Tag: pubmed

Cochrane Database Syst Rev. 2026 Jul 13;7:CD015988. doi: 10.1002/14651858.CD015988.

ABSTRACT

RATIONALE: Childhood obesity is a major global public health concern. Although physical activity is recognised as an effective non-pharmacological intervention, most existing evidence synthesis has primarily focused on the role of physical activity in preventing obesity, with limited attention given to its effects on managing children with obesity.

OBJECTIVES: To synthesise evidence on the benefits and harms of physical activity for the management of obesity in children up to 9 years of age.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries from 2012 to 2 June 2023, with an update on 4 December 2025. We also used Google Scholar to identify additional studies. We did not impose language or publication status restrictions.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) that investigated the effects of physical activity interventions of any frequency, mode (e.g. aerobic, resistance), or intensity, with a minimum intervention duration of 12 weeks, in children up to 9 years of age with obesity (as defined by the trialists) at baseline. Eligible comparators were standard care, waiting-list, no physical activity, or any other active interventions, such as comparisons of different physical activity parameters (e.g. duration, frequency, intensity).

OUTCOMES: Critical outcomes: body mass index (BMI), BMI z-score, body weight, health-related quality of life, adiposity and fat distribution, glycaemia, and adverse events (minor and serious). Important outcomes: physical well-being, mental well-being, physical activity levels, blood pressure, hyperinsulinemia, resistance to insulin, alterations in lipid metabolism, presence of obesity-related comorbidities or any non-communicable diseases, obesity-associated disability, lipid hormones, alterations in hunger or satiety, disability, mortality, prevalence of obesity in adulthood, and access to health services.

RISK OF BIAS: Pairs of review authors independently assessed the risk of bias in included studies using the original version of the Cochrane tool (RoB 1).

SYNTHESIS METHODS: We synthesised results using meta-analysis when appropriate. Given the clinical and statistical heterogeneity, we predominantly used a random-effects model alongside sensitivity analyses. When meta-analysis was not feasible, we employed synthesis without meta-analysis (SWiM) methods. We assessed the certainty of the evidence using the GRADE approach.

INCLUDED STUDIES: We included four studies (five references, 517 children; female 46%; mean age ranged from 8.9 to 9.9) conducted in three countries (the USA, Brazil, and Iran). Three studies (75%) delivered the physical activity interventions in school settings. Three studies (75%) compared physical activity interventions with non-exercise controls, while one compared physical activity with a behaviour-changing intervention. The duration of physical activity interventions ranged from 12 to 32 weeks. We assessed three studies as having an overall high risk of bias.

SYNTHESIS OF RESULTS: Physical activity interventions compared to control The evidence is very uncertain about the effect of physical activity interventions on BMI (mean difference (MD) -1.52 kg/m², 95% confidence interval (CI) -2.74 to -0.29; I² = 0%; 2 studies, 118 children; very low-certainty evidence), BMI z-scores (MD -0.10 z-score units, 95% CI -0.22 to 0.02; I² = 29%; 1 study, 222 children; very low-certainty evidence), body weight (MD -0.86 kg, 95% CI -3.17 to 1.46; I² = 0%; 2 studies, 118 children; very low-certainty evidence), health-related quality of life (MD -0.60 points, 95% CI -4.22 to 3.02; 1 study, 175 children; very low-certainty evidence), adiposity and fat distribution, assessed as body fat percentage (MD -1.23%, 95% CI -2.50 to 0.03; I² = 0%; 3 studies, 456 children; very low-certainty evidence), minor adverse events (risk ratio (RR) 3.58, 95% CI 1.95 to 6.55; 1 study, 222 children; very low-certainty evidence), and serious adverse events (RR 1.08, 95% CI 0.10 to 11.76; 1 study, 222 children; very low-certainty evidence). No studies assessed glycaemia. Combined training (aquatic exercises) versus combined training (video game exercises) The evidence is very uncertain about the effect of combined training in an aquatic setting compared to video-game-based combined training on BMI (MD -0.90 kg/m², 95% CI -3.21 to 1.41; 1 study, 39 children; very low-certainty evidence), BMI at 4-week follow-up (MD 0.03 kg/m², 95% CI -2.54 to 2.60; 1 study, 39 children; very low-certainty evidence), body weight (MD -1.30 kg, 95% CI -5.66 to 3.06; 1 study, 39 children; very low-certainty evidence), and body weight at 4-week follow-up (MD -0.70 kg, 95% CI -5.70 to 4.30; 1 study, 39 children; very low-certainty evidence). This study did not assess the other critical outcomes. Low-dose versus high-dose combined training The evidence is very uncertain about the effect of low-dose versus high-dose combined training on BMI z-scores (MD 0.12 z-score units, 95% CI 0.10 to 0.14; 1 study, 144 children; very low-certainty evidence), adiposity and fat distribution, assessed as body fat percentage (MD 1.07%, 95% CI -0.74 to 2.88; 1 study, 144 children; very low-certainty evidence), glycaemia, assessed as fasting glucose level (MD -0.50 mg/dL, 95% CI -2.77 to 1.77; 1 study, 144 children; very low-certainty evidence), minor adverse events (RR 0.91, 95% CI 0.64 to 1.30; 1 study, 144 children; very low-certainty evidence), and serious adverse events (RR 3.08, 95% CI 0.13 to 74.45; 1 study, 144 children; very low-certainty evidence). This study did not assess the other critical outcomes.

