Citations

Abstract Background and aims Rural communities have a high incidence of stroke driven by high prevalence of risk factors. We hypothesize that patient centric stroke prevention education can be delivered in rural communities. Methods High risk patients defined as Atherosclerotic Cardiovascular Disease (ASCVD) 10-year risk of ≥ 20% cardio-cerebrovascular events were identified through electronic medical records receiving primary care in Greenville and Lakeview (intervention sites) and Muskegon (control site) were included. Education material included lifestyle modification and stroke signs-symptoms information. Patients completed a pre-intervention survey, recieved standardized stroke education, and were assessed for knowledge retention through quarterly telephone follow-ups and completed a 12-month post-intervention survey. Total study cost is 130,000$ over 18 months. Results High ASCVD score was identified in 758 (Intervention) and 1128 (Control) patients. 70 intervention and 73 control patients were enrolled. Time spent consenting patients and delivering education is 5 minutes with additional 10-15 minutes at each 3-month follow-up call. 65 intervention patients completed 12 month follow up. Intervention vs. Control; Median: IQR: Age [74 (68-76) vs. 73(68-75) years; p=0.20]; Initial ASCVD [24.5 (22-30) vs. 28.6 (26-37); p<0.001], 12-month ASCVD [25(21-30) vs. 30(24-39); p=0.002). Post-intervention survey showed significant improvement in recognition of stroke risk factors (p<0.001) and stroke signs-symptoms (p<0.001). 49 (75%) patients adopted healthy lifestyle at 12-month follow up. Conclusions A primary stroke prevention cost-effective education program can be successfully implemented in a high-risk rural population, demonstrating improved stroke literacy and healthy lifestyle adoption. Conflict of interest

Background: Several special tests for detecting medial ulnar collateral ligament (MUCL) injuries of the elbow have been described, but data on the clinical utility of these tests are limited. Purpose: To determine the clinical utility of selected elbow special tests to detect MUCL injuries in an athletic population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 84 consecutive patients with sports-related elbow pain underwent a standardized clinical examination. Overall, 6 special tests (moving valgus stress test, static valgus stress test, modified valgus stress test, milking maneuver, pronation flexion resistance test, and temple/cheek press test) were performed. Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio (LR+ and LR–, respectively) were calculated for individual tests and combinations of tests to detect MUCL injuries. Higher values for the LR+ and lower values for the LR– represent stronger clinical utility. Results: For detecting MUCL injuries, the moving valgus stress test resulted in the highest sensitivity (98%) and accuracy (93%) with the lowest LR– (2%). The milking maneuver had the highest LR+ (5.1) with the second highest sensitivity (77%) and accuracy (79%). The pronation flexion resistance test and the temple/cheek press test had the lowest LR+ (1.5 and 1.8, respectively) and highest LR– (94% and 95%, respectively) in addition to the lowest sensitivity (16% and 9%, respectively) and accuracy (33% and 30%, respectively). No combination of tests resulted in increased clinical utility. Conclusion: The moving valgus stress test and milking maneuver demonstrated acceptable clinical utility in which the moving valgus stress test was better for ruling out MUCL injuries and the milking maneuver was better at ruling in MUCL injuries. There was no added value when combining the 2 tests together or with other maneuvers.

ABSTRACT Clinical worsening events are increasingly recognized as a meaningful outcome in pulmonary arterial hypertension (PAH). We applied machine‐learning models to real‐world data to identify clinical features that may predict clinical worsening events in PAH. Data were obtained retrospectively from the electronic health records of adults diagnosed with PAH at Mayo Clinic locations (January 2015–December 2019). Machine‐learning LASSO regularized logistic regression models were developed to analyze the association between 100 clinical features and occurrence of clinical worsening events. In total, 455 patients were included (mean age 62.1 years; 59.3% female). Of these, 232 (51.0%) experienced a clinical worsening event after a median (quartile 1, quartile 3) of 10.9 (4.1, 21.4) months. The best‐performing model had an area under the curve of 0.78, sensitivity of 78%, and specificity of 59%. The model identified 11 clinical features associated with clinical worsening events in PAH with a non‐zero coefficient: baseline age, body mass index (BMI), creatinine level, red cell (erythrocyte) distribution width (RDW), mean pulmonary arterial pressure, pulmonary vascular resistance, sodium concentration, and QT interval, along with dyspnea, number of clinic visits, and other forms of heart disease within a 1‐month window before a clinical worsening event. Baseline RDW and BMI, and number of clinic visits within the 1‐month window were statistically significantly associated with clinical worsening events. Our study used machine‐learning models to identify clinical features associated with risk of clinical worsening events in PAH. Automation of risk prediction could lead to earlier therapeutic intervention to optimize patient outcomes.

