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Tag: positive results

  • One of Tuberculosis’s Biggest, Scariest Numbers Is Probably Wrong

    One of Tuberculosis’s Biggest, Scariest Numbers Is Probably Wrong

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    Growing up in India, which for decades has clocked millions of tuberculosis cases each year, Lalita Ramakrishnan was intimately familiar with how devastating the disease can be. The world’s greatest infectious killer, rivaled only by SARS-CoV-2, Mycobacterium tuberculosis spreads through the air and infiltrates the airways, in many cases destroying the lungs. It can trigger inflammation in other tissues too, wearing away bones and joints; Ramakrishnan watched her own mother’s body erode in this way. The sole available vaccine was lackluster; the microbe had rapidly evolved resistance to the drugs used to fight it. And the disease had a particularly insidious trait: After entering the body, the bacterium could stow away for years or decades, before erupting without warning into full-blown disease.

    This state, referred to as latency, supposedly afflicted roughly 2 billion people—a quarter of the world’s population. Ramakrishnan, now a TB researcher at the University of Cambridge, heard that fact over and over, and passed it down to her own students; it was what every expert did with the dogma at the time. That pool of 2 billion people was understood to account for a large majority of infections worldwide, and it represented one of the most intimidating obstacles to eradicating the disease. To end TB for good, the thinking went, the world would need to catch and cure every latent case.

    In the years since, Ramakrishnan’s stance on latent TB has shifted quite a bit. Its extent, she argues, has been exaggerated for a good three decades, by at least an order of magnitude—to the point where it has scrambled priorities, led scientists on wild-goose chases, and unnecessarily saddled people with months of burdensome treatment. In her view, the term latency is so useless, so riddled with misinformation, that it should disappear. “I taught that nonsense forever,” she told me; now she’s spreading the word that TB’s largest, flashiest number may instead be its greatest, most persistent myth.

    Ramakrishnan isn’t the only one who thinks so. Together with her colleagues Marcel Behr, of Quebec’s McGill University, and Paul Edelstein, of the University of Pennsylvania (“we call ourselves the three BERs,” Ramakrishnan told me), she’s been on a years-long crusade to set the record straight. Their push has attracted its fair share of followers—and objectors. “I don’t think they’re wrong,” Carl Nathan, a TB researcher at Cornell, told me. “But I’m not confident they’re right.”

    Several researchers told me they’re largely fine with the basic premise of the BERs’ argument: Fewer than 2 billion isn’t that hard to get behind. But how many fewer matters. If current latency estimates overshoot by just a smidge, maybe no practical changes are necessary. The greater the overestimate, though, the more treatment recommendations might need to change; the more research and funding priorities might need to shift; the more plans to control, eliminate, and eventually eradicate disease might need to be wholly and permanently rethought.

    Read: A historical lesson in disease containment

    The muddled numbers on latency seem to be based largely on flawed assumptions about certain TB tests. One of the primary ways to screen people for the disease involves pricking harmless derivatives of the bacterium into skin, then waiting for an inflamed lump to appear—a sign that the immune system is familiar with the microbe (or a TB vaccine), but not direct proof that the bacterium itself is present. That means that positive results can guarantee only that the immune system encountered something resembling MTB at some point—perhaps even in the distant past, Rein Houben, an epidemiologist at the London School of Hygiene & Tropical Medicine, told me.

    But for a long time, a prevailing assumption among researchers was that all TB infections had the potential to be lifelong, Behr told me. The thought wasn’t entirely far-fetched: Other microbial infections can last a lifetime, and there are historical accounts of lasting MTB infections, including a case in which a man developed tuberculosis more than 30 years after his father passed the bacterium to him. Following that logic—that anyone once infected had a good enough chance of being infected now—researchers added everyone still reacting to the bug to the pool of people actively battling it. By the end of the 1990s, Behr and Houben told me, prominent epidemiologists had used this premise to produce the big 2 billion number, estimating that roughly a third of the population had MTB lurking within.

