Citations

Abstract Background Heart failure (HF) is classified by ejection fraction: reduced EF (<40%) is HFrEF and preserved EF (>50%) is HFpEF. Unlike HFrEF, no therapeutic agent improves mortality in HFpEF. The molecular mechanism that produces HFpEF is not completely understood, but the cascade of pathology that produces HFpEF is thought to begin with changes in vascular reactivity, including a decrease in NO mediated vasodilatation, which coupled with subsequent changes in contractility, energetics and coronary blood flow produce HFpEF. If abnormal vascular reactivity is the initial step in the pathological cascade that produces HFpEF, restoring and/or improving vascular reactivity could represent a novel treatment strategy. Vascular reactivity is primarily regulated by myosin light chain phosphatase, which has catalytic, myosin targeting (MYPT1) and 20kDa subunits. Alternative mRNA splicing of exon24 (E24) of the MYPT1 transcript produces MYPT1 isoforms that differ by the presence or absence of a COOH-terminal leucine zipper (LZ+/LZ-); E24 exclusion produces an NO responsive LZ+ MYPT1, while E24 inclusion produces an NO unresponsive LZ- MYPT. Methods We used the mouse two-hit model of HFpEF (high fat diet and L-NAME) and treated mice with an anti-sense octo-guanidine targeting the 5’ splice site of E24 (ASO-E24) to increase the expression of the NO responsive, LZ+ MYPT1 isoform in vascular smooth muscle. Invasive and noninvasive hemodynamics were used to determine LV function. Results Compared to mice with HFpEF, ASO-E24 treatment maintains LZ+ MYPT1 expression (4.7±0.7au v 1.0±0.4au v 2.0±0.4au, control v HFpEF v ASO-E24 Rx, p<0.05), improves diastolic function; LVEDP (10±1mmHg v 20±4mmHg v 14±3mmHg, p<0.05), dP/dtmin (−8000±300mmHg/s v 6000±500mmHg/s v 8500±700mmHg/s, p<0.05), both early (E; 0.60±0.05m/s v 0.42±0.06m/s v 0.64±0.06m/s, p<0.05) and late diastolic filling (A; 0.38±0.03m/s v 0.24±0.02m/s v 0.47±0.04m/s, p<0.050 and also prevents the increase in lung weight (167±5g v 175±7g v 166±5g, p<0.05). Further, mice treated with ASO-E24 maintained normal relaxation to 8Br-cGMP (65±5% v 44±9% v 72±9%, p=0.05). Conclusion These data demonstrate that maintaining normal LZ+ MYPT1 expression and vascular reactivity prevent the development of HFpEF. These results are consistent with the hypothesis that abnormal vascular reactivity is the initial and primary step in the pathological cascade that produces HFpEF and ASO-E24, which is designed to preserve normal LZ+ MYPT1 expression and vascular reactivity, could represent a novel and effective treatment strategy for HFpEF. Clinical Prospective What is New? In HFpEF, an anti-sense octo-guanidine targeting the 5’ splice site of exon 24 (ASO-E24) of the MYPT1 transcript increases the expression of the NO responsive, LZ+ MYPT1 isoform in vascular smooth muscle. Preserving LZ+ MYPT1 expression and normal vascular reactivity prevents the development of HFpEF. A decrease in LZ+ MYPT1 expression contributes to the development of HFpEF. What are the Clinical Implications? The results of the study demonstrate that abnormal vascular reactivity is an important step in the pathological cascade that produces HFpEF Increasing LZ+ MYPT1 expression could represent a novel treatment strategy for HFpEF.

ABSTRACT A previously healthy 29-year-old man presented with abdominal pain and was found to have a liver mass with periductal infiltration and a stricture of the common bile duct, concerning for cholangiocarcinoma. Hepatic function panel disclosed alanine transaminase 293 U/L, aspartate aminotransferase 122 U/L, γ-glutamyl transferase 2019 U/L, normal total bilirubin, carcinoembryonic antigen, and carbohydrate antigen 19-9. Biopsy established the diagnosis of diffuse large B-cell lymphoma, with no underlying hepatic disease. He was started on polatuzumab-rituximab-cyclophosphamide-doxorubicin-prednisone chemotherapy and achieved complete tumor response. This case highlights the importance of a thorough evaluation of liver tumors and the critical role of tissue diagnosis.

