Membrane Tension Regulation is Required for Wound Repair.

Disruptions of the eukaryotic plasma membrane due to chemical and mechanical challenges are frequent and detrimental and thus need to be repaired to maintain proper cell function and avoid cell death. However, the cellular mechanisms involved in wound resealing and restoration of homeostasis are diverse and contended. Here, it is shown that clathrin-mediated endocytosis is induced at later stages of plasma membrane wound repair following the actual resealing of the wound. This compensatory endocytosis occurs near the wound, predominantly at sites of previous early endosome exocytosis which is required in the initial stage of membrane resealing, suggesting a spatio-temporal co-ordination of exo- and endocytosis during wound repair. Using cytoskeletal alterations and modulations of membrane tension and membrane area, membrane tension is identified as a major regulator of the wounding-associated exo- and endocytic events that mediate efficient wound repair. Thus, membrane tension changes are a universal trigger for plasma membrane wound repair modulating the exocytosis of early endosomes required for resealing and subsequent clathrin-mediated endocytosis acting at later stages to restore cell homeostasis and function.

Impact of Aficamten on Disease and Symptom Burden in Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten is a cardiac myosin inhibitor that mitigates left ventricular outflow gradients in obstructive hypertrophic cardiomyopathy (oHCM). The clinical efficacy of aficamten across multiple outcome domains in oHCM has not been fully defined. OBJECTIVES: This responder analysis from the SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) trial characterizes the clinical impact of aficamten. METHODS: Patients who were symptomatic of oHCM were randomized to aficamten (n = 142) or placebo (n = 140) daily for 24 weeks. Outcomes assessed included the proportion of patients with complete hemodynamic response (rest and Valsalva gradient <30 mm Hg and <50 mm Hg, respectively), relief in limiting symptoms (≥1 improvement in NYHA functional class and/or ≥10-point change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score), enhanced exercise capacity (≥1.5 mL/kg/min change in peak oxygen uptake), and ≥50% reduction in N-terminal pro-B-type natriuretic peptide. Eligibility for septal reduction therapy was also evaluated. RESULTS: At 24 weeks, patients treated with aficamten vs placebo showed significant improvement in limiting symptoms (71% vs 42%), were more likely to have complete hemodynamic response (68% vs 7%), demonstrated enhanced exercise capacity (47% vs 24%), and showed a decrease ≥50% in N-terminal pro-B-type natriuretic peptide (84% vs 8%) (P ≤ 0.002 for all). An improvement in ≥1 of these outcome measures was achieved in 97% of patients treated with aficamten (vs 59% placebo), including 23% on aficamten who achieved all 4 outcomes compared with none in placebo. Among 32 patients receiving aficamten and 29 patients receiving placebo who were eligible for septal reduction therapy, 28 (88%) from the aficamten group were no longer eligible at 24 weeks compared with 15 (52%) from the placebo group (P = 0.002). CONCLUSIONS: Treatment with aficamten was associated with substantial improvements across a broad range of clinically relevant efficacy measures. These results underscore the wide-ranging potential of aficamten for treatment of patients with symptomatic oHCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults with oHCM [SEQUOIA-HCM]; NCT05186818).

Hypertranscription: the invisible hand in stem cell biology.

Stem cells are the fundamental drivers of growth during development and adult organ homeostasis. The properties that define stem cells - self-renewal and differentiation - are highly biosynthetically demanding. In order to fuel this demand, stem and progenitor cells engage in hypertranscription, a global amplification of the transcriptome. While standard normalization methods in transcriptomics typically mask hypertranscription, new approaches are beginning to reveal a remarkable range in global transcriptional output in stem and progenitor cells. We discuss technological advancements to probe global transcriptional shifts, review recent findings that contribute to defining hallmarks of stem cell hypertranscription, and propose future directions in this field.

Addressing the 2021 Essentials with new approaches for developing leadership, resilience, and self-care/well-being in undergraduate baccalaureate nursing students.