    That eye-catching figure, once rooted, rapidly spread. It was repeated in textbooks, academic papers and lectures, news articles, press releases, government websites, even official treatment guidelines. The World Health Organization parroted it too, repeatedly calling for research into vaccines and treatments that could shrink the world’s massive latent-TB cohort. “We were all taught this dogma when we were young researchers,” Soumya Swaminathan, the WHO’s former chief scientist, told me. “Each generation passed it on to the next.”

    But, as the BERs argue, for TB to be a lifelong sentence makes very little sense. Decades of epidemiological data show that the overwhelming majority of disease arises within the first two years after infection, most commonly within months. Beyond that, progression to symptomatic, contagious illness becomes vanishingly rare.

    The trio is convinced that a huge majority of people are clearing the bug from their body rather than letting it lie indefinitely in wait—a notion that recent modeling studies support. If the bacteria were lingering, researchers would expect to see a big spike in disease late in life among people with positive skin tests, as their immune system naturally weakens. They would also expect to see a high rate of progression to full-blown TB among people who start taking immunosuppressive drugs or catch HIV. And yet, neither of those trends pans out: At most, some 5 to 10 percent of people who have tested positive by skin test and later sustain a blow to their immune system develop TB disease within about three to five years—a hint that, for almost everyone else, there may not be any MTB left. “If there were a slam-dunk experiment, that’s it,” William Bishai, a TB researcher at Johns Hopkins, told me.

    Read: Tuberculosis got to South America through … seals?

    Nathan, of Cornell, was less sold. Immunosuppressive drugs and HIV flip very specific switches in the immune system; if MTB is being held in check by multiple branches, losing some immune defenses may not be enough to set the bacteria loose. But most of the experts I spoke with are convinced that lasting cases are quite uncommon. “Some people will get into trouble in old age,” Bouke de Jong, a TB researcher at the Institute of Tropical Medicine, in Antwerp, told me. “But is that how MTB hangs out in everybody? I don’t think so.”

    If anything, people with positive skin tests might be less likely to eventually develop disease, Ramakrishnan told me, whether because they harbor defenses against MTB or because they are genetically predisposed to clear the microbe from their airway. In either case, that could radically change the upshot of a positive test, especially in countries such as the U.S. and Canada, where MTB transmission rarely occurs and most TB cases can be traced from abroad. Traditionally, people in these places with positive skin tests and no overt symptoms have been told, “‘This means you’ve got sleeping bacteria in you,’” Behr said. “‘Any day now, it may pop out and cause harm.’” Instead, he told me, health-care workers should be communicating widely that there could be up to a 95 percent chance that these patients have already cleared the infection, especially if they’re far out from their last exposure and might not need a drug regimen. TB drugs, although safe, are not completely benign: Standard regimens last for months, interact with other meds, and can have serious side effects.

    At the same time, researchers disagree on just how much risk remains once people are a couple of years past an MTB exposure. “We’ve known for decades that we are overtreating people,” says Madhu Pai, a TB researcher at McGill who works with Behr but was not directly involved in his research. But treating a lot of people with positive skin tests has been the only way to ensure that the people who are carrying viable bacteria get the drugs they need, Robert Horsburgh, an epidemiologist at Boston University, told me. That strategy squares, too, with the goal of elimination in places where spread is rare. To purge as much of the bug as possible, “clinicians will err on the side of caution,” says JoAnne Flynn, a TB researcher at the University of Pittsburgh.

    Elsewhere in the world, where MTB transmission is rampant and repeat infections are common, “to be honest, nobody cares if there’s latent TB,” Flynn told me. Many people with very symptomatic, very contagious cases still aren’t getting diagnosed or treated; in too many places, the availability of drugs and vaccines is spotty at best. Elimination remains a long-term goal, but active outbreaks demand attention first. Arguably, quibbling about latency now is like trying to snuff stray sparks next to an untended conflagration.

    Read: The dangers of ignoring tuberculosis

    One of the BERs’ main goals could help address TB’s larger issues. Despite decades of research, the best detection tools for the disease remain “fundamentally flawed,” says Keertan Dheda, a TB researcher at the London School of Hygiene & Tropical Medicine and the University of Cape Town. A test that could directly detect viable microbes in tissues, rather than an immune proxy, could definitively diagnose ongoing infections and prioritize people across the disease spectrum for treatment. Such a diagnostic would also be the only way to finally end the fuss over latent TB’s prevalence. Without it, researchers are still sifting through only indirect evidence to get at the global TB burden—which is probably still “in the hundreds of millions” of cases, Houben told me, though the numbers will remain squishy until the data improve.

