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The use of seclusion and physical restraint is viewed as a practice incompatible with the vision of recovery, and its therapeutic benefit remains unsubstantiated. This Open Forum describes an initiative that began in 1999 at two crisis centers that was designed to completely eliminate the practice of seclusion and restraint. Seclusion and restraint elimination strategies included strong leadership direction, policy and procedural change, staff training, consumer debriefing, and regular feedback on progress. Existing records indicated that over a 58-month follow-up period (January 2000 to October 2004), the larger crisis center took ten months until a month registered zero seclusions and 31 months until a month recorded zero restraints. The smaller crisis center achieved these same goals in two months and 15 months, respectively. The success of this initiative suggests that policy makers and organizational leaders familiarize themselves with these and other similar seclusion and restraint reduction strategies that now exist. [ABSTRACT FROM AUTHOR]

Presently, older adults are under-served by psychologists. In part this reflects a lack of psychologists proficient in clinical geropsychology to provide appropriate treatment. The present study provides information gathered from practitioners for planning continuing education programs in clinical geropsychology. The findings describe the characteristics of clinicians pursuing additional training to work with older adults, and their topical preferences and training needs to guide future continuing education offerings. In addition, the practitioners' opinions regarding a possible credential recognizing competence in clinical geropsychology are discussed. [ABSTRACT FROM AUTHOR]

This study compared older women from two age groups in order to refine and extend our understanding of women's development across the life span. Forty-one women from two cohorts aged 60 to 70 and 80 to 90 completed the Measures of Psychosocial Development (MPD), a quantitative measure of Erikson's developmental stages. Age group differences in the resolution of Erikson's identity and trust developmental tasks were found. In addition, these two groups differed on the three summary scales: totals across the positive subscales, negative subscales, and resolution subscales respectively. Implications for women's late life development and possible interventions are discussed. [ABSTRACT FROM AUTHOR]

Aficamten, a small molecule selective inhibitor of cardiac myosin, was characterised in preclinical in vitro and in vivo studies.Protein binding in human plasma was 10.4% unbound and ranged from 1.6% to 24.9% unbound across species. Blood-to-plasma ratios ranged from 0.69 to 1.14 across species. Aficamten hepatic clearance in human was predicted to be low from observed high metabolic stability in vitro in human liver microsomes. Aficamten demonstrated high permeability in Caco-2 cell monolayers.Aficamten in vivo clearance was low across species at 8.8, 2.1, 3.3, and 11 mL/min/kg in mouse, rat, dog, and monkey, respectively. The volume of distribution was low-to-high ranging from 0.53 in rat to 11 L/kg in dog. Oral bioavailability ranged from 41% in monkey to 98% in mouse.Aficamten was metabolised in vitro to eight metabolites with hydroxylated metabolites M1a and M1b predominating. CYP phenotyping indicated multiple CYPs (2C8, 2C9, 2D6, and 3A4) contributing to the metabolism of aficamten.Human clearance (1.1 mL/min/kg) and volume of distribution (6.5 L/kg) were predicted using 4-species allometry employing 'rule-of-exponents'. A predicted 69 hour half-life is consistent with observed half-life in human Phase-1.No CYP-based drug-drug interaction liability as a precipitant was predicted for aficamten.

The pharmacokinetics, metabolism, excretion, mass balance, and tissue distribution of [ 14 C]aficamten were evaluated following oral administration of an 8 mg/kg dose in Sprague Dawley rats and in a quantitative whole-body autoradiography study in Long Evans rats.[ 14 C]Aficamten accounted for ∼80% and a hydroxylated metabolite (M1) accounted for ∼12% of total radioactivity in plasma over 48-h (AUC 0-48 ). Plasma t max was 4-h and the t 1/2 of total plasma radioactivity was 5.8-h.Tissues showing highest C max exposures were myocardium and semitendinosus muscle.Most [ 14 C]aficamten-derived radioactivity was excreted within 48-h post-administration. Mean cumulative recovery in urine and faeces over 168-h was 8.3% and 90.7%, respectively.In urine and bile, unchanged aficamten was detected at <0.1 and <0.2% of dose, respectively; however, based on total radioactivity excreted in urine (8.0%) and bile (51.7%), approximately 60% of dose was absorbed.[ 14 C]Aficamten was metabolised by hydroxylation with subsequent glucuronidation where the most abundant metabolite recovered in bile was M5 (35.2%), the oxygen-linked glucuronide of hydroxylated aficamten (M1a). The major metabolite detected in faeces was a 1,2,4-oxadiazole moiety ring-cleaved metabolite (M18, 35.3%), shown to be formed from the metabolism of M5 in incubations with rat intestinal contents solution.

