Citations

ABSTRACT Background and Objective Despite growing interest in mindfulness‐based interventions for adolescents with chronic pain, the data have not been systematically summarized. We conducted a systematic review and meta‐analyses to estimate the effect of mindfulness‐based interventions on pain intensity, catastrophizing, acceptance and interference; functioning, quality of life, and anxiety and depression in youth with chronic pain. Databases and Data Treatment Electronic databases CINAHL, CCTR, Embase, Medline, PsycINFO, Scopus and Web of Science were systematically searched to January 2, 2025. Studies were included if they were in English, included > 5 patients, were not part of intensive interdisciplinary pain treatment and included pre‐post outcomes from mindfulness‐based interventions delivered to adolescents with chronic pain. Risk of bias was assessed with the Newcastle–Ottawa Scale. Results Fourteen studies including a total of 323 adolescents were identified. There were significant within group improvements in pain intensity, pain catastrophizing, pain acceptance, pain interference, functioning, depression, anxiety, and quality of life, with results maintained or increased at follow‐up effect sizes at follow‐up were moderate to large (e.g., quality of life SMD = 0.33; pain intensity SMD = −0.73; pain interference SMD = −1.44). Heterogeneity of results was generally moderate to high. Compared to standardized long interventions, variable length interventions showed greater pre‐post changes in functioning, pain intensity, and pain catastrophizing. The certainty in the estimates was generally low, due to risk of bias and pre‐post designs. Conclusions Although adolescents with chronic pain report improvements after participating in mindfulness‐based interventions, rigorous RCTs are needed to substantiate these results. Significance Statement Chronic pain in youth is common and difficult to treat. Previous interventions have largely been based on cognitive‐behavioural therapy and not successful for all. This is the first systematic review and meta‐analysis in paediatric chronic pain to focus on mindfulness‐based interventions, highlighting an alternative and potentially effective intervention approach. This study informs clinicians about an effective intervention approach and assists researchers in identifying gaps for further research.

Abstract INTRODUCTION Alzheimer's disease neuropathologic change (ADNC) classification identifies not/low and intermediate/high levels of neuropathology. Our goal was to assess how frequently a positive amyloid positron emission tomography (PET) scan indicates not/low ADNC and whether this autopsy finding can occur >10 years after a positive amyloid PET. METHODS Participants with positive amyloid PET scans were categorized by levels of ADNC at autopsy, grouped by time from initial positive amyloid PET to time of death (<5 years, 5 to <10 years, or 10+ years). RESULTS Among those with a positive amyloid PET scan, the majority had intermediate/high ADNC at autopsy (234/259, 90%). In the group with 10+ years between a positive amyloid PET and death ( n = 39) not/low ADNC occurred in 3/39 (8%). DISCUSSION Not/low ADNC is uncommon among those with positive amyloid PET scans. After 10+ years, it is possible but rare for a positive amyloid PET scan to represent an indolent state of neuropathology.

Abstract INTRODUCTION Prospective studies of blood‐based biomarkers reflecting pathogenic processes, other than Alzheimer‐specific pathologies, that contribute to dementia in diverse cohorts are lacking. METHODS We jointly fitted linear mixed‐effect models and proportional hazards models to examine associations of midlife glial fibrillary acidic protein (GFAP), chitinase‐3‐like protein 1 (YKL‐40), soluble cluster of differentiation‐14 (sCD14), neurofilament light chain (NfL), total tau (t‐tau), and ubiquitin C‐terminal hydrolase L1 (UCHL1) levels in serum (collected in 1993 to 1995) with cognitive decline and incident dementia (ascertained over 29 years through 2022) in the community‐based Atherosclerosis Risk in Communities Study. sCD14 and YKL‐40 were measured in 3082 participants and the other four biomarkers in 1766 participants. RESULTS Higher serum GFAP, YKL‐40, sCD14, and NfL were associated with faster cognitive decline and elevated dementia rate (e.g., 1 standard deviation [SD] higher log‐base2 YKL‐40 was associated with −0.11SD faster 25‐year cognitive decline (95% confidence interval [CI]: −0.15,−0.07) and 45% higher dementia hazard (hazard ratio [HR]: 1.45 [95% CI: 1.25, 1.68]). Higher t‐tau and UCHL1 were also associated with faster cognitive decline. DISCUSSION Midlife blood biomarkers reflecting glial and neuronal dysfunction and neuroinflammation are associated with early cognitive impairment.

