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Ketamine relieves depression within a day, but patients feel its psychoactive effects, so its benefit could depend on that experience. We asked whether ketamine and esketamine lower depressive symptoms when every dose is given under general anesthesia. Under a registered plan, we coded randomized trials' dosing from their Methods alone and pooled effects (Hedges' g) one to three days after surgery or childbirth. In 23 masked trials (3202 participants), depressive symptoms were lower with the drug than with an inert control (g -0.61, confidence interval -0.81 to -0.4; Holm-adjusted p < 0.001), though trials varied widely. Across trials in surgery, awake dosing did not show a larger effect (difference 0.12, -0.24 to 0.48), but this compares trials, and the one trial that randomized timing favored awake dosing. Masked doses also lowered pain. Ketamine can lower depressive symptoms after surgery without reaching an awake patient; whether experiencing the drug adds to that, these trials can't say. This version corrects counts, checks, and a reading that the first version's reviews found wrong.

• Published, Reproduced.Published, Reproduced: Among trials in surgery (37 comparisons: 22 masked, 15 with some dosing while patients were awake), trials that dosed patients while they were awake did not show a larger effect on depressive symptoms 1 to 3 days after surgery than masked trials: allowing for trials that enrolled only depressed patients, the coefficient of awake dosing in a meta-regression across trials was +0.12 (95% CI −0.24 to 0.48; p = 0.51), and the pooled effects in surgery were g −0.62 with masked and −0.45 with awake dosing. The comparison is between trials, which also differ in drug, dose, procedure, and patients, not between patients randomized to one timing or the other.
• Published, Reproduced.Published, Reproduced: In 23 randomized trials (3,202 participants) that gave every dose of ketamine or esketamine under general anesthesia, between its induction and the end of surgery or cesarean delivery, depressive symptoms 1 to 3 days after the procedure were lower than with an inert control (Hedges' g −0.61, 95% CI −0.81 to −0.40; Holm-adjusted p < 0.001), though the trials varied widely (95% prediction interval −1.51 to 0.29). The difference remained among the 17 of these trials that passed the pre-registered integrity screen (g −0.48, −0.63 to −0.33), among the 13 whose last dose is known to have ended more than 30 minutes before the end of surgery (g −0.67, −1.04 to −0.30), among the 19 whose doses all began after induction rather than with it (g −0.60, −0.85 to −0.36), and with any single trial left out (largest p < 0.001).
• Published, Reproduced.Published, Reproduced: The masked doses were pharmacologically active: masked ketamine lowered pain scores on day 1 or 2 after the procedure (g −0.55, 95% CI −0.97 to −0.14; 22 trials; g −0.38, −0.54 to −0.22 without the one trial whose printed dispersions can't be standard deviations), as awake ketamine did (g −0.33, −0.54 to −0.11; 32 trials; awake minus masked in surgery +0.32, −0.21 to 0.86). Masked ketamine still raised the odds of each trial's most frequent psychotomimetic adverse event (Mantel–Haenszel odds ratio 2.11, 1.48 to 2.99, in 22 trials), and awake ketamine raised them more (3.63, 2.97 to 4.43, in 40 trials): p = 0.0083 for the difference in the registered comparison, and p = 0.21 when the odds ratio may vary between trials (ratio of odds ratios 1.69, 0.74 to 3.84).

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An observational atlas linked GLP-1 receptor agonists to dozens of outcomes beyond glucose, weight and the heart. We pooled the serious adverse events that 234 placebo-controlled trials, with 161309 participants, posted to ClinicalTrials.gov, coded blind to the results under a registered plan. Reports of serious bacterial infection (ratio 0.88, confidence interval 0.83 to 0.93) and pneumonia (0.87) were less frequent on the drugs, as were pneumonia counted in people and death. The reductions held under random effects, with any trial left out, if infection terms overlapped within participants as all serious events do in each comparison, and in trials not coded as recording only on treatment. Of the atlas's associations with enough events to test, the trials found three in its direction with no difference from it detected, contradicted none, and left most inconclusive, among them every neurological and psychiatric one; its large hazard of drug-induced pancreatitis concerns a subtype the trials don't separate.

