Trouble Losing Weight?

Two science-based ways I can help you become physically fit

This week I simultaneously reached two personal milestones! The first is having 144 subscribers:

Having light sensitivity means #220000 is a rad background for your browser

I’m not much a fan of decimal (base ten) so much as dozenal or senary, so a hundred subscribers was never the thing I was excited about. A hundred can’t even divide evenly into three, but one gross is a serious milestone. (Sorry to refer to you all as a gross, but if Bilbo Baggins can get away with it, I figure I’m probably good)

I do find I sometimes have trouble keeping up with conversations now. Sorry if I’m slow or bad at responding going forward! If I don’t reply right away, it doesn’t absolutely mean I don’t like you, it might just mean your comment was buried. Don’t feel bad about discretely pestering me for an answer to something you wrote.

This isn’t really the milestone I wanted to write about, though. While it took more than a year to get this blog where I wanted, I also just reached a milestone requiring much more sustained dedication and effort—more than a decade. After spending most of my life underweight, then overweight, and never strong enough to feel satisfied, I finally overcame the ambivalent struggle modern Westerners have with physical fitness: I am finally strong and healthy. It wasn’t always that way.

Americans and Physical Fitness

It’s no secret that Westerners are unhealthy. It doesn’t really matter what country we live in—we’re stressed, we’re under-exercised, and if we’re we’re obese:

The above map comes from Wikipedia; after tracking down the source of the data, I’m not able to determine which percentages were directly measured and which were self-reported, which makes a difference—measured obesity is more prevalent than obesity given by self report by anywhere from from 0.7%-13.4%,¹ for psychological reasons you may be aware of. But when I compare the map to measured data,² it matches fairly well:

Chart made from data at footnote 2

Note that I’m not trying to discuss people who are overweight, here. The problems of being overweight are pretty minor, if they exist at all. A 2016 meta-analysis of 2.88 million people found no elevated mortality risk for those who were overweight (and being overweight possibly even had a minor protective effect, though looking carefully, that might just be the obesity paradox, as it was more pronounced in the over 65 age group).³

Granted, a larger meta-analysis the same year did find the absolute lowest risk of death for never smokers at BMI 23-24, but that’s the upper edge of the normal BMI range, and the difference isn’t much if it took 30 million participants to show that the optimum really wasn’t in the overweight range.⁴ There’s also some evidence that men are happiest when they’re right at the border between normal weight and overweight.⁵ If nothing else, being overweight means you have a cushion there in case of civil war, getting lost in the wilderness, or a good old fashioned zombie outbreak.⁶

But genuine obesity is where enjoyment of life starts to decline—medically speaking, this means being over 180 pounds if you’re 5’5”, or at least 210 pounds if you’re 5’10”. This is where climbing stairs or fitting in airplane seats starts to get a bit unpleasant, and even trying to get some exercise by taking a walk risks your tripping in a pothole, and then you’ve dislocated your big toe and fractured your second metatarsal, and then your husband is miserable over the course of your recovery.

It’s these overall health affects that seem to be the main reason obesity is a problem. We might think that dissatisfaction with appearance, or fat shaming, or something like that would be the main problem, but to quote a nice big study of over 8,000 individuals carried out in Finland: “controlling for health and functional status, we find very limited evidence for any independent influence of obesity on subjective well-being.”⁷ So unless the Finns are somehow unrepresentative, it’s the glow of vitality that makes a healthy BMI more satisfying.

Unfortunately, since my readers are self-selected for living in Anglophone countries with high rates of obesity, but probably not self-selected for physical fitness, it isn’t unreasonable to guess that around a third of you aren’t where you want to be in terms of how healthy you are, in terms of what your body can do, or even in terms of the way you look. Right? Fitness is hard enough that a lot of people just give up, or start to resent the implication they would be better off if they were more fit, or even figure out that if they don’t like facts, hey, this is the 21st century, and we now have plenty of alternative facts that might be right for you:

Is Obesity Really Unhealthy?

Anyone with a search engine and a will to find them will soon discover activists like Brooklyn Reece telling us “Obesity Isn’t Actually Unhealthy — People Just Think It Is,” while Cat Pausé complains that “healthy children are being labelled obese” which is a problem because “the key predictors of good health are actually genetics, socio-economic status, smoking, drinking heavily, [and] eating healthy foods.”

