Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. METHODS: In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. RESULTS: A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).

iPSC-Based Modeling of Variable Clinical Presentation in Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease and a frequent cause of heart failure and sudden cardiac death. Our understanding of the genetic bases and pathogenic mechanisms underlying HCM has improved significantly in the recent past, but the combined effect of various pathogenic gene variants and the influence of genetic modifiers in disease manifestation are very poorly understood. Here, we set out to investigate genotype-phenotype relationships in 2 siblings with an extensive family history of HCM, both carrying a pathogenic truncating variant in the MYBPC3 gene (p.Lys600Asnfs*2), but who exhibited highly divergent clinical manifestations. METHODS: We used a combination of induced pluripotent stem cell (iPSC)-based disease modeling and CRISPR (clustered regularly interspersed short palindromic repeats)/Cas9 (CRISPR-associated protein 9)-mediated genome editing to generate patient-specific cardiomyocytes (iPSC-CMs) and isogenic controls lacking the pathogenic MYBPC3 variant. RESULTS: Mutant iPSC-CMs developed impaired mitochondrial bioenergetics, which was dependent on the presence of the mutation. Moreover, we could detect altered excitation-contraction coupling in iPSC-CMs from the severely affected individual. The pathogenic MYBPC3 variant was found to be necessary, but not sufficient, to induce iPSC-CM hyperexcitability, suggesting the presence of additional genetic modifiers. Whole-exome sequencing of the mutant carriers identified a variant of unknown significance in the MYH7 gene (p.Ile1927Phe) uniquely present in the individual with severe HCM. We finally assessed the pathogenicity of this variant of unknown significance by functionally evaluating iPSC-CMs after editing the variant. CONCLUSIONS: Our results indicate that the p.Ile1927Phe variant of unknown significance in MYH7 can be considered as a modifier of HCM expressivity when found in combination with truncating variants in MYBPC3. Overall, our studies show that iPSC-based modeling of clinically discordant subjects provides a unique platform to functionally assess the effect of genetic modifiers.

Efficacy and Safety of Aficamten in Symptomatic Nonobstructive Hypertrophic Cardiomyopathy: Results From the REDWOOD-HCM Trial, Cohort 4.

BACKGROUND: This open-label phase 2 trial evaluated the safety and efficacy of aficamten in patients with nonobstructive hypertrophic cardiomyopathy (nHCM). METHODS: Patients with symptomatic nHCM (left ventricular outflow tract obstruction gradient ≤ 30 mmHg, left ventricular ejection fraction [LVEF] ≥ 60%, N-terminal pro-B-type natriuretic peptide [NT-proBNP] > 300 pg/mL) received aficamten 5-15 mg once daily (doses adjusted according to echocardiographic LVEF) for 10 weeks. RESULTS: We enrolled 41 patients (mean ± SD age 56 ± 16 years; 59% female). At Week 10, 22 (55%) patients experienced an improvement of ≥ 1 New York Heart Association class; 11 (29%) became asymptomatic. Clinically relevant improvements in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores occurred in 22 (55%) patients. Symptom relief was paralleled by reductions in NT-proBNP levels (56%; P < 0.001) and high-sensitivity cardiac troponin I (22%; P < 0.005). Modest reductions in LVEF (mean ± SD) of -5.4% ± 10 to 64.6% ± 9.1 were observed. Three (8%) patients had asymptomatic reduction in LVEF < 50% (range: 41%-48%), all returning to normal after 2 weeks of washout. One patient with prior history of aborted sudden cardiac death experienced a fatal arrhythmia during the study. CONCLUSIONS: Aficamten administration for symptomatic nHCM was generally safe and was associated with improvements in heart failure symptoms and cardiac biomarkers. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04219826.

Emery-Dreifuss muscular dystrophy Type 1 is associated with a high risk of malignant ventricular arrhythmias and end-stage heart failure.

