Amplifying Youth Voice to Promote Black Youth Mental Health Through Policy in Georgia.

There is an unmet need for mental health policies that are culturally competent, engaging, and equitable for Black youth. This paper describes a youth-adult partnership advisory council approach to identify, assess, and measure the effectiveness of innovative policy solutions to promote Black youth mental health in Georgia.

Dynamic Risk Estimation of Adverse Events in Ambulatory LVAD Patients: A MOMENTUM 3 Analysis.

BACKGROUND: Hemocompatibility-related adverse events affect patients after left ventricular assist device (LVAD) implantation but are hard to predict. OBJECTIVES: Dynamic risk modeling with a multistate model can predict risk of gastrointestinal bleeding (GIB), stroke, or death in ambulatory patients. METHODS: This was a secondary analysis of the MOMENTUM 3 (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3) trial. HeartMate 3 LVAD recipients who survived to hospital discharge and were followed for up to 2 years. A total of 145 variables were included in the multistate model with multivariate logistic regression. Model performance was assessed with the area under the curve in a holdout validation cohort. A risk stratification tool was created by dividing patients into categories of predicted risk using the final model variables and associated OR. RESULTS: Among 2,056 LVAD patients, the median age was 59.4 years (20.4% women, 28.6% Black). At 2 years, the incidence of GIB, stroke, and death was 25.6%, 6.0%, and 12.3%, respectively. The multistate model included 39 total variables to predict risk of GIB (16 variables), stroke (10 variables), and death (19 variables). When ambulatory patients were classified according to their risk category, the 30-day observed event rate in the highest risk group for GIB, stroke, or death was 26.9%, 1.8%, and 4.8%, respectively. The multistate model predicted GIB, stroke, and death at any 30-day period with an area under the curve of 0.70, 0.69, and 0.86, respectively. CONCLUSIONS: The multistate model informs 30-day risk in ambulatory LVAD recipients and allows recalculation of risk as new patient-specific data become available. The model allows for accurate risk stratification that predicts impending adverse events and may guide clinical decision making. (MOMENTUM 3 IDE Clinical Study Protocol; NCT02224755).

Time from admission to randomization and the effect of empagliflozin in acute heart failure: A post-hoc analysis from EMPULSE.

AIMS: Patients hospitalized for acute heart failure (HF) could be enrolled in EMPULSE (NCT04157751) upon haemodynamic stabilization and between 24 h and 5 days after hospital admission. The timing of treatment initiation may influence the efficacy and safety of drugs such as empagliflozin. The aim of this study was to evaluate patient characteristics, clinical events, and treatment effects according to time from admission to randomization. METHODS AND RESULTS: The EMPULSE population was dichotomized by median time from hospital admission to randomization (1-2 days vs. 3-5 days). The primary outcome was a hierarchical composite endpoint of time to all-cause death, number of HF events, time to first HF event, and a ≥5-point difference in Kansas City Cardiomyopathy Questionnaire total symptom score change from baseline after 90 days, analysed using the win ratio (WR) method. Patients randomized later (3-5 days, average time 3.9 days; n = 312) had a higher risk of experiencing clinical events than patients randomized earlier (1-2 days, average time 1.7 days; n = 215). The treatment effect favoured empagliflozin versus placebo in patients randomized later (3-5 days: WR 1.69, 95% confidence interval [CI] 1.26-2.25) but was attenuated in patients randomized earlier (1-2 days: WR 1.04, 95% CI 0.74-1.44) (interaction p = 0.029). A similar pattern was observed for the composite of HF hospitalization or cardiovascular death and all-cause hospitalizations (interaction p < 0.1 for both). The reduction of N-terminal pro-B-type natriuretic peptide levels was more pronounced with empagliflozin among patients randomized later than in patients randomized earlier (interaction p = 0.004). CONCLUSIONS: Among patients hospitalized for acute HF enrolled in EMPULSE, those randomized later after hospital admission (3-5 days) experienced greater clinical benefit with empagliflozin than those randomized earlier (1-2 days). These findings should be confirmed in future studies before clinical application.

Refining Field Cancerization: An Institutional Cohort Analysis of Patient Characteristics in a Validation Cohort.

