University of Texas Southwestern Medical Center

Aim This study aimed to evaluate associations in bipolar disorder (BD) across multimodal measures of white matter microstructure (using diffusion tensor imaging; DTI), cognitive, behavioral, and brain electrophysiological measures (using electroencephalography; EEG). Methods Subjects were recruited through the Psychosis and Affective Research Domains and Intermediate Phenotypes Consortium ( n = 45 bipolar with psychosis, n = 40 bipolar without psychosis, n = 66 healthy subjects). DTI data were used to quantify the white matter variables, fractional anisotropy (FA) and radial diffusivity (RD). The Brief Assessment of Cognition in Schizophrenia (BACS), Stop Signal Task (SST), pro‐ and anti‐saccades, auditory event‐related potentials (ERPs), and intrinsic brain activity were used as estimates of brain function. Results The combined BD group differed from healthy controls, but no differences between BD with and without psychosis were observed. BD‐related white matter abnormalities were seen across multiple tracts: right cingulum–cingulate gyrus, bilateral anterior thalamic radiation, bilateral superior longitudinal fasciculus, right inferior longitudinal fasciculus, and forceps major. Results also showed modestly compromised cognitive performance and elevated intrinsic EEG activity associated with BD. Conclusions Further analysis indicated worse white matter integrity related to higher intrinsic EEG and modestly higher ERPs. These multimodal analyses are likely to aid in creating future informative diagnostic, etiological, and treatment targets for BD.

The most common form of hereditary transthyretin cardiac amyloidosis (hATTR-CA) in the United States and the United Kingdom is the p.V142I variant. About 3% to 4% of patients with African ancestry carry this genetic predisposition to develop signs and symptoms of hATTR-CA. Nevertheless, clinical manifestations of hATTR-CA appear only late in the fifth and sixth decades of life, despite its clear genetic background. Imbalances in native protein-stabilizing and elementary breakdown cellular mechanisms are postulated as potential causes for affecting transthyretin structural integrity and myocardial fibril deposition. Noncoding variants, epigenetic and environmental factors, as well as gut microbiome derangements may serve as disease-modifying factors that feature detrimental amyloidogenic organ involvement and impact disease severity. Organ amyloid deposition varies widely among different carriers of a genetic transthyretin variant. The genotype-phenotype interdependence causes unpredictable phenotypic penetrance that results in a variety of signs and symptoms and patient outcomes. Cardiovascular biomarkers and multimodality imaging may identify initial amyloidogenic organ involvement. These early clinical clues through the course of hATTR-CA offer a window of opportunity for early treatment onset to cease disease progression and alter prognosis. Identifying at-risk patients requires information on the genetic background of probands and their relatives. Initiatives to reveal asymptomatic gene carriers early in the disease should be encouraged, as it necessitates stringent patient follow-up and immediate treatment onset to reduce the burden of heart failure hospitalization and mortality in hATTR-CA.

Background MAPK pathway inhibitors (MAPKi) have shown significant efficacy in treating childhood BRAF-activated brain tumors. For tumors harboring BRAFV600E mutations, the drugs are rarely curative, and patients can become refractory to treatment. MAPKi combining X-radiation therapy (XRT) may improve cure rate, but development of XRT-resistance is a challenge. Methods XRT-resistance was induced by multiple XRT cycles in pediatric BRAFV600E glioma patient-derived xenograft (PDX) models. RNA sequencing was performed to identify differentially expressed genes and pathways potentially contributing to XRT-resistance. Cells isolated from PDXs were used to test the contribution of specific genes and pathways to XRT-resistance. PDX models were used to evaluate the efficacy of targeted treatments combined with XRT. Results Tumors developed resistance after multiple cycles of XRT. MEK inhibition combining XRT significantly improved tumor control, compared to XRT alone, but resistance to combined therapy developed rapidly. RNA-sequencing analysis revealed up-regulation of MAPK and PI3K-mTOR signaling in the XRT-resistant tumors. Isolated cells showed in vitro resistance to XRT, which was partially reversed by inhibiting PI3K-mTOR. Up-regulation of TORC1 signaling in XRT naïve tumor cells, via constitutively active AKT or TSC2 deletion, conferred in vitro XRT-resistance.The pro-survival gene BIRC5 (Survivin), a target of TORC1 signaling, contributed to XRT-resistance. Combining trametinib-rapamycin with XRT significantly enhanced therapeutic efficacy in PDX models and prevented or delayed resistance development. Conclusion PI3K-mTOR activation promotes the development of XRT-resistance in pediatric BRAFV600E glioma. Dual targeting of MAPK and TORC1 signaling significantly enhances the therapeutic efficacy of XRT, and can potentially prevent the development of XRT-resistance. (250 words)

