Background Lumbar facet arthropathy (LFA) is a degenerative, arthritic joint disorder and a common specific cause of axial low back pain and functional impairment. Currently, no disease-modifying therapies are available for symptomatic LFA. Mesenchymal stem/stromal cell (MSC)-based therapy represents an emerging regenerative treatment modality with the promise to target the underlying pathophysiology of LFA. Despite encouraging clinical evidence supporting the safety and efficacy of MSC therapy in other osteoarthritis, its therapeutic utility in LFA remains largely unexplored. We recently completed a prospective, single-arm, open-label phase I clinical trial that demonstrated a favourable safety profile and preliminary clinical benefit following intra-articular administration of bone marrow-derived MSCs (BMSCs) in patients with symptomatic LFA. Building on these findings, we present the protocol for CellKine II, a prospective, randomised, double-blind, placebo-controlled, cross-over phase II clinical trial to evaluate the safety and preliminary efficacy of intra-articular delivery of allogeneic, culture-expanded BMSCs in patients with painful LFA.Methods and analysis This study is a single-centre, randomised, double-blind, placebo-controlled, cross-over phase II trial with a target accrual of 40 patients. Eligible patients will be randomly assigned in a 1:1 ratio to receive a single intra-articular injection of either Arm A: BMSC or Arm B: Placebo (dimethyl sulfoxide). At the 6-month follow-up, all patients will be unblinded. Patients initially randomised to Arm A will continue follow-up for up to 12 months. Patients initially randomised to Arm B may cross over to receive the BMSC treatment, followed by an additional 12 months of post-BMSC treatment follow-up, or they may continue observation for another 6 months without BMSC treatment. Overall, each patient will be followed up to 12 months after BMSC treatment. The primary endpoints are back pain, functional outcomes and adverse events at 6 months post-randomisation.Ethics and dissemination This study will be conducted in compliance with U.S. federal regulations and Mayo Clinic institutional research policies and procedures. The protocol has been approved by the Mayo Clinic Institutional Review Board (IRB) and the Data Safety Monitoring Board (IRB No. 21-013278). The results of this trial will be disseminated through publication in peer-reviewed journals and on ClinicalTrials.gov.Trial registration number NCT06001853.

OBJECTIVES:To evaluate the association between the dietary digestible carbohydrate intake level and the incidence of cardiovascular disease (CVD) and type 2 diabetes (T2D). METHODS:We searched Embase, MEDLINE, and Cochrane Central from January 1, 2000, to July 19, 2024, to find randomized controlled trials and prospective cohort studies evaluating healthy individuals over 2 years of age, isolating for the effect of the digestible carbohydrate intake level from other macronutrients. RESULTS:Thirty prospective cohort studies with more than 1.7 million participants were included. Most of the studies reported inadequate confounding adjustment and were deemed to have serious risks of bias. No eligible studies evaluated children under 18 years. The association between the digestible carbohydrate intake level and CVD and T2D was nonlinear, which was supported by a low strength of evidence. The risk of CVD was the lowest at a carbohydrate intake level of 50% of total energy intake. The risk of CVD significantly increased when the carbohydrate intake level exceeded 65% of total energy intake. The risk of incident T2D gradually reduced with increasing carbohydrate intake levels up to 45% of total energy intake, then plateaued between 45% and 55% of total energy intake, before rising with higher carbohydrate intake levels. The nonlinear relationships were overall similar based on sex or geographic location but with variable intake range associated with the lowest risk. CONCLUSION:A U-shaped relationship was observed between the intake level of digestible carbohydrates and CVD and T2D. The findings have important implications on the incidence and morbidity of chronic conditions and public health. REGISTRATION:clinicaltrials.gov: PROSPERO #CRD42024494567 and CRD42024496101.