Rationales: Atherosclerotic Cardiovascular Disease (ASCVD) is the leading cause of morbidity and mortality in the United States. Suboptimal control of hypertension and hyperlipidemia are common factors contributing to ASCVD risk. The Penn Medicine Healthy Heart (PMHH) Study is a randomized clinical trial testing the effectiveness of a system designed to offload work from primary care clinicians and improve patient follow-through with risk reduction strategies by using a centralized team of nonclinical navigators and advanced practice providers, remote monitoring, and bi-directional text messaging, augmented by behavioral science engagement strategies. The intervention builds on prior nonrandomized evaluations of these design elements that demonstrated significant improvement in patients' systolic blood pressure and LDL Cholesterol (LDL-C)., Primary Hypothesis: Penn Medicine Healthy Heart will significantly improve systolic blood pressure and LDL-C compared to usual care over the 6 months of this intervention., Design: Randomized clinical trial of Penn Medicine Healthy Heart in patients aged 35-80 years at elevated risk of ASCVD whose systolic blood pressure and LDL-C are not well controlled. The intervention consists of 4 modules that address blood pressure management, lipid management, nutrition, and smoking cessation, offered in a phased approach to give the participant time to learn about each topic, adopt any recommendations, and build a relationship with the care team., Sites: University of Pennsylvania Health System at primary care practices located in inner-city urban and rural/semi-rural areas., Primary Outcomes: Improvement in systolic blood pressure and LDL-C., Secondary Outcomes: Cost-effectiveness analyses are planned to evaluate the health care costs and health outcomes of the intervention approach. An implementation evaluation is planned to understand factors influencing success of the intervention., Estimated Enrollment: 2,420 active patients of Penn Medicine primary care practices who have clinical ASCVD, or who are at elevated risk for ASCVD, and who are (a) not on statins or have LDL-C >100 despite being on statins and (b) had systolic blood pressure >140 at 2 recent ambulatory visits., Enrollment Dates: March 2024-March 2025. The intervention will last 6 months with a 12-month follow-up to determine whether its effects persist., Current Status: Enrolling (1,240 enrolled as of August 15, 2024) CLINICAL TRIAL REGISTRATION: NCT06062394., Competing Interests: Conflict of interest Dr. Volpp is a Scientific Board member of THRIVE Global and a part owner of VALHealth, a behavioral economics consulting firm and has received research funding and consulting support from the American Heart Association. Dr. Asch is also a part owner of VALHealth and a Scientific Board member of THRIVE Global., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objectives: Pain catastrophizing (PC) is a cognitive/emotional response to and in anticipation of pain that can be maladaptive, further exacerbating pain and difficulty in emotion regulation (ER). There is a lack of research on the interplay between PC and ER and its impact on pain. Our aim was to investigate whether ER exacerbated the pain experience through PC., Methods: Adults with chronic non-cancer pain of >3 months' duration (n = 150) who were taking opioid medication were recruited from a large medical center in Pennsylvania. A battery of questionnaires was conducted to gather data on demographics, substance use, mental health histories, and health and pain outcomes. Measures used included the 18-Item Difficulties in Emotion Regulation Scale, the Pain Catastrophizing Scale, the Brief Pain Inventory-Short Form, and the Hospital Anxiety and Depression Scale. A structural equation model with latent variables was conducted to examine our aim., Results: Both pain interference and severity were significantly positively associated with several psychosocial variables, such as anxiety, depression, ER constructs, PC, and distress intolerance. The associations between subscales and pain interference were larger than the associations between subscales and pain severity. PC fully mediated the paths from ER to pain experiences., Discussion: Our results highlight the importance of several cognitive and emotional constructs: nonacceptance of negative emotions, lack of emotional awareness, magnification of the pain experience, and a sense of helplessness. Furthermore, by showing the indirect effects of PC in affecting ER and pain, we posit that ER, mediated by PC, might serve a critical role in influencing the pain experience in patients with chronic pain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Novel cardiac troponin activators were identified using a high throughput cardiac myofibril ATPase assay and confirmed using a series of biochemical and biophysical assays. HTS hit 2 increased rat cardiomyocyte fractional shortening without increasing intracellular calcium concentrations, and the biological target of 1 and 2 was determined to be the cardiac thin filament. Subsequent optimization to increase solubility and remove PDE-3 inhibition led to the discovery of CK-963 and enabled pharmacological evaluation of cardiac troponin activation without the competing effects of PDE-3 inhibition. Rat echocardiography studies using CK-963 demonstrated concentration-dependent increases in cardiac fractional shortening up to 95%. Isothermal calorimetry studies confirmed a direct interaction between CK-963 and a cardiac troponin chimera with a dissociation constant of 11.5 ± 3.2 μM. These results provide evidence that direct activation of cardiac troponin without the confounding effects of PDE-3 inhibition may provide benefit for patients with cardiovascular conditions where contractility is reduced.

