Association Between False-Positive Results and Return to Screening Mammography in the Breast Cancer Surveillance Consortium Cohort

Background: False-positive results on screening mammography may affect women’s willingness to return for future screening. Objective: To evaluate the association between screening mammography results and the probability of subsequent screening. Design: Cohort study. Setting: 177 facilities participating in the Breast Cancer Surveillance Consortium (BCSC). Patients: 3 529 825 screening mammograms (3 184 482 true negatives and 345 343 false positives) performed from 2005 to 2017 among 1 053 672 women aged 40 to 73 years without a breast cancer diagnosis. Measurements: Mammography results (true-negative result or false-positive recall with a recommendation for immediate additional imaging only, short-interval follow-up, or biopsy) from 1 or 2 screening mammograms. Absolute differences in the probability of returning for screening within 9 to 30 months of false-positive versus true-negative screening results were estimated, adjusting for race, ethnicity, age, time since last mammogram, BCSC registry, and clustering within women and facilities. Results: Women were more likely to return after a true-negative result (76.9% [95% CI, 75.1% to 78.6%]) than after a false-positive recall for additional imaging only (adjusted absolute difference, −1.9 percentage points [CI, −3.1 to −0.7 percentage points]), short-interval follow-up (−15.9 percentage points [CI, −19.7 to −12.0 percentage points]), or biopsy (−10.0 percentage points [CI, −14.2 to −5.9 percentage points]). Asian and Hispanic/Latinx women had the largest decreases in the probability of returning after a false positive with a recommendation for short-interval follow-up (−20 to −25 percentage points) or biopsy (−13 to −14 percentage points) versus a true negative. Among women with 2 screening mammograms within 5 years, a false-positive result on the second was associated with a decreased probability of returning for a third regardless of the first screening result. Limitation: Women could receive care at non-BCSC facilities. Conclusion: Women were less likely to return to screening after false-positive mammography results, especially with recommendations for short-interval follow-up or biopsy, raising concerns about continued participation in routine screening among these women at increased breast cancer risk. Primary Funding Source: National Cancer Institute.

Comparative Performance of Common Fecal Immunochemical Tests: A Cross-Sectional Study: Annals of Internal Medicine: Vol 177, No 10

Background: Despite widespread use of fecal immunochemical tests (FITs) for colorectal cancer (CRC) screening, data to guide test selection are limited. Objective: To compare the performance characteristics of 5 commonly used FITs, using colonoscopy as the reference standard. Design: Cross-sectional study. (ClinicalTrials.gov: NCT03264898) Setting: Three U.S. academic medical centers and affiliated endoscopy units. Participants: Patients aged 50 to 85 years undergoing screening or surveillance colonoscopy. Intervention: Participants completed 5 different FITs before their colonoscopy, including 4 qualitative tests (Hemoccult ICT, Hemosure iFOB, OC-Light S FIT, QuickVue iFOB) and 1 quantitative test (OC-Auto FIT, which was run at the manufacturer's threshold for positivity of >100 ng/mL). Measurements: The primary outcome was test performance (sensitivity and specificity) for each of the 5 FITs for advanced colorectal neoplasia (ACN), defined as advanced polyps or CRC. Positivity rates, positive and negative predictive values, and rates of unevaluable tests were compared. Multivariable models were used to identify factors affecting sensitivity. Results: A total of 3761 participants were enrolled, with a mean age of 62.1 years (SD, 7.8); 63.2% of participants were female, 5.7% were Black, 86.4% were White, and 28.7% were Hispanic. There were 320 participants with ACN (8.5%), including 9 with CRC (0.2%). The test positivity rate varied 4-fold (3.9% to 16.4%) across FITs. Rates of unevaluable FITs ranged from 0.2% to 2.5%. The sensitivity for ACN varied from 10.1% to 36.7%, and specificity varied from 85.5% to 96.6%. Differences in sensitivity between FITs were all statistically significantly different except between Hemosure iFOB and QuickVue iFOB, and specificity differences were all statistically significantly different from one another. In addition to FIT brand, distal location of ACN was also associated with higher FIT sensitivity. Limitation: The study did not assess the programmatic sensitivity of annual FIT. Conclusion: Although considered a single class, FITs have varying test performance for detecting ACN and should not be considered interchangeable. Primary Funding Source: National Institutes of Health.

