Citations

ABSTRACT Aim To systematically review and meta‐analyze cohort studies evaluating associations of gingival inflammation, periodontitis, and tooth loss with cognitive decline and incident mild cognitive impairment or dementia. Methods PROSPERO‐registered searches of MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library identified cohort studies from inception through October 10, 2025, with a PubMed update on June 24, 2026. Random‐effects meta‐analyses pooled adjusted hazard ratios (HRs) for dementia/MCI; cognitive function outcomes were summarized qualitatively. Risk of bias (RoB) was assessed using the Newcastle–Ottawa Scale. Results Fifty‐nine studies met inclusion criteria; 28 contributed to dementia/MCI meta‐analyses. Severe periodontitis (HR: 1.16; 95% CI: 1.06–1.27; I 2 = 0%; Q ‐test p = 0.49), periodontitis of unspecified severity (HR: 1.45; 95% CI: 1.21–1.73; I 2 = 98%; Q ‐test p < 0.001), edentulism (HR: 1.26; 95% CI: 1.19–1.33), and low tooth count (HR: 1.27; 95% CI: 1.14–1.42; I 2 = 94%; Q ‐test p < 0.001) were associated with elevated dementia/MCI risk. RoB was low in 31 studies (53%), moderate in 25 (42%), and high in 3 (5%); inadequate confounder adjustment was common. Meta‐regression showed stronger estimates for ICD‐code periodontitis definitions (fold change (FC) = 1.44 95% CI: 1.04–2.01), older cohorts (FC per year = 1.02 95% CI: 1.00, 1.05), and weaker estimates with lower RoB (FC per NOS star = 0.81 95% CI: 0.73–0.92). Follow‐up duration, cohort age, and RoB were not associated with tooth‐count estimates. Conclusion Periodontitis and tooth loss are associated with modestly higher dementia/MCI risk and poorer cognitive function, but heterogeneity, residual confounding, and bias temper causal interpretation. Longitudinal studies with rigorous baseline cognition assessment and intervention studies are needed.

ABSTRACT Purpose This study assesses the association between colorectal cancer (CRC) screening and a validated, housing-based measure of individual-level socioeconomic status (SES, called HOUSES hereafter) within rural communities and determines whether HOUSES-integrated geospatial analysis can be used to tailor interventions. Methods We used CRC screening data from a subset of Mayo Clinic Midwest patients living in cities without ready access to routine care in the Mayo Clinic Health System in 2019 to represent rural communities. At the individual level, we assessed the association between CRC screening rates and the HOUSES index, adjusting for age, sex, race/ethnicity, comorbidity, distance from home address to clinic, and area deprivation index, using a multilevel mixed-effects logistic regression model. Additionally, we conducted geospatial analysis to examine the correlation between hotspots of 1) lower CRC screening rates and 2) lower SES of the subject population (HOUSES quartile 1). Findings Among 34,489 individuals (median age 64.0 years, 52.4% female), those with the lowest SES (HOUSES Q1) had 37% lower odds of being CRC screening adherent than those with the highest SES (HOUSES Q4) (adj. OR [95% CI]: 0.63 [0.58-0.69]). In the 14 identified HOUSES Q1 hotspots, there was a significant correlation in counts of HOUSES Q1 and low CRC screening (correlation coefficient=0.81). Conclusion Lower SES was significantly associated with lower CRC screening among rural populations. HOUSES-enabled geospatial analysis identified geographic hotspots with lower CRC screening rates for targeted interventions to address disparities in CRC screening in rural communities. HOUSES may be a useful digital tool for cancer preventive care and research.

