Citations

BACKGROUND: Opioids prescribed for acute pain frequently remain unused, creating opportunities for unintended use, accidental ingestion, or diversion. Little is known about counseling patients receive from prescribers or pharmacists on storage and disposal of opioids. OBJECTIVE: To characterize clinician counseling on opioid disposal and patient-reported storage, use, and disposal practices among opioid-naive patients prescribed opioids for acute pain. DESIGN: Multicenter prospective cohort study with participant recruitment between September 2020 and March 2023. PARTICIPANTS: Opioid-naive patients prescribed opioids for acute pain in emergency departments, primary care or urgent care clinics, inpatient settings, and dental practices. MAIN MEASURES: Patient-reported receipt of counseling on the importance of opioid disposal and appropriate disposal methods; opioid storage practices; use and disposition of prescribed opioids; disposal methods; and reasons for keeping or disposing of leftover opioids. KEY RESULTS: Among 1708 participants, the median age was 38 years (IQR, 28-52); most were recruited from emergency departments (n=915; 53.6%) and primary care or urgent care clinics (n=307; 18.0%). Among 1233 participants who answered the question on counseling about the importance of opioid disposal, 811 (65.8%) reported receiving no counseling. Among 1220 participants who answered the question on counseling about appropriate disposal methods, 832 (68.2%) reported receiving no counseling. Among 812 participants who answered the question about storing opioids in a locked location, 610 (75.1%) reported never doing so. Among 929 participants providing information on opioid leftovers and disposition, 618 (66.5%) did not use all prescribed opioids. Among these 618 participants, 258 (42.8%) kept leftover opioids and 345 (57.2%) disposed of them. Among 256 participants who reported reasons for keeping leftover opioids, 159 (62.1%) wanted medication available for the same condition, 70 (27.3%) wanted medication available for a different condition, and 36 (14.1%) did not know how to properly dispose of the medication. CONCLUSIONS: Among opioid-naive patients prescribed opioids for acute pain, counseling about opioid disposal was uncommon, secure storage was infrequent, and leftover opioids were frequent, with many patients keeping leftover opioids for possible future use. These findings suggest opportunities to improve counseling on opioid storage and disposal and encourage safe disposal of unused opioids after acute pain treatment.

Abstract INTRODUCTION Combining Alzheimer's disease blood biomarkers may improve prediction of amyloid positivity (A+) compared with single biomarkers. METHODS Logistic regression models using plasma phosphorylated tau 217 (p‐tau217), amyloid beta (Aβ) 42, and Aβ40 were developed in cognitively impaired (CI) participants from Mayo Clinic Rochester (MCR) and validated in Alzheimer's Disease Neuroimaging Initiative (ADNI) and Mayo Clinic Florida (MCF) cohorts. Performance was measured by area under the curve (AUC) and Probability of Amyloid Positivity Score (PAPS). RESULTS Plasma p‐tau217 alone showed high AUC (95% confidence intervals) across cohorts MCR, 0.928 (0.900–0.953); ADNI, 0.938 (0.915–0.959); MCF, 0.935 (0.893–0.970). Adding Aβ42 to regression models yielded marginal model improvement MCR, 0.940 (0.915–0.963); ADNI, 0.945 (0.922–0.965); MCF, 0.960 (0.925–0.986). Utilization of two cutpoints (≥ 90% sensitivity and specificity), yielded ≤ 10% intermediate results for p‐tau217, and ≤ 8% for p‐tau217+Aβ42. Addition of Aβ40 did not improve models’ performance. DISCUSSION An immunoassay‐based p‐tau217 PAPS model accurately predicted amyloid positivity across independent CI cohorts and achieved confirmatory‐test performance with two cutpoints. The added value of Aβ42 was modest and cohort dependent, supporting the potential of use of p‐tau217–based PAPS in clinical workflows.