INTRODUCTION: New graduate nurses are not always prepared for the challenges of the chaotic clinical environment or to exercise leadership skills in a clinical capacity. Resilience and self-care are essential facets of successful leadership, as well as necessary components to prevent burnout in nurses. PURPOSE: The purpose of this article is to demonstrate how this School of Nursing implemented approaches to prepare the next generation of nurses with strong skills in the areas of leadership, resilience, and self-care/well-being while addressing the Essentials. METHODS: Faculty explored new ideas, as well as showcased teaching strategies they had already successfully implemented, that aligned with the Essentials with the undergraduate baccalaureate pilot student cohort. RESULTS: Two "Essential" Competencies, Domain 9 Professionalism and Domain 10 Personal, Professional and Leadership Development, as well as related sub-competencies, were addressed by the thirteen teaching strategies. Anecdotal student reflection comments supported high levels of satisfaction with these strategies. CONCLUSIONS: Preparing student nurses to meet the Essentials is critical to helping nurses thrive in contemporary practice settings. Equipping a generation of nurses with self-care practices to protect their own well-being, while at the same time meeting the Essentials expectations, is crucial to cultivating a sustainable nursing workforce.

Extended Ambulatory ECG Monitoring Enhances Identification of Higher-Risk Ventricular Tachyarrhythmias in Patients with Hypertrophic Cardiomyopathy.

BACKGROUND: In hypertrophic cardiomyopathy (HCM), 48-hour ambulatory monitoring has been standard practice to detect nonsustained ventricular tachycardia (NSVT), a sudden death risk marker. Extended wear ambulatory ECG devices have more recently utilized for monitoring HCM patients. OBJECTIVE: Evaluate NSVT burden identified with continuous ambulatory monitoring for up to 2 weeks compared to initial 48 hours. METHODS: 236 consecutive HCM patients (49 ± 12 years) underwent 14-day continuous ambulatory monitoring (Zio XT, iRhythm Technologies); diagnostic yield of NSVT compared for initial 48 hours vs. extended for 14 days. RESULTS: Of 236 patients, 114 (48%) had ≥1 runs of NSVT (median 2) over 14 days. Median length of NSVT was 7 beats (range: 3 to 67) at rates of 120 to 240 bpm (median, 167 bpm). In 42 of the 114 patients (37%), initial NSVT occurred ≤ 48 hours and in 72 (63%) only during the extended monitoring period (3 to 14 days). Diagnostic yield for detecting NSVT over 14 days was 2.7-fold greater than ≤ 48 hours (p<0.001). NSVT judged at higher risk (≥8 beats, >200 bpm, ≥2 runs in consecutive 2-day period) was identified more frequently during extended monitoring, diagnostic yield 3.0-fold greater than ≤ 48 hours (p<0.001). CONCLUSION: In HCM, NSVT episodes are frequent, however, in most patients, both NSVT and higher risk NSVT were not detected during initial 48-hours and confined solely to extended monitoring period. These data support additional clinical studies to evaluate the significance of NSVT on extended monitoring on sudden death risk in HCM.

Designing chemical systems for precision deuteration of medicinal building blocks.

Methods are lacking that can prepare deuterium-enriched building blocks, in the full range of deuterium substitution patterns at the isotopic purity levels demanded by pharmaceutical use. To that end, this work explores the regio- and stereoselective deuteration of tetrahydropyridine (THP), which is an attractive target for study due to the wide prevalence of piperidines in drugs. A series of d0-d8 tetrahydropyridine isotopomers were synthesized by the stepwise treatment of a tungsten-complexed pyridinium salt with H-/D- and H+/D+. The resulting decomplexed THP isotopomers and isotopologues were analyzed via molecular rotational resonance (MRR) spectroscopy, a highly sensitive technique that distinguishes isotopomers and isotopologues by their unique moments of inertia. In order to demonstrate the medicinal relevance of this approach, eight unique deuterated isotopologues of erythro-methylphenidate were also prepared.

Are UV filters better together? A comparison of the toxicity of individual ultraviolet filters and off-the-shelf sunscreens to Daphnia magna.

