Safety and efficacy of ivacaftor in infants aged 1 to less than 4 months with cystic fibrosis.

BACKGROUND: Ivacaftor (IVA) has been shown to be safe and efficacious in children aged ≥4 months with cystic fibrosis (CF) and CFTR gating variants. We evaluated safety, pharmacokinetics (PK), and efficacy of IVA in a small cohort of infants aged 1 to <4 months with CF. METHODS: In this phase 3, open-label study, infants 1 to <4 months with CF and an IVA-responsive CFTR variant received an initial low dose of IVA based on age and weight. Because IVA is a sensitive CYP3A substrate and CYP3A maturation is uncertain in infants, doses were adjusted at day 15 to better match median adult exposures based on individual PK measurements taken on day 4. Primary endpoints were safety and PK measurements. RESULTS: Seven infants (residual function CFTR variants [n=5]; minimal function CFTR variants [n=2]) received ≥1 dose of IVA. Six infants had doses adjusted at day 15 and one infant did not require dose adjustment; subsequent PK analyses showed mean trough concentrations for IVA and metabolites were within range of prior clinical experience. Four infants (57.1%) had adverse events (AEs); no serious AEs were noted. One infant discontinued study drug due to a non-serious AE of elevated alanine aminotransferase >8x the upper limit of normal. Mean sweat chloride concentration decreased (-40.3 mmol/L [SD: 29.2]) through week 24. Improvements in biomarkers of pancreatic function and intestinal inflammation, as well as growth parameters, were observed. CONCLUSIONS: In this small, open-label study, IVA dosing in infants achieved exposures previously shown to be safe and efficacious. Because PK was predictable, a dosing regimen based on age and weight is proposed. IVA was generally safe and well tolerated, and led to improvements in CFTR function, markers of pancreatic function and intestinal inflammation, and growth parameters, supporting use in infants as young as 1 month of age.

Interpersonal and Intimate Violence in Mexican Youth: Drug Use, Depression, Anxiety, and Stress during the COVID-19 Pandemic.

The COVID-19 pandemic may have increased interpersonal and intimate violence, harmful use of alcohol and other drugs (AODs), and mental health problems. This study uses a valid path model to describe relationships between these conditions of young Mexicans during the second year of the pandemic. A sample of 7420 Mexicans ages 18 to 24-two-thirds of whom are women-completed the Life Events Checklist, the Alcohol, Smoking, and Substance Involvement Screening Test, the Major Depressive Episode Checklist, the Generalized Anxiety Scale, and the Post-traumatic Stress Disorder (PTSD) Checklist. Young Mexicans reported higher rates of victimization and perpetration of interpersonal and intimate violence and mental health symptomatology than those noted pre- and in the first year of the pandemic. The harmful use of AOD rates were similar to those reported by adolescents before. The findings suggest asymmetric victimization and perpetration of intimate violence by gender (with women at a higher risk). More men than women have engaged in the harmful use of AODs (except for sedatives, which more women abuse). More women than men were at risk of all mental health conditions. The path model indicates that being a victim of intimate violence predicts the harmful use of tobacco, alcohol, cocaine, and sedatives, depression, anxiety, and specific PTSD symptoms (such as re-experimentation and avoidance symptoms). Being a victim of interpersonal violence resulted in severe PTSD symptoms (including avoidance, negative alterations in cognition-mood, and hyperarousal signs). The harmful use of sedatives predicted depressive symptoms. Men's victimizing intimate violence model contrasted with that of women, which included being the victim of interpersonal violence and severe PTSD symptoms. The high school youth model had three paths: victimizing intimate violence, victimizing interpersonal abuse, and sedative use, which predicted depression. Our findings could serve as the basis for future studies exploring the mechanisms that predict violence to develop cost-effective preventive programs and public policies and to address mental health conditions during community emergencies.

Online Training for Primary Care Staff: Skills development on the Mental Health Gap Action Programme (mhGAP) Intervention Guide / Entrenamiento en línea para personal de atención primaria: Desarrollo de habilidades sobre la Guía de Intervención para Superar las Brechas en Salud Mental (mhGAP)

Abstract Developing effective learning strategies to strengthen mental health professionals' capacities and deliver evidence-based interventions in their communities is urgent. We developed and evaluated an online training program for the Intervention Guide for Mental, Neurological and Substance Use Disorders in Non-specialized Health Settings. Nine hundred and seventy-five health professionals in Mexico were enrolled in the training program, during the period of social distancing brought about by the COVID-19 pandemic. Participants completed a pre-post online evaluation strategy including Knowledge screening, assessment of Learning Activities, and performance in Programmed-Simulated cases to evaluate knowledge and skills for the assessment, management, and follow-up of Mental, Neurological and Substance Use Disorders. We found that participants improved their knowledge and skills from training on the mhGAP online course. Notably we observed these positive results regardless of sex, profession, institution, or social vulnerability rating of participants, suggesting that this is a relevant training program for primary care staff. These results contribute to the Mental Health Gap Action Programme and advance the use of online teaching and evaluation technologies in this field.

