Role of Forkhead box F1 in the Pathobiology of Pulmonary Arterial Hypertension.

Rationale: Approximately 80% of patients with non-familial pulmonary arterial hypertension (PAH) lack identifiable pathogenic genetic variants. While most genetic studies of PAH have focused on predicted loss-of-function variants, recent approaches have identified ultra-rare missense variants associated with the disease. encodes a highly conserved transcription factor, essential for angiogenesis and vasculogenesis in human and mouse lungs.

Considerations for the design and conduct of pediatric obesity pharmacotherapy clinical trials: Proceedings of expert roundtable meetings.

Anti-obesity medications (AOMs) have emerged as one element of comprehensive obesity clinical care intended to improve long-term health outcomes for children and adolescents. The number of pediatric AOM clinical trials has burgeoned in recent years as new pharmacotherapeutics have been developed. Factors related to growth and development in children and adolescents can present unique challenges in terms of designing and conducting clinical trials investigating the safety and efficacy of AOMs.

Marine mammals as indicators of Anthropocene Ocean Health.

The current state of marine mammal populations reflects increasing anthropogenic impacts on the global Ocean. Adopting a holistic approach towards marine mammal health, incorporating healthy individuals and healthy populations, these taxa present indicators of the health of the overall Ocean system. Their present deterioration at the animal, population and ecosystem level has implications for human health and the global system.

High BMI z-Scores from Different Growth References Are Not Comparable: An Example from a Weight Management Trial with an Anti-Obesity Medication in Pubertal Adolescents with Obesity.

The BMI z-score is a standardized measure of weight status and weight change in children and adolescents. BMI z-scores from various growth references are often considered comparable, and differences among them are underappreciated. This study reanalyzed data from a weight management clinical study of liraglutide in pubertal adolescents with obesity using growth references from CDC 2000, CDC Extended, World Health Organization (WHO), and International Obesity Task Force.

Mild Hypoxia Accelerates Cerebral Cavernous Malformation Disease Through CX3CR1-CX3CL1 Signaling.

Background: Heterogeneity in the severity of cerebral cavernous malformations (CCMs) disease, including brain bleedings and thrombosis that cause neurological disabilities in patients, suggests that environmental, genetic, or biological factors act as disease modifiers. Still, the underlying mechanisms are not entirely understood. Here, we report that mild hypoxia accelerates CCM disease by promoting angiogenesis, neuroinflammation, and vascular thrombosis in the brains of CCM mouse models.

Evaluating potential predictors of weight loss response to liraglutide in adolescents with obesity: A post hoc analysis of the randomized, placebo-controlled SCALE Teens trial.

Background: As childhood obesity prevalence increases, determining which patients respond to anti-obesity medications would strengthen personalized approaches to obesity treatment. In the SCALE Teens trial among pubertal adolescents with obesity (NCT02918279), liraglutide 3.0 mg (or maximum tolerated dose) significantly reduced body mass index (BMI) standard deviation score on average versus placebo.

Liraglutide for Weight Management in Children and Adolescents With Prader-Willi Syndrome and Obesity.

Context: Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed.

Objective: To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS.

Regulation of PGC1α Downstream of the Insulin Signaling Pathway Plays a Role in the Hepatic Proteotoxicity of Mutant α1-Antitrypsin Deficiency Variant Z.

Background & Aims: Insulin signaling is known to regulate essential proteostasis mechanisms.

Methods: The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer.

Results: We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption).

The current landscape of immunotherapy for pediatric brain tumors.

Pediatric central nervous system tumors are the most common solid malignancies in childhood, and aggressive therapy often leads to long-term sequelae in survivors, making these tumors challenging to treat. Immunotherapy has revolutionized prospects for many cancer types in adults, but the intrinsic complexity of treating pediatric patients and the scarcity of clinical studies of children to inform effective approaches have hampered the development of effective immunotherapies in pediatric settings. Here, we review recent advances and ongoing challenges in pediatric brain cancer immunotherapy, as well as considerations for efficient clinical translation of efficacious immunotherapies into pediatric settings.