AUTHORS’ CONCLUSIONS: The evidence from four randomised studies on the effects of physical activity interventions in children aged 0 to 9 with obesity is of very low certainty. Serious methodological limitations, clinical heterogeneity, small-study effects, and imprecise results constrained this evidence base. Important knowledge gaps remain because none of the included RCTs enroled children with disabilities. The RCTs provided little information on contextual factors. Future high-quality and better-reported RCTs will likely change our findings.

FUNDING: The Department of Nutrition and Food Safety at the World Health Organization (WHO) commissioned and provided financial support for this work. WHO acknowledges financial support from the Norwegian Agency for Development Cooperation, the Swedish International Development Cooperation Agency, the Government of the Grand Duchy of Luxembourg, and the Government of Germany to the Department of Nutrition and Food Safety.

REGISTRATION: Protocol available via https://doi.org/10.17605/OSF.IO/DSHUP.

PMID:42440326 | DOI:10.1002/14651858.CD015988

JAMA Netw Open. 2026 Jul 1;9(7):e2622743. doi: 10.1001/jamanetworkopen.2026.22743.

ABSTRACT

IMPORTANCE: Genomic screening for Centers for Disease Control and Prevention Tier 1 conditions, ie, hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome, and familial hypercholesterolemia, enables early detection of these rare, but highly penetrant disorders and supports timely, evidence-based interventions. However, states with large rural and socially disadvantaged populations, such as South Carolina, face substantial structural and access-related barriers that limit the reach of population-wide genomic screening (PWGS).

OBJECTIVE: To examine whether combining implementation science and informatics infrastructure supports PWGS and to assess screening coverage and positivity by rurality and social disadvantage.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data from In Our DNA SC, a statewide PWGS program launched on November 8, 2021, in South Carolina. Recruitment and sample collection occurred via the health system, community-based collection events, and at-home kits. Analyses included adults aged 18 or older who completed screening as of July 23, 2025.

EXPOSURE: Genomic screening for Centers for Disease Control and Prevention Tier 1 conditions.

MAIN OUTCOMES AND MEASURES: County-level screening coverage rates (per 100 000 population) and positivity prevalence (per 100 000 valid results) were stratified using rural-urban continuum (RUC) codes (1 = most urban to 9 = most rural) and Social Vulnerability Index (SVI) quartiles (from 1 = least disadvantaged to 4 = most disadvantaged).