Organic ultraviolet filters (UVFs) are known to contaminate many aquatic ecosystems, with much environmental contamination attributed to the use of UVF-containing skin care products such as sunscreens during aquatic recreation. Most studies addressing the impact of sunscreen contamination have focused on the effects of UVFs under the assumption that they are the primary contaminants of concern from sunscreen pollution; however, the extent to which the toxicity of UVFs is representative of the environmental impacts of the whole sunscreen mixture is unknown. To address this knowledge gap, this study compared the mixture toxicity of five off-the-shelf sunscreen spray products containing the UVFs avobenzone, homosalate, octisalate, octocrylene and oxybenzone to the toxicity of each UVF in isolation to the freshwater invertebrate Daphnia magna. It was found that sunscreen toxicity was not proportional to their total UVF content, as the sunscreen containing the fewest UVFs was approximately equivalent to the sunscreen with the most UVFs, causing ≥90 % mortality and inhibiting all daphnid reproduction over 21 d exposures. Sunscreen toxicity was typically lower than expected when compared to the toxicity of each individual UVF within the mixture, as some sunscreens causing ≤20 % mortality contained octocrylene and/or oxybenzone at concentrations exceeding those which caused 90 % mortality during exposure to the UVF alone. Despite sunscreens causing large impairments in reproduction, growth and metabolism, poor correlations existed between the severity of most sublethal endpoints with respect to the measured UVF content of each sunscreen. Overall, these results indicate that potential antagonistic relationships between sunscreen ingredients can greatly reduce the toxicity of UVFs, creating more uncertainty regarding the level of threat that UVFs pose to the environment as a result of sunscreen contamination.

Comparative kinematic analysis of high-speed treadmill vs. overground sprinting across athletic levels and sex.

BACKGROUND: This investigation aimed to dissect the kinematic differences in sprinting between high-speed treadmill and overground conditions, examining how these variations are influenced by the athlete's training status and biological sex. METHODS: A total of 40 participants, 20 NCAA Division 1 sprinters and 20 recreational runners, performed a series of maximal sprints on a high-speed treadmill and on a standardized competition overground track. Sprinting kinematic variables such as stride length, stride frequency, contact time, and flight time were collected via photoelectric sensors. Maximal sprinting kinematics were analyzed by linear mixed-effects models, considering the impacts of sprinting environment (treadmill vs. overground), training level, and sex, with leg length as fixed factors and individual athletes as random effects. Statistical significance was set at a significance level of 0.05. RESULTS: The statistical analysis revealed that high-speed treadmill sprinting significantly affects all measured kinematic variables, leading to increased stride frequency and contact time. Elite sprinters demonstrated enhanced kinematic efficiency over recreational runners, characterized by increased stride length and frequency and reduced contact time. Sex-based kinematic distinctions also emerged, with male athletes exhibiting superior stride length and frequency compared to female athletes. Leg length significantly influenced stride frequency, and an interaction effect was observed for flight time between sprint type and athletic group. CONCLUSIONS: These findings elucidate the distinct biomechanical profiles across sprinting modalities and athlete demographics, emphasizing the need for sprint training customization. This study's insights offer a valuable reference for coaches and athletes to refine training and performance assessment in varied sprinting environments.

Racial Attitudes and Perceptions of Government Response during the COVID-19 Pandemic: Implications for Public Health Strategies.