Is France Once Again Looking for a Scapegoat?

On September 10, 2021, a special tribunal established by the French government launched an inquiry into the activities of former health minister Dr. Agnes Buzyn who was charged with "endangering the lives of others". It is surprising to learn of this accusation and inquiry into the actions of a public health official whose response to the epidemic was, to all appearances, exemplary.

Subthalamic Peak Beta Ratio Is Asymmetric in Glucocerebrosidase Mutation Carriers With Parkinson's Disease: A Pilot Study.

Up to 27% of individuals undergoing subthalamic nucleus deep brain stimulation (STN-DBS) have a genetic form of Parkinson's disease (PD). G () mutation carriers, compared to sporadic PD, present with a more aggressive disease, less asymmetry, and fare worse on cognitive outcomes with STN-DBS. Evaluating STN intra-operative local field potentials provide the opportunity to assess and compare symmetry between and non- mutation carriers with PD; thus, providing insight into genotype and STN physiology, and eligibility for and programming of STN-DBS.

Travel-Related Behaviors and Health Outcomes of Adolescents Compared with Adults on Short-Term International Service Missions.

With an increasing number of adolescents participating in international travel, little is known about travel-related behaviors and health risks in this age group. In the years 2015-2016, we conducted an anonymous, posttravel, questionnaire-based survey with the aim to compare self-reported practices and travel-related symptoms between adolescents (< 18 years old, N = 87) and adults (≥ 18 years old, N = 149) who came to our travel clinic before their humanitarian missions. They had the same pretravel health education, and traveled together to perform similar activities.

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation.

Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in 1 of 3 genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2- and KLF4-dependent elevation of eNOS in CCM endothelium.

Inhibition of the HEG1-KRIT1 interaction increases KLF4 and KLF2 expression in endothelial cells.

The transmembrane protein heart of glass1 (HEG1) directly binds to and recruits Krev interaction trapped protein 1 (KRIT1) to endothelial junctions to form the HEG1-KRIT1 protein complex that establishes and maintains junctional integrity. Genetic inactivation or knockdown of endothelial HEG1 or KRIT1 leads to the upregulation of transcription factors Krüppel-like factors 4 and 2 (KLF4 and KLF2), which are implicated in endothelial vascular homeostasis; however, the effect of acute inhibition of the HEG1-KRIT1 interaction remains incompletely understood. Here, we report a high-throughput screening assay and molecular design of a small-molecule HEG1-KRIT1 inhibitor to uncover acute changes in signaling pathways downstream of the HEG1-KRIT1 protein complex disruption.

Liraglutide pharmacokinetics and exposure-response in adolescents with obesity.

Background: Obesity in adolescence presents a major public health challenge, often leading to obesity in adulthood with associated chronic disease.

Objectives: This study aimed to perform a population pharmacokinetic and exposure-response analysis of liraglutide by meta-analysis of data from trials conducted in children, adolescents and adults with obesity.

Methods: The population pharmacokinetic analysis investigated the effect of covariates body weight, age group (children, adolescents and adults) and sex on liraglutide exposure in adolescents compared with previous results in adults.

Multiple cholinesterase inhibitors have antidepressant-like properties in the mouse forced swim test.

There is high clinical interest in improving the pharmacological treatment of individuals with Major Depressive Disorder (MDD). This neuropsychiatric disorder continues to cause significant morbidity and mortality worldwide, where existing pharmaceutical treatments such as selective serotonin reuptake inhibitors often have limited efficacy. In a recent publication, we demonstrated an antidepressant-like role for the acetylcholinesterase inhibitor (AChEI) donepezil in the C57BL/6J mouse forced swim test (FST).

3D Finite Element Model on Drilling of CFRP with Numerical Optimization and Experimental Validation.