The Effect of Denosumab on Risk for Emergently Treated Hypocalcemia by Stage of Chronic Kidney Disease: A Target Trial Emulation: Annals of Internal Medicine: Vol 178, No 1

Background: There is a paucity of data on treatment of osteoporosis in patients with advanced chronic kidney disease (CKD). Objective: To assess the risk for emergently treated hypocalcemia with denosumab by stage of CKD and presence of CKD–mineral and bone disorder (CKD-MBD). Design: Target trial emulation. Setting: Medicare fee-for-service data with prescription drug coverage, 2012 to 2020. Participants: Female patients aged 65 years or older initiating denosumab, oral bisphosphonates, or intravenous (IV) bisphosphonates for osteoporosis. Measurements: Hospital and emergency department admissions (that is, emergent care) for hypocalcemia were assessed in the first 12 treatment weeks. Inverse probability of treatment weighted cumulative incidence and weighted risk differences (RDs) were calculated. Results: A total of 361 453 patients treated with denosumab, 829 044 treated with oral bisphosphonates, and 160 413 treated with IV bisphosphonates were identified. Risk for emergently treated hypocalcemia with denosumab versus oral bisphosphonates increased with worsening CKD stage (P < 0.001), with greatest risk among dialysis-dependent (DD) patients (3.01% vs. 0.00%; RD, 3.01% [95% CI, 2.27% to 3.77%]) and non–dialysis-dependent (NDD) patients with CKD stages 4 and 5 (0.57% vs. 0.03%; RD, 0.54% [CI, 0.41% to 0.68%]). Among patients with stages 4 and 5 CKD (NDD + DD), denosumab had a greater risk for emergently treated hypocalcemia versus oral bisphosphonates in those with CKD-MBD (1.53% vs. 0.02%; RD, 1.51% [CI, 1.21% to 1.78%]) than in those without CKD-MBD (0.22% vs. 0.03%; RD, 0.19% [CI, 0.08% to 0.31%]). Denosumab also showed increased risk compared with IV bisphosphonates. Limitation: Generalizability to men and non-Medicare populations. Conclusion: Risk for emergently treated hypocalcemia with denosumab increased with worsening CKD stage and was highest in DD patients and those with CKD-MBD. Primary Funding Source: U.S. Food and Drug Administration.

Benefits and Risks Associated With Statin Therapy for Primary Prevention in Old and Very Old Adults: Real-World Evidence From a Target Trial Emulation Study: Annals of Internal Medicine: Vol 177, No 6

Background: There is little consensus on using statins for primary prevention of cardiovascular diseases (CVDs) and all-cause mortality in adults aged 75 years or older due to the underrepresentation of this population in randomized controlled trials. Objective: To investigate the benefits and risks of using statins for primary prevention in old (aged 75 to 84 years) and very old (aged ≥85 years) adults. Design: Sequential target trial emulation comparing matched cohorts initiating versus not initiating statin therapy. Setting: Territory-wide public electronic medical records in Hong Kong. Participants: Persons aged 75 years or older who met indications for statin initiation from January 2008 to December 2015 were included. Participants with preexisting diagnosed CVDs at baseline, such as coronary heart disease (CHD), were excluded from the analysis. Among 69 981 eligible persons aged 75 to 84 years and 14 555 persons aged 85 years or older, 41 884 and 9457 had history of CHD equivalents (for example, diabetes) in the respective age groups. Intervention: Initiation of statin therapy. Measurements: Incidence of major CVDs (stroke, myocardial infarction, or heart failure), all-cause mortality, and major adverse events (myopathies and liver dysfunction). Results: Of 42 680 matched person-trials aged 75 to 84 years and 5390 matched person-trials aged 85 years or older (average follow-up, 5.3 years), 9676 and 1600 of them developed CVDs in each age group, respectively. Risk reduction for overall CVD incidence was found for initiating statin therapy in adults aged 75 to 84 years (5-year standardized risk reduction, 1.20% [95% CI, 0.57% to 1.82%] in the intention-to-treat [ITT] analysis; 5.00% [CI, 1.11% to 8.89%] in the per protocol [PP] analysis) and in those aged 85 years or older (ITT: 4.44% [CI, 1.40% to 7.48%]; PP: 12.50% [CI, 4.33% to 20.66%]). No significantly increased risks for myopathies and liver dysfunction were found in both age groups. Limitation: Unmeasured confounders, such as lifestyle factors of diet and physical activity, may exist. Conclusion: Reduction for CVDs after statin therapy were seen in patients aged 75 years or older without increasing risks for severe adverse effects. Of note, the benefits and safety of statin therapy were consistently found in adults aged 85 years or older. Primary Funding Source: Health Bureau, the Government of Hong Kong Special Administrative Region, China, and National Natural Science Foundation of China.