BACKGROUND:The natural history of asymptomatic moderate or severe aortic regurgitation (AR) remains uncertain, with conflicting reports about its progression and surgical timing. We aimed to quantify adverse outcomes under conservative management and evaluate the association of aortic valve replacement/repair (AVR) with mortality. METHODS:Systematic searches (inception-July 2025) identified cohort studies of asymptomatic moderate/severe AR. Random-effects models estimated pooled incidence rates of adverse events; fixed-effects models were used for hazard ratios (HRs) of AVR vs conservative management. RESULTS:Twenty-seven studies (4720 patients; mean age 49 years; mean follow-up 3.9 years) were included. Pooled incidence rates per 100 person-years were 1.75 (95% CI 1.27 to 2.41) for all-cause mortality, 1.29 for cardiac death, 0.29 for sudden death, 4.30 for new symptoms and 7.01 for AVR. Asymptomatic low left ventricular ejection fraction occurred in only 0.9 per 100 person-years. Mortality rates were more than double those of the general population across age groups-2.45 (1.90 to 3.18) per 100 person-years for cohorts with mean age ≥50 years versus 0.59 (0.29 to 1.21) for younger cohorts. Early AVR was associated with lower mortality (pooled HR 0.33; 95% CI 0.30 to 0.37). CONCLUSION:Asymptomatic moderate/severe AR carries significant excess mortality irrespective of age, contradicting its historically benign reputation. Given the rarity of asymptomatic LV dysfunction, earlier intervention guided by more sensitive markers of LV damage may improve outcomes, although heterogeneity and study quality warrant cautious interpretation. PROSPERO REGISTRATION NUMBER:CRD42024522683.

Objectives To describe the incidence, presentation and long-term health outcomes of suicidal thoughts and behaviours (STBs) in children aged 12 years or under.Methods This population-based study included children identified through the Rochester Epidemiology Project who presented between 2005 and 2023 with STBs across primary, secondary and tertiary care centres in Olmsted County, Minnesota, USA. Information related to the patient and family characteristics, presentation, prior history and outcomes was manually extracted by two independent researchers. Patients were excluded if the index visit note could not be located, the patient had no suicidal ideation, attempts, intent or plan, was older than 12 years 11 months at the index date, less than 2 years old or was a duplicate entry.Results The average annual population was 28,035 children, of which 637 presented with STBs (mean (SD) age, 10.6 (1.7) years; 51.2% girls, 76.3% White, average follow-up 7 years). The majority of the cases presented to the emergency department (ED) 491 (77.1%). The annual incidence per 100,000 person-years tripled from 68.8 in 2005 to 208.6 in 2023. Overall, 105 patients (16.5%) presented with a suicidal attempt. There were no cases of death by suicide. A prior psychiatric diagnosis was present in 454 (71.3%). STB events were preceded by a precipitating event in 471 (73.9%), the most common of which was an argument with a parent, followed by a bullying event and family distress. A specific suicide plan was reported by 328 (51.5%) with laceration reported most frequently, followed by hanging and overdose. Significant predictors of a suicide attempt were previous use of mood stabilisers (OR 3.21; 95% CI 1.24 to 7.97) and having a specific plan (OR 2.73; 95% CI 1.72 to 4.41). Children who had suicidal attempts had more subsequent ED visits (3.50 vs 2.58; p=0.009) and hospitalisations for psychiatric reasons (1.90 vs 1.30; p=0.003) and psychiatric hospitalisation days (12.70 vs 9.04; p=0.048). Subsequent suicide attempts occurred in 31% of the cohort during follow-up.Conclusion STBs in preadolescent children are rare but are increasing in incidence. Such children have significant psychological diagnoses, use of mental health services, and subsequent suicide attempts. Novel age-appropriate interventions are needed.