    That 2 billion number is still around—though not everywhere, thanks in part to the BERs’ efforts. The WHO’s most recent annual TB reports now note that a quarter of the world’s population has been infected with MTB, rather than is infected with MTB; the organization has also officially discarded the term latent from its guidance on the disease, Dennis Falzon, of the WHO Global TB Programme, told me in an email. However subtle, these shifts signal that even the world’s biggest authorities on TB are dispensing with what was once conventional wisdom.

    Losing that big number does technically shrink TB’s reach—which might seem to minimize the disease’s impact. Behr argues the opposite. With a huge denominator, TB’s mortality rate ends up minuscule—suggesting that most infections are benign. Deflating the 2 billion statistic, then, reinforces that “this is one of the world’s nastiest pathogens, not some symbiont that we live with in peace,” Behr told me. Fewer people may be at risk than was once thought. But for those who are harboring the microbe, the dangers are that much more real.

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    Katherine J. Wu

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  • Did Scientists Accidentally Invent an Anti-addiction Drug?

    Did Scientists Accidentally Invent an Anti-addiction Drug?

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    This article was featured in One Story to Read Today, a newsletter in which our editors recommend a single must-read from The Atlantic, Monday through Friday. Sign up for it here.

    All her life, Victoria Rutledge thought of herself as someone with an addictive personality. Her first addiction was alcohol. After she got sober in her early 30s, she replaced drinking with food and shopping, which she thought about constantly. She would spend $500 on organic groceries, only to have them go bad in her fridge. “I couldn’t stop from going to that extreme,” she told me. When she ran errands at Target, she would impulsively throw extra things—candles, makeup, skin-care products—into her cart.

    Earlier this year, she began taking semaglutide, also known as Wegovy, after being prescribed the drug for weight loss. (Colloquially, it is often referred to as Ozempic, though that is technically just the brand name for semaglutide that is marketed for diabetes treatment.) Her food thoughts quieted down. She lost weight. But most surprisingly, she walked out of Target one day and realized her cart contained only the four things she came to buy. “I’ve never done that before,” she said. The desire to shop had slipped away. The desire to drink, extinguished once, did not rush in as a replacement either. For the first time—perhaps the first time in her whole life—all of her cravings and impulses were gone. It was like a switch had flipped in her brain.

    As semaglutide has skyrocketed in popularity, patients have been sharing curious effects that go beyond just appetite suppression. They have reported losing interest in a whole range of addictive and compulsive behaviors: drinking, smoking, shopping, biting nails, picking at skin. Not everyone on the drug experiences these positive effects, to be clear, but enough that addiction researchers are paying attention. And the spate of anecdotes might really be onto something. For years now, scientists have been testing whether drugs similar to semaglutide can curb the use of alcohol, cocaine, nicotine, and opioids in lab animals—to promising results.

    Semaglutide and its chemical relatives seem to work, at least in animals, against an unusually broad array of addictive drugs, says Christian Hendershot, a psychiatrist at the University of North Carolina at Chapel Hill School of Medicine. Treatments available today tend to be specific: methadone for opioids, bupropion for smoking. But semaglutide could one day be more widely useful, as this class of drug may alter the brain’s fundamental reward circuitry. The science is still far from settled, though researchers are keen to find out more. At UNC, in fact, Hendershot is now running clinical trials to see whether semaglutide can help people quit drinking alcohol and smoking. This drug that so powerfully suppresses the desire to eat could end up suppressing the desire for a whole lot more.

    The history of semaglutide is one of welcome surprises. Originally developed for diabetes, semaglutide prompts the pancreas to release insulin by mimicking a hormone called GLP-1, or glucagon-like peptide 1. First-generation GLP-1 analogs—exenatide and liraglutide—have been on the market to treat diabetes for more than a decade. And almost immediately, doctors noticed that patients on these drugs also lost weight, an unintended but usually not unwelcome side effect. Semaglutide has been heralded as a potentially even more potent GLP-1 analog.