Purpose Immune checkpoint inhibitors (ICIs) are integral to first-line treatment of metastatic non–small cell lung cancer (NSCLC). Circadian biology may influence antitumor immunity, raising the hypothesis that time-of-day of ICI administration could affect outcomes. We evaluated the association between initial and cumulative ICI administration time-of-day and clinical outcomes in metastatic NSCLC. Materials and Methods We conducted a retrospective cohort study of 778 patients with metastatic NSCLC treated with first-line ICI-containing therapy across Mayo Clinic sites between January 2021 and March 2024. Patients were stratified by time-of-day of first ICI administration: early (0700-1200) versus late (1201-2400). Primary end points were overall survival (OS) and progression-free survival (PFS); the secondary end point was immune-related toxicity. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates. Exploratory analyses evaluated cumulative infusion time-of-day and alternative administration-time thresholds using spline and cut-point analyses. Results Of 778 patients, 277 received early and 501 received late initial ICI administration. Median OS was 1.33 versus 1.48 versus years and median PFS was 0.65 versus 0.67 years in the late and early groups, respectively. Time-of-day of initial ICI administration was not associated with OS (HR, 1.01 [95% CI, 0.85 to 1.20]) or PFS (HR, 1.03 [95% CI, 0.88 to 1.21]). Findings were unchanged after multivariable adjustment. Immune-related toxicity occurred in 26.9% and 24.2% of patients in the late and early groups, respectively ( P = .40). Cumulative infusion time-of-day was not associated with OS or PFS, and spline analyses identified no significant administration-time threshold associated with outcomes. Conclusion In this large real-world cohort of patients with metastatic NSCLC, neither initial nor cumulative ICI administration time-of-day was associated with survival or immune-related toxicity. Prospective studies incorporating chronotype and circadian biomarkers are warranted to further define the role of chronotherapy in immuno-oncology.

BACKGROUND AND OBJECTIVES: Surgery for cervical spondylotic myelopathy improves quality of life but remains expensive. We conducted a cost-effectiveness analysis of patients treated with anterior cervical diskectomy/fusion (ACDF), posterior cervical decompression/fusion (PCDF), and laminoplasty (LP) in the Cervical Spondylotic Myelopathy Surgical (CSM-S) Trial, a randomized trial comparing surgical approaches for cervical spondylotic myelopathy. METHODS: In the trial, patients were randomized (2:3) to anterior (ACDF) or posterior surgery (LP or PCDF, at surgeon's discretion). A cost-effectiveness analysis was performed from a societal perspective with a 1-year time horizon, including only US patients as-treated. Cumulative costs were estimated using patient data on utilization and lost productivity using a human capital approach. Direct costs were calculated using 2022 Medicare rates for professional fees and cost-to-charge ratios for hospital services. Quality-adjusted life-years (QALYs) were calculated from patient responses to the EuroQol-5-Dimensions instrument at baseline and 3, 6, and 12 months postoperatively. Incremental cost-effectiveness ratio analysis was performed with bootstrapping to address uncertainty. RESULTS: Of 163 total patients enrolled in the CSM-S Trial, 153 from the United States (mean age, 62 years; 80 (52%) female) were included as-treated (ACDF = 61, PCDF = 64, LP = 28) in a cost-effectiveness analysis. Economic data were not available for 9 patients. The remaining 144 patients treated (ACDF = 55, PCDF = 61, LP = 28) had cost data through a 1-year follow-up. Mean hospitalization costs were higher after PCDF than ACDF and LP ($33 410 vs $26 468 vs $25 550; P < .001). Mean total costs were higher after PCDF than ACDF and LP ($62 383 vs $53 074 vs $47 426; P = .017). LP yielded greater QALY gains than ACDF (0.792 vs 0.732; P = .08) and PCDF (0.792 vs 0.698; P = .01). At a willingness-to-pay threshold of $150 000/QALY-gained, the probability that LP was cost-effective compared with PCDF was 99.7% and the probability compared with ACDF was 96%. CONCLUSION: In the CSM-S Trial, LP yielded greater 1-year quality-of-life improvements at lower costs than PCDF and ACDF.