RESULTS: Of a total of 82 420 adults enrolled in the PWGS program, 50 897 completed screening (71.6% aged <65 years and 28.4% aged ≥65 years, 72.6% female). The program enrolled and screened participants from all 46 South Carolina counties. Screening coverage rates varied by RUC code and SVI. Screening rates per 100 000 population exceeded 1000 in RUC codes 1 through 3 and were significantly higher than RUC code 6 (791.4; 95% CI, 757.1-827.2), RUC code 8 (861.4; 95% CI, 801.1-926.2), and RUC code 9 (839.6; 95% CI, 683.6-1030.8). Screening coverage by overall SVI score was significantly higher in quartile 1 (1422.1; 95% CI, 1406.3-1438.1) and quartile 2 (1188.4; 95% CI, 1167.3-1209.9) compared with quartile 3 (888.4; 95% CI, 866.5-910.9) and quartile 4 (839.6; 95% CI, 952.3-1025.4). Positivity prevalence was generally similar across RUC codes, except for HBOC, which was significantly higher per 100 000 in RUC code 2 (801.3; 95% CI, 715.3-897.4) compared with RUC code 1 (268.5; 95% CI, 123.1-584.5). When examined by overall SVI quartiles, positivity prevalence for HBOC, Lynch syndrome, and familial hypercholesterolemia remained consistent, with no statistically significant differences across levels of disadvantage.

CONCLUSIONS AND RELEVANCE: This cross-sectional study of a statewide PWGS program supported by an implementation framework and informatics platform suggests broad geographic and social reach. Evaluation of clinical and behavioral outcomes is the critical next step for determining program effectiveness and performance in community and clinical settings. Taken together, these findings suggest that pairing implementation science with robust informatics infrastructure may support PWGS delivery in diverse communities.

PMID:42440321 | DOI:10.1001/jamanetworkopen.2026.22743

JAMA Netw Open. 2026 Jul 1;9(7):e2622832. doi: 10.1001/jamanetworkopen.2026.22832.

ABSTRACT

IMPORTANCE: It is critical that women undertaking medically assisted reproductive (MAR) treatment and their clinicians know whether the treatments are associated with an increased risk of hormone-related cancers.

OBJECTIVE: To determine the risk of hormone-related cancers following MAR treatment.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used an emulated target trial design including Australian health registries and administrative datasets. Participants included women enrolled in Medicare, Australia’s universal health insurance scheme, aged 18 to 55 years between January 1, 1991, and December 31, 2018. Data were analyzed from April 2024 to July 2025.

EXPOSURES: Exposures were defined from Medicare records: assisted reproduction therapy, intrauterine insemination or ovarian stimulation, and ovulation induction with clomiphene citrate.

MAIN OUTCOMES AND MEASURES: Hormone-related invasive cancers (identified in the Australian Cancer Database) included breast, ovarian, uterine, thyroid, colorectal cancers and melanoma; in situ cancers included breast cancer and melanoma. Three cancers with no hormonal links-pancreatic, lung, and hematological-were included as negative controls. Flexible parametric survival models ascertained hazard ratios (HRs) and cumulative marginal survival differences in incident cancers per 100 000 population. E-values assessed the risk of bias due to unmeasured confounding.

RESULTS: A total of 1 748 927 women were identified, including 396 661 with history of MAR exposure. Although elevated risk of most hormone-related cancers was observed after MAR treatment (HRs, 1.09-1.64), E-value analysis suggested confounding due to underlying infertility conditions (ie, endometriosis, polycystic ovarian syndrome) could account for this observed elevation for uterine, ovarian, and thyroid cancers. For any specific invasive cancer, fewer than 20 extra cancers per 100 000 women each year were estimated for treated vs comparator groups. Emulated trials on the 6 hormone-related cancers and pancreatic and hematological cancers showed increased cancer risk in the first years after treatment, suggesting detection bias. Increased risk of hematological cancers was observed after MAR treatment (HRs, 1.18-1.27), indicating uncontrolled confounding by race and ethnicity may account for observed excess risk seen for several cancers. Some treatments were associated with decreased lung cancer risk (HRs, 0.72-0.82).

CONCLUSIONS AND RELEVANCE: In this cohort study of MAR and cancer using a target trial emulation design, although associations between MAR and some hormone-related cancers were observed, the estimated difference in the number of expected cancers was small and may be explained by unmeasured confounding and detection bias.

