 participants in the UK and 87,388 in the U.S. between December 2020 and February 2021.

“We wanted to compare attitudes toward vaccines and how racial and ethnic minorities experienced receipt of vaccination in these two countries, both of which have racially and ethnically diverse populations that have been disproportionately affected by the COVID-19 pandemic,” Chan said. “From the outset, it was clear that the strategy for vaccine delivery was quite different in the UK than in the U.S. The UK relied on a centralized vaccine distribution system through the National Health Service, while the U.S. resorted to a fragmented approach, leading to widely uneven approaches by individual states and counties.”

Minority populations in both countries expressed more hesitancy or unwillingness to get the vaccine than did white participants. “The more cautious view of the new vaccines among people of color may reflect a greater longstanding mistrust of the medical system and skepticism of clinical trials, which historically have lacked adequate representation from people of diverse races and ethnicities,” Chan said.

Yet minority participants who overcame their hesitancy still faced a barrier in receiving the vaccine in the U.S., he said. Black participants in the U.S. were less likely to report that they had received a vaccine dose than white participants, even if they indicated that they were willing to get vaccinated. This disparity was not observed among UK participants.

“The centralized, national vaccine distribution in the UK appeared better able to deliver vaccines in a more equitable manner than our fragmented approach in the U.S.,” Chan said.

Access to the COVID-19 vaccine in the U.S. is currently less of a problem than it was earlier, when a shortage plagued the initial rollout. But there is still a need for continued outreach to overcome hesitancy among the unvaccinated, Chan said.

“An effective strategy is to enlist trusted messengers, such as members of the communities who are more skeptical of vaccines, to encourage vaccination and help overcome mistrust.”

The study’s results also demonstrated that the U.S. needs a more effective strategy for getting vaccines out quickly and efficiently. “Our experience with COVID-19 boosters taught us that vaccine delivery is still very inefficient in the U.S., with considerable confusion over who should get them and where,” Chan said. “Going forward, we need to be more thoughtful about vaccine distribution. If we can eliminate the access barrier, we can focus our energy on minimizing the greater challenge of vaccine hesitancy.” The next step for the researchers is to study the effectiveness of various strategies that can overcome vaccine hesitancy.

Chan is professor of medicine at Harvard Medical School and chief of the Clinical and Translational Epidemiology Unit at MGH. Other key authors include Long H. Nguyen, an investigator in the Departments of Medicine, Gastroenterology, and Hepatology at MGH and assistant professor of medicine; David A Drew, director of the Biobanking, Clinical and Translational Epidemiology Unit at MGH, and instructor of medicine; and Tim D. Spector, chief of the Department of Twin Research and Genetic Epidemiology and professor of genetic epidemiology at King’s College London.

The work was funded by the Massachusetts Consortium on Pathogen Readiness and the Stuart and Suzanne Steele MGH Research Scholars Award.

The SARS-CoV-2 Omicron variant’s “milder” outcomes are likely due to more population immunity rather than the virus’ properties, according to a paper by William Hanage, associate professor of epidemiology at Harvard T.H. Chan School of Public Health, and Roby Bhattacharyya, assistant professor at Massachusetts General Hospital and Harvard Medical School and associate member at the Broad Institute of MIT and Harvard.

The Perspective article was published online Wednesday in the New England Journal of Medicine.

The Omicron variant was first documented in Botswana and South Africa in late November 2021. Despite three previous waves of infections and a vaccination program initiated in mid-2021, the variant quickly spread throughout the population of South Africa. Compared with earlier variants, Omicron resulted in notably lower hospitalization and death rates, leading some to conclude that the variant causes less severe outcomes or is less virulent than previous variants.

Hanage and Bhattacharyya counter that the perceived lower severity of Omicron infections is most likely due to factors related to the level of immunity in infected people. By the fall of 2021, much of the South African population had been vaccinated or probably infected by another variant during earlier waves of the pandemic. This previous exposure would likely have reduced the severity of a subsequent Omicron infection. The milder symptoms may also be due in part to Omicron’s ability to cause breakthrough infections and reinfections, including in people who have stronger immune systems and are therefore better equipped to fight off an infection, according to the researchers.

