Epigenetic Mechanisms of Gene Regulation in Amyotrophic Lateral Sclerosis.

Despite being clinically described 150 years ago, the mechanisms underlying amyotrophic lateral sclerosis (ALS) pathogenesis have not yet been fully understood. Studies in both animal models of ALS and human patients reveal a plethora of alterations such as increased glutamate-mediated excitotoxicity, redox stress, increased apoptosis, defective axonal transport, protein-misfolding events, mitochondrial impairment and sustained unregulated immune responses. Regardless of being sporadic or familiar ALS, the final outcome at the cellular level is the death of upper and lower motor neurons, and once diagnosed, ALS is typically lethal within the next 5 years. There are neither clear biomarkers nor therapeutic or disease-modifying treatments for ALS.Accumulating evidence supports the concept that epigenetic-driven modifications, including altered chromatin remodelling events, RNA editing and non-coding RNA molecules, might shed light into the pathogenic mechanisms underlying sporadic/familiar ALS onset and/or severity to facilitate the identification of effective therapies, early diagnosis and potentially early-stage therapeutic interventions to increase the survival outcome of ALS patients.

Improving Sleep Using Mentored Behavioral and Environmental Restructuring (SLUMBER).

OBJECTIVES: To evaluate the impact of a mentoring program to encourage staff-delivered sleep-promoting strategies on sleep, function, depression, and anxiety among skilled nursing facility (SNF) residents. DESIGN: Modified stepped-wedge unit-level intervention. SETTING AND PARTICIPANTS: Seventy-two residents (mean age 75 ± 15 years; 61.5% female, 41% non-Hispanic white, 35% Black, 20% Hispanic, 3% Asian) of 2 New York City urban SNFs. METHODS: Expert mentors provided SNF staff webinars, in-person workshops, and weekly sleep pearls via text messaging. Resident data were collected at baseline, post-intervention (V1), and 3-month follow-up (V2), including wrist actigraphy, resident behavioral observations, Pittsburgh Sleep Quality Index (PSQI), Patient Health Questionnaire-9 (PHQ-9) depression scale, Brief Anxiety and Depression Scale (BADS), Brief Cognitive Assessment Tool (BCAT), and select Minimum Data Set 3.0 (MDS 3.0) measures. Linear mixed models were fit for continuous outcomes and mixed-effects logistic models for binary outcomes. Outcomes were modeled as a function of time. Planned contrasts compared baseline to V1 and V2. RESULTS: There was significant improvement in PSQI scores from baseline to V1 (P = .009), and from baseline to V2 (P = .008). Other significant changes between baseline and V1 included decreased depression (PHQ-9) (P = .028), increased daytime observed out of bed (P ≤ .001), and increased daytime observed being awake (P < .001). At V2 (vs baseline) being observed out of bed decreased (P < .001). Daytime sleeping by actigraphy increased from baseline to V1 (P = .004), but not V2. MDS 3.0 activities of daily living and pain showed improvements by the second quarter following implementation of SLUMBER (P's ≤ .034). There were no significant changes in BADS or BCAT between baseline and V1 or V2. CONCLUSIONS AND IMPLICATIONS: SNF residents had improvements in sleep quality and depression with intervention, but improvements were not sustained at 3-month follow-up. The COVID-19 pandemic led to premature study termination, so full impacts remain unknown.

Implementation Outcomes for the SLUMBER Sleep Improvement Program in Long-Term Care.

OBJECTIVES: To describe the implementation of a mentored staff-delivered sleep program in nursing facilities. DESIGN: Modified stepped-wedge unit-level intervention. SETTING AND PARTICIPANTS: This program was implemented in 2 New York City nursing facilities, with partial implementation (due to COVID-19) in a third facility. METHODS: Expert mentors provided staff webinars, in-person workshops, and weekly sleep pearls via text messaging. We used the integrated Promoting Action on Research Implementation in Health Services (i-PARiHS) framework as a post hoc approach to describe key elements of the SLUMBER implementation. We measured staff participation in unit-level procedures and noted their commentary during unit workshops. RESULTS: We completed SLUMBER within 5 units across 2 facilities and held 15 leadership meetings before and during program implementation. Sessions on each unit included 3 virtual webinar presentations and 4 in-person workshops for each nursing shift, held over a period of 3 to 4 months. Staff attendance averaged >3 sessions per individual staff member. Approximately 65% of staff present on each unit participated in any given session. Text messaging was useful for engagement, educational reinforcement, and encouraging attendance. We elevated staff as experts in the care of their residents as a strategy for staff engagement and behavior change and solicited challenging cases from staff during workshops to provide strategies to address resident behavior and encourage adoption when successful. CONCLUSIONS AND IMPLICATIONS: Engaging staff, leadership, residents, and family of nursing facilities in implementing a multicomponent sleep quality improvement program is feasible for improving nursing facilities' sleep environment. The program required gaining trust at multiple levels through presence and empathy, and reinforcement mechanisms (primarily text messages). To improve scalability, SLUMBER could evolve from an interdisciplinary investigator-based approach to internal coaches in a train-the-trainer model to effectively and sustainably implement this program to improve sleep quality for facility residents.