BACKGROUND:Artificial intelligence applications are expanding in medicine, yet the efficacy of artificial intelligence for diagnostic imaging in traumatic femur fractures is unverified. The purpose of this systematic review and meta-analysis is to determine the diagnostic accuracy of artificial intelligence at identifying acute traumatic femur fractures. METHODS:A comprehensive search of 9 databases deployed on May 29, 2025 identified studies related to artificial intelligence applications in acute trauma. Using Covidence and a 2-reviewer method, a systematic review identified 37 studies that met inclusion criteria. Bivariate mixed-effects model was used to pool accuracy measures (area under the receiver operating characteristic curve, specificity, and sensitivity) across the studies. RESULTS:The 37 studies included 95,148 femur images. Pooled artificial intelligence specificity, sensitivity, and area under the receiver operating characteristic curve were 0.94 (95% confidence interval, 0.92-0.97), 0.94 (0.92-0.96), and 0.98 (0.97-0.99), respectively. Humans identified traumatic femur fractures with specificity, sensitivity, and area under the receiver operating characteristic curve of 0.93 (0.90-0.96), 0.91 (0.88-0.94), and 0.97 (0.95-0.98), respectively. When expert (orthopedic surgeons and radiologists) and nonexpert (trainees and physicians in other specialties) human readers were compared, experts demonstrated an area under the receiver operating characteristic curve of 0.989 (0.98-0.99) unaided and 0.99 (0.98-1.0) with artificial intelligence augmentation. Nonexpert readers performed with an area under the receiver operating characteristic curve of 0.95 (0.91-0.97) unaided and 0.97 (0.95-0.98) augmented. CONCLUSION:Current evidence suggests that artificial intelligence can identify traumatic femur fractures with diagnostic performance close to human experts. In addition, artificial intelligence-assisted interpretation improved diagnostic accuracy of nonexperts. While limitations must be considered, these results suggest that artificial intelligence is proficient at identifying acute traumatic femur fractures and has potential for augmenting nonexpert humans.

Background:The ability of large language models (LLMs) to work collaboratively and screen studies in a systematic review (SR) is under-explored. Hence, we aimed to evaluate the effectiveness of LLMs in automating the process of screening in systematic reviews. Methods:This is an observational study which included labeled data (title and abstracts) for five SRs. Originally, two reviewers screened the citations independently for eligibility. A third reviewer cross-checked each citation for quality assurance. GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 were used using zero-shot chain-of-thought prompting. Collaborative approaches included (i): conflict resolution using benefit of the doubt, (ii) majority voting using an independent third LLM and (iii) conflict resolution using an informed third LLM. Performance was assessed using accuracy, precision for exclusion, and recall for inclusion. Work saved over samples (WSS) was computed to estimate the reduction in manual human effort. Results:A total of 11300 articles were included in this study. The individual models, GPT-4, Claude-3-Sonnet, and Gemini-Pro-1.0 exhibited a high precision for exclusion, achieving 99.7%, 99.7%, and 99.2% and high recall for inclusion achieving 95.5%, 96.6% and 85.7%, respectively. However, the collaborative approach utilizing the two best-performing models (GPT-4 and Claude-3S) achieved an average precision of 99.9% and a recall of 98.5% (across all collaborative approaches). Furthermore, the proposed collaborative approach resulted in an average WSS of 63.5%, compared to the average WSS of 45.2% for individual models. Conversational LLM interactions showed a consistent pattern of results. Limitations:This study was limited due to reliance on proprietary models, and evaluation on oncology datasets. Conclusion:Evidence shows that collaborative LLMs enable efficient, high-performing screening in systematic reviews, supporting continuous evidence updates. Primary funding source:NIH (U24CA265879-01-1) and Carolyn-Ann-Kennedy-Bacon Fund.

