Citations

ABSTRACT This manuscript summarizes over 30 years of research that began with the novel concept of using intra‐articular gene transfer to treat joint diseases. A notable milestone in this journey was the first‐in‐human transfer of an exogenous gene to a joint, accomplished by the ex vivo delivery of cDNA encoding the interleukin‐1 receptor antagonist (IL‐1Ra) to joints of patients with rheumatoid arthritis. Responding to lessons learned from this study and the prevailing clinical landscape we next developed an in vivo gene delivery system based on adeno‐associated virus (AAV) with osteoarthritis (OA) as the target disease. The safety and efficacy of this vector, sc‐rAAV2.5IL‐1Ra, was demonstrated in the joints of rats and horses leading to a successful IND application to the FDA. In this clinical trial (ClinicalTrials. gov Identifier: NCT02790723) sc‐rAAV2.5IL‐1Ra was injected at escalating doses into the knee joints of nine patients with OA who were followed for 1 year. This trial met its primary outcome measure, safety, and demonstrated that sustained expression of transgenic IL‐1Ra was possible after a single injection of the vector. Patient‐reported outcomes improved, but without a control group it is not possible to determine the influence of a placebo effect. This and other unresolved matters are addressed in a recently‐completed Phase Ib trial (ClinicalTrials. gov Identifier: NCT05835895). Beyond OA, sc‐rAAV2.5IL‐1Ra has potential therapeutic value in a variety of degenerative, inflammatory, fibrotic and autoimmune conditions. More generally, gene therapy holds much promise in the field of regenerative medicine, including regenerative orthopaedics. Trial Registration: (ClinicalTrials. gov Identifier: NCT02790723, NCT05835895).

ABSTRACT Based on anecdotal observation of fatty infiltration (FI) of the opponens pollicis (OPP) muscle in patients with thumb carpometacarpal (CMC) Osteoarthritis (OA), we sought to examine the association of FI with CMC OA. We reviewed 747 consecutive 3 T wrist magnetic resonance imaging (MRI) studies for evidence of FI in the thenar muscles. This population was divided into two cohorts based on radiographic analysis: a cohort without thumb CMC OA ( n = 440) and a second cohort with thumb CMC OA ( n = 307), staged according to the Eaton–Littler classification. Statistical analysis using logistic regression was performed to investigate clinical factors associated with the presence of FI in the thenar muscles. FI was present in 133 patients with CMC OA (43.3%). FI, when present, was located only in the OPP. We found no OPP FI in the cohort without CMC OA (440 patients). Among patients with CMC OA, increasing age, male sex and advanced OA stage were significantly associated with the presence of OPP FI. OPP FI is a frequent finding in CMC OA. This FI could affect the biomechanical function of the OPP. In the future, we plan to analyze clinical outcomes in CMC OA patients with and without FI, and more focused in vivo studies of OPP function. OPP FI could potentially affect the function and the stability of the thumb CMC joint in patients with CMC OA. Orthopaedic Research Society. Journal of Orthopaedic Research® 00:00–00, 2026.

ABSTRACT Introduction Heart failure with preserved ejection fraction (HFpEF) accounts for about half of the cases of heart failure. HFpEF and atrial fibrillation (AF) often coexist and share similar risk factors. The objective of this study is to examine the differences in risk of clinical outcomes among drug refractory AF patients with concomitant HFpEF treated with catheter ablation (CA) versus antiarrhythmic drugs (AADs). Methods Using the Optum PanTher Electronic Health Record (EHR) database, adult HF patients with left ventricular ejection fraction (LVEF) ≥ 50% and an AF diagnosis with a history of AAD prescription between January 2014 and March 2021 were identified. Patients were classified into CA or AAD groups based on their subsequent treatment for AF. The primary outcome of interest included a composite of AF/atrial flutter (AFL)/atrial tachycardia‐related inpatient admissions and electrical cardioversions in the 57–730 days post‐index treatment period (follow‐up extended to 1095 days for sub‐analysis). Overall HF‐related admissions and systolic HF‐related admissions were assessed as secondary outcomes. Inverse probability of treatment weighting (IPTW) of propensity scores was used to balance the two cohorts on study covariates. Cox regression analyses were performed to examine outcomes in the covariate‐balanced cohorts. Results The final sample included 586 CA and 1436 AAD patients. The cohorts were well balanced on patient demographics and clinical characteristics after applying IPTW. Patients treated with CA had a significantly lower rate of primary composite outcome as compared to those treated with AADs (15.4% vs. 24.9%, log‐rank p test = 0.001). Cox model revealed a 34% lower risk of atrial arrhythmia related admissions and cardioversion among patients treated with CA versus AADs in the 57–730 days post‐index treatment period (Hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.50–0.87, p = 0.003). There were no significant differences in HF and systolic HF‐related admissions between the two groups (except in the subgroup analysis of patients < 70 years of age, patients with paroxysmal AF, and patients with persistent AF). Similar results were observed in sub‐analyses with 57–1095 days of follow‐up. Conclusion Among drug refractory AF patients with concomitant HFpEF, CA was shown to reduce the risk of recurrent arrhythmias as compared to AAD continuation.