BACKGROUND Patients with severe aortic stenosis (AS) exhibit heterogeneous flow-gradient hemodynamics and ventricular remodeling, which may influence symptomatic, functional, and structural responses to transcatheter aortic valve implantation (TAVI). Thus, we evaluated differences in functional recovery and reverse remodeling after transfemoral TAVI across flow-gradient phenotypes. METHODS In this sub-study of the COMPARE-TAVI 1 trial, 975 patients undergoing transfemoral TAVI were classified as classical low-flow low-gradient (cLFLG, 9.1%), paradoxical low-flow low-gradient (pLFLG, 7.7%), low-flow high-gradient (24.7%), normal-flow low-gradient (NFLG, 13.0%), and normal-flow high-gradient (45.4%). The primary functional outcome was longitudinal change in six-minute walk test distance (6MWTD) from baseline to 1 year follow-up. Secondary endpoints included changes in NYHA functional class and reverse remodeling from baseline to 1 year follow-up along with the incidence and risk of all-cause death and a composite MACE-endpoint. RESULTS Mean 6MWTD increased by 59±4 meters at 1-month (p=0.000) with no additional improvement at 1-year, but with heterogeneity between groups (p=0.000). Improvements among NFLG, cLFLG and low-flow high-gradient AS were comparable with normal-flow high-gradient AS, while pLFLG AS exhibited significantly increments at 1-year (−28±15 meters, p=0.007). Patients with NFLG, cLFLG and pLFLG were more symptomatic at baseline (NYHA ≥III: 40.5%, 57.3% and 50.6%, respectively, p=0.000). NYHA improved in all groups at 1-year follow-up (p=0.000), although persistent symptoms at 1-year were most frequent in pLFLG (NYHA ≥II; 38.7%, p=0.012). Reverse remodeling was also comparable between normal-flow high-gradient AS and NFLG, cLFLG, and low-flow high-gradient AS, respectively, but attenuated in pLFLG AS in both unadjusted and adjusted analyses. No differences were observed in the incidence and risk of all-cause death or the composite MACE-endpoint. CONCLUSION TAVI associates with functional recovery across all flow-gradient phenotypes, although with heterogeneous responses. Patients with NFLG showed comparable functional recovery and reverse remodeling at 1-year follow-up compared with normal-flow high-gradient AS, whereas pLFLG demonstrated attenuated benefits across all parameters.

Introduction Endovascular abdominal aortic aneurysm repair (EVAR) is the primary treatment for abdominal aortic aneurysm (AAA). Despite favorable early outcomes, lifelong surveillance is essential as endoleaks remain a major cause of reintervention. Among these, type II endoleaks (T2E) remain controversial regarding optimal management. This study aimed to identify factors associated with intervention for T2E using time-to-event analysis and predefined anatomic thresholds. Secondary objectives included comparing outcomes between T2E patients with (intT2E) and without (nointT2E) intervention. Methods A retrospective review of EVAR procedures from 2011-2024 was performed. Patients with newly diagnosed or persistent T2E were identified on completion and follow-up CT angiography. Patients were categorized as intT2E or nointT2E. Multivariable Cox regression evaluated time to first intervention, and logistic regression served as sensitivity analysis. Kaplan-Meier curves assessed freedom from intervention by inferior mesenteric artery (IMA) size. Results Among 207 EVAR patients, 78 (37.6%) developed T2E over a mean 3.4 ± 2.4 years. Nineteen (24.3%) required intervention. IntT2E patients were younger (74.9 ± 6.8 vs 78.3 ± 7.9 years, P = 0.02), had more frequent anticoagulation use (47.4% vs 20.3%, P = 0.02), larger IMAs (4.2 ± 0.6 vs 3.3 ± 0.7 mm, P < 0.01), and more lumbar arteries (6.0 ± 1.2 vs 5.0 ± 1.3, P = 0.02). IMAs >4 mm occurred in 68.4% of intT2E vs 8.5% of nointT2E ( P < 0.01). Mean sac growth was greater in intT2E (9.7 ± 5.3 mm vs −1.9 ± 6.5 mm, P < 0.01). Thirty-day complications following the index EVAR procedure, mid-term reinterventions, and overall mortality were similar between groups. Post-embolization, T2E resolved in 36.9%, with sac regression in 63.1%. Among embolized patients, 26.3% required a second embolization and one patient required 3 attempts without achieving resolution. IMA >4 mm independently predicted intervention (HR 7.18, 95% CI 1.97-26.16, P < 0.01). Logistic regression confirmed IMA >4 mm (OR 23.4, 95% CI 6.17-88.6, P < 0.01), >6 lumbar arteries (OR 4.2, 95% CI 1.10-15.98, P = 0.02), and anticoagulation (OR 3.4, 95% CI 1.17-10.6, P = 0.02) as predictors. Conclusions Approximately one-quarter of T2E patients required embolization. IMA >4 mm was the strongest predictor of intervention, while anticoagulation and increased lumbar artery number also increased risk. Management should prioritize risk-stratified surveillance and selective intervention.