BACKGROUND: This study explored whether opinions about the government's role in addressing the COVID-19 pandemic vary based on demographic characteristics and racial beliefs. We hypothesized that opinions about the United States (U.S.) government's response to COVID-19 would differ based on an individual's characteristics such as age, race, and racial beliefs. METHODS: We utilized an Inter-University Consortium for Political and Social Research dataset to examine differences in opinion regarding the government's pandemic response, considering personal characteristics and racial beliefs. Descriptive statistics depicted respondents' characteristics, and a Chi-square test for independence assessed whether differences emerged based on racial attitude, self-reported racial identity, sex, income, education, and age. Logistic regression analyses were conducted to independently determine which characteristics were associated with differences in evaluating the government's pandemic response. RESULTS: The sample consisted of 1028 respondents: 47.5% male and 52.5% female. Overall, the group viewed the government unfavorably, with only 40% reporting that the government responded correctly and 54% believing the government is almost always wasteful and inefficient. Hispanics or Latinos were more likely to view the government as wasteful or inefficient, while more Whites rated the government's pandemic response as appropriate. Individuals who believed that racial discrimination is the main reason why many Black people cannot get ahead generally regarded the government's pandemic response more favorably. Only 5% deemed the government's response excessive. Being Black, younger, and female was associated with the view that racial discrimination is the main reason why many Black people cannot get ahead. Individuals who felt this way viewed the government unfavorably by almost a 2:1 ratio. CONCLUSIONS: A majority of U.S. residents do not believe the government responded correctly to the pandemic and more than half viewed the government as wasteful and inefficient. Differences emerged by ethnicity and racial attitudes, with individuals of color holding more negative views of the government's response. Understanding this perspective can help develop messaging and strategies that resonate with communities where racial and minority groups live.

Effects of Obesity and Exercise on Hepatic and Pancreatic Lipid Content and Glucose Metabolism: PET Studies in Twins Discordant for BMI.

Obesity and sedentarism are associated with increased liver and pancreatic fat content (LFC and PFC, respectively) as well as impaired organ metabolism. Exercise training is known to decrease organ ectopic fat but its effects on organ metabolism are unclear. Genetic background affects susceptibility to obesity and the response to training. We studied the effects of regular exercise training on LFC, PFC, and metabolism in monozygotic twin pairs discordant for BMI. We recruited 12 BMI-discordant monozygotic twin pairs (age 40.4, SD 4.5 years; BMI 32.9, SD 7.6, 8 female pairs). Ten pairs completed six months of training intervention. We measured hepatic insulin-stimulated glucose uptake using [18F]FDG-PET and fat content using magnetic resonance spectroscopy before and after the intervention. At baseline LFC, PFC, gamma-glutamyl transferase (GT), and hepatic glucose uptake were significantly higher in the heavier twins compared to the leaner co-twins (p = 0.018, p = 0.02 and p = 0.01, respectively). Response to training in liver glucose uptake and GT differed between the twins (Time*group p = 0.04 and p = 0.004, respectively). Liver glucose uptake tended to decrease, and GT decreased only in the heavier twins (p = 0.032). In BMI-discordant twins, heavier twins showed higher LFC and PFC, which may underlie the observed increase in liver glucose uptake and GT. These alterations were mitigated by exercise. The small number of participants makes the results preliminary, and future research with a larger pool of participants is warranted.

Trait self-control as a determinant of health behavior: Recent advances on mechanisms and future directions for research.

We summarize theory and research testing a mechanistic explanation for the trait self-control-health behavior relationship. Specifically, social cognition constructs summarizing individuals' utility, normative, risk, and capacity beliefs with respect to future health behavior performance are proposed to mediate the self-control-health behavior relationship. The effect represents the informational function of self-control in decision making. We also specify a mechanism wherein trait self-control moderates the intention-behavior relationship such that 'good' self-control affords effective intention-to-action translation. Both effects have pervasive support in the extent literature. We propose ongoing meta-analyses expected to provide further robust support for these mechanistic effects and the need for research employing designs enabling better directional and causal inferences in the effects, including experimental or types of cross-lagged panel design.

Straight from the horse's mouth: The effect of different feedstuffs on oral pH in horses and ponies.