They caution that the situation in South Africa is intrinsically different than that of other countries — especially the young age of its population — meaning that Omicron could progress differently in other populations around the world.

Based on their analysis, Hanage and Bhattacharyya stress that as many people as possible domestically and globally should be vaccinated, and those most vulnerable to disease should receive a third booster shot.

“There must be a renewed push to vaccinate and boost those not yet protected, because Omicron is not necessarily intrinsically milder,” said Hanage. “This is especially true for those struggling to access vaccines, whether in the United States or elsewhere in the world.”

People over age 65 at the highest risk for severe COVID-19 have often been the least likely to receive monoclonal antibodies (mAbs) — a highly effective treatment for the disease, according to new research co-authored by researchers from Harvard T.H. Chan School of Public Health.

The analysis was published online Feb. 4 in JAMA.

“Monoclonal antibodies should first go to patients at the highest risk of death from COVID-19, but the opposite happened — the healthiest patients were the most likely to get treatment. Unfortunately, our federal and state system for distributing these drugs has failed our most vulnerable patients,” said Michael Barnett, assistant professor of health policy and management at Harvard Chan School and lead author of the study.

Monoclonal antibodies are very effective at treating mild to moderate COVID-19 infection among non-hospitalized patients. But during the pandemic, mAbs have been in short supply. Federal guidelines prioritize patients at higher risk of being hospitalized or dying from COVID-19, including older people and those with chronic conditions.

The researchers wanted to learn how the limited supply of mAb therapy was allocated to patients at highest risk for severe disease. They looked at data from more than 1.9 million Medicare beneficiaries who had been diagnosed with COVID-19 between November 2020 and August 2021, and compared rates of receiving mAbs by age, sex, race and ethnicity, region, and number of chronic conditions.

They found that, among Medicare beneficiaries who weren’t hospitalized or who didn’t pass away within seven days of their diagnosis, only 7.2 percent received mAb therapy. The likelihood of receiving mAbs was higher among those with fewer chronic conditions — 23.2 percent of those with no chronic conditions received mAbs, versus 6.3 percent, 6.0 percent, and 4.7 percent of those with 1-3, 4-5, and 6 or more chronic conditions, respectively. The researchers also found that Black people were less likely to receive mAbs than whites — 6.2 percent versus 7.4 percent.

In addition, there were significant differences among states when it came to mAb treatment. For example, Rhode Island and Louisiana administered mAbs to the highest proportion of non-hospitalized patients with COVID-19 (24.9 percent and 21.2 percent), while Alaska and Washington administered the lowest proportion (1.1 percent and 0.7 percent ). Southern states had the highest rates of mAb therapy (10.6 percent of beneficiaries), while states in the West had the lowest rates (2.9 percent).

Speculating as to why mAb therapy often failed to reach the highest-risk COVID-19 patients, the researchers said it’s possible that higher-risk patients may have had difficulty navigating the multiple steps needed to receive mAbs, from receiving a timely diagnosis to referral and scheduling an infusion within 10 days. As for differences among states, they suggested that mAb supply may have been low or less used by clinicians in some regions of the U.S.

“We need new approaches to prevent these inequities from happening again with newer treatments on the horizon,” said Barnett.

Other Harvard Chan School co-authors included Ellen Meara, Arnold Epstein, and E. John Orav.

Funding for the study came from the National Institute on Aging (grant K23 AG058806) and the Agency for Healthcare Research and Quality (award U19 HS024075).

For the past two months your mood has been low, you’ve lost your appetite, and you can’t sleep well. Your family is concerned because you are no longer interested in cooking or reading, activities you had previously enjoyed. The stress of the pandemic has changed your routine, and you struggle to balance your remote work, childcare duties, household management, and the care of your ill father. You tried to reach out to a therapist, but after an extensive search online, you found the first available appointment to be months away. A good friend suggested mobile therapy apps, but do they work?

What does the research say?