Cat Pausé (right) enjoying herself at a 2013 International Women's Day event in New Zealand, in a photo I cleverly found at Wikipedia

But my personal favorite opinion piece argues that “Fat Is Not the Problem—Fat Stigma Is,” as “‘Health experts’ are sending incorrect and destructive messages about the relationship between weight and wellness… with roots in racism, slavery and every other attempt to rank bodies.” Since invocations of racism are basically the corollary of Godwin’s Law for the 2020s, I don’t think many people are really fooled by this anymore.

As for whether obesity is really healthy or not, well, the larger meta-analysis I mentioned earlier published several mortality curves breaking the sample up in various ways.⁸ Here are just two:

Relative risk of all-cause mortality as a function of BMI, adapted from the source cited at footnote 8

Above the obesity cutoff at BMI 30, mortality risk soars, such that among those who don’t smoke, it more than doubles by BMI 40, and triples by 45, which by the looks of things is about where Cat Pausé has been hanging around. The curve is less extreme when smokers are included, not only because the variation from smoking obscures the signal, but because smoking tends to slightly reduce a person’s weight, making heavier people seem healthier than they really were.

That was an early, pre-COVID study, though. The COVID epidemic wasn’t that fun, but at least we were able to learn something from what amounted to a worldwide natural experiment: A 2021 meta-analysis of COVID mortality found people with class I, class II, and class III obesity were 27%, 56%, and 92% more likely to die than controls (with p < 0.01 for all groups).⁹

But for me, the real clincher comes from obesity’s negative association with fertility. I realize most people haven’t made reproduction into a hobby the way the Apple Pie family has, so I’m not going to go into the studies individually. Instead, I’m just going to claim that something which physically impairs your reproductive ability is likely to be unhealthy, point out that other things usually regarded as unhealthy, like smoking, do the same thing,¹⁰¹¹¹² and then say “obesity is a reproductive impairment,” and cite it eight times.¹³¹⁴¹⁵¹⁶¹⁷¹⁸¹⁹²⁰

Obesity doesn’t only reduce our athletic ability. It also makes us unhappy, vulnerable to disease, and less good at reproducing. Any one of these things taken individually may just suggest obesity is a condition to avoid, but taken all together, they suggest human beings are truly not supposed to be obese. Mother Nature did not make us to get fat like this.

And if you don’t really believe me about that, you could ask Cat Pausé for a rebuttal, except for the fact that, like so many of my friends growing up, she died. However where my buddies and girlfriends died of gunshot wounds or automobile accidents, Pausé died in her sleep before the age of 45, leaving those of us who survived her to connect the dots about what exactly it is that kills an obese fat activist in her sleep.

Caitlin Clare Pausé, 1979-2022

But Losing Weight is Seriously Hard

Anyone who has ever even tried to diet knows very well how hard it is to become physically fit. It’s so difficult, in fact, that many people find it is simply impossible to do on their own. Exercise regimens are hard to maintain. Diets often fail. And even when they do work, 80% of dieters regain the lost weight within a year, and 95% of dieters regain the weight within three years.²¹

If you’re going to succeed at improving your physical fitness, it stands to reason that you might need a little something extra. If you’re already satisfied with your fitness, that’s great! But if you aren’t, then I can actually tell you two things that will give you an edge on losing weight, gaining muscle, and maintaining your fitness going forward.

Before I do, it might help if I let you know how I got to where I am. I got there like this:

This

I was on the skinny side in my youth. I’d always been pretty picky, and when I entered high school my BMI was 18 kg/m2, just to the left of the border between normal and underweight:

I’m not telling you my specific height or weight, but the red line was my BMI

I remember sitting down to holiday meals amidst my smiling relatives, the table covered with yams, pilaf, chicken, and beef, and searching for a slice of bread or baked potato. “Oh, your plate is empty,” my relatives would always pretend to notice in the unsubtle way they considered to be the polite manner of putting pressure on a wayward kid, offering various foods and refusing to take no for an answer until I told them directly that I found those dishes nauseating.