PMID:42440318 | DOI:10.1001/jamanetworkopen.2026.22832

JAMA Netw Open. 2026 Jul 1;9(7):e2623006. doi: 10.1001/jamanetworkopen.2026.23006.

ABSTRACT

IMPORTANCE: Early vision screening plays a critical role in detecting and treating vision loss-related conditions in children. Despite this, few studies have examined pediatric vision screening rates alongside vision health outcomes using large primary care electronic health record (EHR) datasets.

OBJECTIVE: To measure annual rates of vision screening at well-child care (WCC) visits and the prevalence of vision loss-related conditions among children aged 3 to 17 years, focusing on American Indian or Alaska Native children.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used patient-level EHR data from a large Minnesota-based health system and included children aged 3 to 17 years with at least 1 WCC visit between January 1, 2018, and December 31, 2023. Analyses were conducted between January 2024 and April 2025.

EXPOSURES: Patient age, self-identified race and ethnicity, and insurance type. Race and ethnicity categories included American Indian or Alaska Native, Asian, Black or African American, Hispanic or Latino, Native Hawaiian or Pacific Islander, White, and other (those who selected “some other race” as an option).

MAIN OUTCOMES AND MEASURES: Primary outcomes were (1) annual vision screening rates during WCC visits and (2) the prevalence of 9 vision loss-related conditions identified using diagnostic codes in the EHR. Two-proportion Z tests were used to test for statistical significance between children who identified as American Indian or Alaska Native and those who did not (ie, those who identified as any other race or ethnicity category).

RESULTS: Overall, 209 775 children (mean [SD] age, 10.8 [4.6] years; 103 605 [49.4%] female) were evaluated, with 1358 children self-identifying as American Indian or Alaska Native (0.6%) and 203 197 (96.9%) identifying as any other race or ethnicity category. The annual vision screening rate at WCC visits was 88.7% (95% CI, 88.6%-88.8%), with small differences by race and ethnicity and insurance type and larger differences by age. Rates were lowest among those aged 3 to 5 years. Screening rates did not differ significantly between children who identified as American Indian or Alaska Native compared with those who did not; however, American Indian or Alaska Native children had a higher prevalence of amblyopia (5.2% [95% CI, 3.8%-6.5%] vs 3.7% [95% CI, 3.6%-3.8%]) and several refractive error conditions, including astigmatism (17.4% [95% CI, 15.3%-19.7%] vs 12.5% [95% CI, 12.3%-12.6%]), hyperopia (13.3% [95% CI, 11.2%-15.3%] vs 10.7% [95% CI, 10.6%-10.9%]), and myopia (11.1% [95% CI, 9.3%-12.9%] vs 8.3% [95% CI, 8.1%-8.4%]).

CONCLUSIONS AND RELEVANCE: In this cross-sectional study of children aged 3 to 17 years, American Indian or Alaska Native children experienced a higher burden of vision loss-related conditions despite comparable screening rates; across all race and ethnicity groups, screening rates were lowest among young children. These findings highlight opportunities to strengthen early vision screening and to better understand factors associated with observed inequities in pediatric vision health.

PMID:42440316 | DOI:10.1001/jamanetworkopen.2026.23006

JAMA Netw Open. 2026 Jul 1;9(7):e2623042. doi: 10.1001/jamanetworkopen.2026.23042.

ABSTRACT

IMPORTANCE: During the COVID-19 pandemic, the major burden of morbidity and mortality was in older age groups. While within-household transmission is well documented, the wider role of social networks for transmission to the older population is less well understood.

OBJECTIVE: To estimate whether children’s birthdays were associated with grandparents’ SARS-CoV-2 infection risk.

DESIGN, SETTING, AND PARTICIPANTS: This nationwide, register-based cohort study included grandparents residing in Denmark with 1 to 5 grandchildren aged 0 to 15 years during the period between February 19, 2020, and February 28, 2022. The timing of birthdays of grandchildren was used as a natural experiment to examine whether birthday-related opportunity for family gatherings was associated with the risk of SARS-CoV-2 infection in grandparents. Family structures were mapped at the individual level. Data were analyzed from June 2024 to December 2026.