Feedstuffs, especially ensiled forage, may be detrimental to equid oral health by exposing the oral cavity to low pH. This study aimed to identify if salivary pH was altered by 1) a range of different feedstuffs and (2) specifically by feeding haylages with differing nutrient profiles. Two studies were conducted. The first measured oral pH following five feedstuffs, (hay, haylage, unmolassed sugarbeet pulp, unmolassed alfalfa chaff and rolled oats), tested individually over five days. Saliva (≥1 ml) was collected in triplicate, prior to feeding, directly after ingesting 500 g of each feedstuff, then 15 min and 30 min post-prandially. Oral pH was determined (pH meter) within 10 min of collection. In study two, eight ponies, were fed as their total diet, four different haylages over four 15-day periods. Saliva was collected, prior to feeding and immediately after ingesting 500 g of forage on day 1, day 6, and day 12 of each period. Samples were collected and analysed as per study one. All data were analysed by repeated measures ANOVA, and in study two linear regression was used to attempt to predict nutrients that influenced oral pH. All statistics were conducted in Genstat 20 th Ed. Only feeding unmolassed sugarbeet caused a reduction (p<0.001) in oral pH. There were differences in oral pH depending on the type of haylage fed in study two but at all times oral pH post-feeding was the same or greater than basal pH. These studies suggest any feed associated modulation of oral pH in horses may only be short-lived and quickly buffered by saliva. However, these studies only reflect oral pH within the oral cavity around the feeding occasion and may not reflect gingival pH or the effects of different feeds over longer time periods.

Cardiac biomarkers and effects of aficamten in obstructive hypertrophic cardiomyopathy: the SEQUOIA-HCM trial.

BACKGROUND AND AIMS: The role of biomarker testing in the management of obstructive hypertrophic cardiomyopathy (oHCM) is not well defined. This pre-specified analysis of SEQUOIA-HCM (NCT05186818) sought to define the associations between clinical characteristics and baseline concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-cTnI), and to evaluate effect of treatment with aficamten on biomarker concentrations. METHODS: Cardiac biomarkers were measured at baseline and serially throughout the study. Regression analyses determined predictors of baseline NT-proBNP and hs-cTnI concentrations, and to evaluate whether early changes in these biomarkers relate to later changes in left ventricular outflow tract gradient (LVOT-G), other echocardiographic measures, health status, and functional capacity. RESULTS: Baseline concentration of NT-proBNP was associated with LVOT-G and measures of diastolic function, while hs-cTnI was associated with left ventricular thickness. Within 8 weeks of treatment with aficamten, NT-proBNP was reduced by 79% (95% CI 83%-76%, P < .001) and hs-cTnI by 41% (95% CI 49%-32%, P < .001); both biomarkers reverted to baseline after washout. Reductions in NT-proBNP and hs-cTnI by 24 weeks were strongly associated with a lowering of LVOT-G, improvement in health status, and increased peak oxygen uptake. NT-proBNP reduction strongly correlated with the majority of improvements in exercise capacity. Furthermore, the change in NT-proBNP by Week 2 was associated with the 24-week change in key endpoints. CONCLUSIONS: NT-proBNP and hs-cTnI concentrations are associated with key variables in oHCM. Serial measurement of NT-proBNP and hs-cTnI appears to reflect clinical response to aficamten therapy.