Part of the trouble was that they had no clue how to deal with me. It was obvious that what they mostly wanted from me was conformity to family norms—my relatives were the same way about turning on the lights too bright, or the heat too high, and everything else. They’d wander into a room where I was minding my own business in order to helpfully open the curtains, turn on the lights, make some banal and distracting comment, and then leave. “Oh, you don’t want that” was their attitude towards everything of value to me, from video games to a piece of plain bread. My entire childhood was a constant struggle merely to exist as a person with actual sensations.

And then another part of the trouble was that, in my day-to-day existence outside of family gatherings, my father was an outrageously bad cook. I realize this may bring to mind a man in a chef’s hat who turns his back on the stove while his spaghetti is on fire, but this wasn’t exactly the problem. My dad wasn’t stupid, but he was absolutely terrible at taking any kind of feedback. He would cure his own olives; he would brew his own beer; he would bake his own pizzas from scratch, spending an afternoon carefully rising the dough. But when things didn’t turn out well, neither I nor my not-at-all picky sibling could convince him that he had created a sodden, malodorous mess. He had spent hours carefully crafting this culinary catastrophe, and where one person might take failure as an opportunity for improvement, this man wasn’t interested in improvement. He didn’t want to become a good cook. He just wanted to be a good cook.

And then part of problem was that, interestingly, my body seems to have excellent iron absorption. It was only after years of my relatives pushing beef at me that my mother got her children’s blood tested in a routine checkup, and found the carnivores in the family had low iron levels in their blood, while mine were high. It wasn’t the meat I didn’t like, it was red meat saturated with heme iron. I could eat it just fine spiced up as pepperoni, or in the occasional burger saturated with liquid smoke. But my body was telling me very directly to take it easy on the iron, and now that I’ve learned to avoid ferrous foods and supplements, I always check out fine.

Any one of these things would probably not have been a big deal. But taken together they taught me to regard very ordinary food, particularly meat, with a deep suspicion.

So it should be no surprise that as an adolescent, I was never as strong as I wanted to be. I loved to run, and I was pretty active jumping fences, kicking punching bags, and bashing my friends with metal pipes wrapped up in socks. But I figured out after a while that my heavier friends could lift more, carry more, and hit harder in large part just because they were heavier. My best friend was about double my weight, and watching him hit the punching bag was hilarious, because it made no difference how bad his form was; the bag would go flying.

One memory that sticks with me was the time I hurt myself in the gym trying to curl a 50 pound dumbbell. It was an arbitrary thing to want; I was curling 40 pounds fine, but (and you may recognize this) I didn’t want to become strong, I wanted to be strong. I wanted to be curling 50 pounds, but I didn’t listen to my body and work up to the weight; I just lifted. Worse, my friends had always told me the smart way to lift was to lift to failure and go home, I so never did any more than stretch out before lifting. As you can imagine, doing this kind of thing without ever bothering to warm up or warm down, I injured myself repeatedly, and couldn’t maintain a regimen. Ultimately, I’d work out, but I wasn’t really gaining, because my body had noting to gain with.

So realizing that the problem had a solution, I set out to gain weight. Doing so required years of focus and changes to personal habits. I gradually forced myself to eat eggs, starting out by making french toast, and then cutting out the milk, and then saturating the bread with eggs, and then having french toast with scrambled eggs, and then eating just scrambled eggs. I gradually added more pepperoni to pizza, and then other meats. I forced myself to eat chicken nuggets. I added small amounts of meat to vegetable stir fries, and then more. But what really helped more than any one action was being a poor college student, and coming to see food as a valuable resource that should not be wasted. Eventually, I was able to eat virtually anything that anyone gave me besides straight beef.

After ten years, eating everything in sight really worked to put on weight. It worked so well that I gained over seventy pounds. I’d completed my bachelor’s degree, gotten married, lost track of my desire to get stronger, and just ended up—suddenly—more than twenty pounds overweight, unable to so much as run around the block without stopping for a rest. What was really embarrassing, and strongly motivated me to do something about it, was feeling the way my chest jiggled when I ran. (Maybe you feel differently, but I have this really strong sense that a breast’s place is on a woman. But on me, on a tree, on a brick wall? That’s just weird.)

