Evolving Strategies for Management of Obstructive Hypertrophic Cardiomyopathy.

For many years, treatment of hypertrophic cardiomyopathy (HCM) has focused on non-disease specific therapies. Cardiac myosin modulators (i.e., mavacamten and aficamten) reduce the pathologic actin-myosin interactions that are characteristic of HCM, leading to improved cardiac energetics and reduction in hypercontractility. Several recently published randomized clinical trials have demonstrated that mavacamten improves exercise capacity, left ventricular outflow tract obstruction, and symptoms in patients with obstructive HCM (oHCM), and may delay the need for septal reduction therapy. Long-term data in real world populations will be needed to fully assess the safety and efficacy of mavacamten. Importantly, HCM is a complex and heterogeneous disease and not all patients will respond to mavacamten; therefore, careful patient selection and shared decision-making will be necessary in guiding the use of mavacamten in oHCM.

Advanced Heart Failure Therapies for Hypertrophic Cardiomyopathy: State-of-the-Art Review and an Updated Analysis From UNOS.

Hypertrophic cardiomyopathy (HCM) is most commonly associated with obstructive symptoms and sudden cardiac death; however, predominantly nonobstructive advanced heart failure in HCM, marked by medically refractory disease with severe functional impairment, occurs in 5% to 7% of patients with HCM. The diagnosis relies on the integration of imaging (echocardiography/cardiac magnetic resonance), hemodynamic data, and cardiopulmonary exercise testing to identify the patients who will benefit from advanced heart failure therapies. Most advanced heart failure therapies focus on systolic dysfunction and are not always applicable to this patient population. Left ventricular assist devices may be an option in a highly selected population with left ventricular dilation. Heart transplantation is often the best option for patients with advanced heart failure in HCM with excellent post-transplantation survival.

Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder often caused by mutations to sarcomeric genes. Many different HCM-associated TPM1 mutations have been identified but they vary in their degrees of severity, prevalence, and rate of disease progression. The pathogenicity of many TPM1 variants detected in the clinical population remains unknown. Our objective was to employ a computational modeling pipeline to assess pathogenicity of one such variant of unknown significance, TPM1 S215L, and validate predictions using experimental methods. Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain. These changes were quantitatively represented in a Markov model of thin-filament activation to infer the impacts of S215L on myofilament function. Simulations of in vitro motility and isometric twitch force predicted that the mutation would increase Ca2+ sensitivity and twitch force while slowing twitch relaxation. In vitro motility experiments with thin filaments containing TPM1 S215L revealed higher Ca2+ sensitivity compared with wild type. Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction. These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype. These simulations and experiments support the classification of S215L as a pathogenic mutation and support the hypothesis that an inability to adequately inhibit actomyosin interactions is the mechanism whereby thin-filament mutations cause HCM.

How Does COVID-19 Affect the Heart?

PURPOSE OF REVIEW: Cardiac consequences occur in both acute COVID-19 and post-acute sequelae of COVID-19 (PASC). Here, we highlight the current understanding about COVID-19 cardiac effects, based upon clinical, imaging, autopsy, and molecular studies. RECENT FINDINGS: COVID-19 cardiac effects are heterogeneous. Multiple, concurrent cardiac histopathologic findings have been detected on autopsies of COVID-19 non-survivors. Microthrombi and cardiomyocyte necrosis are commonly detected. Macrophages often infiltrate the heart at high density but without fulfilling histologic criteria for myocarditis. The high prevalences of microthrombi and inflammatory infiltrates in fatal COVID-19 raise the concern that recovered COVID-19 patients may have similar but subclinical cardiac pathology. Molecular studies suggest that SARS-CoV-2 infection of cardiac pericytes, dysregulated immunothrombosis, and pro-inflammatory and anti-fibrinolytic responses underlie COVID-19 cardiac pathology. The extent and nature by which mild COVID-19 affects the heart is unknown. Imaging and epidemiologic studies of recovered COVID-19 patients suggest that even mild illness confers increased risks of cardiac inflammation, cardiovascular disorders, and cardiovascular death. The mechanistic details of COVID-19 cardiac pathophysiology remain under active investigation. The ongoing evolution of SARS-CoV-2 variants and vast numbers of recovered COVID-19 patients portend a burgeoning global cardiovascular disease burden. Our ability to prevent and treat cardiovascular disease in the future will likely depend on comprehensive understanding of COVID-19 cardiac pathophysiologic phenotypes.

