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Medication-Induced Weight Change Across Common Antidepressant Treatments: A Target Trial Emulation Study: Annals of Internal Medicine: Vol 177, No 8
Background: Antidepressants are among the most commonly prescribed medications, but evidence on comparative weight change for specific first-line treatments is limited. Objective: To compare weight change across common first-line antidepressant treatments by emulating a target trial. Design: Observational cohort study over 24 months. Setting: Electronic health record (EHR) data from 2010 to 2019 across 8 U.S. health systems. Participants: 183 118 patients. Measurements: Prescription data determined initiation of treatment with sertraline, citalopram, escitalopram, fluoxetine, paroxetine, bupropion, duloxetine, or venlafaxine. The investigators estimated the population-level effects of initiating each treatment, relative to sertraline, on mean weight change (primary) and the probability of gaining at least 5% of baseline weight (secondary) 6 months after initiation. Inverse probability weighting of repeated outcome marginal structural models was used to account for baseline confounding and informative outcome measurement. In secondary analyses, the effects of initiating and adhering to each treatment protocol were estimated. Results: Compared with that for sertraline, estimated 6-month weight gain was higher for escitalopram (difference, 0.41 kg [95% CI, 0.31 to 0.52 kg]), paroxetine (difference, 0.37 kg [CI, 0.20 to 0.54 kg]), duloxetine (difference, 0.34 kg [CI, 0.22 to 0.44 kg]), venlafaxine (difference, 0.17 kg [CI, 0.03 to 0.31 kg]), and citalopram (difference, 0.12 kg [CI, 0.02 to 0.23 kg]); similar for fluoxetine (difference, −0.07 kg [CI, −0.19 to 0.04 kg]); and lower for bupropion (difference, −0.22 kg [CI, −0.33 to −0.12 kg]). Escitalopram, paroxetine, and duloxetine were associated with 10% to 15% higher risk for gaining at least 5% of baseline weight, whereas bupropion was associated with 15% reduced risk. When the effects of initiation and adherence were estimated, associations were stronger but had wider CIs. Six-month adherence ranged from 28% (duloxetine) to 41% (bupropion). Limitation: No data on medication dispensing, low medication adherence, incomplete data on adherence, and incomplete data on weight measures across time points. Conclusion: Small differences in mean weight change were found between 8 first-line antidepressants, with bupropion consistently showing the least weight gain, although adherence to medications over follow-up was low. Clinicians could consider potential weight gain when initiating antidepressant treatment. Primary Funding Source: National Institutes of Health.
One Hundred Years of Colposcopy: Reconciling Its Auschwitz Past
The centennial anniversary of Hans Hinselmann’s initial publication describing colposcopy is approaching. In the 100 years since the inventor’s seminal paper, colposcopy has become indispensable in the diagnosis and management of cervical cancer. It remains central in diagnosing precancerous and cancerous cervical lesions and has dramatically reduced cervical cancer incidence and mortality since the mid-20th century. Previous descriptions of colposcopy’s development in medical literature obscure the dark history of its earliest days, arising within the center of German Nazism. The pioneers of colposcopy benefited from the Nazi government’s public health focus and exploited the environment fostered by the Nazi medical establishment. They made use of the apparatus of the Auschwitz concentration camp to position colposcopy for expanded postwar adoption, ultimately accomplishing Hinselmann’s stated goal that colposcopy become a routine part of gynecologic examination and care. This historical exposition clarifies the Nazi past of colposcopy, highlights the important role that unethical treatment of victims of Auschwitz played in cementing this procedure within standard cervical cancer screening programs globally, and offers steps to reckon with this tragic legacy.
Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination: A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial: Annals of Internal Medicine: Vol 177, No 4
Background: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. Objective: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. Design: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004) Setting: The 2022 to 2023 influenza season. Participants: 964 870 Danish citizens aged 65 years or older. Intervention: Usual care or 9 different electronically delivered behavioral nudging letters. Measurements: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. Results: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). Limitation: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. Conclusion: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. Primary Funding Source: Sanofi.