Mental health apps claim to treat depression, anxiety, and other mental illnesses without therapy appointments. There’s no wait time involved, and every person with a smartphone has immediate access. In addition to their convenience, many apps are free. If this sounds too good to be true, you may be right.

Research looking at randomized controlled trials of mobile app mental health interventions with almost 50,000 patients did not find “convincing evidence” that any mobile app intervention greatly improved outcomes related to people’s anxiety, depression, smoking or drinking, thoughts of suicide, or feelings of well-being. While this sounds unfortunate, this may be related to the study methods in which researchers grouped interventions together that may be completely different. A small trial with a positive effect could thus appear unhelpful if its effects are combined with less helpful interventions.

Treatments work when we believe in them. One study compared the popular meditation app Headspace to a sham version (which included guided breathing but without the active component of mindfulness). Study participants reported improved outcomes (critical thinking and mindfulness) with both active and sham versions, which suggests that the active ingredient may not be in the intervention component itself.

What about computerized cognitive behavioral therapy (CBT) programs for depression? Researchers from the UK studied the effects of the most popular CBT programs (Beating the Blues and MoodGYM), and they also did not find any benefit compared to care as usual in primary care.

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

To read the full story

Stephanie Collier is the director of education in the division of geriatric psychiatry at McLean Hospital; consulting psychiatrist for the population health management team at Newton-Wellesley Hospital; and instructor in psychiatry at Harvard Medical School.

A recent letter published in the journal Science aims to jump-start conversations on the importance of inclusive language in the sciences as part of the ongoing fight for transgender rights. The missive, written by Miriam Miyagi, a Harvard graduate student studying organismic and evolutionary biology, and two other transgender scientists, was triggered by the rising hostility faced by transgender and gender-diverse people.

“Transgender issues are in the news and in the national consciousness right now in a way that is very different than before,” Miyagi said. Miyagi teamed up with Simón(e) Sun, a postdoctoral fellow in the J. Tollkuhn Lab at the Cold Spring Harbor Laboratory in New York, and Eartha Mae Guthman, a postdoctoral research associate in the Falkner Lab at the Princeton Neuroscience Institute, to write the December letter following the Senate Judiciary Committee hearings for the Equality Act in March. That measure, which passed in the U.S. House last February, would prohibit discrimination based on sex, sexual orientation, and gender identity.

Sun and Guthman said it was disheartening to see not only their rights being argued at the Senate hearings but the dissemination of scientific misinformation — including claims that there are only two biological sexes — by non-scientists to fit an apparent political narrative. The last five years have seen a record rise in anti-trans legislation, anti-trans violence, and the criminalization of trans health care across the U.S. and the U.K., largely revolving around the issue of treatment for those who are receiving gender-affirming care.

“It’s really an abuse and a misappropriation of the authority of science to try to justify really regressive, harmful policy moves,” Miyagi said. “That’s why we feel that scientists have both a responsibility and a real opportunity to push back against this. When we say, ‘Calling transgender women biological males is not only insensitive, but it’s actually scientifically inaccurate in many ways,’ we’re able to take away one of these weapons in the arsenal of anti-trans activists.”

In their letter, the authors argue that scientists should explicitly define the usage of “male” and “female” in their research, as no single trait, such as chromosomes or genitalia, determines whether a person is singularly male or female. The boundaries between sexes has been found to be more complicated than that. “We have a responsibility to use precise language both as researchers studying sex-associated variables and as members of a diverse academic community,” the three wrote.

Miyagi said that it is particularly important for scientists to specify what definitions of sex they are using in their research and that they be aware that conflating different definitions can create an alienating, non-inclusive, and harmful environment for gender-diverse scientists.

“An important element of our argument is that precise language is both more scientific and more inclusive. This is a really important distinction,” Miyagi said. “There’s a tendency in the scientific community to say, ‘We need to be rigorous. We need to be precise. We need to be as accurate as possible.’ What we want to show is that these goals are actually aligned with inclusivity in this case.”

Inclusive language also reaffirms the human and social component of science, Sun added. “Conscious awareness of the impact of language also can encourage more critical thinking of science, its process, and its consequences,” she said.