Comparison of baseline characteristics and postoperative complications in neuromuscular, syndromic and congenital scoliosis.

Nonidiopathic scoliosis encompasses a group of diagnoses, including neuromuscular scoliosis, syndromic scoliosis and congenital scoliosis. The objective of this study was to compare the preoperative and postoperative clinical differences in pediatric nonidiopathic scoliosis patients with neuromuscular scoliosis vs. syndromic scoliosis/congenital scoliosis. This is a single-center retrospective review of all pediatric patients undergoing spinal instrumentation for nonidiopathic scoliosis during a 5-year period. Neuromuscular scoliosis patients ( n = 144), syndromic scoliosis patients ( n = 44) and congenital scoliosis patients ( n = 52) were compared. Demographics, patient characteristics and outcomes were compared. Neuromuscular scoliosis patients had lower BMI z-scores and were more likely to have pulmonary disease, technology dependence and seizure disorder. Additionally, neuromuscular scoliosis patients underwent bigger procedures with more levels fused and a higher rate of pelvis fixation. By direct comparison, neuromuscular scoliosis patients tended to have more complications including deep surgical site infections, readmission in 30 days, return to operating room in 90 days and emergency care visits in 90 days. When controlling for the differences in their preexisting conditions and surgical procedure, we found that pelvic fixation was a major confounding factor, whereas the others had no effect. We further subanalyzed cerebral palsy patients and found this group to exhibit no difference in complications compared to other neuromuscular scoliosis subtypes. Neuromuscular scoliosis patients have different characteristics and subsequent postoperative complications than those with syndromic scoliosis and congenital scoliosis. The difference in complication profile is mainly due to differences in surgical procedure and a higher rate of pelvic fixation. This should be considered when planning nonidiopathic scoliosis surgery among multidisciplinary teams.

A cross-sectional study on the association between social media addiction, body image, and social comparison among young adult Filipino women aged 18-25 years old in Metro Manila / The Health Sciences Journal

INTRODUCTION@#The Philippines tops globally for time spent on social media. This study aimed to explore the association between social media addiction, body image, and social comparison among young adult Filipino women aged 18-25 years old in Metro Manila.@*METHODS@#The Social Media Addiction Scale (SMAS), Body Image Questionnaire (BIQ), and Iowa-Netherlands Comparison Orientation Measure (INCOM) were used to assess social media addiction, body image, and social comparison, respectively. PRR (CI 95%) assessed the association between SMA and BI, and SMA and SC.@*RESULTS@#Majority of participants had social media addiction (91.11%), while most reported a neutral body image (87.64%). Additionally, more than half of the participants exhibited a high tendency towards social comparison (53.15%). The study found a positive association between social media addiction and negative body image, as well as a significant positive association between social media addiction and social comparison. Obesity showed a significant positive association with negative body image perception, while being overweight was significantly associated with a lower likelihood of having a positive body image. Spending at least 4 hours per day on social media was significantly associated with a higher tendency towards social comparison.@*CONCLUSION@#These findings suggest the presence of social media addiction among young adult Filipino women and its association with body image and social comparison. Awareness of these associations can contribute to the development of targeted interventions and educational programs to promote healthier social media use and positive body image among young adults.

Prospects for remodeling the hypertrophic heart with myosin modulators.