BACKGROUND: Field cancerization is poorly defined in dermatology. The author group previously proposed and applied a classification system in an original cohort to risk-stratify patients with field cancerization. OBJECTIVE: Apply the authors' classification system within a validation cohort. METHODS: Patients with keratinocyte carcinoma history completed a survey regarding demographic information, medical history, and chemoprevention use. Patients were assigned a field cancerization class, and differences between validation and original cohorts were assessed. RESULTS: A total of 363 patients were enrolled (mean age 67.4; 61.7% male). After comparing validation and original cohorts, there were differences in age between class II (p = .02) and class IVb (p = .047), and differences in chemoprevention use in class III (p = .04). Similar to the original cohort, the validation cohort was associated with increases in total number of skin cancers in the last year (p < .001), 5 years (p < .001), lifetime (p < .001), years since first skin cancer (p < .001), and chemoprevention use (p < .001). In the validation cohort, there were increases in age (p = .03) and immunocompromised status (p = .04) with increasing class, which were not observed in the original cohort. CONCLUSION: Differences among field cancerization classes were similar in a validation cohort, further highlighting the importance of class-specific treatment and management.

Fluorescence-Based Proteoliposome Methods to Monitor Redox-Active Transition Metal Transmembrane Translocation by Metal Transporters.

Transmembrane transition metal transporter proteins are central gatekeepers in selectively controlling vectorial metal cargo uptake and extrusion across cellular membranes in all living organisms, thus playing key roles in essential and toxic metal homeostasis. Biochemical characterization of transporter-mediated translocation events and transport kinetics of redox-active metals, such as iron and copper, is challenged by the complexity in generating reconstituted systems in which vectorial metal transport can be studied in real time. We present fluorescence-based proteoliposome methods to monitor redox-active metal transmembrane translocation upon reconstitution of purified metal transporters in artificial lipid bilayers. By encapsulating turn-on/-off iron or copper-dependent sensors in the proteoliposome lumen and conducting real-time transport assays using small unilamellar vesicles (SUVs), in which selected purified Fe(II) and Cu(I) transmembrane importer and exporter proteins have been reconstituted, we provide a platform to monitor metal translocation events across lipid bilayers in real time. The strategy is modular and expandable toward the study of different transporter families featuring diverse metal substrate selectivity and promiscuity.

Varenicline OTC Trial on Efficacy and Safety.

INTRODUCTION: Varenicline helps people who smoke quit at rates 2-3 times greater than placebo. Currently in the U.S., varenicline is not available over the counter (OTC). In this study, we assessed the safety and efficacy of 1mg and 0.5mg varenicline as an OTC medication for smoking cessation in comparison to placebo. METHODS: This randomized, double-blind, placebo-controlled study was performed at two clinical sites in the United States of n=313 people. The treatment period was 12 weeks. During the COVID pandemic, the protocol was modified to allow remote participation; verification of smoking status was via breath carbon monoxide levels for in-person visits and mailed urine cotinine kits for the remote participants. RESULTS: There was no difference in biologically confirmed continuous abstinence by condition between Weeks 8-12; however, the odds of biologically confirmed point prevalence abstinence were higher for those in the 1mg b.i.d. condition than for those in the placebo condition at Week 12 (OR 3.39; 95% CI 1.49, 7.71), and were higher for those assigned to the 1.0mg b.i.d. condition than the 0.5mg b.i.d. condition at Week 12 (OR 2.37; 95% CI 1.11, 5.05). Adverse events were modest, and as expected (vivid dreams and nausea in the medication conditions). CONCLUSIONS: The results are suggestive that varenicline is safe and effective as an OTC medication.

Heart Failure Drug Development Over the Eras: From the Heart Failure Collaboratory.

Over the past decade, the field of heart failure (HF) has witnessed remarkable progress in drug development, resulting in the approval of numerous groundbreaking drugs by the U.S. Food and Drug Administration. To address some of these challenges, the U.S. Food and Drug Administration has issued guidance documents that have been critical in contemporary HF drug development; however, there are still many challenges in need of investigation. This article leverages efforts of the Heart Failure Collaboratory and the scientific community to discuss the critical need for innovative trial designs, important concepts in clinical trials in the modern era, and the utilization of big data to accelerate HF drug development. At this inflection point in HF drug development, it is imperative that, as a global scientific community, we foster increased collaboration among researchers, clinicians, patients, and regulatory bodies. Only through such unified efforts can we navigate the complexities of HF, accelerate the development process, and ultimately deliver effective therapies that transform patient outcomes.

Short-term cold exposure induces persistent epigenomic memory in brown fat.

Deficiency of the epigenome modulator histone deacetylase 3 (HDAC3) in brown adipose tissue (BAT) impairs the ability of mice to survive in near-freezing temperatures. Here, we report that short-term exposure to mild cold temperature (STEMCT: 15°C for 24 h) averted lethal hypothermia of mice lacking HDAC3 in BAT (HDAC3 BAT KO) exposed to 4°C. STEMCT restored the induction of the thermogenic coactivator PGC-1α along with UCP1 at 22°C, which is greatly impaired in HDAC3-deficient BAT, and deletion of either UCP1 or PGC-1α prevented the protective effect of STEMCT. Remarkably, this protection lasted for up to 7 days. Transcriptional activator C/EBPß was induced by short-term cold exposure in mouse and human BAT and, uniquely, remained high for 7 days following STEMCT. Adeno-associated virus-mediated knockdown of BAT C/EBPß in HDAC3 BAT KO mice erased the persistent memory of STEMCT, revealing the existence of a C/EBPß-dependent and HDAC3-independent cold-adaptive epigenomic memory.