It is also critical that transgender and gender-diverse people be included in the actual research as opposed to just being its subject, Guthman said. “People who may not have the same lived experiences as we do may not think about the kind of questions that may be more relevant to trans health care,” she said. “There’s plenty of research at this point, showing that having a more diverse team improves the quality and the breadth of the research.”

The three scientists hope their letter spurs continuing conversation over the issue of inclusive language in the sciences. Sun said there is a need for much more dialogue between the natural and social sciences and the humanities that should be happening in scientific journals and conferences. Future generations of scientists should be able to take classes and seminars to learn about the importance of inclusive language, they said.

Meanwhile, Miyagi said she would like non-trans people to be engaged with the issues affecting gender-diverse people in the U.S., because they cannot be the sole advocates for themselves. “People need to really care about these issues, even if they are not trans themselves,” they said. “It’s really important that people be educated on these issues and know what the dog whistles are, and what the arguments are.”

Some physicians are far more likely to deliver appropriate care than others in the same geographic area or health care system, according to a new study led by Zirui Song of the Department of Health Care Policy in the Blavatnik Institute at Harvard Medical School, in collaboration with colleagues at Massachusetts General Hospital, Brigham and Women’s Hospital, Embold Health, University of Michigan, and Vanderbilt University.

In the study, researchers looked at whether physicians applied evidence-based guidelines to choices they made in common clinical scenarios. The analysis, published Jan. 28 in JAMA Health Forum, found significant, sometimes substantial, differences in how often individual physicians chose the recommended specific treatments or course of action.

“We looked at a set of situations where clear-cut guidelines have been in place for years, with the hope of limiting variation in physician decision-making and promoting the use of the most appropriate care, based on rigorous evidence,” said study lead author Song, HMS associate professor of health care policy and a general internist at MGH.

“In some of the cases we looked at, physicians who made the most clinically appropriate decisions were five to 10 times more likely to use the recommended standard of care than peers in the same specialties and cities whose decisions tended to be the least appropriate. The differences we found are a cause for concern,” Song said.

Many clinical situations are complex, requiring physicians to make clinical decisions without the help of guidelines with a strong evidence base and choose from options that involve substantial uncertainty for patient outcomes.

These are not the type of scenarios the researchers analyzed. Instead, they looked at more straightforward, simpler situations with a clear clinical decision and guideline-recommended pathway of care.

Based on evidence from randomized clinical trials and long-term observational studies, there are many clinical scenarios where a physician can provide effective care that maximizes clinical benefit and minimizes risk to the patient by adhering to well-known clinical guidelines, Song said.

Even if a given patient’s unique circumstances might make the physician deviate from those guidelines, on average across many patients, those guidelines would generally point to higher value care.

For example, most pregnant patients should receive a common set of prenatal screenings, and patients with nonemergency hip or knee problems should receive some physical therapy before the decision is made to undergo surgery.

The researchers examined medical insurance records from 2016 to 2019, involving care provided in 14 common clinical scenarios by 8,788 physicians from seven different specialties across five municipal areas across the United States.

To minimize the chance that variation in the care received may be due to patient differences rather than physician decision-making, the researchers compared similar patients with similar clinical and demographic characteristics.

“One clear example is arthroscopic knee surgery for new osteoarthritis,” Song said. “Several randomized clinical trials have shown that the surgery is no better than no surgery or placebo treatments.”

With such clear-cut evidence, Song said he was surprised and concerned to see a marked variation in arthroscopic knee surgery rates on similar patients with new osteoarthritis among surgeons in the same cities.

For the study, the researchers divided physicians into five quintiles based on how likely they were to follow the guidelines and provide the recommended care.

In the arthroscopic surgery for new osteoarthritis scenario, the top 20 percent of surgeons in the study performed the surgery on only 2 to 3 percent of their patients. By contrast, between 26 and 31 percent of patients with the same condition in the same cities got surgery if they saw a surgeon from the bottom 20 percent.