Abstract Chronic low‐grade inflammation characterizes type 2 diabetes mellitus (T2DM) and underlies the development of peripheral neuropathy, symptoms of which include mechanical allodynia and an exaggerated exercise pressor reflex. The purpose of this study was to determine whether mechanical allodynia and/or specific concentrations of inflammatory mediators coincide with the presence of an exaggerated exercise pressor reflex. Haemoglobin A1c was assessed to detect diabetes onset (threshold ≥5.6%) in male University of California Davis (UCD)‐T2DM rats ( n = 18). Age‐matched, healthy Sprague–Dawley rats ( n = 18) served as controls. Monthly measurements assessed mechanical allodynia (via paw withdrawal threshold), insulin and inflammatory mediators (via ELISA and multiplex kits). Paw withdrawal threshold was not different between groups prior to diabetes onset. However, by 8 weeks post‐onset, T2DM rats demonstrated a significant decrease in pain threshold compared to that before diabetes onset, which persisted for 8 weeks. This is the same period in diabetes progression as when the exercise pressor reflex is exaggerated. Prior to diabetes onset, UCD‑T2DM rats had significantly higher circulating levels of IL‑6 and IL‑1β, and these elevations persisted throughout disease progression, with only CRP showing a significant increase at 8 weeks post‑onset. These findings offer a useful foundation for further exploration into the assessments of mechanical allodynia and inflammation to determine when those with T2DM are at an increased risk for experiencing adverse cardiovascular events.

ABSTRACT Objective Automated insulin delivery (AID) has been established as an effective therapy for individuals with type 1 diabetes. This analysis evaluates the clinical and economic outcomes of AID compared with multiple daily injections plus continuous glucose monitoring (MDI/CGM) in adults with type 2 diabetes. Materials and Methods The IQVIA CORE Diabetes Model v10.0 was employed to simulate the impact of using the t:slim X2 insulin pump with Control‐IQ+ technology (Control‐IQ+) versus MDI/CGM over a 50‐year period using data from the 2IQP randomized controlled trial (NCT05785832). Trial data informed cohort demographics, intervention effects and resource utilization while literature sources provided health state utilities and costs. Scenario analyses examined the effect of Control‐IQ+ on reducing HbA1c based on alternative HbA1c progression estimates from the Swedish National Diabetes Registry and alternative resource use and treatment effects from real‐world evidence. Results The base case analysis indicated that direct medical costs per individual for type 2 diabetes management with Control‐IQ+ were $239 935 compared to $209 792 with MDI/CGM use. Control‐IQ+ resulted in 0.51 additional quality‐adjusted life years (QALYs: 10.36 vs. 9.85 for MDI/CGM), yielding an incremental cost‐effectiveness ratio (ICER) of $59 417 per QALY, 95% CI: ($55 836, $62 998). In probabilistic sensitivity analyses, 89% of simulations produced ICERs below $100 000/QALY. ICERs across all scenarios remained below $100 000 per QALY. Conclusions Control‐IQ+ is associated with increased life expectancy, higher QALYs and reduced complication rates. These findings suggest that Control‐IQ+ is cost‐effective relative to MDI/CGM for managing patients with type 2 diabetes in the United States.

ABSTRACT Background Ab‐interno canaloplasty (ABiC) may be performed as a standalone procedure or in combination with phacoemulsification (ABiC+Phaco). This study aims to examine the comparative surgical outcomes of both procedures. Methods PubMed, EMBASE and CENTRAL were searched for randomised controlled trials, cohort studies and retrospective case series published from inception to 31 March 2025 that compared outcomes of standalone ABiC and ABiC+Phaco in the treatment of open‐angle glaucoma (OAG). Random‐effects meta‐analysis was performed to pool the mean difference in intraocular pressure (IOP) and glaucoma medications compared to baseline. Results Eight studies with a pooled total of 663 eyes were included in final analysis. There was no significant difference in IOP‐lowering efficacy between ABiC+Phaco and standalone ABiC across all timepoints (6 months, 1 year, 2 years and 3 years) with a mean difference of 0.25 mmHg (95% CI: −0.98 to 1.48) at 3 years. There was also no significant difference in glaucoma medication reduction between ABiC+Phaco and standalone ABiC across all timepoints, with a mean difference of 0.03 medication reduction (95% CI: −0.18 to 0.23) at 3 years. A small IOP‐lowering benefit of ABiC+Phaco versus standalone ABiC in primary OAG‐only studies (mean difference 0.75 mmHg, 95% CI: 0.03–1.47) was observed at 3 years. Conclusion Our meta‐analysis suggests that phacoemulsification may not offer significant additional IOP and glaucoma medication reduction to standalone ABiC. However, results should be interpreted with caution due to a moderate risk of bias across all included studies. Regardless, our findings are consistent with existing literature on the effect of adjunctive phacoemulsification on other ab‐interno MIGS.