Single-level lumbar spinal stenosis (LSS) that does not respond to conservative therapy is now of the standard care given due to minimal invasive decompression, but comparative 12-month outcome data of arthroscope-aided single-portal surgery of the lumbar spine (AUSS) and percutaneous endoscopic lumbar decompression (PELD) are scarce. There are also no individual outcome prediction models of these technique specific populations. To compare perioperative and 12-month patient-reported outcomes between AUSS and PELD and to develop and evaluate exploratory machine-learning (ML) models for predicting 12-month favorable outcome, disability (Oswestry Disability Index [ODI]), and back pain (visual analog scale [VAS]) after surgery. This retrospective comparative cohort study analyzed a de-identified patient-level dataset of 865 adults with single-level LSS and complete 12-month follow-up (AUSS n = 445; PELD n = 420). The dataset was provided as a de-identified patient-level file generated directly from source clinical records and was not reconstructed from published aggregate summary statistics; key assumptions include single-center retrospective treatment allocation, imaging-confirmed single-level LSS eligibility, and complete 12-month follow-up as an inclusion criterion. Clinical, perioperative, and complication variables were compared using appropriate nonparametric and parametric tests. Baseline group imbalance was quantified using standardized mean differences (SMDs). Classification and regression ML models were developed using stratified five-fold cross-validation on an 80% development set and evaluated on an independent 20% holdout set. Class imbalance was addressed with inverse-frequency class weighting. Given the exploratory nature of the analysis and dataset provenance, all ML results are interpreted as internal exploratory findings requiring external prospective validation. Mean age was 65.0 years; 89.6% of patients (775/865) achieved a favorable 12-month modified MacNab outcome. AUSS was associated with shorter total operating time (45.47 ± 3.19 vs 54.39 ± 5.24 min; P < 0.001; SMD - 2.07), shorter intracanal decompression time (21.40 ± 2.31 vs 35.49 ± 3.55 min; P < 0.001; SMD - 4.73), and markedly lower fluoroscopy exposure (7.57 ± 2.35 vs 38.41 ± 7.59 s; P < 0.001; SMD - 5.55). PELD showed a less access-traumatic profile with smaller incisions (7.87 ± 1.14 vs 19.71 ± 2.03 mm; P < 0.001; SMD 7.13), lower blood loss (9.41 ± 1.38 vs 17.57 ± 6.35 mL; P < 0.001; SMD 1.75), and lower cost (17 496 ± 603 vs 21 956 ± 581 CNY; P < 0.001). Baseline age imbalance was substantial (SMD = - 0.64), and all group comparisons should be interpreted in this context. Favorable 12-month outcome rates were 93.7% for AUSS and 85.2% for PELD (P < 0.001). Among ML classifiers, random forest showed the most balanced holdout performance: ROC-AUC 0.596, PR-AUC 0.909, sensitivity 0.922, specificity 0.222, and Brier score 0.143. Calibration was suboptimal (intercept 1.72; slope 0.53). Regression performance was limited: holdout R2 = - 0.000 for 12-month ODI and R2 = 0.053 for 12-month back-pain VAS. High rates of 12-month favourable outcome in both procedures had been attained. Operative efficiency and lesser radiations were enhanced by AUSS; PELD was linked with tissue disturbance minimization, a decrease in the amount of blood loss, and low cost. There was no significant difference in overall complication rates. Exploratory ML models demonstrated little predictive power especially in outcomes related to disability, and in unfavorable minority group, and can only be prospectively validated before any personalised clinical usage. Such findings are hypothesis-generating and they should not be relied on to make clinical judgments alone.

BACKGROUND:Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. METHODS:This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). RESULTS:Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. CONCLUSION:PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Background:Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. The purpose of the current study was to compare beta-lactam plus azithromycin or doxycycline vs fluoroquinolones in adults hospitalized with CAP. Methods:We searched several databases from inception to 10 June 2024. Two reviewers independently screened, selected, and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate with the Cochrane Risk of Bias 2 for randomized studies and the Newcastle-Ottawa Scale for nonrandomized studies. Meta-analysis was conducted by a random effect model when feasible. Network meta-analysis was performed to compare direct and indirect evidence. The GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) was followed to rate the certainty of evidence. Results:Twenty studies were included (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin): 6 were randomized, enrolling 861 participants (mean age, 61.8 years; 43.2% women), and 14 were nonrandomized, enrolling 185 928 participants (mean age, 65.2 years; 42.9% women). Direct comparison and network meta-analysis results showed no statistically significant differences and likely equal effectiveness between beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for intensive care unit admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT prolongation. Conclusions:The current evidence demonstrated no likely difference in outcomes between azithromycin and doxycycline in adults hospitalized with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.