Geographic variations

The first observations of widespread differences in clinical decision-making were published two decades ago, including research by the Dartmouth Atlas of Health Care, but focused on geographic variation between different regions of the country.

A 2013 National Academies of Medicine committee led by Alan Garber, provost of Harvard University, and Joseph Newhouse, HMS professor of health care policy, called for a greater emphasis on understanding differences in individual physician decision-making, rather than geography, for improving quality of care.

“In the last decade, however, rigorous measurement of within-area, between-physician variations in decision-making remains sparse,” Song said. “This study aims to help fill that gap.”

Song noted that the variations in the study were most likely related to differences in individual physicians, not differences in practices or health systems, as the variation between individual doctors working in the same organization was greater than the differences in performance between organizations.

Further research into how and why doctors differ in the decisions they make can help medical schools, teaching hospitals, and continuing education programs fine-tune their training and improve value of care.

This type of evidence, if replicated in a rigorous way, may also empower patients, employers, and payers to choose physicians who provide higher value care in their region, allowing consumers voting with their feet to stimulate practice improvement and competition on quality, Song said.

For example, right now some employers and insurers require higher co-pays for patients who go to higher-priced hospitals to encourage use of lower-priced hospitals. Generally, appropriateness of clinical decisions is not factored in.

In the future, Song said, it would make more sense to develop more clinically nuanced incentives to encourage patients to choose physicians who provide higher value care that ensures better patient outcomes aligned with evidence-based approaches.

Some estimates suggest that approximately 25 percent of health care spending in the U.S. is wasteful. Reducing this waste will require addressing multiple sources of unnecessary spending, one of which is inappropriate clinical decision-making, researchers noted.

“Researchers have long suspected that much of that waste lies in the variation of the appropriateness of care from one physician to another,” Song said. “This study offers evidence that this problem is large and widespread across specialties.”

This research was supported by grants from the National Institutes of Health, Arnold Ventures, the National Institute of Diabetes and Digestive and Kidney Disease, and Harvard Catalyst.

As weary Americans hold out hope that the decline of Omicron signals an end to the pandemic’s emergency phase, physicians who treat long COVID are worried about the potential for a new wave of cases.

Experts say that nothing is certain regarding Omicron and long COVID, mainly because the variant roared onto the scene so suddenly in December that too little time has passed to detect a strong Omicron signal in the ongoing stream of long COVID cases. Evidence that the variant causes milder illness has prompted some to speculate that Omicron may mean fewer long COVID cases. But the jury is still out on whether the virus itself causes less-severe illness, as hinted in animal studies, or whether the milder effects are actually due to higher levels of population immunity.

Meanwhile, those who care for long COVID patients say mild initial illness may offer little protection because the majority of cases appear to stem from infections that didn’t require hospitalization. The head of one clinic is starting to see Omicron-related cases and says he has little reason to think the variant will differ from earlier versions of the virus in its ability to generate long COVID.

“Because there are so many people infected with Omicron, we expect those cases, unfortunately, will lead to more cases of long COVID,” said Jason Maley, director of Beth Israel Deaconess Medical Center’s long-COVID clinic, which is part of a multicenter study funded by the National Institutes of Health to explore the causes of the condition. “I don’t think there’s anything that has been seen about the virus itself, the Omicron variant, to say that it won’t cause long COVID.”

Long COVID is an array of symptoms that present four to eight weeks after acute illness has passed. The condition is thought to affect as many as 30 percent of patients and can include a continuation of symptoms suffered during the acute phase — shortness of breath or fatigue, for example — along with new symptoms that occur after patients feel like they’ve recovered: chest discomfort, severe pain, dizziness, vomiting, brain fog.

As more governors end mask mandates, and as Omicron fades and a range of new anti-COVID tools emerge, risk-reduction experts say that now is the time to redefine pandemic living.

“Just like it was not appropriate to use the 2019 playbook in 2020, it’s inappropriate to use the 2020 playbook in 2022,” said Joseph Allen, an associate professor of exposure assessment science at the Harvard T.H. Chan School of Public Health. “The tools we have are changing and so are the conditions on the ground, and we should adapt accordingly.”