Trying to fix this required even more changes. I’d started my career by now and started working at some pretty stressful—yet sedentary—positions. This had solved the chronic money problems of my youth, but it replaced them with other problems: Not sleeping enough and not exercising enough were bad enough, but because I was always flooded with tasks and deadlines coming one after another and unable to rest, I came to see eating fatty food as a way of recharging. Thinking I never had enough to eat was overloading my system with calories. It took a while to adapt psychologically to the idea that I was actually not skinnier than I wanted to be. Gradually I realized that now, when I was overstressed, overtaxed, and my body craved something, what I had to feed it was exercise.

This was a big change. My snacks changed from Snickers and peppermint patties to jogging and pushups. I learned to count calories by the hundred, leaving an extra 200 Kcal as a buffer for vegetables that I never counted, so that if I was hungry, I could always have a high fiber snack that I didn’t need to count. I bought a scale and weighed myself every morning, and the scale proved that I was on track, not going too slow or too fast.

My diets were successful. But the weight kept creeping up in between. I had to make a rule to never be off of some kind of diet—counting calories is frustrating, but for the last ten years, no matter where we lived, our kitchen has always been filled with greens. Every day I have a vegetable dish.

What really worked was setting goals for exercise. If you merely diet, your metabolism will slow and you’ll lose muscle. I set a goal to run a mile without stopping, and didn’t give up until I’d met it. I set a goal to do 50 pushups in a row without rest, and didn’t give up until I met it. And I lifted weights, starting with easy 35 pound dumbbells, moving slowly up by 5 pound increments over months and months, until finally, after twenty years, my BMI is in the upper third of the green, and I curl 50 pounds in sets of six.

I’m never going to be an amazing athlete, or accomplish a truly impressive feat like climbing Mt. Everest. I’m just not motivated to do the kinds of things career athletes do. But I can say what few Americans can say anymore: I am physically fit.

So Congratulations

You now have the first edge I can give you, which is a healthy peer. Just by being one of my readers, finding out I’m physically fit gives you an advantage. Yes, I realize this may sound bizarre because you live in an individualist society where the assumptions are that “I make all the relevant decisions about my life,” but if so, well, this won’t be the first time your cultural assumptions have been wrong. We’re still human, and human beings follow the cues of others around them.

An emerging body of research supports the claim that loss of virginity travels through social networks.²²²³²⁴ A handful of studies finds similar effects for happiness²⁵ and depression²⁶²⁷ traveling across friendships. But the clearest signal is found for obesity, where a review of longitudinal studies found “friendship network characteristics influenced change in individuals' body weight status and/or weight-related behaviour over time.”²⁸ So the obvious implication is that just by being in my network, just by reading about where I am and what I’ve done will make fitness feel easier for you as well.

Think of it like this: So long as YouTube is your friend, you’ll get constant ads for food and sedentary activities. So long as fat activists are your friends, you’ll get constant complaints about how weight loss is impossible, and society is racist for stigmatizing fat people. So long as Apple Pie is your friend, he’ll be constantly like, “Here are a bunch of studies, and let’s talk about moral nihilism, and by the way I was out eating veggies and running the other day when I saw a UFO” and the next thing you know this is what you’ll think of as normal.

Arguably, this may have a greater effect on my male readers who are more likely to see me as a relatable peer than the ladies. I don’t have any information on that, but frankly if you’re suspicious and full of estrogen, my advice is to subscribe to Wood From Eden, read a few posts there, look at a photo of what Tove does all the time, and you’ll gradually start to feel like it’s normal to be Swedish a physically fit lady.

And Congratulations Again

Because if you understand what I’ve just explained, you now have an additional edge on your side, called the placebo effect.

I know, people commonly think that the placebo effect is just something that happens when a patient takes a sugar pill that really does nothing, but placebo actually stacks on top of actual benefits from medical interventions. For instance, a meta-analysis on medication for depression found 68% of the effect was attributable to placebo.²⁹ That’s right—most of what makes medication effective for depression is the way patients think “I’m taking a medication that works.” And while you might think that this was merely a result of people convincing themselves their medication worked really well when it only had a small effect, the meta-analysis found the opposite: effect sizes were stronger when rated by peers than by patients themselves.³⁰

OK, great, but that was depression. Does placebo work for things like physical fitness? The answer is that I wouldn’t be telling you about it if there weren’t good evidence that placebo also worked for achieving a healthy weight. The best paper I’ve found is a 2022 meta-analysis including over 20,000 patients, establishing both placebo and nocebo effects on weight less.³¹

I want to stress here that what makes placebo work is belief, not belief in something that isn’t true. My sense is that I attract readers who are skeptical, slow to accept things other people tell them, and occasionally obnoxiously contrary. I doubt I could get you to believe this would help by writing “Oh wow, hey, this will definitely help!” and just making up a bunch of studies to cite. So go ahead and click through the footnotes; I found these studies on Google Scholar, so they should be readily available and easy to locate. See if you can find limitations in the studies, or things I really shouldn’t have cited at all. I think if you take the time to convince yourself these effects are likely to be real, you’ll increase the benefits you can derive from them.