Tandem occlusions, characterized by the simultaneous occurrence of both extracranial and ipsilateral intracranial arterial occlusions, represents a challenging subset of large vessel occlusion (LVO) strokes. Currently, the treatment choice for tandem infarcts involves intravenous thrombolysis (IVT) followed by endovascular thrombectomy (EVT). In current literature, direct head-to-head comparisons between Alteplase and Tenecteplase for IVT in patients with tandem occlusions remain limited. The goal of this systematic review and meta-analysis is to synthesize the currently available data comparing the efficacy and safety profiles of alteplase and tenecteplase specifically in patients with tandem occlusions. We systematically searched PubMed, Embase and Cochrane from inception to June 2024 for studies enrolling patients with tandem lesions in acute ischemic stroke (AIS) treated with IVT involving Tenecteplase or Alteplase. The primary outcomes of interest were (1) modified Rankin Scale (mRS) 0–1, (2) modified Rankin Scale (mRS) 0–2, (3) successful recanalization (TICI 2b-3), (4) symptomatic intracranial hemorrhage (sICH) and (5) overall mortality. We compared the results using Risk Ratio (RR) with 95% Confidence Intervals (CI). A random effects model was applied for all outcomes. The Mantel–Haenszel method was used to pool results from individual studies. We also used I² statistics and Cochran Q test to verify heterogeneity. Three studies published between 2023 and 2024 were included, two randomized controlled trials (RCTs) and one observational study, comprising 917 patients. Tenecteplase was administered for 230 (25,1%) patients. The age ranged from 57 to 82 years, the baseline NIHSS ranged from 10 to 24 points and there were 314 (34.2%) female patients in total. There was no statistically significant difference between groups for the outcomes of mRS 0–1 (RR 0.80; 95% CI 0.35 to 1.83; p = 0.597; I² = 86%), mRS 0–2 (RR 1.04; 95% CI 0.88 to 1.23; p = 0.630; I² = 0%), TICI 2b-3 (RR 1.00; 95% CI 0.93 to 1.09; p = 0.909; I² = 0%), sICH (RR 1.09; 95% CI 0.64 to 1.84; p = 0.756; I² = 0%), and overall mortality (RR 0.68; 95% CI 0.45 to 1.05; p = 0.081; I² = 17%). This meta-analysis found that tenecteplase achieved similar outcomes to alteplase in improving functional outcomes and recanalization rates. Additionally, there was no significant difference between tenecteplase and alteplase in terms of rates of sICH and mortality. Further large-scale randomized studies are urgently needed to provide a definitive conclusion on the comparative efficacy and safety of tenecteplase versus alteplase in tandem occlusions. Graphical Abstract