EXPOSURES: Birthdays of grandchildren turning 1 to 16 years. A birthday risk window, the period when positive test results could be ascribed to a celebration, was defined as the 7-day time window from 2 to 8 days after the grandchild’s birthday.

MAIN OUTCOMES AND MEASURES: The primary outcome was a positive result on a SARS-CoV-2 test (by polymerase chain reaction or antigen testing) recorded in the national surveillance system. Hazard ratios comparing the hazard of having positive test result for SARS-CoV-2 (outcome) in grandparents in birthday-windows vs grandparents who at the same moment were in nonbirthday periods, were estimated using Cox proportional hazards regression with birthdays as time-varying covariates.

RESULTS: Among 1 106 493 grandparents (median [IQR] age, 67 [60-73] years; 54% female), grandparents had 9.9% (95% CI, 7.9%-12.0%) higher hazard of SARS-CoV-2 infection during birthday risk windows. The hazard varied over time and by variant and was not seen during the period when Alpha dominated. The risk was greater for birthdays of preschool-aged grandchildren (adjusted hazard ratio, 1.15; 95% CI, 1.12-1.18) than during birthdays of school-aged grandchildren (adjusted hazard ratio, 1.07; 95% CI, 1.04-1.09).

CONCLUSIONS AND RELEVANCE: This cohort study of grandparents found that grandchild birthdays, despite official advice not to gather during part of the pandemic, were associated with increased SARS-CoV-2 infection risk among grandparents during much of the pandemic, with magnitude of risk varying over time and by viral variant. These results emphasize the role of culturally important events in intergenerational transmission dynamics, supporting future targeted risk mitigation around small family events.

PMID:42440315 | DOI:10.1001/jamanetworkopen.2026.23042

JAMA Netw Open. 2026 Jul 1;9(7):e2623260. doi: 10.1001/jamanetworkopen.2026.23260.

ABSTRACT

IMPORTANCE: Tenecteplase is an alternative to alteplase for intravenous thrombolysis in acute ischemic stroke given its simplified administration and comparable safety and efficacy. However, its impact on workflow metrics that may affect clinical outcomes, such as door-to-needle and door-in-door-out times, has not been well-characterized.

OBJECTIVE: To compare door-to-needle and door-in-door-out times between tenecteplase-treated and alteplase-treated patients with acute ischemic stroke in US hospitals.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from the American Heart Association’s Get With The Guidelines-Stroke registry between July 1, 2020, and June 30, 2022. The analysis included adult patients with ischemic stroke who received intravenous thrombolysis. Data analysis was conducted from August to November 2023.

EXPOSURE: Tenecteplase or alteplase treatment in a consecutive series of patients with ischemic stroke.

MAIN OUTCOMES AND MEASURES: Primary outcomes were door-to-needle time among patients who arrived directly to the reporting hospital and door-in-door-out time among those transferred after thrombolytic administration. Secondary outcomes were door-to-puncture and other endovascular workflow metrics among patients treated with thrombectomy after thrombolysis. Generalized linear mixed models were used to assess the association between thrombolytic treatment and workflow time intervals outcomes.