The Effect of Open-Label Semaglutide on Metabolic Dysfunction–Associated Steatotic Liver Disease in People With HIV

Efficacy of Voluntary Medical Male Circumcision to Prevent HIV Infection Among Men Who Have Sex With Men: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 177, No 6

Background: Observational studies suggest that voluntary medical male circumcision (VMMC) may lower HIV risk among men who have sex with men (MSM). A randomized controlled trial (RCT) is needed to confirm this. Objective: To assess the efficacy of VMMC in preventing incident HIV infection among MSM. Design: An RCT with up to 12 months of follow-up. (Chinese Clinical Trial Registry: ChiCTR2000039436) Setting: 8 cities in China. Participants: Uncircumcised, HIV-seronegative men aged 18 to 49 years who self-reported predominantly practicing insertive anal intercourse and had 2 or more male sex partners in the past 6 months. Intervention: VMMC. Measurements: Rapid testing for HIV was done at baseline and at 3, 6, 9, and 12 months. Behavioral questionnaires and other tests for sexually transmitted infections were done at baseline, 6 months, and 12 months. The primary outcome was HIV seroconversion using an intention-to-treat analysis. Results: The study enrolled 124 men in the intervention group and 123 in the control group, who contributed 120.7 and 123.1 person-years of observation, respectively. There were 0 seroconversions in the intervention group (0 infections [95% CI, 0.0 to 3.1 infections] per 100 person-years) and 5 seroconversions in the control group (4.1 infections [CI, 1.3 to 9.5 infections] per 100 person-years). The HIV hazard ratio was 0.09 (CI, 0.00 to 0.81; P = 0.029), and the HIV incidence was lower in the intervention group (log-rank P = 0.025). The incidence rates of syphilis, herpes simplex virus type 2, and penile human papillomavirus were not statistically significantly different between the 2 groups. There was no evidence of HIV risk compensation. Limitation: Few HIV seroconversions and limited follow-up period. Conclusion: Among MSM who predominantly practice insertive anal intercourse, VMMC is efficacious in preventing incident HIV infection; MSM should be included in VMMC guidelines. Primary Funding Source: The National Science and Technology Major Project of China.

Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers for Advanced Chronic Kidney Disease: A Systematic Review and Retrospective Individual Participant–Level Meta-analysis of Clinical Trials: Annals of Internal Medicine: Vol 177, No 7