Introduction: Fibrin glue neurorrhaphy (FGN) has demonstrated functional improvements for traumatic peripheral nerve injuries (PNI) in preclinical studies; however, evidence regarding its clinical effectiveness in humans remains limited. Recent advances in regenerative medicine, particularly involving biologics such as platelet-rich plasma (PRP), represent an innovative therapeutic strategy that leverages its neuroprotective, anti-inflammatory, and immunomodulatory effects as well as trophic support for tissue regeneration. To assess the safety and effectiveness of these approaches, we conducted a systematic review comparing FGN and microsuture neurorrhaphy (MN), used either individually or in combination with biologics, for primary peripheral nerve repair. Methods: Systematic literature searches were conducted across multiple databases from 1990 to 2025 in accordance with PRISMA guidelines, and the protocol was registered with PROSPERO. The primary outcome of interest was motor and sensory functional recovery and safety. Other outcomes included neurophysiological examinations, pain or discomfort and operating time. The Revised Cochrane Risk of Bias Tool for Randomized Trials(RoB2) and Newcastle-Ottawa Scale(NOS) were used to assess the risk of bias. Results: A total of 164 patients from six studies were included. The mean patient age was 31.43 years, and 61.6% were female. Compared with MN, FGN achieved comparable motor and sensory recovery while offering shorter operative times and simpler technical execution. When combined with PRP, faster functional recovery was observed, and no major complications were reported. Conclusion: FGN may represent a sutureless alternative to MN with comparable functional outcomes in selected patients for primary peripheral nerve repair. The adjunctive use of PRP may facilitate nerve regeneration and improve functional recovery without introducing major safety concerns. However, given the heterogeneity of nerve types and the high risk of bias among included studies, these findings should be interpreted with caution, and require confirmation in adequately powered future studies.

Objectives This study aims to compare the reliability and accuracy of three large language models (LLMs) (Claude, Gemini and GPT) in assessing the risk of bias of nonrandomised studies using the ROBINS-I tool.Methods and analysis We conducted a secondary analysis of 171 nonrandomised studies previously assessed with Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool by two independent human review teams. Only studies with concordant human domain-level ratings were included. Each study was independently assessed twice by Claude, Gemini and Generative Pre-trained Transformer (GPT) using agent-based structured implementations of the ROBINS-I tool. Reliability (agreement between two runs of the same LLM) was evaluated using percent agreement and Gwet’s AC1. Accuracy (agreement with human reviewers) was assessed only for studies with consistent LLM ratings, using the same metrics.Results Claude demonstrated high reliability across all domains (79.5–98.0% agreement, AC1=0.729–0.975). Gemini showed moderate-to-high reliability (agreement 76.7–100%, AC1=0.680–1.0). GPT exhibited lower reliability overall, though domain-level agreement ranged from 70.9–95.6% (AC1=0.596–0.944). In terms of accuracy, Claude showed overall poor agreement with human reviewers (14.4–68.5% agreement; low AC1 values). Gemini demonstrated moderate-to-high accuracy in several domains, including deviations from intended interventions (79.6%, AC1=0.848) and measurement of outcomes (73.9%, AC1=0.702), with the highest overall agreement (40.0%, AC1=0.672). GPT showed variable accuracy, with the highest in measurement of outcomes (62.8%, AC1=0.571) and classification of interventions (57.8%, AC1=0.498), but poor performance in selection (14.3%, AC1 = −0.041) and overall agreement (23.0%, AC1=0.267).Conclusions Claude was internally consistent but poorly aligned with human reviewers. Gemini achieved both high reliability and moderate-to-high accuracy, whereas GPT had lower reliability and mixed accuracy. Current off-the-shelf LLMs cannot reliably perform ROBINS-I risk of bias assessments.