RESULTS: Of 133 228 thrombolysis-treated patients (mean [SD] age, 68.3 [14.8] years; 64 173 female [48.2%]; median [IQR] National Institutes of Health Stroke Scale score, 7 [3-14]), 13 988 (10.5%) received tenecteplase, and 119 240 (89.5%) received alteplase. The mean (SD) door-to-needle time was significantly shorter with tenecteplase vs alteplase (47.0 [26.8] vs 52.7 [28.0] minutes; adjusted mean difference, -3.13 minutes; 95% CI, -3.84 to -2.42 minutes). Door-to-needle time 30 minutes or less occurred more frequently with tenecteplase than with alteplase (2955 of 9893 patients [29.9%] vs 14 781 of 72 539 patients [20.4%]; adjusted odds ratio [aOR], 1.34; 95% CI, 1.25 to 1.44), as did door-to-needle time 45 minutes or less (5766 of 9893 patients [58.3%] vs 35 238 of 72 539 patients [48.6%]; aOR, 1.24; 95% CI, 1.17 to 1.32) and 60 minutes or less (7670 of 9893 patients [77.5%] vs 51 282 of 72 539 patients [70.7%]; aOR, 1.25; 95% CI, 1.17 to 1.33). Among transferred patients likely eligible for mechanical thrombectomy, mean (SD) door-in-door-out times were shorter for tenecteplase vs alteplase (108.3 [31.6] vs 114.1 [32.0] minutes; adjusted mean difference, -5.94 minutes; 95% CI, -9.10 to -2.77 minutes). Among patients receiving thrombectomy, shorter times were observed in the tenecteplase group for door-to-arterial puncture, door-to-device deployment, and door-to-reperfusion. Hospitals that transitioned to tenecteplase during the study period had faster door-to-needle time times after vs before the switch (mean [SD], 51.1 [12.1] vs 52.7 [10.8] minutes; adjusted mean difference, -1.52 minutes; 95% CI, -2.88 to -0.15 minutes).

CONCLUSIONS AND RELEVANCE: In this analysis of a large nationwide registry, tenecteplase was associated with faster door-to-needle and door-in-door-out times than alteplase. These workflow advantages provide support for broader use of tenecteplase for stroke thrombolysis.

PMID:42440314 | DOI:10.1001/jamanetworkopen.2026.23260

JAMA Intern Med. 2026 Jul 13. doi: 10.1001/jamainternmed.2026.2928. Online ahead of print.

NO ABSTRACT

PMID:42440299 | DOI:10.1001/jamainternmed.2026.2928

J Am Med Inform Assoc. 2026 Jul 13:ocag119. doi: 10.1093/jamia/ocag119. Online ahead of print.

ABSTRACT

BACKGROUND: Distributed Research Networks (DRNs) offer significant opportunities for collaborative multi-site research and have significantly advanced healthcare research based on clinical observational data. However, generating high-quality real-world evidence using fit-for-use data from multi-site studies faces important challenges, including biases associated with various types of heterogeneity within and across sites and data sharing difficulties. Over the last 10 years, Privacy-Preserving Distributed Algorithms (PDA) have been developed and utilized in numerous national and international real-world studies spanning diverse domains, from comparative effectiveness research, target trial emulation, to healthcare delivery, policy evaluation, and system performance assessment. Despite these advances, there remains a lack of comprehensive and clear guiding principles for generating high-quality real-world evidence through collaborative studies leveraging the methods under PDA.

OBJECTIVE: The paper aims to establish 10 principles of best practice for conducting high-quality multi-site studies using PDA. These principles cover all phases of research, including study preparation, protocol development, analysis, and final reporting.

DISCUSSION: The 10 principles for conducting a PDA study outline a principled, efficient, and transparent framework for employing distributed learning algorithms within DRNs to generate reliable and reproducible real-world evidence.

PMID:42440280 | DOI:10.1093/jamia/ocag119

Cochrane Database Syst Rev. 2026 Jul 13;7:CD013562. doi: 10.1002/14651858.CD013562.pub2.

ABSTRACT

RATIONALE: After inadequate response to first-line biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drug (DMARD) therapy in adults with rheumatoid arthritis, there are numerous alternative DMARD options, and current understanding of their comparative benefits and harms is limited.

OBJECTIVES: The aim of this living systematic review and network meta-analysis was to compare the benefits and harms of DMARDs after failure of biologic or targeted synthetic DMARDs in adults with rheumatoid arthritis.

SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trial registries (ClinicalTrials.gov and the WHO ICTRP) from inception until 28 November 2025, with no restrictions on language or date of publication.