Abstract The genetic contributions of the X chromosome to Alzheimer’s disease (AD) remain poorly understood yet are expected to importantly shape sex differences in AD. We therefore performed large-scale X-chromosome-wide association studies (N=1,240,451), evaluating differential risk due to sex, APOE *4, and escape from X-chromosome inactivation, finding most X-linked loci appear relevant to female-biased AD etiology. In evaluating genetic pleiotropy with hormonal, lipid, and brain imaging traits, we discovered X-linked AD loci converged on white matter traits, particularly in the anterior corona radiata and splenium of the corpus callosum. Through brain-centric functional genomics analyses, we then nominated candidate causal genes, including 5 that appeared highly robust. Notably, we found the escape gene RBBP7 decreases AD risk in APOE *4 carriers likely through higher expression in excitatory neurons to counter tau-related neurodegeneration. Altogether, we provide an atlas of sex and APOE *4-informed candidate X-linked AD risk loci, genes, and mechanisms that will guide future studies.

Background: Total knee arthroplasty (TKA) is the treatment of choice for end-stage knee osteoarthritis in many patients. In younger patients with predominantly medial compartment disease, high tibial osteotomy (HTO) is performed as a joint-preserving treatment. However, concerns remain regarding potentially compromised outcomes of TKA after previous HTO given the axial deviation, osteotomy site, secondary surgery, previous hardware, and instrumentation. Therefore, this study compared long-term implant survival, revision, and infection rates, and patient-reported outcomes between patients undergoing TKA after HTO and matched TKA-only controls. Methods: Postoperative complications and revision surgeries were prospectively recorded in patients who underwent TKA from 2000 to 2023 at a single academic center. Patients with previous ipsilateral HTO formed the study group and were propensity matched 1:2 to TKA-only patients without a previous osteotomy based on age, sex, and body mass index. Knee Society Scores (KSS) were collected prospectively. Implant survivorship was analyzed using Kaplan-Meier survival curves and Cox proportional hazards models. Results: The study included 134 HTO-TKA and 268 matched TKA-only patients, with a mean follow-up of 10.5 ± 6.4 years (range: 0-24 years) after TKA. Both groups showed significant postoperative improvements in KSS (p < 0.02) with comparable clinical outcomes (HTO-TKA: 79.0 (6.0), TKA-only: 79.0 (11.8)). Revision arthroplasty rates were 5.2% for HTO-TKA and 4.5% for TKA-only (p = 0.69); the mean time to revision was 8.1 ± 8.7 years vs. 4.4 ± 3.5 years, respectively (p = 0.30). Infection rates were 2.2% and 1.1%, respectively (p = 0.74). Conclusions: Revision and infection rates were comparable between HTO-TKA and matched TKA-only patients, with no statistically significant differences. Our findings demonstrate comparable patient-reported outcomes in both groups. These findings indicate that a previous HTO does not adversely affect TKA implant longevity or clinical outcomes when compared with matched primary TKA patients within the US population. Level of Evidence: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Background: Gender-based reimbursement disparities in orthopedic surgery remain poorly understood, particularly when accounting for practice composition and setting. The purpose of this study was to compare and evaluate gender-based differences in Medicare reimbursement and practice patterns among female and male orthopedic surgeons. Methods: A cross sectional analysis of public Medicare data from 2013 to 2021 was performed. Outcomes included annual Medicare payments, submitted charges, total services, service categories, and beneficiaries treated by orthopedic surgeons who bill Medicare. Univariate and multivariable analyses quantified differences in payment, practice volume and composition, geographic adjustment, and Current Procedural Terminology (CPT)-matched reimbursements. Results: A total of 29,357 orthopedic surgeons (27,442 men and 1,919 women) billed Medicare fee-for-service during the study period. Female surgeons, on average, submitted 48.3% fewer total charges and received 44.1% lower annual Medicare payments per surgeon compared with male surgeons. These differences persisted after multivariable regression adjusted for practice metrics and excluded top and bottom earners. Female surgeons also billed fewer services, treated fewer beneficiaries, and submitted fewer unique CPT codes. However, payment disparities persisted even after matching surgeons by volume of services, beneficiaries, and years in practice. Male surgeons performed higher volumes of all 10 highest-paying orthopedic CPT codes. In CPT matched analyses, female surgeons received lower reimbursement per service than male surgeons performing identical procedures. Conclusion: These findings suggest that the observed gender-based disparities in orthopedic surgery Medicare reimbursement cannot be explained by differences in volume, procedural mix, or geographic practice cost. Instead, they likely reflect a combination of structural and behavioral mechanisms described in prior literature that may influence how access to clinical opportunities, referrals, and reimbursement practices unfold in surgical practices. Variations in coding practices may represent an important focus for future investigation and targeted educational initiatives. Level of Evidence: Level III , Retrospective Cohort Study. See Instructions for Authors for a complete description of levels of evidence.