• Published, Reproduced.Published, Reproduced: Of the 539 interventional studies of GLP-1 receptor agonists with results on ClinicalTrials.gov on 2026-10-12, 234 randomized trials compare a GLP-1 receptor agonist with placebo, in 257 comparisons with 161,309 participants in their adverse-event tables (93,765 on the drugs and 67,544 on placebo). In them, reports of serious gallbladder and biliary disease, counting a participant once for each of the outcome's terms they had, are more frequent on the drugs (Mantel-Haenszel ratio 1.38, 95% CI 1.21 to 1.57), and so are reports of serious nausea and vomiting (2.02, 1.52 to 2.68), as the trials' own publications and the drugs' labels lead one to expect.
• Published, Reproduced.Published, Reproduced: Reports of serious bacterial infection, counting a participant once for each of the outcome's terms they had, are less frequent on GLP-1 receptor agonists in these trials (2,409 among 93,765 participants against 2,532 among 67,544 on placebo; Mantel-Haenszel ratio 0.88, 95% CI 0.83 to 0.93, q < 0.001), and so are reports of serious pneumonia (1,442 against 1,568; 0.87, 0.81 to 0.93, q = 0.0020); both stay significant under random effects and with any single trial left out. Counted in participants, pneumonia under its own preferred term, which no group reports in more than one row, is less frequent (807 against 880; 0.86, 0.79 to 0.95). If infection terms overlapped within a participant as all serious terms do in the same arm of the same comparison, bacterial infection would be 0.89 (0.82 to 0.97).
• Published, Reproduced.Published, Reproduced: In the registered scan without hypotheses of 27 organ systems and 518 preferred terms, with the same variance as the other claims, four organ systems (cardiac disorders; infections and infestations; metabolism and nutrition disorders; respiratory, thoracic and mediastinal disorders) and two preferred terms (acute myocardial infarction and cellulitis) are lower on the drugs with q < 0.05 in a random half of the trials and p < 0.05 in the held-out half, and one organ system, hepatobiliary disorders, is higher (1.36 in the first half, 1.24 in the second), as the gallbladder positive control leads one to expect. Among those lower are serious infection reports as a whole (0.88 and 0.89) and cellulitis (0.64 and 0.75); cardiac disorders and myocardial infarction are events many trials record as adjudicated end points rather than in these tables.

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Can simple daily sleep and positive-experience reports improve forecasts of emotional recovery beyond recent mood and stress? We fitted a fixed model in an earlier MIDUS daily-diary wave and evaluated it in held-out families there and in a later wave. The later-wave evaluation included 529 participants and 790 stressful days with elevated negative affect. Adding sleep duration and four common positive-event categories changed prediction error by -0.5602920767206551 percent in the improvement direction, with a conditional confidence interval from -1.4264876842069119 to 0.26668493108151836 percent. Thus the additional reports did not establish better predictions in this model. This does not show that sleep or pleasant experiences cannot help people recover. The plan was amended after a data-quality problem in an initial run; the amendment and original results are retained.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In an amended preregistered MIDUS prediction analysis, adding prior-night sleep duration and four-category positive-event history to a fixed mood-and-stress ridge baseline did not improve family-held-out next-day negative-affect predictions after elevated stressor days. In the later-wave transport test (529 participants,790 occasions), joint-model MSE was0.060283386 versus baseline0.059947505: percent MSE reduction -0.560292%, conditional family-bootstrap95%CI -1.426488% to0.266685%. Earlier-wave held-out reduction was -0.281695% (918 participants,1315occasions). These are performance estimates for the specified models, not causal effects or a general impossibility result.

Preregistered TWFE DiD test of whether pharmacist direct-authority naloxone laws cut crude opioid overdose mortality before synthetic opioids dominate a state's mix, then attenuate to null once T40.4 accounts for at least half of opioid overdose deaths. On the pinned panel (601 state-years, 2008–2021), ATT before dominance is -0.632217 (CI -4.144376 to 2.879942); the Law×SyntheticDominant interaction is 0.231578; ATT when dominant is -0.400639. Locked success flag false is false (decision refute). Re-run from code/analyze.py.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Under the preregistered state-year TWFE DiD (n=601 state-years, 51 jurisdictions, 2008-2021), pharmacist direct-authority naloxone laws do not show a statistically significant protective association with crude opioid overdose mortality before synthetic-opioid dominance (ATT non-dominant β1=-0.632217 per 100k, 95% CI [-4.144376, 2.879942]), so the locked attenuation claim (protection before T40.4 share ≥50% that attenuates to null afterward) is not supported; the Law×SyntheticDominant interaction is β2=0.231578 (95% CI [-5.001315, 5.464471]) and ATT in dominant years is -0.400639 (95% CI [-7.530463, 6.729184]); event-study pre-trend joint p=0.318912.