Improving sleep using mentored behavioral and environmental restructuring (SLUMBER): A randomized stepped-wedge design trial to evaluate a comprehensive sleep intervention in skilled nursing facilities.

INTRODUCTION: Poor sleep is ubiquitous in skilled nursing facilities (SNFs) and is associated with a myriad of negative symptoms. Non-pharmacological interventions can improve sleep, yet sustainability has not been demonstrated. The Improving Sleep Using Mentored Behavioral and Environmental Restructuring (SLUMBER) trial will test whether a staff mentoring approach to address resident sleep issues positively impacts sleep quality and whether improved sleep benefits mood, cognitive performance, and activity engagement for residents living in SNFs. INTERVENTION: This is a four-year hybrid type I effectiveness/implementation randomized stepped-wedge trial using a comprehensive sleep improvement program conducted in three urban SNFs. METHODS: We will provide SNF staff with sleep promotion strategies over a four-month intervention. Staff will have access to in-person workshops, webinars, weekly sleep pearls via text messaging, environmental data, and expert program mentors. We will consent residents for data collection (at baseline, end of intervention, and three- and six-months post-intervention) including resident observations, questionnaires, and wrist actigraphy (to objectively measure sleep). We will also use selected Minimum Data Set 3.0 (MDS) measures. CONCLUSION: SLUMBER uses a unique strategy to iteratively improve sleep interventions through SNF staff buy-in, expert mentoring, and technological supports within a quality improvement framework. As a stepped-wedge trial, the initial SNF units provide opportunities for program improvement in subsequent units, accounting for variation across resident populations at different sites. Protocol limitations include strategies which may require substantial customization for greater spread. A comprehensive staff training program that addresses both sleep quality and related symptoms has the opportunity for considerable dissemination. TRIAL REGISTRATION: USGOV Clinical Trials ID: NCT03327324.

Peripheral Blood Mitochondrial DNA Levels Were Modulated by SARS-CoV-2 Infection Severity and Its Lessening Was Associated With Mortality Among Hospitalized Patients With COVID-19.

Introduction: During severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the virus hijacks the mitochondria causing damage of its membrane and release of mt-DNA into the circulation which can trigger innate immunity and generate an inflammatory state. In this study, we explored the importance of peripheral blood mt-DNA as an early predictor of evolution in patients with COVID-19 and to evaluate the association between the concentration of mt-DNA and the severity of the disease and the patient's outcome. Methods: A total 102 patients (51 COVID-19 cases and 51 controls) were included in the study. mt-DNA obtained from peripheral blood was quantified by qRT-PCR using the NADH mitochondrial gene. Results: There were differences in peripheral blood mt-DNA between patients with COVID-19 (4.25 ng/µl ± 0.30) and controls (3.3 ng/µl ± 0.16) (p = 0.007). Lower mt-DNA concentrations were observed in patients with severe COVID-19 when compared with mild (p= 0.005) and moderate (p= 0.011) cases of COVID-19. In comparison with patients with severe COVID-19 who survived (3.74 ± 0.26 ng/µl) decreased levels of mt-DNA in patients with severe COVID-19 who died (2.4 ± 0.65 ng/µl) were also observed (p = 0.037). Conclusion: High levels of mt-DNA were associated with COVID-19 and its decrease could be used as a potential biomarker to establish a prognosis of severity and mortality of patients with COVID-19.

Effects of Valproate Monotherapy on the Oxidant-Antioxidant Status in Mexican Epileptic Children: A Longitudinal Study.