Impact of Aficamten on Echocardiographic Cardiac Structure and Function in Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Aficamten, a next-in-class cardiac myosin inhibitor, improved peak oxygen uptake (pVO2) and lowered resting and Valsalva left ventricular outflow (LVOT) gradients in adults with symptomatic obstructive hypertrophic cardiomyopathy (oHCM) in SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM), a phase 3, multicenter, randomized, double-blinded, placebo-controlled study. OBJECTIVES: The authors sought to evaluate the effect of aficamten on echocardiographic measures of cardiac structure and function in SEQUOIA-HCM. METHODS: Serial echocardiograms were performed over 28 weeks in patients randomized to receive placebo or aficamten in up to 4 individually titrated escalating doses (5-20 mg daily) over 24 weeks based on Valsalva LVOT gradients and left ventricular ejection fraction (LVEF). RESULTS: Among 282 patients (mean age 59 ± 13 years; 41% female, 79% White, 19% Asian), mean LVEF was 75% ± 6% with resting and Valsalva LVOT gradients of 55 ± 30 mm Hg and 83 ± 32 mm Hg, respectively. Over 24 weeks, aficamten significantly lowered resting and Valsalva LVOT gradients, and improved left atrial volume index, lateral and septal e' velocities, and lateral and septal E/e' (all P ≤ 0.001). LV end-systolic volume increased and wall thickness decreased (all P ≤ 0.003). Aficamten resulted in a mild reversible decrease in LVEF (-4.8% [95% CI: -6.4 to -3.3]; P < 0.001) and absolute LV global circumferential strain (-3.7% [95% CI: 1.8-5.6]; P < 0.0010), whereas LV global longitudinal strain was unchanged. Several measures, including LVEF, LVOT gradients, and E/e' returned to baseline following washout. Among those treated with aficamten, improved pVO2 and reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with improvement in lateral e' velocity and septal and lateral E/e' (all P < 0.03), whereas improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (KCCQ-CSS) was associated with a decrease in both LVOT gradients (all P < 0.001). CONCLUSIONS: Compared with placebo, patients receiving aficamten demonstrated significant improvement in LVOT gradients and measures of LV diastolic function, and several of these measures were associated with improvements in pVO2, KCCQ-CSS, and NT-proBNP. A modest decrease in LVEF occurred yet remained within normal range. These findings suggest aficamten improved multiple structural and physiological parameters in oHCM without significant adverse changes in LV systolic function. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Aficamten on Cardiac Structure and Function in Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM CMR Substudy.

BACKGROUND: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by left ventricular (LV) hypertrophy, LV outflow tract obstruction, and left atrial dilation, which can be associated with progressive heart failure, atrial fibrillation, and stroke. Aficamten is a next-in-class cardiac myosin inhibitor that reduces outflow tract obstruction by modulating cardiac contractility, with the potential to reverse pathological remodeling and, in turn, reduce cardiovascular events. OBJECTIVES: This study sought to investigate the effect of aficamten on cardiac remodeling compared with placebo using cardiovascular magnetic resonance (CMR) and its association with key clinical endpoints in the SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM) CMR substudy. METHODS: SEQUOIA-HCM was a phase 3 double-blind, placebo-controlled trial for adults with symptomatic oHCM who were randomized 1:1 to 24 weeks of aficamten (dose range: 5-20 mg) or placebo. Eligible participants were offered enrollment in the CMR substudy with studies performed at baseline and week 24. Image analysis was performed in a blinded fashion by a core laboratory. RESULTS: Of the 282 randomized patients, 57 (20%) participated in the substudy, and of those, 50 (88%) completed both baseline and week 24 CMR. Baseline characteristics of the CMR cohort were similar to the overall study population. Of these 50 patients, 21 received aficamten and 29 received placebo. Relative to placebo, patients receiving aficamten demonstrated significant reductions (Δ least-squares mean) in LV mass index (-15 g/m2; 95% CI: -25 to -6 g/m2; P = 0.001), maximal LV wall thickness (-2.1 mm; 95% CI: -3.1 to -1.1 mm; P < 0.001), left atrial volume index (-13 mL/m2; 95% CI: -19 to -7 mL/m2; P < 0.001), native T1 relaxation time (-37 ms; 95% CI: -69 to -5 ms; P = 0.026), indexed extracellular volume fraction (-3.9 g/m2; 95% CI: -7.0 to -0.9 g/m2; P = 0.014), and indexed myocyte mass (-14 g/m2; 95% CI: -23 to -4 g/m2; P = 0.004), while there were no significant changes in LV chamber volumes, LV replacement fibrosis (late gadolinium enhancement mass -0.7 g; 95% CI: -2.9 to 1.6 g; P = 0.54), or extracellular volume (0.7%; 95% CI: -2.2% to 3.6%; P = 0.61). CONCLUSIONS: The CMR substudy of SEQUOIA-HCM demonstrated that treatment with aficamten relative to placebo for 24 weeks resulted in favorable cardiac remodeling. These changes, particularly with regard to LV mass, wall thickness, and left atrial size, could potentially lead to reduced cardiovascular events including heart failure and atrial fibrillation with longer follow-up. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Effect of Aficamten on Health Status Outcomes in Obstructive Hypertrophic Cardiomyopathy: Results from SEQUOIA-HCM.