Cardiac myosin activation has been shown to be a viable approach for the treatment of heart failure with reduced ejection fraction. Here, we report the discovery of nelutroctiv ( CK-136 ), a selective cardiac troponin activator intended for patients with cardiovascular conditions where cardiac contractility is reduced. Discovery of nelutroctiv began with a high-throughput screen that identified compound 1R , a muscle selective cardiac sarcomere activator devoid of phosphodiesterase-3 activity. Optimization of druglike properties for 1R led to the replacement of the sulfonamide and aniline substituents which resulted in improved pharmacokinetic (PK) profiles and a reduced potential for human drug-drug interactions. In vivo echocardiography assessment of the optimized leads showed concentration dependent increases in fractional shortening and an improved pharmacodynamic window compared to myosin activator CK-138 . Overall, nelutroctiv was found to possess the desired selectivity, a favorable pharmacodynamic window relative to myosin activators, and a preclinical PK profile to support clinical development.

Introduction: Implementation Science (IS) is a complex and rapidly evolving discipline, posing challenges for educators. We developed, implemented, and evaluated a novel, pragmatic approach to teach IS., Methods: Getting To Implementation (GTI)-Teach was developed as a seven-step educational model to guide students through the process of developing, conducting, and sustaining an IS research project. During the four-week online course, students applied the steps to self-selected implementation problems. Students were invited to complete two online post-course surveys to assess course satisfaction and self-reported changes in IS knowledge and relevance of GTI-Teach Steps to their work. Results were summarized using descriptive statistics; self-reported post-course changes in IS knowledge were compared using paired t-tests., Results: GTI-Teach was developed to include seven Steps: 1. Define the implementation problem; 2. Conceptualize the problem; 3. Prioritize implementation barriers and facilitators; 4. Select and tailor implementation strategies; 5. Design an implementation study; 6. Evaluate implementation; 7. Sustain implementation. Thirteen students, ranging in experience from medical students to full professors, enrolled in and completed the first GTI-Teach course. Of the seven students (54%) completing an end-of course survey, six (86%) were very satisfied with the course. Ten students (77%) responded to the tailored, 6-month post-course follow-up survey. They retrospectively reported a significant increase in their knowledge across all steps of GTI-Teach (1.3-1.8 points on a 5-point Likert scale) and rated each of the Steps as highly relevant to their work., Conclusions: GTI-Teach is a seven-step model for teaching IS fundamentals that students reported increased their knowledge and was relevant to their work., (© The Author(s) 2022.)

The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.