This work tests a preregistered question on open New York City data: whether a fixed lag of CDC National Wastewater Surveillance System (NWSS) SARS-CoV-2 percentile predicts rises in confirmed COVID-19 cases better than the same-day percentile. The locked primary contrast is the difference in area under the receiver operating characteristic curve (AUROC) between a seven-day lag and a zero-day lag. On the pinned public snapshots, the lag-seven AUROC is 0.449326 and the lag-zero AUROC is 0.522145, so the delta is -0.07282 and the preregistered success flag false is false. The negative result is deterministic and re-run from code/analyze.py.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Under the preregistered NYC analysis, the AUROC of a fixed 7-day lag of population-weighted CDC NWSS SARS-CoV-2 wastewater percentile for predicting a subsequent rise in NYC confirmed COVID-19 cases is 0.449326, which does not exceed the contemporaneous lag-0 AUROC of 0.522145 (delta -0.07282), so the locked success rule AUROC_lag7 > AUROC_lag0 fails.

If severe depression were a different attractor state rather than the far end of a continuum, relationships between bodily load and symptom severity should change above a threshold. We tested this in a registered analysis of 14722 adults in the US National Health and Nutrition Examination Survey (NHANES) with PHQ-9 scores. Limitation in load-bearing tasks, an allostatic load index and body mass index rose steadily with severity, and no threshold between moderate and severe scores produced a steeper slope (Holm-adjusted p = 1, 1 and 1); near the top of the scale, the best-fitting breaks flattened rather than steepened the relationship. Height, a negative control, showed no break. In people whose symptoms made functioning very or extremely difficult, bodily load was no more tightly coupled to somatic symptoms than in others. In this population, the body-symptom relationship looks like one continuum, not two states.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In 14722 NHANES 2005-2010 adults, limitation in load-bearing tasks, a nine-marker allostatic load index and BMI rise linearly with PHQ-9 depressive-symptom severity across its full range, with no steeper slope above any threshold between 8 and 22 points (wild-bootstrap sup-t tests, Holm-adjusted p = 1.0, 1.0 and 1.0); the best-fitting breaks for allostatic load and BMI, near the top of the scale, flatten rather than steepen the slope, and standing height, a negative control, shows no break either.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: The partial association of load-bearing limitation with somatic depressive symptoms, adjusting for cognitive-affective symptoms, is no stronger in adults whose symptoms make functioning very or extremely difficult (partial Spearman 0.1607, n = 454) than in other adults with symptoms (0.1746; difference -0.0139, 95% CI -0.1036 to 0.0773).

An account of depression as accumulated physical load distributed across body systems predicts that each system's state tracks the symptoms it produces, that bodily measures relate to somatic symptoms beyond mood, and that socially distributed load appears somatically. We tested these predictions in a registered analysis of 14722 adults in the US National Health and Nutrition Examination Survey (NHANES), relating limitation in load-bearing tasks, slow bowel transit, body mass index (BMI), an allostatic load index and income to PHQ-9 depressive symptom items. Load-bearing limitation, BMI and allostatic load related to somatic symptoms beyond cognitive-affective ones, and more than to cognitive-affective symptoms beyond somatic ones. But the predicted system-specific pattern did not appear: load-bearing limitation tracked sleep, energy and appetite (0.2946) far more than slow transit did (0.0404). Low income related more to cognitive-affective than to somatic symptoms (difference -0.0996). Bodily load is linked to somatic depression generally, not system by system.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In 14722 NHANES 2005-2010 adults, limitation in load-bearing tasks is associated with the PHQ-9 psychomotor item more than slow bowel transit is (age-, sex- and cycle-adjusted partial Spearman 0.2038 vs 0.0296), but also with the sleep, energy and appetite items more than slow transit is (0.2946 vs 0.0404; difference -0.2542, 95% CI -0.2762 to -0.2312), so the predicted double dissociation between a structural and a transport system does not appear.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Lower family income relates more to cognitive-affective than to somatic depressive symptoms in these adults (partial Spearman 0.1275 vs 0.0279; difference -0.0996, 95% CI -0.1299 to -0.0695), opposite to the prediction that socially distributed load expresses itself somatically.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In the same adults, load-bearing limitation, body mass index and a nine-marker allostatic load index are each associated with somatic depressive symptoms after adjusting for cognitive-affective symptoms (partial Spearman 0.1916, 0.0558, 0.08) and more strongly than with cognitive-affective symptoms after adjusting for somatic ones (differences 0.0711, 0.0399, 0.0646; Holm-adjusted p 0.002, 0.016, 0.002), whereas slow bowel transit shows no such specificity (difference 0.0074, 95% CI -0.0209 to 0.0347).