Importance In a phase 2 randomized clinical trial, high-dose vitamin D 3 added to standard treatment improved progression-free survival (PFS) compared with standard-dose vitamin D 3 in patients with metastatic colorectal cancer (mCRC). Objective To determine if high-dose vitamin D 3 added to standard chemotherapy improves outcomes in patients with previously untreated mCRC. Design, Setting, and Participants Double-blind phase 3 randomized clinical trial enrolling 455 patients with previously untreated mCRC, conducted in the US through the National Clinical Trials Network from October 2019 to December 2022 (database freeze: July 15, 2024). Interventions mFOLFOX6 (modified FOLFOX6 [5-fluorouracil, leucovorin, oxaliplatin]) or FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab every 2 weeks with either high-dose vitamin D 3 (8000 IU daily × 14 days as loading dose followed by 4000 IU daily) or standard-dose vitamin D 3 (400 IU daily) until disease progression, intolerable toxicity, or withdrawal of consent. Main Outcomes and Measures The primary end point was PFS assessed by the unstratified log-rank test. Secondary end points included objective response rate, overall survival, and toxicity. Prespecified subgroup analyses of PFS were performed according to known prognostic factors. Results Among 455 randomized patients (median age, 59 years; 181 [40%] female) with median follow-up 20 months, the median PFS for high-dose vitamin D 3 (n = 228) was 11.8 months (95% CI, 10.3-13.3) vs 10.3 months (95% CI, 9.4-12.2) for standard-dose vitamin D 3 (n = 227) (1-sided log-rank P = .25). There were no significant differences in objective response rate between high-dose and standard-dose vitamin D 3 (51% [95% CI, 44%-58%] vs 44% [95% CI, 37%-50%], respectively; P = .12), or in overall survival (median, 25.6 vs 27.0 months; 1-sided log-rank P = .66). There were no clinically meaningful differences in the most common grade 3 or greater adverse events between the high- and standard-dose groups, including neutropenia (n = 67 [32%] vs n = 62 [30%]) and hypertension (n = 42 [20%] vs n = 49 [23%]) or in incidence of vitamin D–associated toxicities. Conclusions and Relevance Among patients with previously untreated mCRC, addition of high-dose vitamin D 3 , vs standard-dose vitamin D 3 , to standard chemotherapy plus bevacizumab did not improve PFS. Trial Registration ClinicalTrials.gov Identifier: NCT04094688

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Aims: The primary aim of this study was to determine whether CYP2D6 phenotypes are associated with atomoxetine treatment outcomes in children and adolescents with attention-deficit hyperactivity disorder. Patients and Methods: Patients 21 years and younger with a known CYP2D6 genotype and a prescription for atomoxetine were included in this electronic health record review. The primary outcome was defined as discontinuation of atomoxetine due to a lack of efficacy or due to toxicity. CYP2D6 activity scores were adjusted to account for phenoconversion if patients were concomitantly taking a CYP2D6 inhibitor medication. Results: Of 108 patients that met inclusion criteria, including 13 poor, 30 intermediate, 61 normal, and 4 ultra-rapid CYP2D6 metabolizers after adjusting for phenoconversion. Normal/ultrarapid metabolizers were significantly more likely to discontinue atomoxetine due to lack of efficacy (subdistribution hazard ratio [sHR] = 1.9, p = 0.04), while poor/intermediate metabolizers were significantly more likely to stop due to toxicity (sHR 0.4, p = 0.03). A significant nonlinear effect of adjusted activity score on likelihood of discontinuation due to lack of efficacy ( p < 0.001) or toxicity ( p < 0.001) was identified, where higher CYP2D6 activity scores were associated with more discontinuation due to lack of efficacy and lower activity scores were associated with more discontinuation due to toxicity. When CYP2D6 genotype was available prior to prescribing atomoxetine in intermediate/poor metabolizers, lower median initial doses were observed (0.5 mg/kg/day) compared to those who underwent CYP2D6 genotyping after the initial atomoxetine prescription (0.8 mg/kg/day). Conclusion: Patients with normal or increased CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to a lack of efficacy, while those with reduced function CYP2D6 phenotypes may be more likely to discontinue atomoxetine due to toxicity.