BACKGROUND AND AIMS: Emery-Dreifuss muscular dystrophy (EDMD) is caused by variants in EMD (EDMD1) and LMNA (EDMD2). Cardiac conduction defects and atrial arrhythmia are common to both, but LMNA variants also cause end-stage heart failure (ESHF) and malignant ventricular arrhythmia (MVA). This study aimed to better characterize the cardiac complications of EMD variants. METHODS: Consecutively referred EMD variant-carriers were retrospectively recruited from 12 international cardiomyopathy units. MVA and ESHF incidences in male and female variant-carriers were determined. Male EMD variant-carriers with a cardiac phenotype at baseline (EMDCARDIAC) were compared with consecutively recruited male LMNA variant-carriers with a cardiac phenotype at baseline (LMNACARDIAC). RESULTS: Longitudinal follow-up data were available for 38 male and 21 female EMD variant-carriers [mean (SD) ages 33.4 (13.3) and 43.3 (16.8) years, respectively]. Nine (23.7%) males developed MVA and five (13.2%) developed ESHF during a median (inter-quartile range) follow-up of 65.0 (24.3-109.5) months. No female EMD variant-carrier had MVA or ESHF, but nine (42.8%) developed a cardiac phenotype at a median (inter-quartile range) age of 58.6 (53.2-60.4) years. Incidence rates for MVA were similar for EMDCARDIAC and LMNACARDIAC (4.8 and 6.6 per 100 person-years, respectively; log-rank P = .49). Incidence rates for ESHF were 2.4 and 5.9 per 100 person-years for EMDCARDIAC and LMNACARDIAC, respectively (log-rank P = .09). CONCLUSIONS: Male EMD variant-carriers have a risk of progressive heart failure and ventricular arrhythmias similar to that of male LMNA variant-carriers. Early implantable cardioverter defibrillator implantation and heart failure drug therapy should be considered in male EMD variant-carriers with cardiac disease.

Pharmacokinetics of dexmedetomidine in anaesthetized horses following repeated subcutaneous administration and intravenous constant rate infusion.

BACKGROUND: The inclusion of dexmedetomidine (DEX) within a balanced general anaesthesia protocol is effective in improving the clinical outcome and recovery quality of anaesthesia in horses. This study aimed to determine the pharmacokinetic profile of DEX following repeated subcutaneous (SC) administration at 2 µg/kg every 60 min till the end of the procedure in comparison to intravenous constant rate infusion (CRI) at 1 µg/kg/h in anaesthetized horses undergoing diagnostic procedures up to the end of the diagnostic procedure. RESULTS: In the CRI and SC groups DEX maximum concentrations (Cmax) were 0.83 ± 0.27 ng/mL and 1.14 ± 0.71 ng/mL, respectively, reached at a time (Tmax) of 57.0 ± 13.4 min and 105.5 ± 29.9 min. Mean residence time to the last measurable concentration (MRTlast) was 11.7 ± 6.2 and 55.8 ± 19.7 min for the CRI group and SC groups, respectively. The apparent elimination half-life was 18.0 ± 10.0 min in the CRI group and 94.8 ± 69.8 min for the SC group, whereas the area under the curve (AUC0-last) resulted 67.7 ± 29.3 and 83.2 ± 60.5 min*ng/mL for CRI and SC group, respectively. Clearance was 16.26 ± 8.07 mL/min/kg for the CRI group. No signs of adverse effects were recorded in both groups. CONCLUSIONS: The pharmacokinetic profile of DEX following repeated SC administration in anaesthetized horses was comparable to intravenous CRI administration during the intranaesthetic period and beneficial during the recovery phase from general anaesthesia. The SC route could be considered as an alternative to CRI for improving the recovery quality of equine patients undergoing general anaesthesia.

Validation of the Food Purchase Task (FPT) in a clinical sample of smokers with overweight and obesity.