Long-Term Effect of Salt Substitution for Cardiovascular Outcomes: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 177, No 5
Background: Salt substitution is a simple yet increasingly promising strategy to improve cardiovascular outcomes. Purpose: To evaluate the long-term effects of salt substitution on cardiovascular outcomes. Data Sources: PubMed, EMBASE, Cochrane CENTRAL, and CINAHL searched from inception to 23 August 2023. Trial registries, citation analysis, and hand-search were also done. Study Selection: Randomized controlled trials (RCTs) comparing provision of or advice to use a salt substitute with no intervention or use of regular salt among adults for 6 months or longer in total study duration. Data Extraction: Two authors independently screened articles, extracted data, and assessed risk of bias. Primary outcomes include mortality, major cardiovascular events (MACE), and adverse events at 6 months or greater. Secondary and post hoc outcomes include blood pressure, cause-specific mortality, and urinary excretion at 6 months or greater. Random-effects meta-analyses were done and certainty of effect estimates were assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). Data Synthesis: Of the 16 included RCTs, 8 reported on primary outcomes. Most (n = 7 of 8) were done in China or Taiwan, 3 were done in residential facilities, and 7 included populations of older age (average 62 years) and/or with higher-than-average cardiovascular risk. In this population, salt substitute may reduce risk for all-cause mortality (6 RCTs; 27 710 participants; rate ratio [RR], 0.88 [95% CI, 0.82 to 0.93]; low certainty) and cardiovascular mortality (4 RCTs; 25 050 participants; RR, 0.83 [CI, 0.73 to 0.95]; low certainty). Salt substitute may result in a slight reduction in MACE (3 RCTs; 23 215 participants; RR, 0.85 [CI, 0.71 to 1.00]; very low certainty), with very low-certainty evidence of serious adverse events (6 RCTs; 27 995 participants; risk ratio, 1.04 [CI, 0.87 to 1.25]) Limitations: The evidence base is dominated by a single, large RCT. Most RCTs were from China or Taiwan and involved participants with higher-than-average cardiovascular risk; therefore, generalizability to other populations is very limited. Conclusion: Salt substitution may reduce all-cause or cardiovascular mortality, but the evidence for reducing cardiovascular events and for not increasing serious adverse events is uncertain, particularly for a Western population. The certainty of evidence is higher among populations at higher cardiovascular risk and/or following a Chinese diet. Primary Funding Source: National Health and Medical Research Council. (PROSPERO: CRD42022327566)
Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women: Postintervention Follow-up of a Randomized Clinical Trial: Annals of Internal Medicine: Vol 177, No 4
Background: Although calcium and vitamin D (CaD) supplementation may affect chronic disease in older women, evidence of long-term effects on health outcomes is limited. Objective: To evaluate long-term health outcomes among postmenopausal women in the Women’s Health Initiative CaD trial. Design: Post hoc analysis of long-term postintervention follow-up of the 7-year randomized intervention trial of CaD. (ClinicalTrials.gov: NCT00000611) Setting: A multicenter (n = 40) trial across the United States. Participants: 36 282 postmenopausal women with no history of breast or colorectal cancer. Intervention: Random 1:1 assignment to 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D3 daily or placebo. Measurements: Incidence of colorectal, invasive breast, and total cancer; disease-specific and all-cause mortality; total cardiovascular disease (CVD); and hip fracture by randomization assignment (through December 2020). Analyses were stratified on personal supplement use. Results: For women randomly assigned to CaD versus placebo, a 7% reduction in cancer mortality was observed after a median cumulative follow-up of 22.3 years (1817 vs. 1943 deaths; hazard ratio [HR], 0.93 [95% CI, 0.87 to 0.99]), along with a 6% increase in CVD mortality (2621 vs. 2420 deaths; HR, 1.06 [CI, 1.01 to 1.12]). There was no overall effect on other measures, including all-cause mortality (7834 vs. 7748 deaths; HR, 1.00 [CI, 0.97 to 1.03]). Estimates for cancer incidence varied widely when stratified by whether participants reported supplement use before randomization, whereas estimates on mortality did not vary, except for CVD mortality. Limitation: Hip fracture and CVD outcomes were available on only a subset of participants, and effects of calcium versus vitamin D versus joint supplementation could not be disentangled. Conclusion: Calcium and vitamin D supplements seemed to reduce cancer mortality and increase CVD mortality after more than 20 years of follow-up among postmenopausal women, with no effect on all-cause mortality. Primary Funding Source: National Heart, Lung, and Blood Institute of the National Institutes of Health.