Abstract Unvetted scientific claims about vaccines can spread rapidly and undermine decades of progress in immunization and public trust. A recent non-peer-reviewed analysis, promoted at political hearings, in the documentary “An Inconvenient Study,” and on social media, has been used to suggest that vaccinated children experience higher rates of chronic illness than unvaccinated peers. Despite standard regression models, critical flaws - uncontrolled confounding, exposure misclassification, unequal follow-up, and outcome multiplicity, invalidate causal inference. An independent group of international experts critically appraises this analysis and contrast its claims with the consistent evidence confirming vaccine safety and effectiveness. We also show how poorly designed studies can distort public discourse, amplify misinformation, and fuel vaccine hesitancy. We outline actions to strengthen research integrity, such as transparent data sharing, labeling of non-peer-reviewed content, and evidence-based communication. Safeguarding public health demands that vaccine evidence be methodologically sound, reviewed, and interpreted by qualified experts.

Racial and ethnic survival disparities exist in pediatric and young adult acute lymphoblastic leukemia (ALL), with differential treatment toxicity and setting of care as possible drivers. Whether treatment cost and utilization disparities exist, or how they may contribute to differences in ALL survival, is unknown. Patients with ALL diagnosed between 2000 and 2019 at ages 1 to 24 years were identified using ICD-9/10 codes in the administrative claims data from the OptumLabs Data Warehouse and the Surveillance, Epidemiology, and End Results program. Sex, race and ethnicity, age, year, and subtype of ALL diagnosis were collected. Reimbursed treatment cost and utilization (number of inpatient and outpatient days) were computed over the initial 8 months of treatment. Regression models assessed associations with demographic and clinical characteristics. Survival analyses assessed associations between race and ethnicity and overall survival. Among 374 individuals with ALL, treatment costs were 57% lower for Black patients than for White patients (estimate 0.43, 95% CI: 0.19-0.96; P =0.04). Utilization was similar across groups, though Black patients had 24% fewer outpatient visits (estimate 0.76, 95% CI: 0.58-0.99; P =0.04). No significant differences in survival were detected, but observations are consistent with previous reports. Despite a small sample size, the statistically significantly lower cost and utilization among Black relative to White ALL patients are concerning and warrant further research.

Abstract Background Data on respiratory syncytial virus (RSV) acute respiratory infection (ARI) among community-dwelling U.S. adults aged 18 to 64 years, particularly those with high-risk conditions (HRC), remain limited. This study estimated incidence and attack rates of RSV-ARI and RSV lower respiratory tract disease (LRTD) in adults with and without HRCs. Methods A multistate, community-based prospective cohort of adults aged 18 to 64 years with and without HRCs was followed from October 2022 to September 2024. Incidence rates and annual attack rates of RSV-ARI and RSV-LRTD were calculated by HRC presence and age group. Results Of 3375 adults with at least 1 HRC, the RSV-ARI incidence rate was 17.9 per 1000 person-years (attack rates: year 1, 1.87%; year 2, 1.56%), compared with 14.8 per 1000 person-years (year 1, 1.33%; year 2, 1.50%) among adults without HRCs. RSV-LRTD incidence was 10.0 per 1000 person-years in adults with HRCs versus 5.7 per 1000 person-years in those without. Asthma, congenital immunodeficiency, and immunosuppressive medication use were associated with increased incidence of RSV-ARI and RSV-LRTD; whereas adults with solid organ transplant and chronic kidney disease had a significantly higher incidence rate of RSV-LRTD compared to those without these conditions. Adults aged 18 to 49 years with HRCs had significantly higher RSV-LRTD incidence (9.6 vs 4.3 per 1000 person-years). After adjustment for age and sex, having ≥1 HRC was associated with a 62% increased RSV-LRTD risk, rising to 117% among adults aged 18 to 49 years. Conclusions Adults with HRCs—particularly asthma, congenital immunodeficiency, chronic kidney disease, immunosuppressive medication use, and solid organ transplant—experienced higher RSV-ARI and RSV-LRTD incidence. The elevated RSV-LRTD burden was most pronounced in adults aged 18 to 49 years with HRCs.