    Experts now believe GLP-1 analogs affect more than just the pancreas. The exact mechanism in weight loss is still unclear, but the drugs likely work in multiple ways to suppress hunger, including but not limited to slowing food’s passage through the stomach and preventing ups and downs in blood sugar. Most intriguing, it also seems to reach and act directly on the brain.

    GLP-1 analogs appear to actually bind to receptors on neurons in several parts of the brain, says Scott Kanoski, a neurobiologist at the University of Southern California. When Kanoski and his colleagues blocked these receptors in rodents, the first-generation drugs exenatide and liraglutide became less effective at reducing food intake—as if this had eliminated a key mode of action. The impulse to eat is just one kind of impulse, though. That these drugs work on the level of the brain—as well as the gut—suggests that they can suppress the urge for other things too.

    In particular, GLP-1 analogs affect dopamine pathways in the brain, a.k.a. the reward circuitry. This pathway evolved to help us survive; simplistically, food and sex trigger a dopamine hit in the brain. We feel good, and we do it again. In people with addiction, this process in the brain shifts as a consequence or cause of their addiction, or perhaps even both. They have, for example, fewer dopamine receptors in part of the brain’s reward pathway, so the same reward may bring less pleasure.

    In lab animals, addiction researchers have amassed a body of evidence that GLP-1 analogs alter the reward pathway: mice on a version of exenatide get less of a dopamine hit from alcohol; rats on the same GLP-1 drug sought out less cocaine; same for rats and oxycodone. African vervet monkeys predisposed to drinking alcohol drank less on liraglutide and exenatide. Most of the published research has been conducted with these two first-generation GLP-1 drugs, but researchers told me to expect many studies with semaglutide, with positive results, to be published soon.

    In humans, the science is much more scant. A couple of studies of exenatide in people with cocaine-use disorder were too short or small to be conclusive. Another study of the same drug in people with alcohol-use disorder found that their brain’s reward centers no longer lit up as much when shown pictures of alcohol while they were in an fMRI machine. The patients in the study as a whole, however, did not drink less on the drug, though the subset who also had obesity did. Experts say that semaglutide, if it works at all for addiction, might end up more effective in some people than others. “I don’t expect this to work for everybody,” says Anders Fink-Jensen, a psychiatrist at the University of Copenhagen who conducted the alcohol study. (Fink-Jensen has received funding from Novo Nordisk, the maker of Ozempic and Wegovy, for separate research into using GLP-1 analogs to treat weight gain from schizophrenia medication.)  Bigger and longer trials with semaglutide could prove or disprove the drug’s effectiveness in addiction—and identify whom it is best for.

    Semaglutide does not dull all pleasure, people taking the drug for weight loss told me. They could still enjoy a few bites of food or revel in finding the perfect dress; they just no longer went overboard. Anhedonia, or a general diminished ability to experience pleasure, also hasn’t shown up in cohorts of people who take the drug for diabetes, says Elisabet Jerlhag Holm, an addiction researcher at the University of Gothenburg. Instead, those I talked with said their mind simply no longer raced in obsessive loops. “It was a huge relief,” says Kimberly Smith, who used to struggle to eat in moderation. For patients like her, the drug tamed behaviors that had reached a level of unhealthiness.

    The types of behaviors in which patients have reported unexpected changes include both the addictive, such as smoking or drinking, and the compulsive, such as skin picking or nail biting. (Unlike addiction, compulsion concerns behaviors that aren’t meant to be pleasurable.) And although there is a body of animal research into GLP-1 analogues and addiction, there is virtually none on nonfood compulsions. Still, addictions and compulsions are likely governed by overlapping reward pathways in the brain, and semaglutide might have an effect on both. Two months into taking the drug, Mary Maher woke up one day to realize that the skin on her back—which she had picked compulsively for years—had healed. She used to bleed so much from the picking that she avoided wearing white. Maher hadn’t even noticed she had stopped picking what must have been weeks before. “I couldn’t believe it,” she told me. The urge had simply melted away.