Background Limited data exist on noncardiac surgery patients with prior percutaneous coronary intervention (PCI) in the contemporary era. The objective was to examine rate, characteristics, and outcomes of patients who underwent noncardiac surgery within 2 years of PCI and develop a risk model of factors that predict long‐term postoperative outcomes among patients with recent PCI. Methods and Results Patients in the Veterans Affairs Surgical Quality Improvement Program database who underwent noncardiac surgery between October 1, 2017 and September 30, 2021 were included. Patients with versus without PCI within 2 years were propensity matched to examine major adverse cardiovascular events (MACE), defined as a 1‐year composite of mortality, revascularization, and rehospitalization for myocardial infarction or stroke. Among patients with recent PCI, multivariable logistic regression was used to develop a risk model to predict 1‐year postoperative MACE. Among 334 828 patients undergoing surgery, 2297 (0.68%) had PCI within 2 years. Among 9160 propensity‐matched veterans, there was no difference in MACE between patients with and without preceding PCI (hazard ratio [HR], 1.04 [95% CI, 0.96–1.17]). Patients with versus without preceding PCI within 2 years had lower risk of all‐cause death (HR, 0.83 [95% CI, 0.72–0.96]) but higher risk of revascularization (HR, 1.88 [95% CI, 1.50–2.36]) at 1 year. A 13‐component MACE prediction model among patients with recent PCI had moderate discrimination (area under the receiver operating characteristic curve 0.73 derivation, 0.72 validation). Conclusions Among patients who underwent surgery, risk of MACE did not differ, but the risk of revascularization was higher and all‐cause death was lower in patients with versus without recent PCI. A risk model can be used to stratify risk of surgery among patients with preceding PCI.

Background Black and Hispanic patients with heart failure (HF) have a higher risk of adverse clinical outcomes. Currently, it is unclear whether there are disparities in referral to outpatient HF management programs based on race and ethnicity. Methods and Results We used the American Heart Association GWTG‐HF (Get With The Guidelines‐Heart Failure) registry to examine 402 225 patients hospitalized for acute HF from January 1, 2010 to December 31, 2021. Logistic regression was used to examine the association of race and ethnicity with the likelihood of referral to outpatient HF management programs, adjusted for demographics, hospital characteristics, distressed community index score, comorbidities, and indicators of HF severity. Of the 402 225 patients hospitalized for acute HF during the study period (mean age 72 years, 47% female, 44% with ejection fraction <40%), 220 354 (55%) patients were referred to an outpatient HF management program at hospital discharge. In fully adjusted models, patients who self‐identified as Hispanic (odds ratio [OR], 0.87 [95% CI, 0.84–0.90]), Asian (OR, 0.74 [95% CI, 0.70–0.78]), and other (American Indian, Alaska Native, Hawaiian Native, or Pacific Islander, OR, 0.85 [95% CI, 0.82–0.89]) had a lower likelihood of referral to outpatient HF management programs than White patients. There were no differences in referral likelihood between Black and White patients. Conclusions In the GWTG‐HF registry, patients from minoritized racial and ethnic groups, aside from Black patients, were less likely than White patients to be referred to outpatient HF management programs after HF hospitalization. Addressing these differences in referral practices may improve HF outcomes in minoritized communities.

Context Patients with familial partial lipodystrophy (FPLD) have increased risk of hepatic steatosis and its complications for which there is no approved therapy. Objective To investigate the efficacy and safety of obeticholic acid, a farnesoid X receptor agonist, for reducing hepatic steatosis in patients with FPLD. Design Randomized, double-blind, placebo-controlled, cross-over trial. Setting Academic referral center. Patients 10 females with Dunnigan variety of FPLD (FPLD2), harboring pathogenic heterozygous variants in lamin A/C gene, (age 19-60 years) and hepatic steatosis (liver fat > 5.6% by proton-density fat fraction mapping by magnetic resonance imaging). Intervention Obeticholic acid 25 mg daily versus matched placebo for 4 months each with a 4 month wash out period in-between. Main Outcome Measures Primary end point variable was liver fat. Secondary endpoint variables were serum triglycerides and aminotransferases levels. Results All patients completed the trial. Obeticholic acid therapy caused significant (39.6%) reduction in liver fat as compared to placebo (median liver fat (minimum – maximum); 6.4% (2.4% - 18.0%) vs. 10.6% (3.4% - 29.3%), respectively; P value for treatment x month interaction = 0.03). There were no significant differences in serum triglycerides or aminotransferases levels during obeticholic acid and placebo therapy. Overall, obeticholic acid was well tolerated except for itching in four patients compared to two on placebo. Obeticholic acid, as compared to placebo, caused 24% increase in serum low density lipoprotein-cholesterol (mean 129 mg/dL vs. 104 mg/dL, respectively; P = 0.0016). Conclusions Obeticholic acid is safe and effective in lowering hepatic triglyceride levels in patients with FPLD2.