ELIGIBILITY CRITERIA: We included randomised controlled trials (RCTs) of adults aged 18 years or older diagnosed with rheumatoid arthritis according to 1958, 1987, or 2010 classification criteria who previously demonstrated inadequate response to a b/ts DMARD. Eligible interventions included conventional synthetic DMARDs (methotrexate, antimalarials, sulfasalazine, leflunomide, ciclosporin, and azathioprine), biologic DMARDs (adalimumab, certolizumab, etanercept, golimumab, infliximab, abatacept, rituximab, tocilizumab, sarilumab, and anakinra), and targeted synthetic DMARDs (tofacitinib, baricitinib, and upadacitinib).

OUTCOMES: Our critical outcomes were American College of Rheumatology 50% (ACR50) response, withdrawals due to adverse events, radiographic progression, Disease Activity Score 28 (DAS28) remission, pain as measured by visual analogue scale, function as measured by the Health Assessment Questionnaire (HAQ), and serious adverse events. Important outcomes included ACR20, ACR70, serious infections, fatigue, and quality of life.

RISK OF BIAS: We used Cochrane’s RoB 1 tool to assess risk of bias in the included studies.

SYNTHESIS METHODS: We first screened the records using an approach that combined machine learning and crowdsourcing to identify probable RCTs. We then reviewed the records identified as RCTs for eligibility and simultaneously classified them to the appropriate Population, Intervention, Comparator, and Outcome (PICO) question(s). Two review authors then extracted relevant data from the included studies in duplicate and independently, with any disagreements resolved by a third review author. A Bayesian random-effects network meta-analysis was conducted using a semi-informative prior probability distribution. We assessed the certainty of evidence for each outcome using the GRADE approach.

INCLUDED STUDIES: We included 19 unique studies (4779 participants) in the review, all of which were parallel-design RCTs. Eleven trials were placebo controlled; two trials had an inactive comparator arm; and six trials had an active comparator arm. The trials were performed in a well-established rheumatoid arthritis population, with the median baseline disease duration ranging from 6.4 to 14 years, median age of participants ranging from 49 to 58 years, and median baseline disease activity (DAS28) ranging from 4.87 to 6.79.

SYNTHESIS OF RESULTS: ACR50 response We found moderate-/high-certainty evidence that using a tumour necrosis factor (TNF) inhibitor not previously tried, interleukin-6 (IL-6) inhibitors, abatacept, rituximab, and Janus kinase (JAK) inhibitors was more effective than placebo: TNF inhibitor not previously tried (odds ratio (OR) 6.04, 95% credible interval (CrI) 2.49 to 16.3; high-certainty evidence), sarilumab (OR 3.11, 95% CrI 1.25 to 7.76; high-certainty evidence), tocilizumab 4 mg/kg intravenous (OR 5.31, 95% CrI 2.09 to 12.09; high-certainty evidence), tocilizumab 8 mg/kg intravenous (OR 10.03, 95% CrI 3.65 to 31.27; high-certainty evidence), subcutaneous abatacept (OR 4.31, 95% CrI 0.97 to 18.28; moderate-certainty evidence), intravenous abatacept (OR 4.57, 95% CrI 2.21 to 10.18; high-certainty evidence), rituximab (OR 5.50, 95% CrI 2.31 to 13.12; high-certainty evidence), upadacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), tofacitinib (OR 3.93, 95% CrI 1.53 to 10.32; high-certainty evidence), baricitinib 2 mg (OR 2.00, 95% CrI 0.77 to 5.23; moderate-certainty evidence), baricitinib 4 mg (OR 2.79, 95% CrI 1.10 to 7.22; high-certainty evidence). With an assumed risk for placebo of 78 out of 1000 patients, the expected effects for the active drugs ranged from 143 (baricitinib 2 mg) to 455 (tocilizumab 8 mg/kg). Withdrawals due to adverse events For most interventions, there were sparse data with low-certainty evidence, except for TNF inhibitor not previously tried (risk ratio (RR) 0.32, 95% CrI 0.07 to 1.1; moderate-certainty evidence), which is probably less harmful than placebo, and sarilumab (RR 1.98, 95% CrI 0.57 to 7.19; moderate-certainty evidence), which is probably more harmful than placebo. Low-certainty evidence suggests that intravenous abatacept (RR 0.92, 95% CrI 0.34 to 2.79), upadacitinib (RR 0.41, 95% CrI 0.08 to 1.83), and baricitinib 2 mg (RR 0.93, 95% CrI 0.22 to 4.01) may be less harmful than placebo. Low-certainty evidence suggests that tocilizumab 4 mg/kg (RR 1.39, 95% CrI 0.39 to 5.28), tocilizumab 8 mg/kg (RR 1.49, 95% CrI 0.51 to 4.81), subcutaneous abatacept (RR 3.11, 95% CrI 0.05 to 249.6), rituximab (RR 2.38, 95% CrI 0.44 to 23.31), tofacitinib (RR 1.37, 95% CrI 0.35 to 5.58), and baricitinib 4 mg (RR 1.43, 95% CrI 0.38 to 5.81) may be more harmful than placebo. Data were insufficient to perform a network meta-analysis for radiographic progression. For DAS28 and the HAQ, there was mostly moderate-/high-certainty evidence of a benefit, with some exceptions for comparisons with indirect evidence only that was of low or very low certainty. For the other efficacy outcomes, data were sparse with wide credible intervals, and the certainty of evidence was typically low.

