IMPORTANCE: Clinical trials evaluating population-based screening tests or other interventions likely to affect care delivery in real-world settings often do not consider spillover effects, such as whether the interventi...IMPORTANCE: Clinical trials evaluating population-based screening tests or other interventions likely to affect care delivery in real-world settings often do not consider spillover effects, such as whether the intervention rollout affects access to limited health care services. OBJECTIVE: To examine whether regional participation in a population-based screening trial (NHS-Galleri) of a cell-free DNA-based multicancer early detection (MCED) test was associated with changes in cancer diagnostic delay rates. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of all 21 cancer alliance regions in England, 8 of which participated in the population-based MCED screening trial. An event study using difference-in-differences design evaluated changes from 6 months before (April 2021) to 3 years after trial start (September 2024). EXPOSURES: Regional participation in the population-based MCED screening trial. MAIN OUTCOMES AND MEASURES: The primary outcome was diagnostic delay rates (percentage of patients referred for suspected cancer evaluation taking longer than 28 days to reach diagnostic resolution), a surrogate measure for system-level spillover effects; the secondary outcome was patient referral rates. Analysis focused on a primary group of 3 cancer types (head and neck, lung, and upper gastrointestinal) that were identified in the trial protocol and were not subject to routine screening. RESULTS: Overall, 1 875 236 patient referrals for suspected head and neck, lung, or upper gastrointestinal cancers were recorded across all 21 regions. In the first 6 months of the population-based screening trial, diagnostic delay rates increased in participating regions (28.6% before trial start and 29.6% after) and decreased in nonparticipating regions (28.9% to 26.3%), an adjusted difference-in-differences estimate of 3.4 percentage points (95% CI, 1.9-5.0; P < .001). This increase persisted during the second 6-month period (adjusted difference-in-differences estimate of 4.8 percentage points [95% CI, 1.9-7.7; P = .003]) and was no longer statistically significant thereafter. Patient referral rates for suspected head and neck, lung, and upper gastrointestinal cancers were also higher in participating regions in the first 6 months (adjusted difference-in-differences estimate of 23.8 per 100 000 population [95% CI, 0.9-46.8; P = .04]). CONCLUSIONS AND RELEVANCE: Regional participation in a population-based MCED screening trial was associated with a modest increase in diagnostic delay rates for patients referred for suspected head and neck, lung, and upper gastrointestinal cancers. This increase is unlikely to have materially affected interpretation of the MCED screening trial primary findings. Future trials of population-based screening interventions likely to affect demand for limited health care resources should consider monitoring for system-level spillover effects.
IMPORTANCE: Male hypogonadism is a clinical syndrome of signs and symptoms of testosterone deficiency and consistently low morning serum testosterone concentrations. The prevalence of hypogonadism due to hypothalamus, pi...IMPORTANCE: Male hypogonadism is a clinical syndrome of signs and symptoms of testosterone deficiency and consistently low morning serum testosterone concentrations. The prevalence of hypogonadism due to hypothalamus, pituitary, or testes pathology is less than 1%, and the prevalence due to obesity (body mass index ≥30) is from 2% to 8%. OBSERVATIONS: The most common signs and symptoms of hypogonadism are decreased libido, decreased spontaneous erections, and small testes. Primary hypogonadism is characterized by deficient testicular production of testosterone despite elevated luteinizing hormone (LH) concentrations. The most common cause of primary hypogonadism is Klinefelter syndrome (≥2 X chromosomes and 1 Y chromosome), which affects 2 in 1000 men and is frequently undiagnosed. Secondary hypogonadism is caused by hypothalamic or pituitary dysfunction and is characterized by low testosterone concentrations and low or inappropriately normal LH and follicle-stimulating hormone (FSH) concentrations. The most common permanent causes of secondary hypogonadism are head and neck radiation and severe head trauma. The most common potentially reversible causes of secondary hypogonadism are obesity, severe illness, and medication use (opioids, corticosteroids, checkpoint inhibitors, and medications that cause hyperprolactinemia). Testing for hypogonadism is reserved for men with signs and symptoms of androgen deficiency. Hypogonadism is confirmed if an individual's serum testosterone concentration is less than 264 to 300 ng/dL in at least 2 fasting samples collected between 7 and 10 am and measured with an accurate and external quality-controlled assay. Assessment of calculated free testosterone concentration derived using total testosterone and sex hormone-binding globulin (SHBG) concentrations is necessary for men with obesity, diabetes, and other conditions that cause low serum SHBG concentrations. Patients diagnosed with hypogonadism should have serum FSH and LH concentrations measured to distinguish primary from secondary hypogonadism. For men with obesity-induced hypogonadism, the recommended first-line management is weight loss. In men with obesity, weight loss of at least 5% typically increases serum total testosterone concentration significantly, and weight loss is associated with improved physical function, libido, and erectile function. Men with permanent hypogonadism, or those unable to discontinue medications that cause hypogonadism, may be treated with testosterone. The testosterone formulation (injection, gel, or pill) and dosage should be individualized with monitoring of serum testosterone concentration, hematocrit percentage, and possibly prostate-specific antigen concentration. CONCLUSIONS AND RELEVANCE: Primary hypogonadism affects less than 1% of men, whereas secondary hypogonadism due to obesity (body mass index ≥30) occurs in 2% to 8%. First-line treatment for obesity-induced hypogonadism is weight loss. Testosterone therapy should be initiated for men with permanent hypogonadism or those who are unable to discontinue medications that cause hypogonadism.
