Category: Statistics

J Clin Pharmacol. 2026 Apr;66(4):e70192. doi: 10.1002/jcph.70192.

ABSTRACT

Labetalol is widely prescribed as a first-line antihypertensive in pregnancy; however, rare but potentially severe idiosyncratic hepatotoxicity has been reported, with a disproportionately strong reporting signal for liver injury relative to other β-blockers. In this report, a fatal case is described in which mild initial symptoms rapidly progressed to fulminant hepatocellular injury and acute liver failure within days, underscoring the importance of early recognition of drug-induced liver injury and prompt discontinuation of labetalol. A PRISMA-guided systematic review of MEDLINE, Embase, CINAHL, Cochrane Library, PubMed, and Google Scholar (from inception to December 2025) identified 27 published case reports. Patients were predominantly female (≈80%), and one-third were pregnant or postpartum. Latency ranged from 7 to 365 days (median ≈60 days). The injury phenotype was consistently hepatocellular, often with autoimmune-like serologic or histologic features. Outcomes included full recovery in most (≈75%), but also liver transplantation and death. In the FDA Adverse Event Reporting System (2020Q1-2025Q1), labetalol showed strong disproportionality signals for DILI (PRR 22.7, 95% CI 15.6-33.1; ROR 23.7, 95% CI 16.0-35.1; IC025 2.5) and autoimmune hepatitis (PRR 59.8, 95% CI 34.1-104.8; ROR 60.9, 95% CI 34.4-108.1; IC025 2.8), which persisted when restricted to other β-blockers as comparators. Signals for acute hepatic failure and hyperbilirubinemia were elevated but less statistically robust. The available evidence is consistent with a clinically meaningful and biologically plausible association between labetalol and idiosyncratic hepatotoxicity, supporting heightened clinical awareness and further mechanistic and population-based study.

PMID:42030085 | DOI:10.1002/jcph.70192

Chaos. 2026 Apr 1;36(4):043133. doi: 10.1063/5.0324747.

ABSTRACT

The renewal process is a key statistical model for describing a wide range of stochastic systems in physics. This work investigates the behavior of the probability distribution of the number of renewals in renewal processes at the short time limit, with a focus on cases where the number of renewals is large. We find that the specific details of the sojourn time distribution ϕ(τ) in this limit can significantly modify the behavior in the large-number-of-renewals regime. We explore both ordinary and equilibrium renewal processes, deriving results for various forms of ϕ(τ). Using saddle-point approximations, we analyze cases where ϕ(τ) follows a power-series expansion, includes a cutoff, or exhibits non-analytic behavior near τ=0. Additionally, we show how the short-time properties of ϕ(τ) shape the decay of the number of renewals in equilibrium compared to ordinary renewal processes. The probability of the number of renewals plays a crucial role in determining rare event behaviors, such as Laplace tails. The results obtained here are expected to help advance the development of a theoretical framework for rare events in transport processes in complex systems.

PMID:42030067 | DOI:10.1063/5.0324747

Chaos. 2026 Apr 1;36(4):043134. doi: 10.1063/5.0323615.

ABSTRACT

The bystander effect is a social psychological phenomenon in which individuals are less likely to help a person potentially in need if there are others present. Sociologists and psychologists have proposed multiple plausible reasons for the bystander effect, from situational ambiguity and social contagion to diffusion of responsibility and mutual denial. We build a new model of an individual’s decision to intervene in a bystander situation based on these social psychological hypotheses, along with ideas borrowed from prospect theory. The model yields an explicit bystander curve, which demonstrates, for the first time, that the bystander effect emerges from social risk perception among non-coordinating individuals in ambiguous bystander situations. Expanding upon this static model, we explore the effect of social learning, where individuals update their perceived risk of intervening after experiencing or witnessing the social repercussions of previous interventions. A novel result of this piecewise-smooth dynamical system model, with threshold-driven switching behavior, is that social learning exacerbates the bystander effect. We validate both the static and dynamic models using a new database of 42 experimental and observational studies across a wide range of bystander situations, demonstrating the importance of both population heterogeneity and social learning rates on the emergence of observed bystander curves. This provides a straightforward and generalizable explanation for the observed phenomenon, which may suggest effective interventions tailored to specific bystander situations.

PMID:42030065 | DOI:10.1063/5.0323615

JAMA Health Forum. 2026 Apr 3;7(4):e260874. doi: 10.1001/jamahealthforum.2026.0874.