BACKGROUND: A primary goal in treating obstructive hypertrophic cardiomyopathy (oHCM) is to improve patients' health status: their symptoms, function, and quality of life. The health status benefits of aficamten, a novel cardiac myosin inhibitor, have not been comprehensively described. OBJECTIVES: This study sought to determine the effect of aficamten on patient-reported health status, including symptoms of fatigue, shortness of breath, chest pain, physical and social limitations, and quality of life. METHODS: SEQUOIA-HCM (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM) randomized symptomatic adults with oHCM to 24 weeks of aficamten (n = 142) or placebo (n = 140), followed by a 4-week washout. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and Seattle Angina Questionnaire 7-item (SAQ7) were serially administered. Changes in mean KCCQ-Overall Summary Score (KCCQ-OSS) and SAQ7-Summary Score (SAQ7-SS) from baseline to 24 weeks and following treatment withdrawal were compared using linear regression adjusted for baseline scores and randomization strata. Proportions of patients with clinically important changes were compared. RESULTS: Among 282 participants, the mean age was 59 ± 13 years, 115 (41%) were female, and 223 (79%) were White. Baseline KCCQ-OSS (69.3 ± 20.1 vs 67.3 ± 18.8) and SAQ7-SS (72.0 ± 21.0 vs 72.4 ± 18.3) were similar between aficamten and placebo groups. Treatment with aficamten, compared with placebo, improved both the mean KCCQ-OSS (13.3 ± 16.3 vs 6.1 ± 12.6; mean difference: 7.9; 95% CI: 4.8-11.0; P < 0.001) and SAQ7-SS (11.6 ± 17.4 vs 3.8 ± 14.4; mean difference: 7.8; 95% CI: 4.7-11.0; P < 0.001) at 24 weeks, with benefits emerging within 4 weeks. No heterogeneity in treatment effect was found across subgroups. A much larger proportion of participants experienced a very large health status improvement (≥20 points) with aficamten vs placebo (KCCQ-OSS: 29.7% vs 12.4%, number needed to treat: 5.8; SAQ7-SS: 31.2% vs 13.9%, number needed to treat: 5.8). Participants' health status worsened significantly more after withdrawal from aficamten than placebo (KCCQ-OSS: -16.2 ± 19.0 vs -3.0 ± 9.6; P < 0.001; SAQ7-SS: -17.4 ± 21.4 vs -2.5 ± 13.3), further confirming a causal effect of aficamten. CONCLUSIONS: In patients with symptomatic oHCM, treatment with aficamten resulted in markedly improved health status, including significant improvement in chest pain-related health status, than placebo. (Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM [SEQUOIA-HCM]; NCT05186818).

Predicting alcohol consumption: Application of an integrated social cognition model of intentions, habits, and cue consistency.

Drinking alcohol in excess is associated with deleterious health outcomes, highlighting the need for research to identify potentially modifiable correlates of excessive alcohol consumption to target in behavioral interventions. The present two-wave prospective correlational study applied an integrated theoretical model that included theory of planned behavior constructs alongside habit, cue consistency, affective attitudes, and past behavior as predictors of two alcohol-related behaviors, drinking within safe limits and regular alcohol drinking, in separate samples of Australian undergraduate students (total N = 474). Structural equation models identified direct effects of habit, affective attitude, and subjective norms on intention for both behaviors. Habit at follow-up, cue consistency, and past behavior directly predicted behavior in both samples, whereas intention predicted behavior only for drinking within safe limits, and affective attitude only predicted behavior for regular drinking. Cue consistency moderated the effects of habit on behavior for both behaviors and moderated the effect of past behavior on regular drinking. Results corroborate past behavior and habit as key correlates of behavior and provide preliminary evidence of the importance of integrating cue consistency, a defining characteristic of habit, as a moderator of habit and past behavior effects an integrated theory test.