Epilepsy is a neurological disorder that can produce brain injury and neuronal death. Several factors such as oxidative stress have been implicated in epileptogenesis. Valproic acid (VPA) is a widely used drug for the treatment of epilepsy, but the mechanisms underlying these benefits are complex and still not fully understood. The objective of this study was to evaluate, for the first time, the effects of VPA on the oxidant-antioxidant status in Mexican epileptic children before and after 6 or 12 months of treatment with VPA by determining the activities of several plasmatic antioxidant enzymes (glutathione reductase (GR), glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT)) and oxidant marker (malondialdehyde (MDA), hydrogen peroxide (H2O2), 8-hydroxy-2-deoxyguanosine (8-OHdG), and 3-nitrotyrosine (3-NT) levels) profiles. The possible relationships between these markers and some clinicopathological factors were also evaluated. Plasma samples were obtained from the peripheral blood of 16 healthy children and 32 patients diagnosed with epilepsy, and antioxidant/oxidant markers were measured spectrometrically. Significant decreases in all antioxidant enzyme activities, with the exception of GPx, and increases in all oxidant markers in epileptic subjects versus healthy children were observed. Interestingly, all these effects reverted after VPA monotherapy, although the results were different depending on the treatment period (6 or 12 months). These changes were contingent upon brain imaging findings, type of epilepsy, etiology of epilepsy, and the efficacy of 6 months of VPA monotherapy. Significant and positive correlations of GPx and SOD activities and H2O2 and 8-OHdG levels with the age of children at the beginning of treatment were observed. H2O2 levels were also positively correlated with number of seizures before VPA monotherapy. VPA showed significant antioxidant effects decreasing seizure activity, possibly depending on the presence of cerebral structural alterations, treatment time, and age.

Experiencia de una niña de nueve años ante la separación parental / Effects of parental separation: listening to a nine-year-old girl / Efeitos da separação parental: ouvindo uma menina de nove anos

Resumen (analítico) En este estudio cualitativo se describen y analizan los efectos de la separación parental, a través de la mirada y voz de una niña de nueve años. Se empleó como instrumento una entrevista semiestructurada y un análisis de resultados de tipo categórico. Las repercusiones observadas se clasificaron en efectos individuales como el manejo de la información y la construcción de explicaciones, así como una mayor independencia y mejora en su autoconcepto; y efectos en su entorno familiar, tales como la modificación en los vínculos afectivos con sus padres, dinámicas familiares más consistentes y mayores momentos de bienestar. Concluyendo que los infantes son participantes activos en la construcción de sus significados y que la separación de los padres puede permitir la generación de experiencias de crecimiento.

Abstract (analytical) In this qualitative study, the effects of parental separation are described and analyzed through the voice and point of view of a nine-year-old girl. The authors used a semi-structured interview and categorical data analysis to identify these effects. The identified repercussions of the parental separation were classified into individual effects, such as information management and construction of explanations, as well as higher levels of independence and improvements in self-awareness. The authors also identified effects on the family environment such as modification of affective bonding with parents, more consistent family dynamics and increased moments of wellbeing. The study concludes that children perform an active role in the construction of their meaning and parental separation can facilitate the generation of self-growth experiences.

Resumo (analítico) Neste estudo qualitativo, são descritos e analisados os efeitos da separação parental através da visão e da voz de uma menina de nove anos. Utilizou-se como instrumento uma entrevista semiestruturada e uma análise dos resultados categóricos. As repercussões observadas foram classificadas em efeitos individuais, como gerenciamento de informações e construção de explicações, além de maior independência e melhoria de seu autoconceito; Os efeitos no ambiente familiar, como mudanças nos laços emocionais com os pais, dinâmicas familiares mais consistentes e mais momentos de bem-estar, concluindo que as crianças são participantes ativas na construção de seus significados. E, por último, que a separação dos pais pode gerar experiências de crescimento.

Lack of alterations on meiotic chromosomes and morphological characteristics of male germ cells in mice exposed to a 60 Hz and 2.0 mT magnetic field.

The effect of in vivo exposure of mice to a 60 Hz sinusoidal magnetic field (MF) at 2.0 mT on male germ cells was studied. The cytological endpoints measured included meiotic chromosome aberrations in spermatocytes and sperm morphology. Three independent experiments were carried out: (a) animals exposed for 72 h, (b) 10 days/8 h daily, and (c) 72 h exposure to MF plus 5 mg/kg of Mitomycin-C. No statistically significant differences indicative of MF effects were observed between MF exposed and control animals. In addition, an opposite effect between MF exposure and Mitomycin-C treatment in terms of chromosomal aberrations and sperm morphology was observed.