ABSTRACT

IMPORTANCE: To increase the use of home dialysis and kidney transplant, the Centers for Medicare & Medicaid Services launched the End-Stage Renal Disease Treatment Choices (ETC) model, a mandatory, randomized pay-for-performance program applied to 30% of US hospital referral regions. Its impact after 4 years of implementation is uncertain.

OBJECTIVE: To assess the ETC model’s impact on home dialysis, kidney transplant, and transplant waitlist, as well as measure the rate of financial penalties.

DESIGN, SETTING, AND PARTICIPANTS: This retrospective cross-sectional study used traditional Medicare claims and enrollment data for beneficiaries with kidney failure linked to concurrent transplant data from the United Network for Organ Sharing from January 1, 2017 (4 years before model implementation), to September 30, 2024 (3.75 years postimplementation).

EXPOSURES: Receiving dialysis treatment in a region randomly assigned to the ETC model.

MAIN OUTCOMES AND MEASURES: Primary outcomes were rates of home dialysis, kidney transplant, and transplant waitlist, as well as facility-level financial penalization. Facility-level financial penalties were assessed using Centers for Medicare & Medicaid Services-published performance data.

RESULTS: The study population included 795 232 persons with kidney failure (mean [SD] age, 61.8 [14.4] years; 41.5% female), reflecting 20 729 696 person-months from January 1, 2017, to September 30, 2024. The rate of home dialysis increased from 12.8% to 16.7% of attributed patient-months in ETC regions (change of 3.9 percentage points [pp]) and from 13.7% to 17.3% in control regions (change of 3.7 pp), yielding an adjusted differences-in-differences of -0.1 pp (95% CI, -0.6 to 0.5 pp). The number of kidney transplants per 1000 patient-months increased from 3.3 to 4.5 in ETC regions (change of 1.2) and from 3.4 to 4.4 in control regions (change of 1.0), resulting in a differences-in-differences of 0.2 pp (95% CI, -0.1 to 0.4 pp). The percentage of patients per month on the transplant waitlist decreased from 16.1% to 15.5% in ETC regions (change of -0.5 pp) and from 17.7% to 16.7% in control regions (change of -1.0 pp). The adjusted differences-in-differences for transplant waitlist was 0.6 pp (95% CI, -0.3 to 1.6 pp). The proportion of ETC facilities receiving financial penalties increased from 13.8% in 2021 to 25.1% in 2023. Subgroup analyses showed no meaningful differential effects of the model.

CONCLUSIONS AND RELEVANCE: This cross-sectional study shows that after nearly 4 years, the ETC model was not associated with meaningful increases in home dialysis, kidney transplant, or transplant waitlist, while the proportion of facilities receiving financial penalties increased. Future value-based payment models may need to move beyond narrowly targeted financial incentives to address the broader structural and patient-level barriers that influence access to complex specialty care.

PMID:42030054 | DOI:10.1001/jamahealthforum.2026.0874

JAMA Netw Open. 2026 Apr 1;9(4):e267403. doi: 10.1001/jamanetworkopen.2026.7403.

ABSTRACT

IMPORTANCE: Targeting impaired reward processing that underlies anhedonia and diminished positive affect is essential for reducing key risk factors in depression and anxiety, including suicidality and relapse. However, mechanistic research in this area remains limited.

OBJECTIVES: To assess whether a novel psychosocial intervention engages reward systems more than a mechanistically distinct comparison therapy, and whether alterations in reward and threat processing differentially mediate clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: This was an assessor-blinded, parallel-group, multisite, 2-arm randomized clinical superiority trial. Study recruitment was from December 2021 to January 2024, with final assessment in July 2024. Participants were recruited from academic outpatient treatment centers in Los Angeles, California, and Dallas, Texas, and included treatment-seeking adults with severely low positive affect and moderate to severe depression or anxiety that was functionally impairing. Analyses were conducted with intent-to-treat principles.

INTERVENTION: Participants underwent 15 weekly individual therapy sessions of positive affect treatment (PAT) or negative affect treatment (NAT).

MAIN OUTCOMES AND MEASURES: Clinical status was self-reported positive affect (using the Positive and Negative Affect Schedule-Positive subscale), interviewer-rated anhedonia (embedded within the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition), and self-reported depression and anxiety (using the Depression, Anxiety, and Stress Scale). Target measures were 14 self-reported, behavioral, and physiological measures of reward anticipation-motivation, response to reward attainment, reward learning, and threat. Analyses included mixed-effects multilevel models.