When drilling Carbon Fibre-Reinforced Plastic (CFRP) materials, achieving acceptable hole quality is challenging while balancing productivity and tool wear. Numerical models are important tools for the optimization of drilling CFRP materials in terms of material removal rate and hole quality. In this research, a macro-Finite Element (FE) model was developed to accurately predict the effect of drill tip geometry on hole entry and exit quality.

Effect of liraglutide treatment on body mass index and weight parameters in children and adolescents with type 2 diabetes: Post hoc analysis of the ellipse trial.

Background: Weight loss in children and adolescents with type 2 diabetes (T2D) is associated with improved glycaemic control.

Objectives: To assess the effects of liraglutide vs placebo on body mass index (BMI) and weight parameters in children and adolescents with T2D using data from the ellipse trial (NCT01541215).

Methods: The ellipse trial randomized participants (10-<17 years old, BMI >85th percentile, T2D, glycated haemoglobin [HbA ] 7.

Repurposing Cholinesterase Inhibitors as Antidepressants? Dose and Stress-Sensitivity May Be Critical to Opening Possibilities.

When stress becomes chronic it can trigger lasting brain and behavioral changes including Major Depressive Disorder (MDD). There is conflicting evidence regarding whether acetylcholinesterase inhibitors (AChEIs) may have antidepressant properties. In a recent publication, we demonstrated a strong dose-dependency of the effect of AChEIs on antidepressant-related behavior in the mouse forced swim test: whereas the AChEI donepezil indeed promotes depression-like behavior at a high dose, it has antidepressant-like properties at lower doses in the same experiment.

A cost/benefit analysis of clinical trial designs for COVID-19 vaccine candidates.

We compare and contrast the expected duration and number of infections and deaths averted among several designs for clinical trials of COVID-19 vaccine candidates, including traditional and adaptive randomized clinical trials and human challenge trials. Using epidemiological models calibrated to the current pandemic, we simulate the time course of each clinical trial design for 756 unique combinations of parameters, allowing us to determine which trial design is most effective for a given scenario. A human challenge trial provides maximal net benefits-averting an additional 1.

Safety evaluation of a strategy to restart elective orthopaedic surgery during the de-escalation phase of the COVID-19 pandemic.

Aims: To evaluate safety outcomes and patient satisfaction of the re-introduction of elective orthopaedic surgery on 'green' (non-COVID-19) sites during the COVID-19 pandemic.

Methods: A strategy consisting of phased relaxation of clinical comorbidity criteria was developed. Patients from the orthopaedic waiting list were selected according to these criteria and observed recommended preoperative isolation protocols.

Using Informatics to Build a Digital Health Footprint of Patients Living With Inherited Metabolic Disorders Identified by Newborn Screening.

Newborn screening is a process identifying people with inherited metabolic disorders (IMDs) at birth, but these patients are often lost to follow-up, and limited data on their long-term needs are available to advocate for policies that will help this vulnerable community. Using informatics best practices, the Medical Nutrition Therapy for Prevention (MNT4P) program and the Public Health Informatics Institute successfully deployed a minimally viable product-that is, the most basic working version that is scalable-allowing for lifelong patient follow-up and outcome and needs tracking, and that can address national data gaps. The new system offers a HIPAA-compliant, efficient record-keeping system that allows data standardization and harmonization.

Liraglutide pharmacokinetics and exposure-response in pediatric patients with type 2 diabetes.

Objectives Based on the ellipse trial, liraglutide was recently approved for use in pediatric patients with type 2 diabetes. We report the comparative exposure of liraglutide in pediatric vs. adult patients.

The cholinesterase inhibitor donepezil has antidepressant-like properties in the mouse forced swim test.

Finding new antidepressant agents is of high clinical priority given that many cases of major depressive disorder (MDD) do not respond to conventional monoaminergic antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants, and monoamine oxidase inhibitors. Recent findings of effective fast-acting antidepressants indicate that there are biological substrates to be taken advantage of for fast relief of depression and that we may find further treatments in this category. In this vein, the cholinergic system may be a relatively overlooked target for antidepressant medications, given its major role in motivation and attention.