Hypertrophic cardiomyopathy (HCM) is a complex but relatively common genetic disease that usually arises from pathogenic variants that disrupt sarcomere function and lead to variable structural, hypertrophic, and fibrotic remodeling of the heart which result in substantial adverse clinical outcomes including arrhythmias, heart failure, and sudden cardiac death. HCM has had few effective treatments with the potential to ameliorate disease progression until the recent advent of inhibitory myosin modulators like mavacamten. Preclinical investigations and clinical trials utilizing this treatment targeted to this specific pathophysiological mechanism of sarcomere hypercontractility in HCM have confirmed that myosin modulators can alter disease expression and attenuate hypertrophic remodeling. Here, we summarize the state of hypertrophic remodeling and consider the arguments for and against salutary HCM disease modification using targeted myosin modulators. Further, we consider critical unanswered questions for future investigative and therapeutic avenues in HCM disease modification. We are at the precipice of a new era in understanding and treating HCM, with the potential to target agents toward modifying disease expression and natural history of this most common inherited disease of the heart.

Retention, Fasting Patterns, and Weight Loss With an Intermittent Fasting App: Large-Scale, 52-Week Observational Study.

BACKGROUND: Intermittent fasting (IF) is an increasingly popular approach to dietary control that focuses on the timing of eating rather than the quantity and content of caloric intake. IF practitioners typically seek to improve their weight and other health factors. Millions of practitioners have turned to purpose-built mobile apps to help them track and adhere to their fasts and monitor changes in their weight and other biometrics. OBJECTIVE: This study aimed to quantify user retention, fasting patterns, and weight loss by users of 2 IF mobile apps. We also sought to describe and model starting BMI, amount of fasting, frequency of weight tracking, and other demographics as correlates of retention and weight change. METHODS: We assembled height, weight, fasting, and demographic data of adult users (ages 18-100 years) of the LIFE Fasting Tracker and LIFE Extend apps from 2018 to 2020. Retention for up to 52 weeks was quantified based on recorded fasts and correlated with user demographics. Users who provided height and at least 2 readings of weight and whose first fast and weight records were contemporaneous were included in the weight loss analysis. Fasting was quantified as extended fasting hours (EFH; hours beyond 12 in a fast) averaged per day (EFH per day). Retention was modeled using a Cox proportional hazards regression. Weight loss was analyzed using linear regression. RESULTS: A total of 792,692 users were followed for retention based on 26 million recorded fasts. Of these, 132,775 (16.7%) users were retained at 13 weeks, 54,881 (6.9%) at 26 weeks, and 16,478 (2.1%) at 52 weeks, allowing 4 consecutive weeks of inactivity. The survival analysis using Cox regression indicated that retention was positively associated with age and exercise and negatively associated with stress and smoking. Weight loss in the qualifying cohort (n=161,346) was strongly correlated with starting BMI and EFH per day, which displayed a positive interaction. Users with a BMI ≥40 kg/m2 lost 13.9% of their starting weight by 52 weeks versus a slight weight gain on average for users with starting BMI <23 kg/m2. EFH per day was an approximately linear predictor of weight loss. By week 26, users lost over 1% of their starting weight per EFH per day on average. The regression analysis using all variables was highly predictive of weight change at 26 weeks (R2=0.334) with starting BMI and EFH per day as the most significant predictors. CONCLUSIONS: IF with LIFE mobile apps appears to be a sustainable approach to weight reduction in the overweight and obese population. Healthy weight and underweight individuals do not lose much weight on average, even with extensive fasting. Users who are obese lose substantial weight over time, with more weight loss in those who fast more.

Physiological calcium combined with electrical pacing accelerates maturation of human engineered heart tissue.

Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have wide potential application in basic research, drug discovery, and regenerative medicine, but functional maturation remains challenging. Here, we present a method whereby maturation of hiPSC-CMs can be accelerated by simultaneous application of physiological Ca2+ and frequency-ramped electrical pacing in culture. This combination produces positive force-frequency behavior, physiological twitch kinetics, robust ß-adrenergic response, improved Ca2+ handling, and cardiac troponin I expression within 25 days. This study provides insights into the role of Ca2+ in hiPSC-CM maturation and offers a scalable platform for translational and clinical research.

Specificity and sensibility of the Spanish version of the COMFORT Behaviour Scale for assessing pain, grade of sedation and withdrawal syndrome in the critically ill paediatric patient. Multicentre COSAIP study (Phase 1).