RESULTS: In total, 98 participants (mean [SD] age, 32.8 [12.2] years; 65 [66.3%] female) were randomized to receive PAT (n = 51) or NAT (n = 47). Multivariate multilevel model analyses of the 3 clinical status variables as a multivariate outcome showed that clinical status improved more with PAT than NAT (b = -0.06 [95% CI, -0.11 to -0.01]; t3039 = 2.43; P = .02; d = 0.27) and that PAT had better (higher) scores on clinical status than NAT at the 1-month follow-up (b = -0.21 [95% CI, -0.41 to -0.02]; t3039 = 2.11; P = .04; d = 0.21). Improvements in reward anticipation-motivation (b = 0.02 [95% CI, 0.01-0.03]; t1307 = 4.36; P < .001; d = 0.40) and reward attainment (b = 0.04 [95% CI, 0.01-0.06]; t1405 = 3.16; P = .002; d = 0.18) targets were comparable for PAT and NAT. Of 7 reward and threat self-reported target measures, 6 mediated improvements in clinical status, but none of the behavioral or physiological measures did. There was limited evidence for moderated mediation.

CONCLUSIONS AND RELEVANCE: In this randomized clinical trial of 98 adults with severely low positive affect, depression, and anxiety, findings suggested that modulation of reward and threat processes was a central mechanism of therapeutic improvement, with a reward-focused intervention producing superior clinical outcomes.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05203861.

PMID:42030048 | DOI:10.1001/jamanetworkopen.2026.7403

JAMA Netw Open. 2026 Apr 1;9(4):e268631. doi: 10.1001/jamanetworkopen.2026.8631.

ABSTRACT

IMPORTANCE: Motor vehicle collisions are a leading cause of death among teenagers. Effective strategies to reduce risky driving, especially for teenage drivers cited for traffic violations, are critical yet underdeveloped.

OBJECTIVE: To evaluate the effectiveness of ProjectDRIVE, an in-vehicle and smartphone-based driving feedback intervention combined with parent communication training, in reducing risky driving events and unsafe driving behaviors among teenagers with traffic violations.

DESIGN, SETTING, AND PARTICIPANTS: This 3-arm, parallel randomized clinical trial enrolled 240 parent-teenager dyads, randomized evenly (80 per arm) to the control arm (device installed without feedback), the driving feedback only arm, or the driving feedback plus parent training arm. Enrollment occurred from September 28, 2020, to June 30, 2024, with 6 months of follow-up. Participants included teenagers aged 16 to 17 years with an intermediate license and a moving violation, and their parent or guardian, enrolled from 6 juvenile traffic courts across Ohio.

INTERVENTIONS: Intervention teenagers received real-time, in-vehicle and smartphone-based feedback, as well as biweekly emailed reports. Parents in the driving feedback plus parent training arm accessed their teenager’s driving reports, completed virtual communication training, and received an online guide for discussing safe driving.

MAIN OUTCOMES AND MEASURES: Intent-to-treat analyses assessed intervention effects on the incidence rate of risky driving events per 1000 miles and the proportion of miles driven involving unsafe driving behaviors, measured using telematics.

RESULTS: Among 240 parent-teenager dyads (teenager mean [SD] age, 16.7 [0.5] years; 123 female teenagers [51.3%]), teenagers completed 160 095 trips. Compared with control, driving feedback plus parent training significantly reduced risky driving event incidence (adjusted incidence rate ratio [AIRR], 0.68; 97.5% CI, 0.51-0.90) and the proportion of miles driven while speeding (adjusted exponentiated β coefficient, 0.54; 97.5% CI, 0.47-0.68). Driving feedback alone did not significantly reduce risky driving but did reduce miles driven while speeding (adjusted exponentiated β coefficient, 0.64; 97.5% CI, 0.54-0.79). Male teenagers exhibited higher rates of risky driving compared with female teenagers, including hard braking (AIRR, 1.39; 95% CI, 1.11-1.73) and sudden acceleration (AIRR, 2.13; 95% CI, 1.42-3.19), as well as greater proportions of miles driven while speeding.

CONCLUSIONS AND RELEVANCE: Combining driving feedback with parent communication training reduced risky driving among teenagers with traffic violations. Continued parental engagement after licensure, especially after traffic violations, might be key to reinforcing driving safety among teenagers.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04317664.