Things that Won’t Work

In writing this post, I’ve tried to be a bit disclosing to give you a real sense of myself as at least a vaguely genuine connection. I doubt that restacking this or getting other people who aren’t one of my 144 subscribers to read it will actually do much of anything beneficial for them. So far as I can tell what matters is that I seem real to you, and if I don’t, then I’m just some hypothetical person with zero ability to influence your own success.

Unfortunately, I also suspect that if I keep writing about this, then eventually my subscriber network would just start to look like a bunch of health nuts self selected for physical fitness. The people I really want to talk to about this—especially people already committed to assuaging their feelings about their weight by claiming there’s nothing to be done, and weight loss is impossible, and also who cares—aren’t going to hang around while I barrage them about it all the time.

So this is basically it, this is all I can do for you in this regard. If you want it to work, get on it, folks.

1. Maukonen, M., Männistö, S., & Tolonen, H. (2018). A comparison of measured versus self-reported anthropometrics for assessing obesity in adults: a literature review. Scandinavian journal of public health, 46(5), 565-579.

2. Janssen, F., Bardoutsos, A., & Vidra, N. (2020). Obesity prevalence in the long-term future in 18 European countries and in the USA. Obesity facts, 13(5), 514-527.

3. Flegal, K. M., Kit, B. K., Orpana, H., & Graubard, B. I. (2013). Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. Jama, 309(1), 71-82.

4. Aune, D., Sen, A., Prasad, M., Norat, T., Janszky, I., Tonstad, S., ... & Vatten, L. J. (2016). BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. bmj, 353.

5. Linna, M. S., Kaprio, J., Raevuori, A., Sihvola, E., Keski-Rahkonen, A., & Rissanen, A. (2013). Body mass index and subjective well-being in young adults: a twin population study. BMC public health, 13, 1-10.

6. Readers familiar with Project Zomboid may have already figured out that overweight is one of the best “negative” traits to pick. “Oh gosh, rather than scrambling to find enough dog food over the first week, I guess I’ll just have to focus on leveling up my carpentry and gathering enough weapons for when that damned helicopter shows up”

7. Böckerman, P., Johansson, E., Saarni, S. I., & Saarni, S. E. (2014). The negative association of obesity with subjective well-being: Is it all about health?. Journal of Happiness Studies, 15, 857-867.

8. Aune, D., Sen, A., Prasad, M., Norat, T., Janszky, I., Tonstad, S., ... & Vatten, L. J. (2016). BMI and all cause mortality: systematic review and non-linear dose-response meta-analysis of 230 cohort studies with 3.74 million deaths among 30.3 million participants. bmj, 353.

9. Poly, T. N., Islam, M. M., Yang, H. C., Lin, M. C., Jian, W. S., Hsu, M. H., & Jack Li, Y. C. (2021). Obesity and mortality among patients diagnosed with COVID-19: a systematic review and meta-analysis. Frontiers in medicine, 8, 620044.

10. Khan, H. M., Khan, M. Y., & Minhas, L. A. (2008). Effect of passive tobacco smoking on fertility of female mice. J Coll Physicians Surg Pak, 18(11), 708-712.

11. Dai, J. B., Wang, Z. X., & Qiao, Z. D. (2015). The hazardous effects of tobacco smoking on male fertility. Asian journal of andrology, 17(6), 954-960.

12. Soares, S. R., Simon, C., Remohi, J., & Pellicer, A. (2007). Cigarette smoking affects uterine receptiveness. Human reproduction, 22(2), 543-547.

13. MacDonald, A., Herbison, G. P., Showell, M., & Farquhar, C. M. (2010). The impact of body mass index on semen parameters and reproductive hormones in human males: a systematic review with meta-analysis. Human reproduction update, 16(3), 293-311.