Introduction: Although the role of cardiometabolic risk factors (CMRF) has been characterized in steatotic liver disease, their role in the severity of alcohol-associated hepatitis (AH) remains unclear. We aimed to evaluate the impact of CMRF on mortality. Methods: Multinational prospective cohort study (2015–2024) including hospitalized patients with severe AH across 32 centers in 14 countries. Diagnosis of AH was made using the NIAAA criteria. Analyses included adjusted competing-risk models by age, sex, ethnicity, history of cirrhosis, CMRF, corticosteroid use, MELD, and ACLF grade, with liver transplantation as a competing risk. Results: 936 participants were included; mean age 48±11.2 years, and 88.9% were male. At least one CMRF was present in 46.6%; median body mass index (BMI) was 24.2 kg/m 2 [IQR: 22.8–28.2], prevalence of diabetes 17.6%, hypertension 16.5%, and dyslipidemia 5.8%. Median MELD was 24.4 [19.3–31.4], 86.7% had severe AH, and 180-day survival was 72.9%. Survival did not differ by CMRF status (log-rank p =0.453). In adjusted competing-risk models, higher age (sHR 1.02; 95%CI:1.01–1.04), greater alcohol intake (per g/day; sHR 1.001; 95%CI:1.000–1.002), MELD (sHR 1.04; 95%CI:1.01–1.06), and ACLF grade 2–3 (sHR 2.34 and 4.34) predicted mortality. However, no individual CMRF independently increased mortality. A prespecified non-linear BMI analysis showed modestly lower mortality between 25–40 kg/m², with a higher risk above 40 kg/m². Conclusion: Among patients with severe AH, metabolic dysfunction was not associated with increased mortality. Although a higher BMI was associated with slightly lower mortality in AH, this may reflect better nutritional status rather than a true protective effect.

Background: Considering the pathophysiological importance of the intestine-passing microbiota, we hypothesized that the mutational and microbial profiles of colorectal cancer might gradually change along detailed anatomical locations and that these trends might differ by the age of diagnosis and the microsatellite instability (MSI) status. Methods: We assessed somatic mutations and selected bacterial species in colorectal carcinomas along the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum, utilizing targeted sequencing data ( N = 5685) from the Genetics and Epidemiology of Colorectal Cancer Consortium and tissue microbial data ( N = 1389) from the Health Professionals Follow-up Study and Nurses’ Health Study. Results: There were decreasing trends from the cecum to rectum in the prevalence of gene mutations in the IGF/PI3K, receptor tyrosine kinase (RTK)/RAS, TGFB, and WNT signaling pathways (all P trend < 0.0001), as well as high levels of Bacteroides fragilis ( P trend < 0.0001) and high levels of Fusobacterium nucleatum ( P trend = 0.0029) (but not enterotoxigenic Bacteroides fragilis or pks+ Escherichia coli ). Conversely, TP53 pathway mutations showed an increasing cecum-to-rectum trend ( P trend < 0.0001). Similar to later-onset cases diagnosed at ages 50 years and older, in early-onset cases diagnosed under the age of 50 years, we found generally decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, TGFB, and WNT pathway mutations and an increasing cecum-to-rectum trend in TP53 pathway mutations. By contrast, the cecum-to-rectum prevalence-changing trends in IGF/PI3K, RTK/RAS, TGFB, and TP53 pathway mutations were present in non–MSI-high tumors but not in MSI-high tumors (all P interaction < 0.0052). Conclusion: Non–MSI-high colorectal cancers exhibited decreasing cecum-to-rectum trends of IGF/PI3K, RTK/RAS, and TGFB pathway mutations (and an increasing trend of TP53 pathway mutations), in contrast to MSI-high tumors that demonstrated no such trends. Our study highlights the importance of detailed colorectal subsite information combined with tumor molecular and microbial characteristics in colorectal cancer research.