Skin Pigmentation Affects ViOptix T.Ox Performance in Variably Pigmented Preclinical Model of Flap Ischemia and Congestion.

Background: Free flap monitoring is more difficult in patients with dark skin because ischemia and congestion can be masked by pigmentation. For this reason, adjunct methods such as cutaneous near-infrared spectroscopy are of elevated importance in patients with highly pigmented skin. The purpose of this experiment is to determine if ViOpitx T.Ox performance is affected by cutaneous pigmentation. Methods: Swine with naturally occurring areas of nonpigmented and pigmented skin were used. Pigmentation of each animal was assessed using spectrophotometry and histopathology. During normoxemia, tissue oxygenation (StO2) measurements were taken of nonpigmented and pigmented skin using the T.Ox device. A bicolor pedicled rectus abdominis myocutaneous flap was raised, and T.Ox probe was adhered to adjacent areas of opposite coloration on the same flap. StO2 was measured continuously during reversible episodes of flap ischemia and congestion (n = 4 swine, n = 6 flaps). Results: There was not a significant difference between baseline StO2 values of nonpigmented (49% ± 7.9%) and pigmented skin (47% ± 6.2%). The absolute change in StO2 was significantly larger during both ischemia (6%) and congestion (16%) in nonpigmented skin compared with adjacent pigmented skin. Conclusions: T.Ox detects flap ischemia and congestion in both highly pigmented and nonpigmented skin. However, surgeons need to be aware that StO2 changes related to complete flap ischemia or congestion may be much more subtle than what is seen in nonpigmented skin. This study establishes a novel internally controlled porcine model that isolates the impact of skin pigmentation when assessing cutaneous devices measuring tissue oxygenation.

Nocturnal Hypoxemia Is Associated with Sarcopenia in COPD Patients.

OBJECTIVE: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Our previous studies have identified that nocturnal hypoxemia causes skeletal muscle loss (i.e. sarcopenia) in in vitro models of COPD. RATIONALE: We aimed to extend our preclinical mechanistic findings by analyzing a large sleep registry to determine whether nocturnal hypoxemia is associated with sarcopenia in COPD patients. METHODS: Sleep studies from COPD patients (n=479) and control subjects without COPD (n=275) were analyzed. Patients with obstructive sleep apnea (OSA), as defined by apnea hypopnea index >5, were excluded. Pectoralis muscle cross sectional area (PMcsa) was quantified using CT scans performed within one year of the sleep study. We defined sarcopenia as less than the lowest 20% residuals for PMcsa of controls, which was adjusted for age, BMI, and stratified by sex. Youden's optimal cutpoint criteria was used to predict sarcopenia based on mean oxygen saturation (mean SaO2) during sleep. Additional measures of nocturnal hypoxemia were analyzed. Pectoralis muscle index (PMI) was defined as PMcsa normalized to BMI. RESULTS: On average, COPD males had 16.6% lower PMI than control males (1.41+0.44 vs 1.69+0.56 cm2/BMI, p<0.001), while COPD females had 9.4% lower PMI than control females (0.96+0.27 vs 1.06+0.33 cm2/BMI, p<0.001). COPD males with nocturnal hypoxemia had a 9.5% decrease in PMI versus COPD with normal O2 (1.33+0.39 vs 1.47+0.46 cm2/BMI, p<0.05), and 23.6% decrease compared to controls (1.33+0.39 vs 1.74+0.56 cm2/BMI, p<0.001). COPD females with nocturnal hypoxemia had a 11.2% decrease versus COPD with normal O2 (0.87+0.26 vs 0.98+0.28 cm2/BMI, p<0.05), and 17.9% decrease compared to controls (0.87+0.26 vs 1.06+0.33 cm2/BMI, p<0.001). These findings were largely replicated using multiple measures of nocturnal hypoxemia. CONCLUSIONS: We defined sarcopenia in the pectoralis muscle using residuals that take into account age, BMI, and sex. We found that COPD patients have lower PMI than non-COPD patients, and that nocturnal hypoxemia was associated with an additional decrease in the PMI of COPD patients. Additional prospective analyses are needed to determine a protective threshold of oxygen saturation to prevent or reverse sarcopenia due to nocturnal hypoxemia in COPD.