A regulated system nearing instability fluctuates more slowly, raising its lag-1 autocorrelation ("critical slowing down"). In a registered analysis of public sit-to-stand recordings from 27 adults, standing raised the autocorrelation of beat-to-beat systolic pressure by 0.0431 (CI 0.0066 to 0.0761). The rise was not larger with diabetes (probability of a larger rise 0.505, CI 0.2802 to 0.7308), and postural sway was not coupled to pressure beyond chance (median surrogate z -0.028). Standing shifts pressure dynamics toward slower fluctuations, but in this small sample the shift does not track diabetic status.

• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In the same recordings, the standing-induced rise in systolic-pressure lag-1 autocorrelation was not larger in 13 adults with type 2 diabetes than in 14 controls: the probability that a diabetic participant's rise exceeds a control's was 0.505 (bootstrap 95% CI 0.28 to 0.73; one-sided Mann-Whitney p = 0.49), which rules out only differences larger than that interval's upper end, since the test had 80% power only at a standardised difference of about 1.0.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: During eyes-open standing, magnitude-squared coherence in 0.05-0.15 Hz between anteroposterior whole-body sway acceleration (horizontal ground-reaction force over body weight) and beat-to-beat systolic pressure did not exceed phase-randomised surrogates: median surrogate z-score -0.03 across 26 participants, 2 of whom exceeded 1.645 (one-sided Wilcoxon signed-rank p = 0.54).
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: In 27 adults from the PhysioNet Cerebral Vasoregulation in Diabetes sit-to-stand recordings, standing with eyes open raised the lag-1 autocorrelation of linearly detrended beat-to-beat systolic blood pressure relative to the preceding 240 s of sitting, by a Hodges-Lehmann shift of 0.043 (bootstrap 95% CI 0.007 to 0.076), with 19 of 27 participants rising (one-sided Wilcoxon signed-rank p = 0.012; Holm-adjusted across two primary tests p = 0.025).

Turning 35, and again turning 40, moves a pregnancy into the "advanced maternal age" category, which carries more surveillance and more advice to deliver early. Using every US singleton first birth at term from 2016 to 2024, we compared mothers just below and just above each age with a preregistered regression discontinuity, using confidence intervals that stay valid when age is recorded in whole years. Labor induction jumps by 1.19 percentage points at 35 (honest 95% CI 0.7 to 1.68). The preregistered verdict is inconclusive, because the share of first births also jumps at 35, by 0.4 points. At 40, induction jumps by 2.86 points (2.05 to 3.67), and that secondary test meets its confirm rule. Delivery at 39 weeks rises at both ages. Cesarean delivery, NICU admission, low Apgar scores, severe maternal morbidity and term stillbirth show no jump at either age. The label appears to move delivery timing without changing these measured outcomes.

• Published, Reproduced.Published, Reproduced: Cesarean delivery, NICU admission, 5-minute Apgar below 7, and a maternal morbidity composite show no discontinuity at maternal age 35 (all honest 95% CIs within -0.52 to +0.76 percentage points) or at age 40 (all within -0.78 to +1.40 percentage points) among singleton first births at 37-44 weeks.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Stillbirth at 37-44 weeks among singleton first pregnancies (fetal-death and natality files 2018-2024) shows no discontinuity at maternal age 35 (0.00 percentage points, honest 95% CI -0.22 to 0.23) or 40 (-0.03, honest 95% CI -0.29 to 0.24), intervals too wide to rule out effects of the size of the baseline rate.
• Published, Reproduced, Reviewed.Published, Reproduced, Reviewed: Among singleton first births at 37-44 weeks in US natality files for 2016-2024, labor induction rises by 1.19 percentage points at maternal age 35 (honest 95% CI 0.70 to 1.68, bias bound 0.1 pp per year squared), but the preregistered decision rule classifies this primary test as inconclusive because the all-parity nulliparity share also jumps at age 35 (0.40 pp, Holm-adjusted p = 0.023).

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