Background: In patients with advanced chronic kidney disease (CKD), the effects of initiating treatment with an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin-receptor blocker (ARB) on the risk for kidney failure with replacement therapy (KFRT) and death remain unclear. Purpose: To examine the association of ACEi or ARB treatment initiation, relative to a non–ACEi or ARB comparator, with rates of KFRT and death. Data Sources: Ovid Medline and the Chronic Kidney Disease Epidemiology Collaboration Clinical Trials Consortium from 1946 through 31 December 2023. Study Selection: Completed randomized controlled trials testing either an ACEi or an ARB versus a comparator (placebo or antihypertensive drugs other than ACEi or ARB) that included patients with a baseline estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73 m2. Data Extraction: The primary outcome was KFRT, and the secondary outcome was death before KFRT. Analyses were done using Cox proportional hazards models according to the intention-to-treat principle. Prespecified subgroup analyses were done according to baseline age (<65 vs. ≥65 years), eGFR (<20 vs. ≥20 mL/min/1.73 m2), albuminuria (urine albumin–creatinine ratio <300 vs. ≥300 mg/g), and history of diabetes. Data Synthesis: A total of 1739 participants from 18 trials were included, with a mean age of 54.9 years and mean eGFR of 22.2 mL/min/1.73 m2, of whom 624 (35.9%) developed KFRT and 133 (7.6%) died during a median follow-up of 34 months (IQR, 19 to 40 months). Overall, ACEi or ARB treatment initiation led to lower risk for KFRT (adjusted hazard ratio, 0.66 [95% CI, 0.55 to 0.79]) but not death (hazard ratio, 0.86 [CI, 0.58 to 1.28]). There was no statistically significant interaction between ACEi or ARB treatment and age, eGFR, albuminuria, or diabetes (P for interaction > 0.05 for all). Limitation: Individual participant–level data for hyperkalemia or acute kidney injury were not available. Conclusion: Initiation of ACEi or ARB therapy protects against KFRT, but not death, in people with advanced CKD. Primary Funding Source: National Institutes of Health. (PROSPERO: CRD42022307589)

Progressive Resistance Training or Neuromuscular Exercise for Hip Osteoarthritis: A Multicenter Cluster Randomized Controlled Trial: Annals of Internal Medicine: Vol 177, No 5

Background: Exercise is recommended as first-line treatment for patients with hip osteoarthritis (OA). However, randomized controlled trials providing evidence for the optimal exercise type are lacking. Objective: To investigate whether progressive resistance training (PRT) is superior to neuromuscular exercise (NEMEX) for improving functional performance in patients with hip OA. Design: Multicenter, cluster-randomized, controlled, parallel-group, assessor-blinded, superiority trial. (ClinicalTrials.gov: NCT04714047) Setting: Hospitals and physiotherapy clinics. Participants: 160 participants with clinically diagnosed hip OA were enrolled from 18 January 2021 to 28 April 2023 and randomly assigned to PRT (n = 82) or NEMEX (n = 78). Intervention: Twelve weeks of PRT or NEMEX with 2 supervised 60-minute group sessions each week. The PRT intervention consisted of 5 high-intensity resistance training exercises targeting muscles at the hip and knee joints. The NEMEX intervention included 10 exercises and emphasized sensorimotor control and functional stability. Measurements: The primary outcome was change in the 30-second chair stand test (30s-CST). Key secondary outcomes were changes in scores on the pain and hip-related quality of life (QoL) subscales of the Hip Disability and Osteoarthritis Outcome Score (HOOS). Results: The mean changes from baseline to 12-week follow-up in the 30s-CST were 1.5 (95% CI, 0.9 to 2.1) chair stands with PRT and 1.5 (CI, 0.9 to 2.1) chair stands with NEMEX (difference, 0.0 [CI, −0.8 to 0.8] chair stands). For the HOOS pain subscale, mean changes were 8.6 (CI, 5.3 to 11.8) points with PRT and 9.3 (CI, 5.9 to 12.6) points with NEMEX (difference, −0.7 [CI, −5.3 to 4.0] points). For the HOOS QoL subscale, mean changes were 8.0 (CI, 4.3 to 11.7) points with PRT and 5.7 (CI, 1.9 to 9.5) points with NEMEX (difference, 2.3 [CI, −3.0 to 7.6] points). Limitation: Participants and physiotherapists were not blinded. Conclusion: In patients with hip OA, PRT is not superior to NEMEX for improving functional performance, hip pain, or hip-related QoL. Primary Funding Source: Independent Research Fund Denmark.