Resumen El desarrollo de estrategias efectivas de aprendizaje para fortalecer las competencias de los profesionales de la salud mental y brindar intervenciones basadas en evidencia en sus comunidades es necesario. El objetivo del presente trabajo fue desarrollar y evaluar un programa de entrenamiento en línea para la Guía de Intervención en Trastornos Mentales, Neurológicos y por Uso de Sustancias en nivel de atención de salud no especializada. Participaron 975 profesionales de la salud mexicanos durante el período de distanciamiento social provocado por la pandemia de COVID-19. Los participantes completaron una evaluación previa y posterior que incluyó un cuestionario de conocimientos, actividades de aprendizaje y la ejecución en casos simulados programados para evaluar el conocimiento y las habilidades para la evaluación, el manejo y el seguimiento de los trastornos mentales, neurológicos y por uso de sustancias. Los resultados indicaron que los participantes mejoraron sus conocimientos y habilidades en función de su participación en el curso en línea, independientemente del sexo, la profesión, la institución o la vulnerabilidad social de los participantes, sugiriendo que se trata de un programa de formación relevante para el personal de atención primaria. Los resultados contribuyen al Programa de Acción para la Brecha de Salud Mental y promueven el uso de tecnologías de evaluación y enseñanza en línea en este campo.

The Gpn3 Q279* cancer-associated mutant inhibits Gpn1 nuclear export and is deficient in RNA polymerase II nuclear targeting.

Gpn3 is required for RNA polymerase II (RNAPII) nuclear targeting. Here, we investigated the effect of a cancer-associated Q279* nonsense mutation in Gpn3 cellular function. Employing RNAi, we replaced endogenous Gpn3 by wt or Q279* RNAi-resistant Gpn3R in epithelial model cells. RNAPII nuclear accumulation and transcriptional activity were markedly decreased in cells expressing only Gpn3R Q279*. Wild-type Gpn3R localized to the cytoplasm but a fraction of Gpn3R Q279* entered the cell nucleus and inhibited Gpn1-EYFP nuclear export. This property and the transcriptional deficit in Gpn3R Q279*-expressing cells required a PDZ-binding motif generated by the Q279* mutation. We conclude that an acquired PDZ-binding motif in Gpn3 Q279* caused Gpn3 nuclear entry, and inhibited Gpn1 nuclear export and Gpn3-mediated RNAPII nuclear targeting.

Effect of substance use on condom use in the Theory of Planned Behavior: Analysis of differential item functioning / Efecto del consumo de sustancias en la Teoría de la Conducta Planeada en Uso de Condón: Análisis del funcionamiento diferencial de los ítems

Abstract Introduction. Substance use is one of the factors associated with lower condom use in young adults, which increases the likelihood of HIV infection. The Theory of Planned Behavior (TPB) is one of the most useful models for explaining this phenomenon since it considers the aim of engaging in a behavior based on attitudes, subjective norms and self-efficacy. Objective. To develop a questionnaire and to evaluate the Differential Item Functioning (DIF) caused by substance use in TPB indicators, using the Multiple Indicators Multiple Causes Analysis (MIMIC). Method. The study was conducted in two phases with Mexico City college students age 18 to 25. Results. Adequate goodness of fit was obtained in all three models of the TPB: attitudes χ2S-B(2) = 3.902, p < .001; CFIs = .999; TLIs = .996; RMSEAs = .037, 90% CI ≤ .001-.095; subjective norms χ2S-B(7) = 9.103, p < .245; CFIs = .999; TLIs = .998; RMSEAs = .022, 90% CI ≤ .001-.056; and self-efficacy χ2S-B(25) = 65.115, p < .001; CFIs = .982; TLIs = .974; RMSEAs = .050, 90% CI = .036-.066; in one item in attitudes and two items in subjective norms a DIF effect was observed, while no item proved significant regarding self-efficacy. Discussion and conclusion. There is little evidence in the detection of DIF due to substance use in TPB indicators in condom use, and this is the first study to conduct this type of analysis. Items presenting DIF open the door to future research due to the importance of assessing how the indicator behaves with a population displaying a particular trait.

Resumen Introducción. El consumo de sustancias es uno de los factores asociados a un menor uso de condón en jóvenes adultos, lo cual aumenta la probabilidad de contagio de VIH. La Teoría de la Conducta Planeada (TCP) es uno de los modelos más útiles para explicar este fenómeno ya que considera la intención de llevar a cabo una conducta basándose en actitudes, normas subjetivas y autoeficacia. Objetivo. Desarrollar un cuestionario y evaluar el Funcionamiento Diferencial de los Ítems (DIF) ocasionado por el consumo de sustancias en los indicadores de la TCP, utilizando el análisis Múltiples Ítems Múltiples Causas (MIMIC). Método. El estudio se llevó a cabo en dos etapas con estudiantes universitarios de 18 a 25 años de la Ciudad de México. Resultados. Se obtuvo una adecuada bondad de ajuste en los tres modelos de la TCP: actitudes χ2S-B(2) = 3.902, p < .001; CFIs = .999; TLIs = .996; RMSEAs = .037, 90% IC ≤ .001-.095; normas subjetivas χ2S-B(7) = 9.103; p < .245; CFIs = .999; TLIs = .998; RMSEAs = .022, 90% IC ≤ .001-.056; y autoeficacia χ2S-B(25) = 65.115; p < .001; CFIs = .982; TLIs = .974; RMSEAs = .050, 90% IC = .036-.066; un ítem en actitudes y 2 ítems en normas subjetivas se observó un efecto DIF, y en autoeficacia ningún ítem salió significativo. Discusión y conclusión. Existe poca evidencia en la detección de DIF por uso de sustancias en los indicadores de la TCP en uso de condón, siendo éste el primer estudio que lleva a cabo este tipo de análisis. Los ítems que presenten DIF abren la puerta a futuras investigaciones, debido a la importancia de evaluar cómo se comporta el indicador con una población que tenga un rasgo en particular.