Obesity is a major health problem associated with disease burden and mortality. In this context, analyzing food as a powerful reinforcer from a behavioral economics framework could be relevant for the treatment and prevention of obesity. The purposes of this study were to validate a food purchase task (FPT) in a clinical sample of Spanish smokers with overweight and obesity and to assess the internal structure of the FPT. We also analyzed the clinical utility of single-item breakpoint (i.e., commodity price that suppresses demand). A total of 120 smokers [% females: 54.2; Mage = 52.54; SD = 10.34] with overweight and obesity completed the FPT and weight/eating-related variables. Principal component analysis was used to examine the FPT structure, and a set of correlations were used to examine the relationship between the FPT, eating and weight-related variables. The FPT demonstrated robust convergent validity with other measures of eating. Higher food demand was related to higher food craving (r = .33), more binge eating problems (r = .39), more weight gain concerns (r = .35), higher frequency of both controlled (r = .37) and uncontrolled (r = .30) grazing, as well as to an eating style in response to emotions (r = .34) and external eating (r = .34). Of the demand indices, Intensity and Omax showed the highest magnitudes of effects. The FPT factors, persistence and amplitude, do not improve individual FPT indices; and the single-item breakpoint was not related to any eating or weight variable. The FPT is a valid measure of food reinforcement with potential clinical utility in smokers with obesity/overweight.

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator.

AIMS: To study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS AND RESULTS: The study cohort comprised 554 patients with a definite diagnosis of ARVC and no history of sustained ventricular arrhythmia (VA). During a median follow-up of 6.0 (3.1,12.5) years, 100 patients (18%) experienced the primary VA outcome (sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator intervention, aborted sudden cardiac arrest, or sudden cardiac death) corresponding to an annual event rate of 2.6% [95% confidence interval (CI) 1.9-3.3]. Risk estimates for VA using the 2019 ARVC risk model showed reasonable discriminative ability but with overestimation of risk. The ARVC risk model was compared in four gene groups: PKP2 (n = 118, 21%); desmoplakin (DSP) (n = 79, 14%); other desmosomal (n = 59, 11%); and gene elusive (n = 160, 29%). Discrimination and calibration were highest for PKP2 and lowest for the gene-elusive group. Univariable analyses revealed the variable performance of individual clinical risk markers in the different gene groups, e.g. right ventricular dimensions and systolic function are significant risk markers in PKP2 but not in DSP patients and the opposite is true for left ventricular systolic function. CONCLUSION: The 2019 ARVC risk model performs reasonably well in gene-positive ARVC (particularly for PKP2) but is more limited in gene-elusive patients. Genotype should be included in future risk models for ARVC.

Post-Cessation Weight Gain among Smokers with Depression Predicts Smoking Relapse.

Objective: Weight gain (WG) is one of the most widespread consequences of smoking cessation, although there is a great variability of post-cessation weight changes among smokers. Its approach is critical because it depicts an important barrier to trying to quit smoking and because it has been considered as a long-term predictor of relapse. Notwithstanding, little is known about post-cessation WG specifically among depressed smokers. The current study sought to: (1) describe the WG at posttreatment and follow-ups in smokers with depression, (2) examine the predictors of posttreatment WG, and (3) analyze whether post-cessation WG predicts smoking relapse at 6-month follow-up. Methods: The sample was comprised of 125 smokers with depression who achieved tobacco abstinence at posttreatment following a psychological smoking cessation intervention. Smoking abstinence was biochemically verified through carbon monoxide and urine cotinine. Multiple linear and hierarchical logistic regressions were conducted to examine predictors of WG at posttreatment and tobacco relapse at 6-month follow-up, respectively. Results: Abstinent participants gained an average of 3.55 kg at 6-month follow-up compared to 1.49 kg among participants who relapsed. Greater nicotine dependence (ß = .372, p = .001) and diastolic pressure at baseline (ß = .252, p = .021) predicted higher WG at end of treatment. WG at posttreatment increased the likelihood of relapse 6 months later (B = .303, OR = 1.354; 95% CI [1.006, 1.822]). Limitations: Weight concerns, disordered eating, and BMI were not recorded, and they could be related to the present findings. Conclusions: These results suggest that individuals with depression during treatment for smoking cessation should be regularly screened and offered treatment to prevent WG.

Lamin A/C Ablation Restricted to Vascular Smooth Muscle Cells, Cardiomyocytes, and Cardiac Fibroblasts Causes Cardiac and Vascular Dysfunction.