AUTHORS’ CONCLUSIONS: We found high-certainty evidence that nine therapies and moderate-certainty evidence that two therapies provide a clinically important benefit in improving disease activity compared to placebo for people with rheumatoid arthritis after failure of b/ts DMARD therapy. There was significant uncertainty surrounding treatment-related harms, with the evidence having been downgraded for serious or extremely serious imprecision. Pair-wise comparisons showed no significant differences among therapies, although the certainty of evidence was low. The lack of clarity regarding safety and comparative efficacy suggests that treatment decisions should be guided by individual patient characteristics and preferences.

FUNDING: This work was supported by grants from the Canadian Institutes for Health Research (CIHR) [Funding Reference Numbers (FRN) 178375 and 180324] and the National Health and Medical Research Council (NHMRC) Cochrane Collaboration. This research was supported by Arthritis Society Canada (Doctoral Studentship TGP-23-0211).

REGISTRATION: This study was outlined in a Cochrane protocol (CD013562; DOI 10.1002/14651858.CD013562).

PMID:42440279 | DOI:10.1002/14651858.CD013562.pub2

Otol Neurotol. 2026 Aug 1;47(7):860-867. doi: 10.1097/MAO.0000000000004933. Epub 2026 May 1.

ABSTRACT

OBJECTIVE: To evaluate whether cochlear implantation reduces listening-related fatigue in children with unilateral hearing loss.

STUDY DESIGN: Prospective within-subjects crossover study.

SETTING: Three academic medical centers specializing in pediatric cochlear implantation.

METHODS: Fatigue was assessed using the Vanderbilt Fatigue Scale and PedsQL™ 3.0 Multidimensional Fatigue Scale. Parent- and child-reported versions were completed after consecutive days of baseline cochlear implant use and following a three-day discontinuation during a holiday break. Paired t-tests compared conditions (P <0.05). Univariable regressions examined associations with age, sex, and deafness duration. Intraclass correlation coefficients assessed parent-child agreement.

RESULTS: Of 69 eligible patients, 37 responded; 18 declined due to reluctance to discontinue CI use. Nineteen children (mean age 8.6 y, 26.3% male, mean deafness duration 3.4 y) completed the study. Parent-reported fatigue significantly worsened after implant non-use in mental (P=0.01) and physical domains (P=0.04) on the Vanderbilt scale, and in cognitive fatigue (P=0.03) on the PedsQL. Child-reported scores trended toward greater fatigue during non-use, though not statistically significant. Younger age and male sex were associated with higher fatigue in parent reports. Intraclass correlation coefficients indicated moderate to good parent-child agreement.

CONCLUSION: Cochlear implantation alleviates listening-related fatigue in children with unilateral hearing loss, particularly in cognitive and physical domains as perceived by parents. Fatigue represents a clinically meaningful, non-audiological outcome in candidacy assessment and postoperative evaluation.

PMID:42440270 | DOI:10.1097/MAO.0000000000004933