AIM: The main aim of this investigation was to analyse the specificity and sensibility of the COMFORT Behaviour Scale (CBS-S) in assessing grade of pain, sedation, and withdrawal syndrome in paediatric critical care patients. METHOD: An observational, analytical, cross-sectional and multicentre study conducted in Level III Intensive Care Areas of 5 children's university hospitals. Grade of sedation was assessed using the Spanish version of the CBS-S and the Bispectral Index on sedation, once per shift over one day. Grade of withdrawal was determined using the CBS-S and the Withdrawal Assessment Tool-1, once per shift over three days. RESULTS: A total of 261 critically ill paediatric patients with a median age of 5.07 years (P25:0.9-P75:11.7) were included in this study. In terms of the predictive capacity of the CBS-S, it obtained a Receiver Operation Curve of .84 (sensitivity of 81% and specificity of 76%) in relation to pain; .62 (sensitivity of 21% and specificity of 78%) in relation to sedation grade, and .73% (sensitivity of 40% and specificity of 74%) in determining withdrawal syndrome. CONCLUSIONS: The Spanish version of the COMFORT Behaviour Scale could be a useful, sensible and easy scale to assess the degree of pain, sedation and pharmacological withdrawal of critically ill paediatric patients.

Muscle LIM Protein Force-Sensing Mediates Sarcomeric Biomechanical Signaling in Human Familial Hypertrophic Cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and is typically caused by mutations in genes encoding sarcomeric proteins that regulate cardiac contractility. HCM manifestations include left ventricular hypertrophy and heart failure, arrythmias, and sudden cardiac death. How dysregulated sarcomeric force production is sensed and leads to pathological remodeling remains poorly understood in HCM, thereby inhibiting the efficient development of new therapeutics. METHODS: Our discovery was based on insights from a severe phenotype of an individual with HCM and a second genetic alteration in a sarcomeric mechanosensing protein. We derived cardiomyocytes from patient-specific induced pluripotent stem cells and developed robust engineered heart tissues by seeding induced pluripotent stem cell-derived cardiomyocytes into a laser-cut scaffold possessing native cardiac fiber alignment to study human cardiac mechanobiology at both the cellular and tissue levels. Coupled with computational modeling for muscle contraction and rescue of disease phenotype by gene editing and pharmacological interventions, we have identified a new mechanotransduction pathway in HCM, shown to be essential in modulating the phenotypic expression of HCM in 5 families bearing distinct sarcomeric mutations. RESULTS: Enhanced actomyosin crossbridge formation caused by sarcomeric mutations in cardiac myosin heavy chain (MYH7) led to increased force generation, which, when coupled with slower twitch relaxation, destabilized the MLP (muscle LIM protein) stretch-sensing complex at the Z-disc. Subsequent reduction in the sarcomeric muscle LIM protein level caused disinhibition of calcineurin-nuclear factor of activated T-cells signaling, which promoted cardiac hypertrophy. We demonstrate that the common muscle LIM protein-W4R variant is an important modifier, exacerbating the phenotypic expression of HCM, but alone may not be a disease-causing mutation. By mitigating enhanced actomyosin crossbridge formation through either genetic or pharmacological means, we alleviated stress at the Z-disc, preventing the development of hypertrophy associated with sarcomeric mutations. CONCLUSIONS: Our studies have uncovered a novel biomechanical mechanism through which dysregulated sarcomeric force production is sensed and leads to pathological signaling, remodeling, and hypertrophic responses. Together, these establish the foundation for developing innovative mechanism-based treatments for HCM that stabilize the Z-disc MLP-mechanosensory complex.