Sodium–Glucose Cotransporter-2 Inhibitors, Dulaglutide, and Risk for Dementia: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 177, No 10

Background: Both sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may have neuroprotective effects in patients with type 2 diabetes (T2D). However, their comparative effectiveness in preventing dementia remains uncertain. Objective: To compare the risk for dementia between SGLT2 inhibitors and dulaglutide (a GLP-1 RA). Design: Target trial emulation study. Setting: Nationwide health care data of South Korea obtained from the National Health Insurance Service between 2010 and 2022. Patients: Patients aged 60 years or older who have T2D and are initiating treatment with SGLT2 inhibitors or dulaglutide. Measurements: The primary outcome was the presumed clinical onset of dementia. The date of onset was defined as the year before the date of dementia diagnosis, assuming that the time between the onset of dementia and diagnosis was 1 year. The 5-year risk ratios and risk differences comparing SGLT2 inhibitors with dulaglutide were estimated in a 1:2 propensity score–matched cohort adjusted for confounders. Results: Overall, 12 489 patients initiating SGLT2 inhibitor treatment (51.9% dapagliflozin and 48.1% empagliflozin) and 1075 patients initiating dulaglutide treatment were included. In the matched cohort, over a median follow-up of 4.4 years, the primary outcome event occurred in 69 participants in the SGLT2 inhibitor group and 43 in the dulaglutide group. The estimated risk difference was −0.91 percentage point (95% CI, −2.45 to 0.63 percentage point), and the estimated risk ratio was 0.81 (CI, 0.56 to 1.16). Limitation: Residual confounding is possible; there was no adjustment for hemoglobin A1c levels or duration of diabetes; the study is not representative of newer drugs, including more effective GLP-1 RAs; and the onset of dementia was not measured directly. Conclusion: Under conventional statistical criteria, a risk for dementia between 2.5 percentage points lower and 0.6 percentage point greater for SGLT2 inhibitors than for dulaglutide was estimated to be highly compatible with the data from this study. However, whether these findings generalize to newer GLP-1 RAs is uncertain. Thus, further studies incorporating newer drugs within these drug classes and better addressing residual confounding are required. Primary Funding Source: Ministry of Food and Drug Safety of South Korea.

Effect of Weight Loss Interventions on the Symptomatic Burden and Biomarkers of Polycystic Ovary Syndrome: A Systematic Review of Randomized Controlled Trials: Annals of Internal Medicine: Vol 177, No 12

Background: Polycystic ovary syndrome (PCOS) is common in women of reproductive age and is associated with obesity. Clinical guidelines recommend weight loss, but the impact on the clinical manifestations of PCOS is unclear. Purpose: To quantify the effect of weight loss interventions on clinical features of PCOS, compared with usual care. Data Sources: MEDLINE, Embase, PsycINFO, CINAHL, Cochrane, Web of Science, and trial registries were searched from inception through June 2024. Study Selection: Randomized controlled trials comparing interventions aiming to reduce weight against usual care, including lower-intensity weight loss interventions in people with PCOS. Conversations with people with PCOS informed the outcomes. Data Extraction: Pairs of independent reviewers screened studies, extracted data, and assessed risk of bias (RoB). Outcomes included glycemic control (Homeostasis Model Assessment for Insulin Resistance [HOMA-IR], fasting insulin and glucose), hormonal markers (free androgen index [FAI] and other sex hormones), menstrual frequency, hirsutism, and PCOS-related quality of life (QoL). Pooled mean differences were obtained from random-effects meta-analysis with Knapp–Hartung adjustment. Data Synthesis: Primary analyses included 29 comparisons with 1529 participants: 13, 12, and 4 comparisons were judged as high, some, or low RoB, respectively. Twelve used behavioral interventions, 9 used glucagon-like peptide-1 (GLP1) agonists, and 8 used other weight loss medications. Weight loss interventions were associated with significantly greater improvements in HOMA-IR (mean difference, −0.45 [−0.75 to −0.15]; I 2 = 24%), FAI (mean difference, −2.03 [−3.0 to −1.07]; I 2 = 48%), and menstrual frequency (mean difference, 2.64 [0.65 to 4.63]; I2  = 43%). There was no evidence that weight loss interventions were associated with clinically or statistically significant improvements in hirsutism, QoL, or other sex hormones, which may be due to the limited power of the available data. Limitation: There was high statistical heterogeneity in the interventions, comparators, and outcomes, largely unexplained by sensitivity and subgroup analyses. Conclusion: Weight loss interventions were associated with improvements in some important features of PCOS and should be considered as a routine treatment option for people with PCOS. Primary Funding Source: National Institute for Health and Care Research School for Primary Care Research. (PROSPERO: CRD42022367488)