Introduction Experts suggest doxorubicin clearance is decreased in women with a body mass index (BMI) of ≥35 kg/m ² . However, few data support this recommendation. Methods Women receiving doxorubicin for breast cancer in three BMI groups were recruited (n = 15). Doxorubicin dosing was determined by body surface area and was administered by 30-min intravenous infusion. Blood samples were obtained at 0 h (pre-dose) and 0.5, 1, 1.5, 2, 3, 4, 5, 12–24, and 24–72 h following the beginning of infusion. Concentrations of doxorubicin and its metabolite, doxorubicinol, were assayed by LC-MS/MS. Non-compartment analysis was done using PKanalix2021R2 for pharmacokinetic (PK) analyses. Results The median [range] BMI and age were 30.3 [23.5–57] kg/m ² and 53 [31–69] years. Thirteen of the 15 women had samples available for analysis. Four of the 13 had a BMI ≥ 35.0 kg/m ² . PK parameters ranged from 37.8% (AUC 0−inf ) to 91.0% (Vd). Doxorubicinol PK parameters ranged from 37.8% (C max ) to 67.6% (AUC 0−inf ). The average doxorubicinol:doxorubicin AUC lasts ratio was 0.26 (range: 0.04–0.88). A t-test didn’t suggest a significant difference in individual PK parameters (BMI < 35 kg/m ² vs. ≥35.0 kg/m ² ). The two highest clearances (380 L/h and 250 L/h) had a BMI ≥ 35.0 kg/m ² ; also, the highest clearance (1114 L/h) for doxorubicinol was ≥35.0 kg/m ² . Conclusions Large interindividual variabilities in doxorubicin PK were observed in women up to a BMI of 57 kg/m ² and a total body weight of 141.5 kg. Women with a BMI ≥ 35.0 kg/m ² and breast cancer did not appear to have lower clearances of doxorubicin. ClinicalTrials.gov ID NCT01537029.

BACKGROUND Despite the high morbidity and mortality of heart failure with preserved ejection fraction (HFpEF), treatment options remain limited. The HFpEF syndrome is associated with a high comorbidity burden, including high prevalence of obesity and hypertension. Although inflammation is implicated to play a key role in HFpEF pathophysiology, underlying causal mechanisms remain unclear. METHODS Comparing patient samples and animal models, we defined the innate immune response during HFpEF in situ and through flow cytometry and single-cell RNA sequencing. After identifying transcriptional and cell signatures, we implemented a high-fat diet and hypertensive model of HFpEF and tested roles for myeloid and hematopoietic stem cells during HFpEF. Contributions of macrophage metabolism were also evaluated, including through mass spectrometry and carbon labeling. Primary macrophages were studied ex vivo to gain insight into complementary cell-intrinsic mechanisms. RESULTS Here we report evidence that patients with cardiometabolic HFpEF exhibit elevated peripheral blood hematopoietic stem cells. This phenotype was conserved across species in a murine mode of high-fat diet and hypertension. Hematopoietic stem cell proliferation was coupled to striking remodeling of the peripheral hematopoietic stem cell niche and expression of the macrophage adhesion molecule Vcam1 . This could be partially inhibited by sodium-glucose cotransporter-2 inhibitors and explained by elevated fatty acid metabolism in macrophage mitochondria, which in turn remodeled the Vcam1 promoter to enhance its expression. CONCLUSIONS These findings identify a significant new stem cell signature of cardiometabolic HFpEF and support a role for myeloid maladaptive fatty acid metabolism in the promotion of systemic inflammation and cardiac diastolic dysfunction.