Objectives:Systematic evidence reviews (SERs) produced by the U.S. Agency for Healthcare Research and Quality (AHRQ) Evidence-based Practice Center (EPC) Program use contextual questions to provide context and background information on the topic. There is currently no standardized approach to address contextual questions in systematic reviews. This study explored the use of publicly available large language models (LLMs) in addressing contextual questions. Study Design:Using a set of 20 published and 5 yet to be published SERs, we selected one contextual question per report and used it as a prompt to elicit answers from an LLM (ChatGPT, Bard, Claude, or Perplexity). Two independent reviewers rated the results using a priori established evaluation criteria (https://osf.io/4k3cu/), comparing the response in the SER to LLM-generated responses. The study was guided by six research questions addressing feasibility, validity of content, validity of structure, mistakes, congruence between responses, and incremental validity of using LLMs to address contextual questions. Results:Using minimal prompt engineering produced relevant responses and documented the feasibility of LLM-generated answers to contextual questions. Responses differed in content and format and are not reproducible (e.g., LLMs update regularly), but LLMs were able to produce articulate, clinically plausible, and well-structured responses. We detected few factual errors, contradictions, and no instance of suspected bias, but citations supporting LLM-generated responses could often not be produced or could not be verified ('confabulations'). Congruence with human generated responses varied, with LLM-generated responses providing more background on the topic and SERs providing more nuanced answers in response to the contextual question. Results regarding incremental validity were mixed and may depend on the tool. Conclusion:LLMs are potentially helpful in addressing contextual questions in systematic reviews but human expertise remains essential for using the generated information in a meaningful way.

Background. Epidemiological studies have shown inconsistent findings regarding the effect of dietary digestible carbohydrate intake on the risk of cardiovascular disease and type 2 diabetes (T2D). Synthesis of such evidence is important for determining the Dietary Reference Intakes (DRI) for carbohydrates, which can have consequences on incidence and morbidity of chronic conditions. Methods. Two systematic reviews were conducted, one addressing cardiovascular outcomes and the second addressing incidence of T2D, body weight, and composition. We searched several databases from January 1, 2000, to July 19, 2024, and searched gray literature. Eligible studies evaluated the outcomes of interest in healthy individuals over 2 years old and isolated the effect of digestible carbohydrate intake from other macronutrients in grams per day or percent of total energy intake. Random-effects dose-response meta-analyses were conducted when feasible. Results. The systematic review on cardiovascular outcome included 21 prospective cohort studies with 1,277,621 participants. The majority of the studies reported inadequate confounding adjustment (73%) and were deemed to have serious risks of bias (80%). No eligible studies evaluated children under 18 years. The association between digestible carbohydrate intake and cardiovascular outcomes was nonlinear and was supported by low strength of evidence. When carbohydrate intake was analyzed as the percentage of total energy intake, the risk of incident cardiovascular disease significantly increased when carbohydrate intake exceeded 65 percent total energy intake, compared with the carbohydrate intake reference level of 50 percent total energy intake. The lowest risk was at a carbohydrate intake level of 50 percent total energy intake. The risk of incident coronary heart disease increased starting at a carbohydrate intake level of 45 percent total energy intake. When carbohydrate intake was analyzed as grams per day, the risk of incident cardiovascular disease significantly increased when carbohydrate