Especificidad y sensibilidad de la COMFORT Behavior Scale-Versión española para valorar el dolor, el grado de sedación y síndrome de abstinencia en el paciente crítico pediátrico. Estudio multicéntrico COSAIP (Fase 1) / Specificity and sensibility of the Spanish version of the COMFORT Behaviour Scale for assessing pain, grade of sedation and withdrawal syndrome in the critically ill paediatric patient. Multicentre COSAIP study (Phase 1)

Objetivo: El objetivo principal de la investigación fue analizar la especificidad y sensibilidad de la escala COMFORT Behavior Scale-Versión española (CBS-ES) en la determinación del grado de dolor, sedación y síndrome de abstinencia.Método: Se llevó a cabo un estudio observacional, analítico y transversal y multicéntrico en unidades de cuidados intensivos pediátricas de 5 hospitales españoles. Se valoró el grado de sedación del paciente crítico pediátrico de forma simultánea empleando para ello la CBS-ES y registrando los valores del Bispectral Index Sedation, una vez por turno durante un día. El grado de abstinencia se determinó una vez por turno, durante 3 días, empleando de forma simultánea la CBS-ES y la Withdrawal Assessment Tool-1.Resultados: Se incluyeron en el estudio un total de 261 pacientes críticos pediátricos con una mediana de 1,61 años (P25: 0,35-P75: 6,55). Por lo que a la capacidad predictiva de la CBS-ES se refiere se obtuvo un área bajo la curva de 0,84 (sensibilidad del 81% y especificidad del 76%) con relación al dolor; de 0,62 (sensibilidad del 27% y especificidad del 78%) en el caso de la sedación, y de 0,73 (sensibilidad del 40% y especificidad del 74%) en el del síndrome de abstinencia.Conclusiones: Se ha podido contrastar que la CBS-ES podría ser un instrumento sensible, útil y fácil de emplear para valorar el grado de dolor, sedación y síndrome de abstinencia farmacológico del paciente crítico pediátrico.

Aim: The main aim of this investigation was to analyse the specificity and sensibility of the COMFORT Behaviour Scale (CBS-S) in assessing grade of pain, sedation, and withdrawal syndrome in paediatric critical care patients.Method: An observational, analytical, cross-sectional and multicentre study conducted in Level III Intensive Care Areas of 5 children's university hospitals. Grade of sedation was assessed using the Spanish version of the CBS-S and the Bispectral Index on sedation, once per shift over one day. Grade of withdrawal was determined using the CBS-S and the Withdrawal Assessment Tool-1, once per shift over three days.Results: A total of 261 critically ill paediatric patients with a median age of 5.07 years (P25:0.9-P75:11.7) were included in this study. In terms of the predictive capacity of the CBS-S, it obtained a Receiver Operation Curve of .84 (sensitivity of 81% and specificity of 76%) in relation to pain; .62 (sensitivity of 21% and specificity of 78%) in relation to sedation grade, and .73% (sensitivity of 40% and specificity of 74%) in determining withdrawal syndrome.Conclusions: The Spanish version of the COMFORT Behaviour Scale could be a useful, sensible and easy scale to assess the degree of pain, sedation and pharmacological withdrawal of critically ill paediatric patients.

GC-MS determination of malondialdehyde, acrolein, and 4-hydroxy-2-nonenal by ultrasound-assisted dispersive liquid-liquid microextraction in beverages.

A new, fast, simple, and effective ultrasound-assisted dispersive liquid-liquid microextraction procedure (UA-DLLME) for the gas chromatography-mass spectrometry (GC-MS) determination of malondialdehyde, acrolein, and 4-hydroxy-2-nonenal in beverages was successfully developed. 2,4-Dinitrophenylhydrazine derivatization was performed during extraction. An asymmetrical 3541//18 screening design and a central composite surface response design were used to investigate the influence of the most critical factors during the extraction process (ultrasound time and temperature, extraction and disperser solvents volumes, salt addition, and derivatization reagent concentration). According to FDA guidelines, the method was validated, achieving good linearities with r2 ≥ 0.9982, recoveries between 94.0 and 102.4%, and reproducibility with RSD lower than 4.5%. The method was applied to simultaneously determine the compounds in 60 different beverage samples, including beer, coffee, black tea, and fruit juices. The presence of secondary lipid oxidation products is demonstrated in beverages with a strong roasting process or oxidation.

Mortality Rates Among Hospitalized Patients With COVID-19 Infection Treated With Tocilizumab and Corticosteroids: A Bayesian Reanalysis of a Previous Meta-analysis.