Background Sudden cardiac death (SCD) is the leading cause of duty‐related death among firefighters. Understanding postmortem cardiovascular abnormalities associated with SCD is critical to guiding fire service cardiovascular disease screening and prevention programs. Methods This study included US firefighters who had a duty‐related death over a 16‐year period (1999–2014) with available postmortem reports (autopsy/medical examiner reports). Cases were systematically reviewed to identify cases of SCD. For each SCD case, the primary etiology of SCD was adjudicated by experts in sports cardiology and cardiovascular pathology. Results Postmortem evaluations were available for 794 of 2100 (37.8%) on‐duty firefighter deaths over the study period (average age, 44±13 years; age range, 17–82 years; 4.0% women). A total of 312 of 794 (39.3%) firefighter deaths were adjudicated as SCD. A total of 255 of 312 (81.8%) SCD events were attributable to coronary artery disease/ischemic heart disease or hypertensive heart disease, which both are associated with traditional cardiovascular risk factors. The leading etiology of SCD among young firefighters (aged <40 years) was also coronary artery disease/ischemic heart disease (24/50 [48.0%]). Of firefighters who had an exertional SCD event thought to be secondary to coronary artery disease (n=97), a total of 62 of 91 (68.1%) had severe fixed coronary stenosis, while 29 of 91 (31.9%) demonstrated acute plaque rupture/thrombosis. Conclusions More than 80% of on‐duty SCD events among US firefighters are due to coronary artery disease and hypertensive heart disease that may be prevented by early disease identification and risk factor modification. Future studies should assess the efficacy of more rigorous firefighter cardiovascular disease screening and management practices.

ABSTRACT Artificial intelligence (AI) has emerged as a transformative technology in the fields of medicine and ophthalmology. Recent advances in machine learning, deep learning and convolutional neural networks have significantly improved cataract detection and grading, intraocular lens power calculations, surgical decision‐making, risk prediction and patient education. Intraoperative AI‐assisted surgical phase recognition, workflow analysis, real‐time guidance, robotic technologies and femtosecond laser integration can improve surgical precision, efficiency and safety. AI has shown promise in predicting visual outcomes, detecting postoperative complications and facilitating telemedicine follow‐up. Though challenges with AI include transparency, data diversity, regulatory oversight and clinical validation, continued advances are expected to further personalise cataract surgery, support clinical decision‐making, optimise surgical performance and improve patient outcomes. This narrative summarises the current and emerging applications of AI in preoperative, intraoperative and postoperative management of cataracts.

ABSTRACT Background and Objectives Among patient with early‐stage breast cancer, breast conservation surgery (BCS) is the most performed surgery, utilized in approximately two‐thirds of patients. While 5‐year overall‐survival rates are strong—typically above 90%—additional re‐excisions can occur in up to 25% of patients who undergo index BCS and some patients will require subsequent surgery for new breast cancer or recurrences. As such, these additional procedures can complicate patients’ pathway to survivorship, negatively impact quality of life, and lead to excess healthcare costs. Methods This retrospective cohort study used linked claims and an electronic healthcare record database to (1) characterize patients at higher risk for additional breast oncologic surgery (aBOS) following BCS, and (2) quantify the long‐term financial impact of aBOS after BCS. In total, 87,190 patients with breast cancer, who had an index BCS between January 1, 2012, to March 31, 2023, were followed for up to 5‐years post‐operatively. Patients with and without aBOS were analyzed, comparing demographics, tumor characteristics, healthcare utilization, and per‐person‐per‐month (PPPM) costs. Results Twenty‐three percent ( n = 20,212) of patients underwent aBOS. These patients were younger, had higher tumor grades and larger tumor sizes, and incurred greater healthcare costs compared to patients who did not undergo a secondary surgery. Conclusion This study highlights significant factors influencing BCS outcomes and healthcare utilization, underscoring the need for tailored therapeutic strategies for patients with breast cancer.