Mutations in the LMNA gene (encoding lamin A/C proteins) cause several human cardiac diseases, including dilated cardiomyopathies (LMNA-DCM). The main clinical risks in LMNA-DCM patients are sudden cardiac death and progressive left ventricular ejection fraction deterioration, and therefore most human and animal studies have sought to define the mechanisms through which LMNA mutations provoke cardiac alterations, with a particular focus on cardiomyocytes. To investigate if LMNA mutations also cause vascular alterations that might contribute to the etiopathogenesis of LMNA-DCM, we generated and characterized Lmnaflox/floxSM22αCre mice, which constitutively lack lamin A/C in vascular smooth muscle cells (VSMCs), cardiac fibroblasts, and cardiomyocytes. Like mice with whole body or cardiomyocyte-specific lamin A/C ablation, Lmnaflox/floxSM22αCre mice recapitulated the main hallmarks of human LMNA-DCM, including ventricular systolic dysfunction, cardiac conduction defects, cardiac fibrosis, and premature death. These alterations were associated with elevated expression of total and phosphorylated (active) Smad3 and cleaved (active) caspase 3 in the heart. Lmnaflox/floxSM22αCre mice also exhibited perivascular fibrosis in the coronary arteries and a switch of aortic VSMCs from the 'contractile' to the 'synthetic' phenotype. Ex vivo wire myography in isolated aortic rings revealed impaired maximum contraction capacity and an altered response to vasoconstrictor and vasodilator agents in Lmnaflox/floxSM22αCre mice. To our knowledge, our results provide the first evidence of phenotypic alterations in VSMCs that might contribute significantly to the pathophysiology of some forms of LMNA-DCM. Future work addressing the mechanisms underlying vascular defects in LMNA-DCM may open new therapeutic avenues for these diseases.

Association between e-cigarette and conventional cigarette use among Spanish adolescents. / Asociación entre el uso de cigarrillos electrónicos y cigarrillos convencionales en adolescentes españoles.

In recent years, studies have highlighted the upward trend in electronic cigarette use among adolescents, as well as the potential of e-cigarette use to lead to subsequent conventional cigarette use. The study's aims were two-fold: 1) to examine the progression from e-cigarette use to conventional cigarette use; and 2) to analyze the differences in the severity of smoking pattern among dual users (i.e., e-cigarette and conventional cigarette use), cigarette-only smokers, and e-cigarette-only users in a Spanish adolescent population. Data were obtained from the ESTUDES, a representative survey of addictive behaviors of Spanish adolescents aged 14-18, which was comprised of 38,010 adolescents (Mage = 15.69; SD = 1.19; 51.35% females). Results indicate that lifetime e-cigarette use increased the prevalence of subsequent conventional cigarette use by 1.86 times (95% CI 1.74, 1.99), and the prevalence of conventional cigarette use in the last month by 2.38 times (95% CI 2.19, 2.58), independently of whether the e-cigarette contains nicotine or not. Dual users showed a higher percentage of daily smokers, and a greater number of cigarettes per day, a higher use of e-cigarettes with nicotine, and an earlier age of smoking onset. Regarding risk perception, e-cigarette-only users perceived both conventional tobacco and e-cigarettes as less harmful (all p-values < .001). These findings document the strength of association between e-cigarette and conventional cigarettes, and underscore the importance of developing legal restrictions and prevention strategies aimed at reducing e-cigarette use, which in turn would reduce tobacco use.

En los últimos años, algunos estudios han destacado la tendencia ascendente en el uso del cigarrillo electrónico entre adolescentes, así como el potencial para el posterior consumo de cigarrillos convencionales. Este estudio tuvo dos objetivos: 1) examinar la progresión del cigarrillo electrónico al cigarrillo convencional; y 2) analizar las diferencias en el patrón de gravedad del tabaquismo entre consumidores duales (i.e., cigarrillos electrónicos y convencionales), fumadores de cigarrillos y consumidores de cigarrillos electrónicos. Los datos se obtuvieron de la encuesta ESTUDES, una encuesta nacional que recoge información de conductas adictivas en adolescentes entre 14 y 18 años, la cual consta de 38 010 personas (Medad = 15,69; DT = 1,19; 51,35% mujeres). Los resultados indicaron que haber usado alguna vez un cigarrillo electrónico incrementó la probabilidad de un consumo posterior de cigarrillos 1,86 veces (IC 95% 1,74-1,99), y la probabilidad de consumir tabaco en el último mes 2,38 veces (IC 95% 2,19-2,58), independientemente de si los cigarrillos electrónicos contienen o no nicotina. Los consumidores duales mostraron un mayor porcentaje de fumadores diarios, un mayor número de cigarrillos al día, un mayor uso de cigarrillos electrónicos con nicotina y una edad de inicio más temprana. Con respecto a la percepción de riesgo, los adolescentes que han usado solo cigarrillos electrónicos percibían tanto el tabaco como los cigarrillos electrónicos como menos dañinos (todos los valores p < ,001). Estos hallazgos indican la fuerte asociación entre los cigarrillos electrónicos y los convencionales, y subrayan la importancia de desarrollar restricciones legales y estrategias preventivas dirigidas al cigarrillo electrónico, lo que reduciría a su vez el consumo de tabaco.

Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. Variants in MYBPC3, the gene encoding cardiac myosin-binding protein C (cMyBP-C), are the leading cause of HCM. However, the pathogenicity status of hundreds of MYBPC3 variants found in patients remains unknown, as a consequence of our incomplete understanding of the pathomechanisms triggered by HCM-causing variants. Here, we examined 44 nontruncating MYBPC3 variants that we classified as HCM-linked or nonpathogenic according to cosegregation and population genetics criteria. We found that around half of the HCM-linked variants showed alterations in RNA splicing or protein stability, both of which can lead to cMyBP-C haploinsufficiency. These protein haploinsufficiency drivers associated with HCM pathogenicity with 100% and 94% specificity, respectively. Furthermore, we uncovered that 11% of nontruncating MYBPC3 variants currently classified as of uncertain significance in ClinVar induced one of these molecular phenotypes. Our strategy, which can be applied to other conditions induced by protein loss of function, supports the idea that cMyBP-C haploinsufficiency is a fundamental pathomechanism in HCM.

An expert consensus on practical clinical recommendations and guidance for patients with classic Fabry disease.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

Clonidine and Brain Mitochondrial Energy Metabolism: Pharmacodynamic Insights Beyond Receptorial Effects.

Clonidine is an anti-hypertensive drug that inhibits the release of norepinephrine from pre-synaptic terminals binding to pre-synaptic α2-adrenoreceptors. Some studies suggest that this drug decreases brain energy expenditure, particularly in hypoxic-ischemic injury. However, data about clonidine effects on the functional parameters regulating brain energy metabolism are lacking. In this study, the effects of acute clonidine treatment (5 µg×kg-1 i.p., 30 min) were evaluated on the catalytic activity of regulatory energy-linked enzymes of Krebs' cycle, Electron Transport Chain and glutamate metabolism of temporal cerebral cortex of 3-month-old male Sprague-Dawley rats. Enzyme activities were assayed on non-synaptic "free" mitochondria (FM) of neuronal perikaryon and partly of glial cells, and on intra-synaptic "light" (LM) and "heavy" mitochondria (HM), localized within synaptic terminals. This subcellular analysis differentiates clonidine effects on post-synaptic and pre-synaptic neuronal compartments. The results showed that clonidine increased citrate synthase, cytochrome oxidase and glutamate-oxaloacetate transaminase activities of FM. In LM, citrate synthase activity was decreased, while cytochrome oxidase and glutamate-oxaloacetate transaminase activities were increased; on the contrary, citrate synthase, cytochrome oxidase and glutamate dehydrogenase were all decreased in HM. Therefore, clonidine exerted different effects with respect to brain mitochondria, coherently with the in vivo energy requirements of each synaptic compartment: the drug increased energy-linked enzyme activities in post-synaptic compartment, while the metabolic variations were complex in the pre-synaptic one, being enzyme activities heterogeneously modified in LM and decreased in HM. This study highlights the relationships existing between the clonidine-induced neuroreceptorial effects and the energy metabolism in pre- and post- synaptic bioenergetics.

Effects of Risk Perception and Accessibility on Cannabis Use among Young Population in Spain: Findings from the 2016 National Survey (ESTUDES).