The conditions include a significant drop in COVID infections in recent weeks. The CDC reported just 34,034 new cases on Sunday, down from 1.3 million on Jan. 10. Hospitalizations and deaths, which have begun to decline, trail cases by several weeks.

Allen, a healthy buildings expert who has helped schools, airlines, and businesses respond to COVID, said vaccines and boosters are the most powerful tools in the pandemic. Healthy people who are vaccinated and boosted have extremely low risk of serious illness from SARS-CoV-2, he noted. Widespread availability of masks and rapid tests, the recent approval of new antiviral pills, and two years’ worth of experience by the health care community in handling COVID are each significant developments and together create a dramatically different landscape, he said.

“We have a lot of new tools that we didn’t have and this is why I think it’s appropriate that governors are starting to change or remove mask mandates,” Allen said.

James Hammitt, a professor of economics and decision science at the Harvard Chan School and director of the Harvard Center for Risk Analysis, noted that as government controls recede, risk management will fall to individuals. Exposure potential is related to levels of community transmission, the number of people at a particular location, whether the event is indoors or outdoors, and duration, Hammitt said. Social, educational, economic, and many other factors also come into the equation.

Meanwhile, the risk calculus at schools has changed, even amid conflicting guidance on masking, with recent Harvard-MGH research warning that community case levels are still too high to warrant lifting mandates for most elementary schools. While kids have always been at low risk for serious illness, early in the pandemic there was considerable risk they’d transmit to unprotected adults. With those adults — and many students — now vaccinated, the landscape has shifted. Nonetheless, Allen urged vigilance. Given the unpredictable nature of the virus, he said, communities should move to boost ventilation and filtration in schools and offices, increase vaccination rates, and step up production of rapid tests and N95 masks.

Two treatments that have been shown to be ineffective against COVID-19 — hydroxychloroquine and ivermectin — were more heavily prescribed in the latter part of 2020 in U.S. counties with a higher Republican vote share in the 2020 presidential election, according to a new research letter co-authored by researchers from Harvard T.H. Chan School of Public Health.

The study was published online today in JAMA Internal Medicine.

“We’d all like to think of the health care system as basically non-partisan, but the COVID-19 pandemic may have started to chip away at this assumption,” said Michael Barnett, assistant professor of health policy and management and lead author of the study.

The study compared prescription rates for hydroxychloroquine and ivermectin with rates for two control medications, methotrexate sodium and albendazole, which are similar drugs but have not been proposed as COVID-19 treatments. Researchers looked at deidentified medical claims data from January 2019 through December 2020 from roughly 18.5 million adults across the U.S., as well as U.S. Census data and 2020 U.S. presidential election results.

Overall, hydroxychloroquine prescribing volume from June through December 2020 was roughly double what it had been the previous year, while ivermectin prescribing volume was seven-fold higher in December 2020 than it had been the previous year. In 2019, prescribing of hydroxychloroquine and ivermectin did not differ according to county Republican vote share. But that changed in 2020.

After June 2020 — coinciding with when the U.S. Food and Drug Administration revoked emergency use authorization for hydroxychloroquine — prescribing volume for the drug was significantly higher in counties with the highest Republican vote share as compared to counties with the lowest vote share.

As for ivermectin, prescribing volume was significantly higher in the highest versus lowest Republican vote share counties in December 2020 — 964 percent higher than 2019 overall prescribing volume. The spike aligned with several key events, such as the mid-November 2020 release of a now-retracted manuscript claiming that the drug was highly effective against COVID-19, and a widely publicized U.S. Senate hearing in early December that included testimony from a doctor promoting ivermectin as a COVID-19 treatment.

Neither of the control drugs had differences in overall prescribing volume or in prescribing by county Republican vote share.

The findings suggest that the prescribing of hydroxychloroquine and ivermectin could have been influenced by physician or patient political affiliation, the authors concluded. “This is the first evidence, to our knowledge, of such a political divide for a basic clinical decision like infection treatment or prevention,” said Barnett.