REIMAGINE: A central nervous system basket trial showing safety and efficacy of vafidemstat on aggression in different psychiatric disorders.

Aim: Vafidemstat is a brain-penetrant, orally bioavailable, small molecule irreversible inhibitor of the histone lysine-specific demethylase KDM1A (also known as LSD1), which corrects memory deficits and behavior alterations including aggression and social interaction deficits in preclinical models.

Methods: Here, we report the results of REIMAGINE, a phase IIa, single-center, open-label, one-arm basket trial that evaluated the safety and efficacy of vafidemstat on aggression in adult patients with borderline personality disorder (BPD), attention-deficit/hyperactivity disorder (ADHD), and autistic spectrum disorder (ASD). Participants received 1.

Iadademstat in combination with azacitidine in patients with newly diagnosed acute myeloid leukaemia (ALICE): an open-label, phase 2a dose-finding study.

Background: Iadademstat is a potent, selective, oral inhibitor of both the enzymatic and scaffolding activities of the transcriptional repressor lysine-specific demethylase 1 (LSD1; also known as KDM1A) that showed promising early activity and safety in a phase 1 trial and strong preclinical synergy with azacitidine in acute myeloid leukaemia cell lines. Therefore, we aimed to investigate the combination of iadademstat and azacitidine for the treatment of adult patients with newly diagnosed acute myeloid leukaemia.

Methods: The open-label, phase 2a, dose-finding ALICE study was conducted at six hospitals in Spain and enrolled patients aged 18 years or older with newly diagnosed acute myeloid leukaemia not eligible for intensive chemotherapy and an ECOG performance status of 0-2.

Gonadal hormone deprivation regulates response to tibolone in neurodegenerative pathways.

Gonadal hormone deprivation (GHD) and decline such as menopause and bilateral oophorectomy are associated with an increased risk of neurodegeneration. Yet, hormone therapies (HTs) show varying efficacy, influenced by factors such as sex, drug type, and timing of treatment relative to hormone decline. We hypothesize that the molecular environment of the brain undergoes a transition following GHD, impacting the effectiveness of HTs.

Neonatal inhibition of androgen activity alters the programming of body weight and orexinergic peptides differentially in male and female rats.

The involvement of androgens in the regulation of energy metabolism has been demonstrated. The main objective of the present research was to study the involvement of androgens in both the programming of energy metabolism and the regulatory peptides associated with feeding. For this purpose, androgen receptors and the main metabolic pathways of testosterone were inhibited during the first five days of postnatal life in male and female Wistar rats.

Interaction of gonadal hormones, dopaminergic system, and epigenetic regulation in the generation of sex differences in substance use disorders: A systematic review.

Substance use disorder (SUD) is a chronic condition characterized by pathological drug-taking and seeking behaviors. Remarkably different between males and females, suggesting that drug addiction is a sexually differentiated disorder. The neurobiological bases of sex differences in SUD include sex-specific reward system activation, influenced by interactions between gonadal hormone level changes, dopaminergic reward circuits, and epigenetic modifications of key reward system genes.

An expert patient program to improve the empowerment and quality of life of people with multiple sclerosis: protocol for a multicenter pre-post intervention study.

Introduction: Multiple sclerosis (MS) causes a progressive disability, which substantially impacts the quality of life (QoL). Health interventions that meet the needs and demands of people with MS are essential to minimize QoL impairment. Expert patient programs (EPPs) facilitate health-related empowerment through peer learning.

Validation of the Spanish version of DYsphagia in MUltiple Sclerosis questionnaire (DYMUS).

Background: Dysphagia is a common symptom in multiple sclerosis that can occur even early in the disease course and can lead to serious complications. Early recognition and treatment can promote comfort, safety and optimal nutritional status. Few dysphagia rating scales are available in Spanish.

Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons.

Introduction: Neurons are polarized cells, and their ability to change their morphology has a functional implication in the development and plasticity of the nervous system in order to establish new connections. Extracellular factors strongly influence neuronal shape and connectivity. For instance, the developmental actions of estradiol on hippocampal neurons are well characterized, and we have demonstrated in previous studies that Ngn3 mediates these actions.

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain.

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology.

Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain.

For many decades to date, neuroendocrinologists have delved into the key contribution of gonadal hormones to the generation of sex differences in the developing brain and the expression of sex-specific physiological and behavioral phenotypes in adulthood. However, it was not until recent years that the role of sex chromosomes in the matter started to be seriously explored and unveiled beyond gonadal determination. Now we know that the divergent evolutionary process suffered by X and Y chromosomes has determined that they now encode mostly dissimilar genetic information and are subject to different epigenetic regulations, characteristics that together contribute to generate sex differences between XX and XY cells/individuals from the zygote throughout life.

Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner.

Kdm6a is an X-chromosome-linked H3K27me2/3 demethylase that promotes chromatin accessibility and gene transcription and is critical for tissue/cell-specific differentiation. Previous results showed higher levels in XX than in XY hypothalamic neurons and a female-specific requirement for Kdm6a in mediating increased axogenesis before brain masculinization. Here, we explored the sex-specific role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus.

A Rapid, Whole Genome Sequencing Assay for Detection and Characterization of Novel Coronavirus (SARS-CoV-2) Clinical Specimens Using Nanopore Sequencing.

A new human coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged at the end of 2019 in Wuhan, China that caused a range of disease severities; including fever, shortness of breath, and coughing. This disease, now known as coronavirus disease 2019 (COVID-19), quickly spread throughout the world, and was declared a pandemic by the World Health Organization in March of 2020. As the disease continues to spread, providing rapid characterization has proven crucial to better inform the design and execution of control measures, such as decontamination methods, diagnostic tests, antiviral drugs, and prophylactic vaccines for long-term control.