Importance: A World Health Organization (WHO) meta-analysis found that tocilizumab was associated with reduced mortality in hospitalized patients with COVID-19. However, uncertainty remains concerning the magnitude of tocilizumab's benefits and whether its association with mortality benefit is similar across respiratory subgroups. Objective: To use bayesian methods to assess the magnitude of mortality benefit associated with tocilizumab and the differences between respiratory support subgroups in hospitalized patients with COVID-19. Design, Setting, and Participants: A bayesian hierarchical reanalysis of the WHO meta-analysis of tocilizumab studies published in 2020 and 2021 was performed. Main results were estimated using weakly informative priors to exert little influence on the observed data. The robustness of these results was evaluated using vague and informative priors. The studies featured in the meta-analysis were randomized clinical tocilizumab trials of hospitalized patients with COVID-19. Only patients receiving corticosteroids were included. Interventions: Usual care plus tocilizumab in comparison with usual care or placebo. Main Outcomes and Measures: All-cause mortality at 28 days after randomization. Results: Among the 5339 patients included in this analysis, most were men, with mean ages between 56 and 66 years. There were 2117 patients receiving simple oxygen only, 2505 receiving noninvasive ventilation (NIV), and 717 receiving invasive mechanical ventilation (IMV) in 15 studies from multiple countries and continents. Assuming weakly informative priors, the overall odds ratios (ORs) for survival were 0.70 (95% credible interval [CrI], 0.50-0.91) for patients receiving simple oxygen only, 0.81 (95% CrI, 0.63-1.03) for patients receiving NIV, and 0.89 (95% CrI, 0.61-1.22) for patients receiving IMV, respectively. The posterior probabilities of any benefit (OR <1) were notably different between patients receiving simple oxygen only (98.9%), NIV (95.5%), and IMV (75.4%). The posterior probabilities of a clinically meaningful association (absolute mortality risk difference >1%) were greater than 95% in patients receiving simple oxygen only and greater than 90% in patients receiving NIV. In contrast, the posterior probability of this clinically meaningful association was only approximately 67% in patients receiving IMV. The probabilities of tocilizumab superiority in the simple oxygen only subgroup compared with the NIV and IMV subgroups were 85% and 90%, respectively. Predictive intervals highlighted that only 72.1% of future tocilizumab IMV studies would show benefit. The conclusions did not change with different prior distributions. Conclusions and Relevance: In this bayesian reanalysis of a previous meta-analysis of 15 studies of hospitalized patients with COVID-19 treated with tocilizumab and corticosteroids, use of simple oxygen only and NIV was associated with a probability of a clinically meaningful mortality benefit from tocilizumab. Future research should clarify whether patients receiving IMV also benefit from tocilizumab.

Anti-Myeloperoxidase (MPO) associated Vasculitis in a young Filipino Male with Bronchiectasis: A case report

Background@#ANCA-associated vasculitis and its subtypes have been associated with pulmonary manifestations, with bronchiectasis being a unique clinical presentation.@*Case Summary@# We report the case of a 26-year-old Filipino male who presented with progressive dyspnea, neuropathic pain, and purpuric rash. Diagnostic evaluation revealed upper lobe bronchiectasis and lower lobe pneumonia, as well as hematuria and proteinuria. ANCA-associated vasculitis (AAV) and tuberculosis were considered. There was improvement of dyspnea, cough and rashes with antibiotics, glucocorticoids (GC), and anti-TB coverage. However, neuropathic pain progressed to the upper and lower extremities with development of weakness. Anti-myeloperoxidase (MPO) Anti-Neutrophil Cytoplasmic Antibody (ANCA) was positive, Electromyography-Nerve Conduction Velocity (EMG-NCV) revealed diffuse sensorimotor axonal polyradiculopathy of both upper and lower extremities. Cyclophosphamide was then given. The patient gradually regained his motor strength while sensory deficits persisted. He was referred to rehabilitation medicine for physical therapy and eventually discharged. This case highlights vasculitis as an associated extrapulmonary manifestation of bronchiectasis, and the possible role of bronchiectasis in the immune-mediated pathogenesis of ANCA- associated vasculitides.