intake exceeded 300 grams per day, compared with a reference level of 300 grams per day. The lowest risk was at a carbohydrate intake level of 250 grams per day. The risk of incident coronary heart disease increased starting at 250 grams per day of carbohydrates. The nonlinear relationships were overall similar based on sex or geographic location but with variable intake range associated with the lowest risk. Higher carbohydrate intake was associated with lower levels of high-density lipoprotein-cholesterol and higher levels of triglycerides. The systematic review on diabetes and body composition included 17 studies with 497,941 participants. The majority of the studies reported inadequate confounding adjustment (79%) and were deemed to have serious risks of bias (92%). No eligible studies evaluated children under 18 years. The association between carbohydrate intake and incident T2D was nonlinear and was supported by low strength of evidence. Analyzing carbohydrate intake as a percentage of total energy intake showed a gradual reduction in the risk of incident T2D up to 45 percent total energy intake. The risk then plateaued between 45 percent and 55 percent total energy intake before rising with higher carbohydrate intake levels. Similarly, analyzing carbohydrate intake in grams per day revealed a gradually reduced risk up to 270 grams per day, followed by a plateau between 270–350 grams per day and increased risk after 350 grams per day. The evidence was insufficient to determine an association between carbohydrate intake and weight or body composition. The nonlinear relationships were overall similar based on sex but with variable intake range associated with the lowest risk. Very few studies evaluated intermediate outcomes. Conclusion. Dose-response meta-analyses suggest a nonlinear relationship between the intake of digestible carbohydrates and cardiovascular disease and incident T2D. These associations appear to be U-shaped and suggest certain ranges of carbohydrate intake that were associated with the lowest risk. Such ranges can help in establishing future DRI for carbohydrates, which can have important consequences on incidence and morbidity of chronic conditions and public health.

Background:Nonsuicidal self-injury (NSSI) is a major public health problem leading to psychological problems in adolescents and young adults, similar to disorders such as depression and anxiety. Objective:The aims of this study were to investigate (1) the interaction between BMI and socioenvironmental factors (including chronotype and mental health) that contribute to NSSI, and (2) whether self-esteem plays a mediating role in this association. Methods:From May to June 2022, the multistage cluster sampling method was used to sample college students in four grades, including freshmen and seniors. The baseline participants were followed up 6 months later, excluding those who did not qualify, and the participants included 1772 college students. Socioenvironmental factors (chronotype/mental health), self-esteem, and NSSI were measured using a questionnaire. Multivariate linear regression models and chi-square analysis were used to evaluate the linear relationship between BMI, socioenvironmental factors, and self-esteem and the NSSI status. We use a process approach (mediation-moderation analysis) to explore the complex relationships between these variables. Results:The mean age of the participants was 20.53 (SD 1.65) years at baseline. A significant association was revealed, suggesting that a high BMI (β=.056, 95% CI 0.008-0.086, P=.018) was associated with a higher NSSI. There was also an interaction among BMI, socioenvironmental factors, and NSSI. Socioenvironmental factors played both moderating and mediating roles in the relationship between BMI and NSSI, whereas self-esteem only played a mediating role. Conclusions:Paying attention to factors such as overweight and obesity is important for early BMI control to identify other potential risk factors for NSSI and to evaluate how self-esteem can be improved considering multiple perspectives to improve the effect of BMI on NSSI in adolescents.