Can Cognitive training Reignite Compensatory Mechanisms in Advanced Multiple Sclerosis Patients? An Explorative Morphological Network Approach.

Multiple Sclerosis (MS) has been shown to significantly impair brain connectivity, as alterations in functional and structural networks have been identified and associated with clinical status, particularly cognitive deficits. We aimed to identify structural connectivity changes in grey matter networks following cognitive rehabilitation (CR) in persons with MS (PwMS). Fifteen long-standing PwMS underwent a 5-week CR-program and five healthy controls (HC) were also investigated.

Clinical Factors Associated With Long-Term Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Axitinib: Real-World AXILONG Study.

Background: Axitinib monotherapy obtained approval in pre-treated mRCC patients and recently in combination with pembrolizumab or avelumab in the first-line setting. However, patient profiles that may obtain increased benefit from this drug and its combinations still need to be identified.

Patients And Methods: Retrospective multicentre analysis describing clinical characteristics associated with axitinib long-responder (LR) population by comparing two extreme-response sub-groups (progression-free survival [PFS] ≥9 months vs.

X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons.

Several X-linked genes are involved in neuronal differentiation and may contribute to the generation of sex dimorphisms in the brain. Previous results showed that XX hypothalamic neurons grow faster, have longer axons, and exhibit higher expression of the neuritogenic gene neurogenin 3 (Ngn3) than XY before perinatal masculinization. Here we evaluated the participation of candidate X-linked genes in the development of these sex differences, focusing mainly on Kdm6a, a gene encoding for an H3K27 demethylase with functions controlling gene expression genome-wide.

Effect of Changes in MS Diagnostic Criteria Over 25 Years on Time to Treatment and Prognosis in Patients With Clinically Isolated Syndrome.

Background And Objectives: To explore whether time to diagnosis, time to treatment initiation, and age to reach disability milestones have changed in patients with clinically isolated syndrome (CIS) according to different multiple sclerosis (MS) diagnostic criteria periods.

Methods: This retrospective study was based on data collected prospectively from the Barcelona-CIS cohort between 1994 and 2020. Patients were classified into 5 periods according to different MS criteria, and the times to MS diagnosis and treatment initiation were evaluated.

High-fat diet alters stress behavior, inflammatory parameters and gut microbiota in Tg APP mice in a sex-specific manner.

Long-term high-fat diet (HFD) consumption commonly leads to obesity, a major health concern of western societies and a risk factor for Alzheimer's disease (AD). Both conditions present glial activation and inflammation and show sex differences in their incidence, clinical manifestation, and disease course. HFD intake has an important impact on gut microbiota, the bacteria present in the gut, and microbiota dysbiosis is associated with inflammation and certain mental disorders such as anxiety.

First-in-Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat.

Background: Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo.

What Should Clinicians Do When a Patient's Autonomy Undermines Her Being Treated Equitably?

Language and cultural barriers can impede communication between patients and clinicians, exacerbating health inequity. Additional complications can arise when family members, intending to protect their loved ones, ask clinicians to lie or not disclose to patients their diagnoses, prognoses, or intervention options. Clinicians must express respect for patients' and families' cultural, religious, and social norms regarding health care decision making, but they might also be ethically troubled by some decisions' effects on patients' health outcomes.

New Proteomic Signatures to Distinguish Between Zika and Dengue Infections.

Distinguishing between Zika and dengue virus infections is critical for accurate treatment, but we still lack detailed understanding of their impact on their host. To identify new protein signatures of the two infections, we used next-generation proteomics to profile 122 serum samples from 62 Zika and dengue patients. We quantified >500 proteins and identified 13 proteins that were significantly differentially expressed (adjusted p-value < 0.

Electrochemical Reduction of Carbon Dioxide on Graphene-Based Catalysts.

The current environmental situation requires taking actions regarding processes for energy production, thus promoting renewable energies, which must be complemented with the development of routes to reduce pollution, such as the capture and storage of CO. Graphene materials have been chosen for their unique properties to be used either as electrocatalyst or as catalyst support (mainly for non-noble metals) that develop adequate efficiencies for this reaction. This review focuses on comparing experimental and theoretical results of the electrochemical reduction reaction of carbon dioxide (ECORR) described in the scientific literature to establish a correlation between them.

Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons.

Hypothalamic neurons show sex differences in neuritogenesis, female neurons have longer axons and higher levels of the neuritogenic factor neurogenin 3 (Ngn3) than male neurons in vitro. Moreover, the effect of 17-β-estradiol (E2) on axonal growth and Ngn3 expression is only found in male-derived neurons. To investigate whether sex chromosomes regulate these early sex differences in neuritogenesis by regulating the E2 effect on Ngn3, we evaluated the growth and differentiation of hypothalamic neurons derived from the "four core genotypes" mouse model, in which the factors of "gonadal sex" and "sex chromosome complement" are dissociated.

Urban Transformations and Health: Methods for TrUST-a Natural Experiment Evaluating the Impacts of a Mass Transit Cable Car in Bogotá, Colombia.

Cable cars provide urban mobility benefits for vulnerable populations. However, no evaluation has assessed cable cars' impact from a health perspective. TransMiCable in Bogotá, Colombia, provides a unique opportunity to (1) assess the effects of its implementation on the environmental and social determinants of health (microenvironment pollution, transport accessibility, physical environment, employment, social capital, and leisure time), physical activity, and health outcomes (health-related quality of life, respiratory diseases, and homicides); and (2) use citizen science methods to identify, prioritize, and communicate the most salient negative and positive features impacting health and quality of life in TransMiCable's area, as well as facilitate a consensus and advocacy-building change process among community members, policymakers, and academic researchers.