Grado de sedación del paciente crítico pediátrico y variables sociodemográficas y clínicas correlacionadas. Estudio multicéntrico COSAIP / Grade of sedation in the critically ill paediatric patient and its correlation with sociodemographic and clinical variables. Multicentre COSAIP study

Objetivos Determinar los niveles de sedación del paciente crítico pediátrico mediante el Biespectral Index Sensor (BIS) y analizar la relación entre el grado de sedación y las variables sociodemográficas y clínicas del paciente. Métodos Estudio observacional, analítico, transversal y multicéntrico de mayo de 2018 a enero de 2020 desarrollado en 5unidades de cuidados intensivos pediátricas del territorio español. Se registraron como variables sociodemográficas y clínicas el sexo, la edad, motivo de ingreso, si el paciente tenía enfermedad crónica, el tipo y número de fármacos que se le estaban administrando y la duración de la estancia. Además, se anotaron los valores del BIS una vez por turno, mañana y noche, durante 24 h. Resultados Se incluyó en el estudio a un total de 261 pacientes, de los cuales el 53,64% eran del sexo masculino, con una edad mediana de 1,61 años (0,35-6,55). El 70,11% (n=183) estaban analgosedados y monitorizados con el sensor BIS. Se observó una mediana en las puntuaciones globales de BIS de 51,24±14,96 en el turno de mañana y de 50,75±15,55 en el de noche. No se detectó significación estadística al comparar los niveles de BIS y las diversas variables sociodemográficas y clínicas del paciente crítico pediátrico. Conclusiones A pesar de las limitaciones inherentes al sensor BIS, los estudios existentes y el que aquí se presenta muestran que el BIS es un instrumento útil para monitorizar el grado de sedación en el paciente crítico pediátrico. Se requieren más investigaciones que objetiven qué variables relacionadas con el paciente tienen más peso en al grado de analgosedación y que contrasten clínicamente la eficacia de escalas como, por ejemplo, la COMFORT Behavior Scale versión española. (AU)

Aims To determine the grade of sedation in the critically ill paediatric patient using Biespectral Index Sensor (BIS) and to analyse its relationship with sociodemographic and clinical patient variables. Methods Observational, analytical, cross-sectional and multicentre study performed from May 2018 to January 2020 in 5 Spanish paediatric critical care units. Sex, age, reason for admission, presence of a chronic pathology, type and number of drugs and length of stay were the sociodemographic and clinical variables registered. Furthermore, the grade of sedation was assessed using BIS, 11per shift over 24hours. Results A total of 261 paediatric patients, 53.64% of whom were male, with a median age of 1.61 years (0.35-6.55), were included in the study. Of the patients, 70.11% (n=183) were under analgosedation and monitored using the BIS sensor. A median of BIS values of 51.24±14.96 during the morning and 50.75±15.55 during the night were observed. When comparing BIS values and sociodemographic and clinical paediatric variables no statistical significance was detected. Conclusions Despite the limitations of the BIS, investigations and the present study show that BIS could be a useful instrument to assess grade of sedation in critically ill paediatric patients. However, further investigations which determine the sociodemographic and clinical variables involved in the grade of paediatric analgosedation, as well as studies that contrast the efficacy of clinical scales like the COMFORT Behaviour Scale-Spanish version, are required. (AU)

Grade of sedation in the critically ill pediatric patient and its correlation with sociodemographic and clinical variables. Multicentre COSAIP study.

AIMS: To determine the grade of sedation in the critically ill paediatric patient using Biespectral Index Sensor (BIS) and to analyse its relationship with sociodemographic and clinical patient variables. METHODS: Observational, analytical, cross-sectional and multicentre study performed from May 2018 to January 2020 in 5 Spanish paediatric critical care units. Sex, age, reason for admission, presence of a chronic pathology, type and number of drugs and length of stay were the sociodemographic and clinical variables registered. Furthermore, the grade of sedation was assessed using BIS, once per shift over 24 h. RESULTS: A total of 261 paediatric patients, 53.64% of whom were male, with a median age of 1.61 years (0.35-6.55), were included in the study. Of the patients, 70.11% (n = 183) were under analgosedation and monitored using the BIS sensor. A median of BIS values of 51.24 ±â€¯14.96 during the morning and 50.75 ±â€¯15.55 during the night were observed. When comparing BIS values and sociodemographic and clinical paediatric variables no statistical significance was detected. CONCLUSIONS: Despite the limitations of the BIS, investigations and the present study show that BIS could be a useful instrument to assess grade of sedation in critically ill paediatric patients. However, further investigations which determine the sociodemographic and clinical variables involved in the grade of paediatric analgosedation, as well as studies that contrast the efficacy of clinical scales like the COMFORT Behaviour Scale-Spanish version, are required.