BackgroundCannabis use in the young population has undergone a significant increase in Europe. Empirical assessments of individual and contextual mediating variables in relation to cannabis use are informative for prevention actions and have yet to be conducted in Spain. Objectives: This study used the 2016 National Survey on Drug Use in Secondary Education in Spain (ESTUDES) to inform on potentially relevant cannabis prevention targets. We examined individual variables (sex, age, and cannabis risk perception), past 30-day legal and illicit substance use, substance-free activities, and contextual factors (perceived accessibility to cannabis) associated to past 30-day cannabis use. Methods: Data were drawn from 35,369 adolescents (% females: 50.1). Structural equation modeling (SEM) was implemented to identify predictors of cannabis use, and indirect paths were tested via bootstrapping to examine the mediating effects of cannabis risk perception and accessibility. Results: Demographics (male sex, higher age), and past 30-day tobacco, alcohol, and illicit substance use were associated with past 30-day cannabis use. Frequency of past-year engagement in hobbies and reading did also predict past 30-day cannabis use. The mediators worked on most of the relationships examined, except for hobbies and illegal substance use in the case of accessibility and reading and hobbies in the case of risk perception. Conclusions/importance: Cannabis use is more likely to emerge in the event of low risk perception and high accessibility. Lower frequency of past year reading and higher engagement in some hobbies that are often carried out alone represent risk factors, which could potentially influence prevention programs.

Cat scratch lesions as a manifestation of chronic colitis due to spirochetosis.

Barotrauma or cat scratch is an unusual finding on colonoscopy. The etiology is unknown, but insufflation associated with increased rigidity of the colonic wall due to various pathological processes has been postulated as a pathogenic mechanism. Some authors observed the same associated with collagenous colitis, IBD(Inflammatory Bowel Diseases), intestinal ischemia, shunt colitis and intake of NSAIDs (Non-steroidal anti-inflammatory drugs). In all the cases described, Co2 was used for insufflation.

How does smoking tobacco affect choosing a stable partner? / ¿Cómo afecta el tabaquismo en la elección de pareja estable?

This study aimed to analyze the rejection towards smokers when considering a stable relationship. The sample included 445 participants who were recruited using the snowball method. A questionnaire created ad hoc was answered online by each participant. The effect of tobacco use was evaluated in choosing a stable partner, a stable partner to live with, and a stable partner to live with and have children. The results showed a significant rejection towards smokers for the different types of relationships. Statistically significant differences were found depending on the participants' educational background and tobacco use, and their partner's tobacco use. A higher level of rejection towards smokers was found in participants with university studies, in non-smokers, and those with a non-smoker partner. The main reasons for rejection were related to hygiene, health, and household economy. In conclusion, tobacco use can interfere with the establishment of a stable relationship. This argument could be added to the list of drawbacks associated with tobacco use for prevention and treatment.

El objetivo de este estudio fue analizar el rechazo hacia los fumadores de cara al establecimiento de una relación de pareja estable. La muestra constó de 445 participantes que fueron reclutados mediante el método de bola de nieve. Se utilizó un cuestionario elaborado ad hoc que fue aplicado en línea de forma individual. Se evaluó la influencia del tabaquismo en la elección de pareja estable, estable con convivencia en el mismo hogar y estable con convivencia en el hogar e hijos en común. Los resultados mostraron un importante rechazo hacia personas fumadoras para los distintos tipos de relación. Se hallaron diferencias estadísticamente significativas en función del nivel de estudios, el tabaquismo de los participantes y el tabaquismo de sus parejas. Se encontró mayor nivel de rechazo hacia personas fumadoras en los participantes con estudios universitarios, en los no fumadores y en aquellos con pareja no fumadora. Los principales motivos de rechazo hicieron referencia a higiene, salud y gasto económico. En conclusión, el tabaquismo puede obstaculizar el establecimiento de una relación de pareja estable. Este argumento podría ser incorporado al listado de inconvenientes asociados al tabaquismo de cara a la prevención y el tratamiento.