    The long-term impacts of semaglutide, especially on the brain, remain unknown. In diabetes and obesity, semaglutide is supposed to be a lifelong medication, and its most dramatic effects are quickly reversed when people go off. “The weight comes back; the suppression of appetite goes away,” says Janice Jin Hwang, an obesity doctor at UNC School of Medicine. The same could be true in at least certain forms of addiction too. Doctors have noted a curious link between addiction and another obesity treatment: Patients who undergo bariatric surgery sometimes experience “addiction transfer,” where their impulsive behaviors move from food to alcohol or drugs. Bariatric surgery works, in part, by increasing natural levels of GLP-1, but whether the same transfer can happen with GLP-1 drugs still needs to be studied in longer trials. Semaglutide is a relatively new drug, approved for diabetes since 2017. Understanding the upshot of taking it for decades is, well, decades into the future.

    Maher told me she hopes to stay on the drug forever. “It’s incredibly validating,” she said, to realize her struggles have been a matter of biology, not willpower. Before getting on semaglutide, she had spent 30 years trying to lose weight by counting calories and exercising. She ran 15 half marathons. She did lose weight, but she could never keep it off. On semaglutide, the obsessions about food that plagued her even when she was skinny are gone. Not only has she stopped picking her skin; she’s also stopped biting her nails. Her mind is quieter now, more peaceful. “This has changed my thought processes in a way that has just improved my life so much,” she said. She would like to keep it that way.

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    Sarah Zhang

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  • How Democrats Avoided a Red Wave

    How Democrats Avoided a Red Wave

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    The coalition of voters who turned out to oppose Donald Trump in 2018 and 2020 largely reassembled yesterday, frustrating Republican expectations of a sweeping red wave.

    Under the pressure of high inflation and widespread disenchantment with President Joe Biden’s job performance, that coalition of young voters, people of color, college-educated white voters, and women eroded at its edges. And because Democrats began the night with so little margin for error in Congress, that erosion—combined with high Republican turnout—seemed likely to allow the GOP to seize control of the House, and possibly the Senate as well.

    But even if the GOP does squeeze out majorities in one or both chambers when the final votes are counted, its margins will be exceedingly narrow, with control of the Senate, once again, possibly turning on another Georgia runoff. Up and down the ballot, Democrats dominated among voters who believe that abortion should remain legal—despite predictions from Republicans and many media analysts that the issue had faded in importance. Democrats held House seats in states including Rhode Island, Virginia, Michigan, and Ohio that Republicans had confidently expected to capture. And with the exception of Georgia, which reelected Governor Brian Kemp, Democrats could win gubernatorial races in each of the five swing states that flipped from Trump to Biden in 2020—a development that would greatly ease Democratic fears of Trump allies trying to rig the vote (and potentially the presidency) in 2024.

    David Frum: Trump lost the midterms. DeSantis won.

    The results largely followed the outline of what I’ve called a “double negative” election. On balance, voter dissatisfaction with Biden’s performance meant that Democrats faced more losses, but the continuing unease about the Republican Party lowered the ceiling on GOP gains well below what the party might have expected.

    These relatively positive results for Democrats were so striking because the findings of the national exit poll conducted by Edison Research for a consortium of media organizations, like virtually all preelection polling, showed deeply pessimistic attitudes that typically spell doom for the sitting president’s party. More than three-fourths of voters, Edison found, described the economy as only “fair” or “poor.” Four-fifths of voters said inflation had caused them either severe or moderate hardship. Fifty-five percent of respondents said they disapproved of Biden’s job performance as president. His approval stood even lower in many of the key Senate battleground states: 43 percent in Nevada and Arizona, 42 percent in New Hampshire, just 41 percent in Georgia.

    Exit polls suggested that unhappiness over the economy could doom the most embattled Democratic Senate incumbent, Catherine Cortez Masto in Nevada, though that race remains on a knife’s edge awaiting the counting of the last mail ballots. Across a wide array of other battleground states, Republicans carried significant majorities of voters who expressed negative views on the economy.