Abstract Alzheimer’s disease (AD) is a multifactorial disease with mixed pathologies. Consequentially, drugs targeting multiple pathological processes may offer synergistic benefits. While histone deacetylase (HDAC) inhibitors have demonstrated efficacy in alleviating AD-related pathologies in animal models, the neuroprotective Wnt/β-catenin signaling pathway remains compromised in AD brain. CI-994 is a class I HDAC inhibitor containing N-(2-aminophenyl)-benzamide. Our recent studies indicate that CI-994 is also an activator of Wnt/β-catenin signaling by stabilizing Wnt co-receptor LRP6. We herein use CI-994 as a scaffold to develop novel potent dual modulators of class I HDACs and Wnt/β-catenin signaling for AD therapy. Our lead compound, W2A-28, selectively inhibits class I HDAC1, 2 and 3 with IC 50 values of 0.51 μM, 0.68 μM, and 0.22 μM, respectively, and shows no inhibitory activities on other HDACs. Furthermore, W2A-28 potently activates Wnt reporter activity with an EC 50 value of 1.61 μM in Wnt-3A-expressing HEK293 cells. As expected, activation of Wnt/β-catenin signaling by W2A-28 is associated with elevated LRP6 protein level. Importantly, W2A-28 displays excellent microsomal stability in both mouse and human liver microsomal stability assays, alongside high permeability and a lack of active efflux in MDR1-MDCKII models. Critically, W2A-28 treatment significantly enhances histone acetylation, activates Wnt/β-catenin signaling, and suppresses tau phosphorylation in AD patient-specific cerebral organoids carrying APOE ε4/ε4 or APOE ε3/ε4 with PSEN1 M146V mutation. Our findings position W2A-28 as a promising multi-target drug candidate for AD therapy.

ABSTRACT Serine–aspartate repeat-containing protein D (SdrD) is a Staphylococcus aureus cell wall–anchored, calcium-binding adhesin member of the MSCRAMM Sdr subfamily that may contribute to bacterial adhesion and virulence. S. aureus is the most common cause of periprosthetic joint infection (PJI). Population-level distribution and sequence diversity of SdrD among clinical PJI isolates have not been systematically characterized, and the SdrD binding mechanism is still not well understood. To address these gaps, sdrD alleles were queried across 156 newly sequenced PJI isolates and compared to publicly available S. aureus genomes, and nucleotide– and protein-level phylogenies of the sdrCDE locus constructed. The SdrD crystal structure from S. aureus JH1 was determined, with solution small-angle X-ray scattering (SAXS) and molecular dynamics (MD) simulations, and assessment of conformational changes with calcium depletion. Three dominant sdrD subtypes were defined, associating with USA300, JH1, and TCH60; the JH1 sdrD subtype was predominant among PJI isolates. Structural studies showed that the conformation of individual domains and interdomain organization of the multidomain SdrD have limited flexibility in solution, and that the calcium-binding B domain retains its core fold under conditions of calcium depletion. Together, the findings presented support functional diversification among Sdr family members in mediating host attachment and inform a re-evaluation of the ligand-binding mechanism previously proposed for SdrD. AUTHOR SUMMARY Staphylococcus aureus is the leading cause of infections that develop around joint implants (periprosthetic joint infection, PJI). This bacterium has a large arsenal of surface proteins that allow it to stick to human tissues and implanted devices. This work focused on one such protein, SdrD, which has been linked to implant-associated infections but the structure and diversity of which among patients with PJI had not been well characterized. The genetic sequences of SdrD were analyzed across thousands of bacterial genomes, including those from patients with PJI. Distinct genetic variants of the protein were found, one of which was particularly common with PJI. The three-dimensional structure of SdrD was determined at atomic resolution and solution small-angle X-ray scattering (SAXS) and molecular dynamics used to study how it moves and responds to changes in its environment. Contrary to what was previously described, SdrD was shown to be relatively rigid. These findings change how SdrD’s mechanism of action should be considered, potentially informing design strategies to block bacterial attachment before infection takes hold.

Type 2 diabetes mellitus is associated with an increased risk of several malignancies, prompting interest in the potential oncologic effects of antidiabetic therapies, particularly metformin. This study evaluated cancer-related adverse event reporting associated with metformin compared with other antidiabetic agents using real-world pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS) between Q1 2023 and Q4 2024. A disproportionality analysis was conducted on over 3.2 million reports, including 66,187 metformin cases and 55,257 comparator cases comprising GLP-1 receptor agonists, SGLT2 inhibitors, sulfonylureas, and insulin. Reporting odds ratios (ROR), proportional reporting ratios (PRR), information components (IC), and chi-squared tests were applied across twelve pre-specified cancer types.<br /> Metformin was associated with significantly lower reporting of hepatocellular carcinoma (ROR 0.377, 95% CI 0.181–0.782) and pancreatic carcinoma (ROR 0.669, 95% CI 0.493–0.908). In contrast, increased reporting signals were observed for prostate cancer (ROR 2.065, 95% CI 1.435–2.972), leukaemia (ROR 2.388, 95% CI 1.155–4.939), and breast cancer (ROR 1.404, 95% CI 1.023–1.926). Drug-specific comparisons indicated relatively lower overall cancer reporting for metformin compared with sitagliptin and empagliflozin, but higher reporting compared with insulin. Temporal analyses demonstrated variability in reporting patterns across study quarters.<br /> These findings represent disproportionality signals reflecting reporting associations rather than causal effects and may be influenced by reporting bias, residual confounding, and differences in healthcare utilization. Overall, the results suggest a heterogeneous, cancer-type-specific reporting profile for metformin and highlight the value of pharmacovigilance analyses in generating real-world safety signals. Further confirmation in prospective and mechanistic studies is required.