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Cardiac muscle hypercontractility is a key pathophysiological abnormality in hypertrophic cardiomyopathy, and a major determinant of dynamic left ventricular outflow tract (LVOT) obstruction. Available pharmacological options for hypertrophic cardiomyopathy are inadequate or poorly tolerated and are not disease-specific. We aimed to assess the efficacy and safety of mavacamten, a first-in-class cardiac myosin inhibitor, in symptomatic obstructive hypertrophic cardiomyopathy. METHODS: In this phase 3, randomised, double-blind, placebo-controlled trial (EXPLORER-HCM) in 68 clinical cardiovascular centres in 13 countries, patients with hypertrophic cardiomyopathy with an LVOT gradient of 50 mm Hg or greater and New York Heart Association (NYHA) class II-III symptoms were assigned (1:1) to receive mavacamten (starting at 5 mg) or placebo for 30 weeks. Visits for assessment of patient status occurred every 2-4 weeks. Serial evaluations included echocardiogram, electrocardiogram, and blood collection for laboratory tests and mavacamten plasma concentration. The primary endpoint was a 1·5 mL/kg per min or greater increase in peak oxygen consumption (pVO2) and at least one NYHA class reduction or a 3·0 mL/kg per min or greater pVO2 increase without NYHA class worsening. Secondary endpoints assessed changes in post-exercise LVOT gradient, pVO2, NYHA class, Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS), and Hypertrophic Cardiomyopathy Symptom Questionnaire Shortness-of-Breath subscore (HCMSQ-SoB). This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned to mavacamten (n=123 [49%]) or placebo (n=128 [51%]). 45 (37%) of 123 patients on mavacamten versus 22 (17%) of 128 on placebo met the primary endpoint (difference +19·4%, 95% CI 8·7 to 30·1; p=0·0005). Patients on mavacamten had greater reductions than those on placebo in post-exercise LVOT gradient (-36 mm Hg, 95% CI -43·2 to -28·1; p<0·0001), greater increase in pVO2 (+1·4 mL/kg per min, 0·6 to 2·1; p=0·0006), and improved symptom scores (KCCQ-CSS +9·1, 5·5 to 12·7; HCMSQ-SoB -1·8, -2·4 to -1·2; p<0·0001). 34% more patients in the mavacamten group improved by at least one NYHA class (80 of 123 patients in the mavacamten group vs 40 of 128 patients in the placebo group; 95% CI 22·2 to 45·4; p<0·0001). Safety and tolerability were similar to placebo. Treatment-emergent adverse events were generally mild. One patient died by sudden death in the placebo group. INTERPRETATION: Treatment with mavacamten improved exercise capacity, LVOT obstruction, NYHA functional class, and health status in patients with obstructive hypertrophic cardiomyopathy. The results of this pivotal trial highlight the benefits of disease-specific treatment for this condition. FUNDING: MyoKardia.

One-Year Efficacy and Incremental Cost-effectiveness of Contingency Management for Cigarette Smokers With Depression.

INTRODUCTION: Contingency management (CM) is efficacious for smoking cessation. To date, the number of cost-effectiveness evaluations of behavioral and pharmacological smoking cessation treatments far outnumbers the ones on CM. This study estimated 1-year efficacy and incremental cost-effectiveness of adding CM in relation to abstinence outcomes for a cognitive-behavioral therapy (CBT)+behavioral activation (BA) treatment. METHODS: The study sample comprised 120 smokers with depression (% females: 70.8%; mean age: 51.67 [SD = 9.59]) enrolled in an 8-week randomized controlled clinical trial. Clinical effectiveness variables were point-prevalence abstinence, continuous abstinence, longest duration of abstinence (LDA), and Beck-Depression Inventory-II (BDI-II) scores at 1-year follow-up. Cost-effectiveness analyses were based on resource utilization, unit costs per patient, and incremental cost per additional LDA week at 1 year. RESULTS: There was a significant effect of time by treatment group interaction, which indicated superior effects of CBT+BA+CM across time. Point-prevalence abstinence (53.3% [32/60]) was superior in participants receiving CBT+BA+CM compared with those in CBT+BA (23.3% [14/60]), but both groups were equally likely to present sustained reductions in depression. The average cost per patient was €208.85 (US$236.57) for CBT+BA and €410.64 (US$465.14) for CBT+BA+CM, p < .001. The incremental cost of using CM to enhance 1-year abstinence by one extra LDA week was €18 (US$20.39) (95% confidence interval: 17.75-18.25). CONCLUSIONS: Behavioral treatments addressing both smoking and depression are efficacious for sustaining high quit rates at 1 year. Adding CM to CBT+BA for smoking cessation is highly cost-effective, with an estimated net benefit of €4704 (US$5344.80). IMPLICATIONS: Informing on the cost-effectiveness of CM might expedite the translation of research findings into clinical practice. Findings suggested that CM is feasible and highly cost-effective, confirming that its implementation is worthwhile. At a CM cost per patient of €410.64 (US$465.14), the net benefit equals €4704 (US$5344.80), although even starting from a minimum investment of €20 (US$22.72) was cost-effective. CLINICALTRIALS-GOV IDENTIFIER: NCT03163056.