Hypercontractility of the cardiac sarcomere may be essential for the underlying pathological hypertrophy and fibrosis in genetic hypertrophic cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor that was discovered from the optimization of indoline compound 1 . The important advancement of the optimization was discovery of an Indane analogue ( 12 ) with a less restrictive structure-activity relationship that allowed for the rapid improvement of drug-like properties. Aficamten was designed to provide a predicted human half-life ( t 1/2 ) appropriate for once a day (qd) dosing, to reach steady state within two weeks, to have no substantial cytochrome P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship. In a phase I clinical trial, aficamten demonstrated a human t 1/2 similar to predictions and was able to reach steady state concentration within the desired two-week window.

Study Question: Are preconception urinary concentrations of phthalates and phthalate alternatives associated with diminished early stage embryo quality in couples undergoing IVF?, Summary Answer: Male, but not female, urinary concentrations of select metabolites of phthalates and phthalate alternatives are associated with diminished blastocyst quality., What Is Known Already: Although phthalates are endocrine disrupting compounds associated with adverse reproductive health, they are in widespread use across the world. Male and female preconception exposures to select phthalates have been previously associated with adverse reproductive outcomes in both the general population and in those undergoing IVF., Study Design, Size, Duration: This prospective cohort included 50 subfertile couples undergoing IVF in western Massachusetts., Participants/materials, Setting, Methods: This study includes the first 50 couples recruited from the Baystate Medical Center's Fertility Center in Springfield, MA, as part of the Sperm Environmental Epigenetics and Development Study (SEEDS). Relevant data from both partners, including embryo quality at the cleavage (Day 3) and blastocyst (Day 5) stages, were collected by clinic personnel during the normal course of an IVF cycle. A spot urine sample was collected from both male and female partners on the same day as semen sample procurement and oocyte retrieval. Concentrations of 17 urinary metabolite were quantified by liquid chromatography mass spectrometry and normalized via specific gravity. Generalized estimating equations were used to estimate odds ratios (OR) and 95% CI, with urinary phthalates and phthalate alternatives fitted as continuous variables and embryo quality as a binary variable., Main Results and the Role of Chance: The 50 couples contributed 761 oocytes, of which 423 progressed to the cleavage stage, 261 were high-quality cleavage stage embryos, 137 were transferrable quality blastocysts and 47 were high-quality blastocysts. At the cleavage stage, male urinary monoethyl phthalate concentrations were positively associated with high-quality cleavage stage embryos (OR = 1.20, 95% CI 1.01-1.43, P = 0.04); no other significant associations were observed at this stage. At the blastocyst stage, male urinary concentrations of monobenzyl phthalate (OR = 0.55, 95% CI 0.36-0.84, P = 0.01), mono-3-hydroxybutyl phthalate (OR = 0.37, 95% CI 0.18-0.76, P = 0.01), mono-n-butyl phthalate (OR = 0.55, 95% CI 0.42-0.73, P < 0.01) and monomethyl phthalate (OR = 0.39, 95% CI 0.26-0.60, P < 0.01) were inversely associated with high-quality blastocysts. A borderline statistically significant relationship was observed for male concentrations of mono(2-ethylhexyl) phthalate (OR = 0.52, 95% CI 0.27-1.00, P = 0.05) and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (OR = 0.21, 95% CI 0.04-1.03, P = 0.05) at the blastocyst stage. Similar inverse associations were observed between male urinary phthalate metabolite concentrations and likelihood of transferrable quality blastocysts. For female partners, select metabolites were positively associated with odds of high or transferrable blastocyst quality, but the observed associations were not consistent across blastocyst quality measures or between sex-specific and couples-level models. All models were adjusted for age of both partners, urinary metabolite concentrations of female partners and male infertility status, while models of blastocysts were additionally adjusted for embryo quality at cleavage stage., Limitations, Reasons for Caution: Our modest sample included only 50 couples contributing one cycle each. In addition, non-differential misclassification of exposure remains a concern given the single-spot urine collection and the short half-life of phthalates., Wider Implications of the Findings: Our results suggest an inverse association between male preconception concentrations of select phthalate metabolites and blastocyst quality, likely occurring after genomic activation. If corroborated with other studies, such findings will have public health and clinical significance for both the general population and those undergoing IVF., Study Funding/competing Interests: This work was generously supported by grant K22-ES023085 from the National Institute of Environmental Health Sciences. The authors declare no competing interests., Trial Registration Number: N/A., (© The Author 2016. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)