Abstract Optimal dosing of prophylactic enoxaparin for individuals ≥150 kg is unknown due to limited inclusion in previous studies. Estimate an optimal weight-based prophylactic enoxaparin dose for individuals ≥150 kg. This multicenter, retrospective study included ≥150 kg adult patients admitted to the hospital between January 2014 and April 2024, who received twice daily prophylactic enoxaparin (goal peak anti-Xa 0.2–0.4 IU/mL). At least one peak anti-Xa was required, obtained 3 to 5 hours after the 3rd consecutive dose. The primary outcome was the range of dosing that produced goal prophylactic peak anti-Xa following linear regression modeling. Secondary outcomes were hospital and intensive care unit (ICU)/progressive care unit (PCU) length of stay (LOS), in-hospital mortality, and VTE/bleed events within 72 hours after an eligible peak anti-Xa. A total of 311 encounters and 388 peak anti-Xa levels were assessed. Patients were 46 (37–55) years old, 53.1% were male, and weighed 183.3 kg (166.1–204.1) with a BMI of 61.3 kg/m2 (54.8–69.4). Creatinine clearance was 179.6 mL/min (126.5–228.2) and patients received 4 doses (4–6) before peak anti-Xa, with a time between of 249 minutes (227–271). Linear regression modeling revealed a statistically significant correlation (r2 = 0.27) between weight-based dose and peak anti-Xa (p < 0.0001). Enoxaparin 0.34 mg/kg (95% CI 0.33–0.36) twice daily was predicted to achieve a peak anti-Xa of 0.3 IU/mL. Hospital LOS was 8 days (4–15), ICU/PCU LOS was 8 days (4–14, n = 158), and only two patients (0.6%) died during hospitalization. One VTE event was observed. Our results suggest an appropriate empiric weight-based prophylactic enoxaparin dose for hospitalized patients ≥150 kg is 0.34 mg/kg twice daily.

Background Patient complaints provide a complementary lens on surgical safety, yet prior analyses have been small and specialty specific. We aimed to characterise themes, perioperative processes, system factors and outcomes in surgical complaints using a scalable, large language model (LLM)-assisted approach. Methods We performed a national, retrospective, cross-sectional, sequential methods study of publicly available investigation reports from the Aotearoa New Zealand Health and Disability Commissioner. All reports published since 1998 were retrieved and screened for relevance across all surgical specialties. A fixed-parameter LLM workflow extracted demographics, clinical context, complications, breached patient rights, system factors and outcomes. An inductive LLM-supported thematic synthesis generated complaint themes, followed by rescoring of theme relevance across reports. Human validation supported the LLM-assisted process (Cohen’s κ >0.85). Results Of 1827 reports screened, 650 involved surgical care. Postoperative complications were frequent (84.2%), commonly accompanied by permanent disability (33.2%) or death (24.2%). Delays in recognition of deterioration (76.1%), escalation (58.3%) and definitive management (49.5%) of complications were common and associated with higher mortality. Prominent themes concerned postoperative clinical management/monitoring, communication/informed consent and professional conduct/competence. Technical/procedural errors and medication errors were comparatively less common. Breaches are most often related to reasonable care and skill, and to informed consent, with marked variation across specialties. Conclusions Complaints about surgical care predominantly reflect postoperative monitoring, escalation and communication rather than intraoperative technical errors. System priorities should include robust deterioration recognition and response, reliable handover and escalation pathways, and strengthened consent and communication processes. An LLM-assisted pipeline can scale complaint analysis to support organisational learning and quality improvement.

Acute kidney injury (AKI) affects thousands of hospitalized patients annually, yet early detection remains challenging as serum creatinine elevation lags behind clinical deterioration. Decreased urine output (UO) represents a key diagnostic criterion of AKI, sometimes manifesting hours before biochemical changes; however, current manual monitoring methods are labor-intensive and prone to error. Here, we developed and validated a simple, cost-effective automated urine flow meter using non-contact optical sensors, a peristaltic pump, and microcontroller-based automation for precise, real-time monitoring of urine output in clinical settings, named P-meter. Three successive prototypes (V1, V2, V3) were validated against gold-standard gravimetric measurements over 285 h of testing during animal experiments that required bladder catheterization. Iterative refinement addressed miniaturization challenges, fluid dynamics optimization, and sensor positioning to achieve progressively improved accuracy. The optimized V3 prototype demonstrated further enhanced volumetric precision, stability, and flow accuracy with near-unity linearity vs. reference method (R2 = 0.9889), minimal bias (mean error −0.1 mL), and 94.18% agreement within confidence limits (n = 86), outperforming the initial V1 prototype (R2 = 0.9971, mean error −1.69 mL, n = 207) and intermediate V2 design (R2 = 0.9941, mean error 3.63 mL, n = 390), primarily in terms of reduced bias and improved agreement. The P-meter offers accurate urine output monitoring at a lower cost than commercial systems, facilitating its use in early AKI detection and thereby improving patient outcomes.