The Benefits and Risks of Receiving Investigational Solid Tumor Drugs in Randomized Trials: A Systematic Review and Meta-analysis: Annals of Internal Medicine: Vol 177, No 6
Background: Many patients participate in cancer trials to access new therapies. The extent to which new treatments produce clinical benefit for trial participants is unclear. Purpose: To estimate the progression-free survival (PFS) and overall survival (OS) advantage of assignment to experimental groups in randomized trials for 6 solid tumors. Data Sources: ClinicalTrials.gov was searched for trials of investigational drugs with results posted between 2017 and 2021. Study Selection: Investigational drugs were defined as those not yet having full approval from the U.S. Food and Drug Administration for the study indication. Trials were included if they were randomized and tested drugs or biologics. Data Extraction: Data extraction was completed by 2 independent reviewers. Data were pooled using a random-effects model. Data Synthesis: The sample included 128 trials comprising 141 comparisons of a new drug and a comparator. These comparisons included 47 050 patients. The pooled hazard ratio for PFS was 0.80 (95% CI, 0.75 to 0.85), indicating statistically significant benefit for patients in experimental groups. This corresponded to a median PFS advantage of 1.25 months (CI, 0.80 to 1.68 months). The pooled hazard ratio for OS was 0.92 (CI, 0.88 to 0.95), corresponding to a survival gain of 1.18 months (CI, 0.72 to 1.71 months). The absolute risk for a serious adverse event for comparator group patients was 29.56% (CI, 26.64% to 32.65%), with an increase in risk of 7.40% (CI, 5.66% to 9.14%) for patients in experimental groups. Limitations: Trials in this sample were heterogeneous. Comparator group interventions were assumed to reflect standard of care. Conclusion: Assignment to experimental groups produces statistically significant survival gains. However, the absolute survival gain is small, and toxicity is statistically significantly greater. The findings of this review provide reassuring evidence that patients are not meaningfully disadvantaged by assignment to comparator groups. Primary Funding Source: Canadian Institutes of Health Research.
Diagnostic Discordance, Uncertainty, and Treatment Ambiguity in Community-Acquired Pneumonia: A National Cohort Study of 115 U.S. Veterans Affairs Hospitals: Annals of Internal Medicine: Vol 177, No 9
Background: Evidence-based practice in community-acquired pneumonia often assumes an accurate initial diagnosis. Objective: To examine the evolution of pneumonia diagnoses among patients hospitalized from the emergency department (ED). Design: Retrospective nationwide cohort. Setting: 115 U.S. Veterans Affairs medical centers. Patients: Aged 18 years or older and hospitalized from the ED between 1 January 2015 and 31 January 2022. Measurements: Discordances between initial pneumonia diagnosis, discharge diagnosis, and radiographic diagnosis identified by natural language processing of clinician text, diagnostic coding, and antimicrobial treatment. Expressions of uncertainty in clinical notes, patient illness severity, treatments, and outcomes were compared. Results: Among 2 383 899 hospitalizations, 13.3% received an initial or discharge diagnosis and treatment of pneumonia: 9.1% received an initial diagnosis and 10.0% received a discharge diagnosis. Discordances between initial and discharge occurred in 57%. Among patients discharged with a pneumonia diagnosis and positive initial chest image, 33% lacked an initial diagnosis. Among patients diagnosed initially, 36% lacked a discharge diagnosis and 21% lacked positive initial chest imaging. Uncertainty was frequently expressed in clinical notes (58% in ED; 48% at discharge); 27% received diuretics, 36% received corticosteroids, and 10% received antibiotics, corticosteroids, and diuretics within 24 hours. Patients with discordant diagnoses had greater uncertainty and received more additional treatments, but only patients lacking an initial pneumonia diagnosis had higher 30-day mortality than concordant patients (14.4% [95% CI, 14.1% to 14.7%] vs. 10.6% [CI, 10.4% to 10.7%]). Patients with diagnostic discordance were more likely to present to high-complexity facilities with high ED patient load and inpatient census. Limitation: Retrospective analysis; did not examine causal relationships. Conclusion: More than half of all patients hospitalized and treated for pneumonia had discordant diagnoses from initial presentation to discharge. Treatments for other diagnoses and expressions of uncertainty were common. These findings highlight the need to recognize diagnostic uncertainty and treatment ambiguity in research and practice of pneumonia-related care. Primary Funding Source: The Gordon and Betty Moore Foundation.