    But Republicans did not win those economically pessimistic voters by quite as big a margin as midterm precedents had suggested. Usually, the party out of power has dominated voters with those views: Democrats, for instance, in 2018 won about 85 percent of those who described the economy as either not so good or poor. This year, Republicans slightly exceeded that result among those who called the economy “poor,” the most negative designation. But among those who gave the equivocal verdict of “not so good,” Republicans won only 62 percent, way down from the Democrats’ total four years ago.

    The relationship between presidential-approval ratings and the midterm vote was similar. Biden’s national job-approval rating in the exit poll (44 percent positive, 55 percent negative) resembled Trump’s in 2018 (45–54). But, compared with Republicans in 2018, Democrats this year carried slightly more of the voters who disapproved of Biden, as well as slightly more of those who approved of him. Particularly noteworthy: Democrats won almost exactly half of voters who said they “somewhat disapproved” of Biden, whereas about two-thirds of voters who “somewhat disapproved” of both Trump in 2018 and Barack Obama in 2010 voted against their party in House races.

    These effects were even more pronounced in several of the battleground states. In 2018, no Republican Senate candidate in a competitive race carried more than 8 percent of the voters who disapproved of Trump, the exit polls found. But Cortez Masto and Raphael Warnock in Georgia carried about 10 percent of them, while Senator Mark Kelly in Arizona and Lieutenant Governor John Fetterman in Pennsylvania reached about 15 percent of support with Biden disapprovers, the exit polls found. In New Hampshire, the exit poll found Senator Maggie Hassan winning a striking one-fifth of voters who disapproved of Biden. Similarly, Warnock won about one-third of voters who described the economy as only fair or poor, while Kelly and Fetterman approached 40 percent with them in the exit polls. All of this may sound like a small difference—but it proved to be the margin between defeat and victory for Democrats in Pennsylvania and New Hampshire, and potentially in Arizona and Georgia.

    David A. Graham: The divided states of America

    How did Democrats overperform recent historical trends with voters dissatisfied with the economy or the president? Attitudes about the former president, and the party he has reshaped in his image, may largely explain the difference. In the exit poll, nearly three-fifths of voters said they had an unfavorable view of Trump, and more than three-fourths of them voted Democratic this year. Many of the Republican Senate and gubernatorial candidates he helped propel to their nominations also faced negative assessments from voters. And despite predictions from both Republicans and media analysts that abortion had faded as a galvanizing issue, a clear three-fifths majority of all voters in the national exit poll said they believed that the procedure should remain legal in all or most circumstances—and about three-fourths of them voted Democratic. Democrats also won about three-fourths of the voters who said abortion should remain mostly legal in the key Senate states of Arizona, Georgia, and Pennsylvania, and two-thirds of them in New Hampshire. In Michigan, Governor Gretchen Whitmer won a stunning four-fifths of the voters who said abortion should remain legal.

    These concerns about Trump and abortion rights didn’t completely erase voter discontent over the economy and inflation. Inflation still ranked highest when the exit polls asked voters what issues most concerned them (with abortion a very close second). And Republicans still won most of the voters who expressed the purest “double negative” views—those with unfavorable opinions of both Biden and Trump. But it’s hardly a surprise that the party out of the White House might win most voters who express an unfavorable view of the sitting president, no matter what other attitudes they hold. The notable part was that the exit poll found Democrats holding 40 percent of those double-negative voters—a number that helped them apparently avoid a titanic red wave.

    In the past, when midterms have turned decisively against the sitting president’s party, one reason is a backlash among independent voters, who are the most likely to shift allegiance based on current conditions in the country. Each time the president’s party suffered especially large losses in a midterm since the mid-1980s (a list of electoral calamities that includes 1986, 2006, and 2018 for Republicans and 1994, 2010, and 2014 for Democrats), independents have voted by a double-digit margin for House candidates from the other party, according to exit polls. But yesterday’s exit polls showed the two parties splitting independent voters about evenly on a national basis and Democrats winning among them in the Arizona, Georgia, New Hampshire, and Pennsylvania Senate races.

    The other ingredient in decisive midterm losses has been what political strategists call “differential turnout.” Almost always in American history, the party out of the White House has shown more urgency about voting in midterms than the side in power, but when midterms get really bad, that disparity becomes especially pronounced.