The treament of hyperglycemia in acute ischemic stroke with incretin-based drugs.

Stroke is a major cause of mortality and morbidity worldwide. Considerable experimental and clinical evidence suggests that both diabetes mellitus (DM) and post-stroke hyperglycemia are associated with increased mortality rate and worsened clinical conditions in acute ischemic stroke (AIS) patients. Insulin treatment does not seem to provide convincing benefits for these patients, therefore prompting a change of strategy. The selective agonists of Glucagon-Like Peptide-1 Receptors (GLP-1Ras) and the Inhibitors of Dipeptidyl Peptidase-IV (DPP-IVIs, gliptins) are two newer classes of glucose-lowering drugs used for the treatment of DM. This review examines in detail the rationale for their development and the physicochemical, pharmacokinetic and pharmacodynamic properties and clinical activities. Emphasis will be placed on their neuroprotective effects at cellular and molecular levels in experimental models of acute cerebral ischemia. In perspective, an adequate basis does exist for a novel therapeutic approach to hyperglycemia in AIS patients through the additive treatment with GLP-1Ras plus DPP-IVIs.

Latent Structure of the Cigarette Purchase Task Among Treatment-Seeking Smokers With Depression and Its Predictive Validity on Smoking Abstinence.

INTRODUCTION: Research has recently shown that nicotine reinforcement is better characterized by a bifactorial latent structure: persistence (insensitivity to cigarette pricing) and amplitude (consumption at inexpensive prices). No study to date has examined its value as a predictor of abstinence. This study aimed to provide new evidence on the latent structure of the cigarette purchase task (CPT) in smokers with depressive symptoms and to examine whether the latent structure performs better as a predictor of continuous abstinence than do the individual indices. METHODS: Participants (n = 205 smokers; 72% female: Beck Depression Inventory, Second Edition, M = 24.68, SD = 10.45) were randomized to two smoking cessation treatments for quitting smoking: cognitive behavioral treatment (CBT) or CBT + contingency management (CM). A principal-components analysis was conducted to examine the latent structure of the CPT and a set of regression models were performed to assess its predictive validity. RESULTS: The principal-components analysis revealed a bifactorial solution, which was interpreted as persistence (breakpoint, Omax, Pmax, and elasticity) and psychological inertia (intensity and elasticity of demand). Evidence on the convergent validity was obtained through significant associations between the two latent factors and smoking variables (all r values ≥.17). Psychological inertia was negatively related to the number of days of continuous abstinence at the end of treatment regardless of the treatment condition [R2 = .038; F(2, 202) = 4.989, p = .008]. CONCLUSIONS: Psychological inertia informs on which patients benefit less from smoking cessation treatments incorporating CM and CBT. Treatment components that affect individuals' excessive valuation of cigarettes might improve cessation outcomes. IMPLICATIONS: This is the first attempt to examine the latent structure of the CPT in depressed smokers and to yield evidence on its predictive validity. A specific bifactorial solution exists for this population: persistence (breakpoint, Omax, Pmax, and elasticity) and psychological inertia (intensity and elasticity). Isolating demand indices and factors provides a high-resolution characterization of nicotine reinforcement for depressed smokers in that it informs on treatment response. Compared to the individual CPT indices, psychological inertia more effectively predicts which patients benefit most from either CM or CBT. Treatment components that affect individuals' excessive valuation of cigarettes (eg, episodic future thinking) should be integrated into smoking cessation treatments.