Background: Increased posterior tibial slope (PTS) has been associated with higher revision rates after anterior cruciate ligament reconstruction (ACLR). Whether the addition of lateral extra-articular tenodesis (LET) mitigates the risk associated with increased PTS is unclear. Purpose: To determine the prevalence of increased PTS (≥12°) in a young high-risk primary ACLR population and evaluate whether LET is associated with lower revision rates in patients with increased PTS. Study Design: Cohort study; Level of evidence, 3. Methods: This study included patients aged ≤25 years undergoing primary ACLR across 3 high-volume centers with ≥2 years between surgery and data collection. PTS was measured on lateral radiographs for medial and lateral plateaus. Primary analyses consisted of 4 prespecified multivariable logistic regression models with different PTS operationalizations as continuous predictors per 1° increase (medial PTS, lateral PTS, the maximum [PTSmax], and the lateral-medial difference), adjusted for patient and surgical covariates including graft type, with surgical center as a fixed effect. Secondary analyses used PTS dichotomized at 12°; revision rates were compared between isolated ACLR and ACLR with LET, with the treatment effect quantified as absolute risk reduction and number needed to treat. Results: A total of 780 patients were included; 84 (10.8%) underwent revision ACLR. Increased PTS (≥12°) was present in 28.2% of patients and more common in those requiring revision (38.6% vs 27.0%; P = .03). In patients with PTSmax ≥12°, revision occurred in 21.0% without LET and 9.2% with LET (absolute risk reduction, 11.8% [95% CI, 2.3%-21.3%]; number needed to treat, 9); in patients with PTSmax <12°, revision occurred in 13.2% without LET and 5.4% with LET (absolute risk reduction, 7.8% [95% CI, 3.0%-12.6%]; number needed to treat, 13). In the 4 prespecified multivariable models with PTS as a continuous predictor, LET was independently associated with substantially lower odds of revision ACLR (odds ratio [OR], 0.37; 95% CI, 0.22-0.62; P < .001). Lateral PTS (OR, 1.09 per 1° increase; 95% CI, 1.00-1.18; P = .04) and PTSmax (OR, 1.09; 95% CI, 1.00-1.19; P = .04) were independently associated with revision ACLR. The lateral-medial PTS difference was not associated with revision ACLR. Conclusion: In a young high-risk primary ACLR population, increased PTS was present in nearly 30% of patients. LET was associated with a lower risk of revision irrespective of PTS, while increased PTS was independently associated with revision ACLR.

Importance Patients undergoing cardiac surgery with cardiopulmonary bypass often require platelet transfusions for bleeding. Platelets are routinely stored at room temperature (20-24 °C) for up to 5 to 7 days; however, cold storage (1-6 °C) may allow for increased storage duration without loss of hemostatic function. Objective To determine the maximum cold-storage duration, up to 21 days, for which cold-stored platelets (CSPs) are noninferior or superior in hemostatic efficacy to room-temperature platelets (RTPs) when transfused in actively bleeding patients undergoing cardiac surgery with cardiopulmonary bypass. Design, Setting, and Participants A phase 3, multicenter, randomized, partially blinded, adaptive, noninferiority, storage duration–ranging trial conducted in pediatric and adult patients undergoing cardiac surgery with planned cardiopulmonary bypass at 27 sites in the US and Australia from December 2021 to March 2025. Statistical analysis was conducted from September 9 to October 3, 2025. Intervention Patients were randomized 2:1 to receive CSPs with a maximum of 21 days of storage vs RTPs with a maximum of 7 days of storage. Main Outcomes and Measures The primary outcome was a hemostatic efficacy score with values ranging from 1 to 5 and higher values indicating greater bleeding. The noninferiority margin was 1 point. The success criterion was met if at least 1 cold-storage duration of 7 days or more had a posterior probability of noninferiority of at least 97.5%. The secondary outcome was 24-hour chest tube output. Results Of the 1000 patients who underwent platelet transfusion, 989 were included in the primary analysis (650 CSPs and 339 RTPs). The cohort had a mean (SD) age of 42.1 (30.1) years and 67.8% were male. CSPs were noninferior to RTPs for the primary outcome, with a probability of greater than 99.9% for all cold-storage durations. Pooled across storage durations, CSPs had a mean difference from RTPs of 0.09 (95% credible interval, −0.06 to 0.23). Median (IQR) chest tube output at 24 hours (8.9 mL/kg [5.2-15.4] for CSPs vs 8.4 mL/kg [5.5-15.9] for RTPs; difference in medians, 0.4 [95% CI, −1.0 to 1.5]) was not statistically different between study groups. In a post hoc analysis, as all storage durations were noninferior, considering the CSPs as a single group, the hemostatic efficacy score was similar between both groups: mean (SD) of 3.08 (1.15) CSPs vs 2.99 (1.10) RTPs. There were no differences in venous or arterial thrombotic events, transfusion-associated adverse events, acute respiratory distress syndrome, kidney failure, septic shock, and mortality between the study groups, except for increased reexploration rates in the CSP group. Conclusions and Relevance For patients undergoing cardiac surgery, CSPs stored up to 21 days are noninferior to RTPs for the control of active surgical bleeding. Use of CSPs may allow for increased availability of platelets by reducing wastage and shortages and may allow for incorporation of platelets into inventory at locations where platelets cannot be maintained due to the 5- to 7-day shelf life of RTPs. Trial Registration ClinicalTrials.gov Identifier: NCT04834414