    A complete picture of this midterm won’t be available for months. But the early indications are that this year’s electorate leaned more toward the GOP than the past few campaigns. In 2020 and 2018, the exit polls found that self-identified Democrats made up slightly more of the voters than Republicans. But the exit polls yesterday showed Republicans with a slight edge.

    Young people gave Democrats preponderant margins in most races, but likely made up slightly less of the electorate than they did in 2018. Among voters of color, the story was similar—some erosion in support for Democrats, but not a catastrophic decline. The exit polls showed Democrats winning about 60 percent of Latino voters and 85 percent of Black voters. That was down just slightly from their level in 2020, though it represented a bigger fall from the party’s support with those voters in 2018. Republicans in the coming days will likely trumpet the continuing gains—though Democrats can fairly rebut that they have a clear opportunity to rebound if and when the economy recovers.

    Caroline Mimbs Nyce: Five things to know about midterm election results

    Before Election Day, conservative pundits speculated rampantly about a sweeping shift toward the GOP among nonwhite voters without a college degree—what Axios breathlessly declared “a political realignment in real time.” But Democrats nationally carried about two-thirds of those non-college-educated voters of color, almost exactly their share among minorities with degrees; the picture was similar in the heavily diverse states across the Sun Belt, the exit polls found. Among white voters, the familiar educational divides held: The national exit poll showed Democrats slightly underperforming expectations among college-educated whites (winning only about half of them) but still showing much better with them than among non-college-educated whites, who once again broke about two-to-one for the GOP. (College-educated white voters did provide more resounding margins for Kelly, Hassan, and Fetterman, the polls found.)

    The full results won’t be known for days, and control of the Senate may not be settled until another runoff election in Georgia. But the 2024 presidential contest will likely kick into motion almost immediately. Trump has repeatedly hinted that he may announce a 2024 candidacy as soon as next week—and the GOP’s gains, even if less than the party anticipated, will only encourage him.

    Throughout American history, midterm results have had little relationship to the results in the next presidential contest. Presidents Jimmy Carter and George H. W. Bush had relatively good first-term midterm results in 1978 and 1990, and then lost for reelection two years later. Harry Truman, Ronald Reagan, Bill Clinton, and Barack Obama were all shellacked in their first midterm and then won reelection.

    Could Biden follow those precedents and recover in time for 2024? Much will depend on the economy. Doug Sosnik, a senior White House adviser to President Clinton during his recovery after the 1994 midterm, pointed out that the period from fall of the third year to spring of the fourth year is when voters really lock in their judgment about a first-term president. That doesn’t leave Biden much runway to dispel the economic pessimism that weighed so heavily on Democrats yesterday. Many economists believe that the Federal Reserve Board’s actions will trigger at least a mild recession before squeezing out inflation, potentially by late next year.

    Given the doubts many voters have expressed about Biden’s age, it’s not clear that a rising economic tide would lift his prospects as much as it did for Reagan, Clinton, and Obama. Many Republicans (and even some Democrats) believe that the loss of the House, and possibly still the Senate, when all of this year’s votes are counted will increase pressure on Biden to step aside in 2024. In the exit polls, two-thirds of voters said they did not want to see Biden run again.

    Yet the GOP may be saddled with a 2024 nominee carrying even more baggage. Trump will inevitably interpret any GOP gains as a demand for his return. But even in a Republican-leaning electorate, the exit polls still registered enormous resistance to him.

    One of the night’s clearest winners was Trump’s most serious competitor for the next GOP nomination, Governor Ron DeSantis of Florida, who won a convincing victory that included breakthrough results in heavily Latino Miami-Dade County. His success will likely embolden the Republicans urging the party to turn the page from Trump—though Trump has already signaled his willingness to bludgeon DeSantis to secure the nomination, the way he did Marco Rubio and Ted Cruz in 2016.

    For Biden, the situation will likely be more equivocal: The results for Democrats probably won’t prove good enough to completely quiet the chatter about replacing him, but nor will they likely prove so bad as to significantly amplify it. After this double-negative election produced something of a standoff between the parties in 2022, it remains entirely possible that the nation may find itself plunged into the same grueling trench warfare between Trump and Biden again two years from now.

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    Ronald Brownstein

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