Aficamten and Cardiopulmonary Exercise Test Performance: A Substudy of the SEQUOIA-HCM Randomized Clinical Trial.

Importance: Impaired exercise capacity is a cardinal manifestation of obstructive hypertrophic cardiomyopathy (HCM). The Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic Obstructive HCM (SEQUOIA-HCM) is a pivotal study characterizing the treatment effect of aficamten, a next-in-class cardiac myosin inhibitor, on a comprehensive set of exercise performance and clinical measures. Objective: To evaluate the effect of aficamten on exercise performance using cardiopulmonary exercise testing with a novel integrated measure of maximal and submaximal exercise performance and evaluate other exercise measures and clinical correlates. Design, Setting, and Participants: This was a prespecified analysis from SEQUOIA-HCM, a double-blind, placebo-controlled, randomized clinical trial. Patients were recruited from 101 sites in 14 countries (North America, Europe, Israel, and China). Individuals with symptomatic obstructive HCM with objective exertional intolerance (peak oxygen uptake [pVO2] ≤90% predicted) were included in the analysis. Data were analyzed from January to March 2024. Interventions: Randomized 1:1 to aficamten (5-20 mg daily) or matching placebo for 24 weeks. Main Outcomes and Measures: The primary outcome was change from baseline to week 24 in integrated exercise performance, defined as the 2-component z score of pVO2 and ventilatory efficiency throughout exercise (minute ventilation [VE]/carbon dioxide output [VCO2] slope). Response rates for achieving clinically meaningful thresholds for change in pVO2 and correlations with clinical measures of treatment effect (health status, echocardiographic/cardiac biomarkers) were also assessed. Results: Among 282 randomized patients (mean [SD] age, 59.1 [12.9] years; 115 female [40.8%], 167 male [59.2%]), 263 (93.3%) had core laboratory-validated exercise testing at baseline and week 24. Integrated composite exercise performance improved in the aficamten group (mean [SD] z score, 0.17 [0.51]) from baseline to week 24, whereas the placebo group deteriorated (mean [SD] z score, -0.19 [0.45]), yielding a placebo-corrected improvement of 0.35 (95% CI, 0.25-0.46; P <.001). Further, aficamten treatment demonstrated significant improvements in total workload, circulatory power, exercise duration, heart rate reserve, peak heart rate, ventilatory efficiency, ventilatory power, and anaerobic threshold (all P <.001). In the aficamten group, large improvements (≥3.0 mL/kg per minute) in pVO2 were more common than large reductions (32% and 2%, respectively) compared with placebo (16% and 11%, respectively). Improvements in both components of the primary outcome, pVO2 and VE/VCO2 slope throughout exercise, were significantly correlated with improvements in symptom burden and hemodynamics (all P <.05). Conclusions and Relevance: This prespecified analysis of the SEQUOIA-HCM randomized clinical trial found that aficamten treatment improved a broad range of exercise performance measures. These findings offer valuable insight into the therapeutic effects of aficamten. Trial Registration: ClinicalTrials.gov Identifier: NCT05186818.

The preferred retinal loci when the eyes converge.

The preferred retinal locus (PRL) is the position on the retina to which humans direct stimuli during fixation. In healthy normal eyes, it has been shown to be very stable across time and between different tasks. Previous measurements of the PRL have been made under monocular viewing conditions. The current study examines where the PRLs in the two eyes' retinas are when subjects fixate binocularly and whether they shift when the demand for the eyes to converge is changed. Our apparatus allows us to see exactly where binocular stimuli fell on the two retinas during binocular fixation. Thus, our technique bypasses some of the issues involved in measuring binocular alignment with subjective techniques and previous objective techniques that use conventional eye trackers. These results show that PRLs shift slightly but systematically as the demand for convergence increases. The shifts cause under-convergence (also called exo fixation disparity) for near targets. They are not large enough to cause a break in binocular fusion. The fixation disparity we observed with increasing vergence demand is similar to fixation disparity observed in previous reports.