PMID:42030047 | DOI:10.1001/jamanetworkopen.2026.8631

JAMA Netw Open. 2026 Apr 1;9(4):e269261. doi: 10.1001/jamanetworkopen.2026.9261.

ABSTRACT

IMPORTANCE: Systemic glucocorticoids have little or no demonstrated efficacy for acute respiratory infections (ARIs) and have known adverse effects. Clinicians in urgent care centers vary widely in their use of glucocorticoids for patients seen for ARIs.

OBJECTIVE: To develop and test a multifaceted urgent care stewardship program to reduce the use of glucocorticoids for ARIs.

DESIGN, SETTING, AND PARTICIPANTS: This quality improvement study included clinicians seeing patients from January 2023 through April 2025 presenting with ARIs at 2 urgent care centers within an academic health system.

INTERVENTIONS: Beginning in February 2024, clinicians were emailed a survey about steroid stewardship, received brief virtual clinician education, and were provided with educational pamphlets to distribute to patients. In May and December 2024, they received email feedback using peer comparison with descriptive and injunctive norms.

MAIN OUTCOMES AND MEASURES: Segmented Poisson regression with clinician-level random effects was used to analyze monthly clinician-level rates of ARI urgent care visits where a systemic glucocorticoid was prescribed (steroid stewardship-eligible visits) before (January 2023 to January 2024) and after (February 2024 to April 2025) steroid stewardship. Visits were excluded for patients with conditions where glucocorticoid treatment may be clinically appropriate. Retrospective interrupted time series modeling of glucocorticoid prescriptions was performed before and after stewardship program implementation.

RESULTS: From January 2023 to April 2025, 10 808 patients (mean [SD] age, 58 [24] years; 6879 [64%] female; 3929 [36%] male) were seen for ARI by 96 clinicians (78 [81%] females; 18 [19%] male; 32 [33%] advance practice nurses; 38 [40%] physicians; 26 [27%] physician assistants) presenting with ARIs at 2 urgent care centers within an academic health system. Participating clinicians attended 14 530 steroid stewardship-eligible visits (7130 before and 7400 during stewardship). The most common diagnoses were nonspecific upper respiratory infection (17%), acute pharyngitis (15%), and acute bronchitis (7%). The mean (SD) clinician-level observed rate per 100 stewardship-eligible visits of systemic glucocorticoid prescriptions decreased from 20.4 (17.8) in the period before stewardship to 8.8 (14.5) during the stewardship period (P <.001). During the stewardship period, the relative rate of glucocorticoid prescribing decreased by 0.94 (95% CI, 0.92 to 0.96; P <.001) per month compared with the period before stewardship.

CONCLUSIONS AND RELEVANCE: In this quality improvement study of a multi-faceted, behavioral science-informed intervention to promote glucocorticoid stewardship for ARIs in urgent care settings, implementation was associated with reductions in glucocorticoid prescribing.

PMID:42030044 | DOI:10.1001/jamanetworkopen.2026.9261

J Eval Clin Pract. 2026 Apr;32(3):e70431. doi: 10.1111/jep.70431.

ABSTRACT

RATIONALE: Meta-analysis is central to evidence-based medicine, yet the implications of model choice remain poorly understood among clinicians. The distinction between fixed-effect and random-effects models is often treated as a technical detail, although it fundamentally defines the scope of inference.

AIMS AND OBJECTIVES: To provide a conceptually grounded and practically oriented tutorial on how to choose, perform, and interpret fixed-effect and random-effects meta-analyses in clinical research.

METHOD: This tutorial combines conceptual explanations, simulated data and re-analyses of published meta-analyses to illustrate how different modelling frameworks influence pooled estimates, uncertainty intervals and clinical interpretation. Contemporary methodological guidance, including Cochrane recommendations, is integrated throughout.

RESULTS: Fixed-effect models yield conditional inferences restricted to the included studies, often producing narrower confidence intervals by ignoring between-study variability. In contrast, random-effects models account for heterogeneity and provide unconditional inferences that generalise to a broader range of clinical settings, typically resulting in wider intervals. Re-analyses demonstrate that statistically significant findings under fixed-effect models may become non-significant when appropriate random-effects methods are applied, particularly when using robust estimators and Hartung-Knapp-Sidik-Jonkman adjustments. Prediction intervals further illustrate the expected variability of effects across future comparable settings.