Specificity and sensibility of the Spanish version of the COMFORT Behaviour Scale for assessing pain, grade of sedation and withdrawal syndrome in the critically ill paediatric patient. Multicentre COSAIP study (Phase 1). / Especificidad y sensibilidad de la COMFORT Behavior Scale-Versión española para valorar el dolor, el grado de sedación y síndrome de abstinencia en el paciente crítico pediátrico. Estudio multicéntrico COSAIP (Fase 1).

AIM: The main aim of this investigation was to analyse the specificity and sensibility of the COMFORT Behaviour Scale (CBS-S) in assessing grade of pain, sedation, and withdrawal syndrome in paediatric critical care patients. METHOD: An observational, analytical, cross-sectional and multicentre study conducted in Level III Intensive Care Areas of 5 children's university hospitals. Grade of sedation was assessed using the Spanish version of the CBS-S and the Bispectral Index on sedation, once per shift over one day. Grade of withdrawal was determined using the CBS-S and the Withdrawal Assessment Tool-1, once per shift over three days. RESULTS: A total of 261 critically ill paediatric patients with a median age of 5.07 years (P25:0.9-P75:11.7) were included in this study. In terms of the predictive capacity of the CBS-S, it obtained a Receiver Operation Curve of .84 (sensitivity of 81% and specificity of 76%) in relation to pain; .62 (sensitivity of 21% and specificity of 78%) in relation to sedation grade, and .73% (sensitivity of 40% and specificity of 74%) in determining withdrawal syndrome. CONCLUSIONS: The Spanish version of the COMFORT Behaviour Scale could be a useful, sensible and easy scale to assess the degree of pain, sedation and pharmacological withdrawal of critically ill paediatric patients.

Loss of crossbridge inhibition drives pathological cardiac hypertrophy in patients harboring the TPM1 E192K mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder caused primarily by mutations to thick and thinfilament proteins. Although thin filament mutations are less prevalent than their oft-studied thick filament counterparts, they are frequently associated with severe patient phenotypes and can offer important insight into fundamental disease mechanisms. We have performed a detailed study of tropomyosin (TPM1) E192K, a variant of uncertain significance associated with HCM. Molecular dynamics revealed that E192K results in a more flexible TPM1 molecule, which could affect its ability to regulate crossbridges. In vitro motility assays of regulated actin filaments containing TPM1 E192K showed an overall loss of Ca2+ sensitivity. To understand these effects, we used multiscale computational models that suggested a subtle phenotype in which E192K leads to an inability to completely inhibit actin-myosin crossbridge activity at low Ca2+. To assess the physiological impact of the mutation, we generated patient-derived engineered heart tissues expressing E192K. These tissues showed disease features similar to those of the patients, including cellular hypertrophy, hypercontractility, and diastolic dysfunction. We hypothesized that excess residual crossbridge activity could be triggering cellular hypertrophy, even if the overall Ca2+ sensitivity was reduced by E192K. To test this hypothesis, the cardiac myosin-specific inhibitor mavacamten was applied to patient-derived engineered heart tissues for 4 d followed by 24 h of washout. Chronic mavacamten treatment abolished contractile differences between control and TPM1 E192K engineered heart tissues and reversed hypertrophy in cardiomyocytes. These results suggest that the TPM1 E192K mutation triggers cardiomyocyte hypertrophy by permitting excess residual crossbridge activity. These studies also provide direct evidence that myosin inhibition by mavacamten can counteract the hypertrophic effects of mutant tropomyosin.