Wang N, Van Der Hoorn S, Pant R
… +13 more, Kumar A, Dhurjatic R, Haghdoost F, Abhayaratna C, Egan B, Schutte AE, Berwanger O, Patel A, Schlaich M, Rahimi K, Whelton PK, Rodgers A, Salam A
IMPORTANCE: Adverse drug effects from blood pressure (BP)-lowering drugs contribute to significant undertreatment and poor overall BP control rates. OBJECTIVE: To review adverse effects and discontinuation of BP-lowering...IMPORTANCE: Adverse drug effects from blood pressure (BP)-lowering drugs contribute to significant undertreatment and poor overall BP control rates. OBJECTIVE: To review adverse effects and discontinuation of BP-lowering drugs and their combinations from the 5 major classes in short-term clinical trials. DATA SOURCES AND STUDY SELECTION: Cochrane Central Register of Controlled Trials for randomized clinical trials, MEDLINE, and Epistemonikos were searched from the date of inception until December 31, 2024, for double-blind randomized clinical trials of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers (ARBs), β-blockers, calcium channel blockers (CCBs), thiazide and thiazide-like diuretics, or their combinations, with follow-up durations between 4 and 26 weeks. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed by 2 independent reviewers. Synthesis was performed using fixed-effect network meta-analyses according to drug class, summarized using odds ratios (ORs) and 95% credible intervals (CrIs) and surface under the cumulative ranking curves. Final statistical analysis was conducted in April 2026. MAIN OUTCOMES AND MEASURES: Treatment discontinuation due to adverse events (AEs), defined as discontinuation of randomized treatment due to an AE. Secondary outcomes included headache, dizziness, edema, and cough. RESULTS: A total of 716 trials were included, with mean (SD) follow-up of 8.6 (5) weeks, including 159 362 participants (mean [SD] age, 54.6 [7] years; 44% female; mean baseline BP, 158/100 mm Hg). Compared with placebo, treatment discontinuation due to AEs was significantly increased by CCBs (OR, 1.43 [95% CrI, 1.23-1.67]; risk difference [RD], 1.2% [95% CrI, 0.6%-2.0%]), angiotensin-converting enzyme inhibitors plus CCBs (OR, 1.46 [95% CrI, 1.13-1.87]; RD, 1.1% [95% CrI, 0.2%-2.4%]), and β-blockers plus thiazide diuretics (OR, 1.58 [95% CrI, 1.04-2.47]; RD, 1.7% [95% CrI, 0.1%-4.3%]). All ARB-containing regimens had fewer treatment discontinuations due to AEs than placebo, and these differences were statistically significant for ARB monotherapy (OR, 0.73 [95% CrI, 0.61-0.86]; RD, -0.8% [95% CrI, -1.3% to -0.4%]) and ARBs plus CCBs (OR, 0.61 [95% CrI, 0.47-0.79]; RD, -1.2% [95% CrI, -1.8% to -0.6%]). In network meta-analyses, 5 combination and 2 monotherapy regimens had higher surface under the cumulative ranking curve values than placebo for treatment discontinuation due to AEs, suggesting overall symptomatic improvement compared with placebo. All regimens significantly increased dizziness, and all but CCBs significantly decreased headache compared with placebo. CONCLUSIONS AND RELEVANCE: This meta-analysis of short-term randomized clinical trials found that adverse drug effects that led to discontinuation of BP-lowering therapy varied by drug class and regimen, with several combination therapies being better tolerated than monotherapies. Some regimens were associated with fewer drug withdrawals than placebo, suggesting a net symptomatic improvement. These findings are based on trial-level results and rely on assumptions underlying the network meta-analysis; they may not apply to individual patients.