CONCLUSION: Model choice in meta-analysis is not a statistical afterthought but a conceptual decision that determines the inferential target. Random-effects models will often be more appropriate when the aim is to inform clinical practice across diverse settings, whereas fixed-effect models are appropriate only under strict assumptions or as sensitivity analyses. Transparent reporting and alignment with contemporary methodological standards are essential to ensure valid and clinically meaningful evidence synthesis.

PMID:42030028 | DOI:10.1111/jep.70431

Support Care Cancer. 2026 Apr 24;34(5):461. doi: 10.1007/s00520-026-10642-w.

ABSTRACT

OBJECTIVE: To evaluate the disproportionality, times to onset, and outcomes of cardiac adverse events (AEs) associated with axitinib, using data from the Japanese Adverse Drug Event Report (JADER) database.

METHODS: We analyzed data for the period from April 2004 to December 2024. Those on cardiac AEs were extracted and the disproportionality of axitinib-associated AEs was assessed by calculating reporting odds ratios (RORs).

RESULTS: Of the 2,988,681 reports with sex and age information, we identified 4788 reports of AEs associated with axitinib, including 508 cardiac AEs. Signals were detected for 16 cardiac AEs after adjustment for sex and age. Fatal outcomes were reported for five of these events with particularly high rates observed for cardiac failure, myocarditis, and immune-mediated myocarditis. Median times to onset indicated that cardiac AEs associated with axitinib occurred 14 to 420 days after administration. Weibull distributions showed that seven AEs (blood pressure increased, myocardial infarction, acute myocardial infarction, blood pressure systolic increased, oedema peripheral, oedema, and generalised oedema) occurred constantly throughout the exposure period (random failure type), and stress cardiomyopathy and immune-mediated myocarditis developed in a dose-dependent manner (wear-out failure-type).

CONCLUSIONS: We focused on cardiac AEs associated with axitinib as post-marketing AEs. Some with fatal outcomes may occur not only early in treatment but also later in the course. Continuous monitoring is essential to ensure timely detection and management of these potentially serious AEs in clinical practice.

PMID:42030026 | DOI:10.1007/s00520-026-10642-w

Saudi Dent J. 2026 Apr 24;38(5):52. doi: 10.1007/s44445-026-00154-y.

ABSTRACT

Root canal treatment aims to eliminate organisms within the canal system through the removal of pulp tissue, infected dentin, and necrotic materials. However, experiencing pain or swelling after root canal operations can be a significant concern. Minimally invasive (MI) techniques, such as the TruNatomy rotary file system, are intended to preserve tooth structure. However, conventional systems, such as ProTaper Gold rotary file system, aim for complete debridement. In this meta-analysis, we aim to assess the efficacy of the TruNatomy and ProTaper Gold in reducing postoperative pain. In November 2025, we conducted a systematic search of PubMed, Scopus, Web of Science, and the Cochrane Library for randomized controlled trials (RCTs) comparing TruNatomy to ProTaper Gold in adult patients with pulpitis. For the meta-analysis, we used R 4.5.0 with R Studio 2024.12.1 + 563. Using a random-effects model, we evaluated dichotomous data using risk ratios (RRs) and 95% confidence intervals (95% CI); whereas continuous data were analyzed using standardized mean difference (SMD) and 95% CI. Visual inspection of the forest plot was used to determine statistical heterogeneity between trials, in addition to I-squared (I2) and chi-squared (Chi2) statistics. Our analysis included four RCTs comprising 381 patients. Pooled analysis showed no statistically significant difference between TruNatomy and ProTaper Gold in pain intensity at 24 h (SMD = 0.03, 95% CI -0.17; 0.23), 48 h (SMD = 0.13, 95% CI -0.16; 0.42), or 72 h (SMD = -0.59, 95% CI -1.33; 0.14). There was no significant difference between the two groups in analgesic intake (RR = 1.2, 95% CI 0.70; 2.06). Also, the presence of postoperative pain at 24 and 48 h was similar in both groups. The results showed low statistical heterogeneity for most outcomes; however, the results should be interpreted with consideration of the clinical variability between the included studies. According to our data, the TruNatomy showed no superiority over ProTaper Gold rotary file systems in managing postoperative pain following root canal therapy. The choice of either approach may be based on other criteria, such as dentin preservation or operator preference. Thus, future large-scale clinical trials should validate these findings.

PMID:42030017 | DOI:10.1007/s44445-026-00154-y