Despite advances in pharmacogenomics that have led to innovative therapeutic strategies, substantial interindividual variability in drug efficacy and toxicity persists. Both endogenous and exogenous factors contribute to this unexplained variation, resulting in suboptimal treatment effectiveness, unnecessary healthcare costs, preventable mortality, and significant human suffering. The emerging field of exposomics is aimed at addressing the complex exposures that impact human health and offers an opportunity to interrogate how these exposures influence drug actions and outcomes. Here, we introduce pharmacoexposomics as a complementary framework that systematically quantifies the body's metabolic response to drug and environmental exposures using high-resolution mass spectrometry. We then present IndiPHARM (Individualized Pharmacology), a multi-institution, Advanced Research Projects Agency for Health–supported platform designed to integrate population-scale pharmacoexposomics with pharmacogenomics and clinical data to elucidate interindividual variability in drug response, identify adverse reactions, and inform tailored, effective treatment strategies that advance precision medicine.

Financial toxicity is a significant but often overlooked consequence of cancer for adolescents and young adults (AYAs, 15–39 years old), who face limited savings, unstable employment, and insurance gaps that heighten financial stress. As part of a larger initiative to determine whether our cancer center can use an existing social drivers of health (SDOH) screening process to identify patients who may benefit from targeted supportive interventions, we sought to characterize financial strain, toxicity, and SDOH needs in AYAs treated in our cancer center and compare them to both younger and older cancer patients. This is a cross-sectional observational study at Mayo Clinic of patients with an oncology-related department visit between 8 September 2023–4 June 2024 (N = 81,731) who completed routine institutional electronic screenings for financial strain and SDOH. Survey items assessed financial strain, transportation barriers, and food insecurity; institutional billing data captured financial toxicity (unresolved balances, collection referrals, write-offs). AYAs (n = 5655) were more likely than non-AYAs to report medium/high financial strain, have unpaid debt, or have an unresolved balance, referral to a collection agency, or bad debt write-off, with nearly double the odds of medium/high financial strain compared to patients over 40 (OR 2.02, 95% CI 1.84–2.23, p < 0.001). Within AYAs, ages 26–32 bore the greatest burden: 24.2% in the medium/high-risk category, 9.4% with unresolved billing issues or collections, and 11.6% reporting food insecurity. These findings identify AYAs—particularly those 26–32—as a distinct high-risk group for financial toxicity and health-related social needs, underscoring the need for targeted interventions, tailored financial navigation, and policy efforts to reduce economic barriers to care. Future research should evaluate the effectiveness of these interventions in mitigating financial toxicity, addressing health-related social needs, and improving patient outcomes in this population.

ABSTRACT Objectives To investigate pharmacological treatment patterns in individuals with bipolar disorder (BD) with and without comorbid substance use disorder (SUD) and anxiety disorder (AX), we leveraged the Global Bipolar Cohort to analyze cross‐regional practices across North America, Europe, and the Pacific. Methods Fourteen cohorts contributed aggregate data on pharmacotherapy, demographics, diagnostic subtypes, and comorbidities. Proportional meta‐analyses using generalized linear mixed models were conducted to examine prescription trends and identify clinical differences. Results The sample ( N = 11,521) was 60% female and 84% Caucasian. Participants were categorized into four mutually exclusive groups based on comorbidity status: those with comorbid AX only, comorbid SUD only, both AX and SUD, or neither. The AX+SUD subgroup showed higher rates of attention‐deficit/hyperactivity disorder (ADHD), post‐traumatic stress disorder (PTSD), rapid cycling, obesity, and unemployment, reflecting a more severe clinical profile. Regional variations were notable: North American cohorts reported higher prevalence of AX and SUD than European and Pacific cohorts. Antidepressants use for AX were more common in Europe and the Pacific, while North American prescribing patterns were more variable. Benzodiazepine use was high among individuals with SUD across all regions. Lithium and first‐generation antipsychotic prescriptions varied, with higher rates observed in Europe. Conclusions Findings underscore the heterogeneity of BD and the influence of comorbid AX and SUD on illness burden and treatment. Regional prescribing variations underscore the need for context‐specific guidelines. Gaps in data on medication‐assisted treatment for SUD point to areas for future research. These insights can support more individualized and effective care for complex BD presentations.