572 Background: Neoadjuvant endocrine therapy (NET) is sometimes used to shrink hormone receptor-positive (HR+) breast cancers to improve breast conservation rates and reduce axillary nodal burden. At the beginning of the COVID-19 pandemic, several organizations endorsed NET use to mitigate the harm of surgery delay when cancer operations were less available due to infection transmission concerns. However, the real-world patterns of NET during this period are understudied. This study investigated the alteration of NET utilization patterns during the COVID-19 pandemic in the United States using the National Cancer Database (NCDB). Methods: We identified patients diagnosed with stage I-III invasive HR+/human epidermal growth factor receptor 2-negative (HER2-) breast cancer between 2018-2022 in the NCDB. Estrogen receptor and/or progesterone receptor positivity was required for inclusion in the cohort. Receipt of NET was defined as initiation of endocrine therapy ≥ 14 days before the patient’s first surgical procedure. The study cohort generation and statistical analysis were conducted using Stata and R 4.4.3. A two-tailed p value < 0.05 was considered statistically significant. Results: 495,098 patients were included in the cohort, 195,371 in 2018-2019 (pre-pandemic), 91,686 in 2020 (early pandemic), 106,157 in 2021 (mid-pandemic), and 101,884 in 2022 (late pandemic). NET utilization was increased in the early pandemic compared to the pre-pandemic (seen in 5.8% vs 2.4% of the cohort, Chi-square p value < 0.001), but this use fell back to 3.4% in the mid-pandemic and 3.5% in the late-pandemic. The median (IQR) duration of NET was 15.7 (6.4-26.6) weeks in the pre-pandemic, 9.3 (5.4-18.7) weeks in the early pandemic, 13.2 (5.8-25.7) weeks in the mid-pandemic, and 12.0 (6-24.6) weeks in late pandemic (Kruskal-Wallis p value = 0.001). The transient increase in NET utilization during the early pandemic was more pronounced among patients with tumors < 5 cm and node-negative disease. Conclusions: Our study identified a significant shift in the utilization of NET for HR+/HER2- breast cancer during the COVID-19 pandemic. Pandemic-era NET policies produced a short-lived practice change that was only partially sustained once surgical access normalized. NET utilization (%) by subgroup and year for stage I-III HR+/HER2- breast cancer. Variable Category 2018-2019 2020 2021 2022 Overall NET Use 2.4 5.8 3.4 3.5 Age Group (years old) <50 2.2 4.9 3.9 4.0 >=50 2.4 6.0 3.3 3.4 Tumor Size <5 cm 2.0 5.5 2.9 3.1 >=5 cm 9.0 9.7 11.2 11.6 Histology Subtype Ductal 2.2 5.5 3.3 3.4 Lobular 3.6 7.1 4.4 4.8 Ductal/Lobular 2.6 6.2 4.3 3.6 Other 1.9 6.7 2.5 2.6 KI67 <20% 2.5 6.4 3.4 3.3 >=20% 2.3 5.5 3.5 3.7 Tumor Grade Well differentiated 1.9 5.8 2.4 2.6 Moderately differentiated 2.7 6.1 3.9 3.9 Poorly differentiated/undifferentiated 2.9 4.8 4.3 4.8 Node Positivity Positive 5.2 5.6 9.3 9.5 Negative 2.0 5.8 2.6 2.7

Background:Transcatheter aortic valve replacement (TAVR) has become a standard treatment for severe aortic stenosis (AS). Concomitant mitral regurgitation (MR) is observed in approximately 19%-29% of these patients. Although MR frequently improves after TAVR, persistent MR is associated with worse clinical outcomes, highlighting the need for reliable predictors of MR persistence. Methods:We conducted a single-center, retrospective study that included 53 patients with severe AS and moderate-to-severe MR who underwent TAVR between 2017 and 2024. The primary outcome was MR improvement, defined as a reduction of at least one grade at the 1-year follow-up. To identify independent predictors, we performed multivariable logistic regression analysis. Results:At 1-year follow-up, MR improvement was observed in 67.9% of patients. Multivariable analysis identified persistent atrial fibrillation [odds ratio (OR): 0.099, 95% CI: 0.017-0.575; P = 0.01] and eccentric MR (OR: 0.066, 95% CI: 0.012-0.370; P = 0.002) as independent negative predictors of improvement. Conversely, greater interventricular septal thickness (OR: 1.825, 95% CI: 1.075-3.099; P = 0.026) was a positive predictor. A composite predictive index integrating these three variables demonstrated excellent discriminative ability, with an area under the receiver operating characteristic curve of 0.909. Conclusion:This study identifies persistent atrial fibrillation, eccentric MR, and interventricular septal thickness as key independent predictors of MR improvement after TAVR. The derived composite index, with its outstanding predictive performance, provides a novel tool to aid in patient selection and prognostic assessment.