14. Best, D., & Bhattacharya, S. (2015). Obesity and fertility. Hormone molecular biology and clinical investigation, 24(1), 5-10.

15. Chambers, T. J., & Anderson, R. A. (2015). The impact of obesity on male fertility. Hormones, 14(4), 563-568.

16. Campbell, J. M., Lane, M., Owens, J. A., & Bakos, H. W. (2015). Paternal obesity negatively affects male fertility and assisted reproduction outcomes: a systematic review and meta-analysis. Reproductive biomedicine online, 31(5), 593-604.

17. Lan, L., Harrison, C. L., Misso, M., Hill, B., Teede, H. J., Mol, B. W., & Moran, L. J. (2017). Systematic review and meta-analysis of the impact of preconception lifestyle interventions on fertility, obstetric, fetal, anthropometric and metabolic outcomes in men and women. Human Reproduction, 32(9), 1925-1940.

18. Ribeiro, L. M., Sasaki, L. M., Silva, A. A., Souza, E. S., Lyrio, A. O., Figueiredo, A. C., & Gottems, L. B. (2022). Overweight, obesity and assisted reproduction: A systematic review and meta-analysis. European Journal of Obstetrics & Gynecology and Reproductive Biology, 271, 117-127.

19. Sermondade, N., Huberlant, S., Bourhis-Lefebvre, V., Arbo, E., Gallot, V., Colombani, M., & Fréour, T. (2019). Female obesity is negatively associated with live birth rate following IVF: a systematic review and meta-analysis. Human reproduction update, 25(4), 439-451.

20. Moslehi, N., Shab-Bidar, S., Tehrani, F. R., Mirmiran, P., & Azizi, F. (2018). Is ovarian reserve associated with body mass index and obesity in reproductive aged women? A meta-analysis. Menopause, 25(9), 1046-1055.

21. Spreckley, M., Seidell, J., & Halberstadt, J. (2021). Perspectives into the experience of successful, substantial long-term weight-loss maintenance: a systematic review. International Journal of Qualitative Studies on Health and Well-being, 16(1), 1862481.

22. Sieving, R. E., Eisenberg, M. E., Pettingell, S., & Skay, C. (2006). Friends' influence on adolescents' first sexual intercourse. Perspectives on sexual and reproductive health, 38(1), 13-19.

23. Sieving, R. E., Eisenberg, M. E., Pettingell, S., & Skay, C. (2006). Friends' influence on adolescents' first sexual intercourse. Perspectives on sexual and reproductive health, 38(1), 13-19.

24. Laflin, M. T., Wang, J., & Barry, M. (2008). A longitudinal study of adolescent transition from virgin to nonvirgin status. Journal of Adolescent Health, 42(3), 228-236.

25. Fowler, J. H., & Christakis, N. A. (2008). Dynamic spread of happiness in a large social network: longitudinal analysis over 20 years in the Framingham Heart Study. Bmj, 337.

26. Van Zalk, M. H. W., Kerr, M., Branje, S. J., Stattin, H., & Meeus, W. H. (2010). It takes three: selection, influence, and de-selection processes of depression in adolescent friendship networks. Developmental Psychology, 46(4), 927.

27. Kiuru, N., Burk, W. J., Laursen, B., Nurmi, J. E., & Salmela-Aro, K. (2012). Is depression contagious? A test of alternative peer socialization mechanisms of depressive symptoms in adolescent peer networks. Journal of Adolescent Health, 50(3), 250-255.

28. Zhang, S., De La Haye, K., Ji, M., & An, R. (2018). Applications of social network analysis to obesity: a systematic review. Obesity reviews, 19(7), 976-988.

29. Rief, W., Nestoriuc, Y., Weiss, S., Welzel, E., Barsky, A. J., & Hofmann, S. G. (2009). Meta-analysis of the placebo response in antidepressant trials. Journal of affective disorders, 118(1-3), 1-8.

30. Ibid.

31. Chin, Y. H., Ng, C. H., Chew, N. W., Kong, G., Lim, W. H., Tan, D. J. H., ... & Muthiah, M. D. (2022). The placebo response rate and nocebo events in obesity pharmacological trials. A systematic review and meta-analysis. EClinicalMedicine, 54.