BACKGROUND: Type 2 long-QT syndrome results from KCNH2 -encoded Kv11.1 loss-of-function, but whether secondary inward-current dysfunction amplifies dysfunction remains unclear. METHODS: We characterized sodium ( SCN5A , I Na ) and L-type calcium channel ( CACNA1C , I Ca ) function in KCNH2-G604S and variant-corrected isogenic control induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs). Whole-cell patch-clamp measured action potential duration at 90% repolarization (APD90), and potassium (I Kr ), sodium (I Na ), and calcium (I Ca, L ) currents. Fluo-4 imaging quantified calcium transients. A modified Kernik-Clancy iPSC-CM model incorporated experimentally measured persistent I Na,L and I Ca,L fractions and simulated isolated and combined current defects. RESULTS: KCNH2-G604S caused severe I Kr loss-of-function (72.5% reduction). APD90 was prolonged in G604S-iPSC-CMs (765±58 ms) compared with isogenic controls (368±37 ms; P <0.005), with early afterdepolarizations in 50% of G604S cells. Nifedipine, verapamil, and mexiletine successfully shortened APD90 and abolished early afterdepolarizations. Compared with isogenic control, I Na,L (0.60±0.1% versus 0.26±0.06%; P <0.01), persistent I Ca,L (2.88±0.55% versus 1.26±0.35%; P <0.05), and calcium transient decay times ( P <0.0001) were greater in G604S iPSC-CMs. Increased persistent I Ca,L was phenocopied by E-4031 in isogenic controls and reduced by nifedipine in G604S iPSC-CMs. In silico modeling revealed that the I Kr defect alone prolonged APD90 to only 620 ms. The addition of the observed I Na,L defect had a small additive effect (+20 ms); however, incorporating persistent I Ca,L synergistically extended APD90 to 758 ms, replicating the experimental phenotype. Flux dynamics analysis indicated that this persistent Ca 2+ entry suppresses the forward-mode sodium-calcium exchanger, forcing a compensatory reliance on sarcoplasmic-endoplasmic reticulum Ca-ATPase that primes for calcium instability. CONCLUSIONS: The KCNH2-G604S variant drives a severe multihit phenotype via primary I Kr loss-of-function and secondary state-dependent gain-of-function in persistent I Ca,L . These comprehensive validations demonstrate that the remodeled persistent I Ca,L acts as the essential amplifier driving extreme action potential duration prolongation and Ca 2+ mishandling.

ABSTRACT Background Left atrial appendage occlusion (LAAO) has emerged as a non‐pharmacological alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). Following the publication of recent CHAMPION‐AF and CLOSURE‐AF trials, an updated synthesis of evidence is warranted to clarify the long‐term comparative efficacy and safety of LAAO versus OAC in patients with AF. Methods We conducted a systematic review and meta‐analysis of randomized controlled trials (RCTs) comparing LAAO with OAC in adults with AF. A comprehensive search of major databases was performed from inception to April 2026. The primary efficacy outcomes were major adverse cardiovascular events (MACE) and stroke. The primary safety outcome was non–procedure‐related bleeding. Random‐effects models were used to calculate pooled risk ratios (RRs) with 95% confidence intervals (CIs). Results Six RCTs including 7,004 patients (3,681 LAAO; 3,323 OAC) were analyzed. No statistically significant difference was observed for MACE (7.5% vs 6.9%; RR 1.03, 95% CI 0.79‐1.34) or stroke (3.7% vs 3.2%; RR 1.07, 95% CI 0.80‐1.43). LAAO was associated with a significantly lower risk of non‐procedure‐related bleeding (9.8% vs 16.7%; RR 0.63, 95% CI 0.52‐0.77), corresponding to an absolute risk reduction of 6.9% and an approximate number needed to treat of 15 based on crude pooled event rates over the observed trial follow‐up. Trial sequential analysis indicated that the accumulated evidence for MACE and stroke remained inconclusive. Comparator‐type subgroup analyses showed no significant interaction for MACE ( p = 0.67) or stroke ( p = 0.81) between contemporary predominantly‐DOAC and VKA comparator trials. Conclusions LAAO was associated with lower non‐procedure‐related bleeding, while no statistically significant differences were observed for MACE or stroke. The available efficacy evidence remains inconclusive regarding equivalence or non‐inferiority, and larger trials are needed. These findings support individualized consideration of LAAO when the long‐term bleeding burden of anticoagulation is clinically important.