Nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants enhances autophagic clearance in Pompe disease.

Alglucosidase alpha is an orphan drug approved for enzyme replacement therapy (ERT) in Pompe disease (PD); however, its efficacy is limited in skeletal muscle because of a partial blockage of autophagic flux that hinders intracellular trafficking and enzyme delivery. Adjunctive therapies that enhance autophagic flux and protect mitochondrial integrity may alleviate autophagic blockage and oxidative stress and thereby improve ERT efficacy in PD. In this study, we compared the benefits of ERT combined with a ketogenic diet (ERT-KETO), daily administration of an oral ketone precursor (1,3-butanediol; ERT-BD), a multi-ingredient antioxidant diet (ERT-MITO; CoQ10, α-lipoic acid, vitamin E, beetroot extract, HMB, creatine, and citrulline), or co-therapy with the ketone precursor and multi-ingredient antioxidants (ERT-BD-MITO) on skeletal muscle pathology in GAA-KO mice. We found that two months of 1,3-BD administration raised circulatory ketone levels to ≥1.2 mM, attenuated autophagic buildup in type 2 muscle fibers, and preserved muscle strength and function in ERT-treated GAA-KO mice. Collectively, ERT-BD was more effective vs. standard ERT and ERT-KETO in terms of autophagic clearance, dampening of oxidative stress, and muscle maintenance. However, the addition of multi-ingredient antioxidants (ERT-BD-MITO) provided the most consistent benefits across all outcome measures and normalized mitochondrial protein expression in GAA-KO mice. We therefore conclude that nutritional co-therapy with 1,3-butanediol and multi-ingredient antioxidants may provide an alternative to ketogenic diets for inducing ketosis and enhancing autophagic flux in PD patients.

Kussmaul's sign for the diagnosis of right ventricular myocardial infarction: a systematic review and meta-analysis of diagnostic test accuracy studies.

INTRODUCTION: Kussmaul's sign, the absence of a drop in jugular venous pressure or a paradoxical increase in jugular venous pressure on inspiration, can be evaluated as an indicator of right ventricular myocardial infarction. Right ventricular myocardial infarction complicates 30-50% of inferior myocardial infarctions and is associated with increased mortality when compared to inferior myocardial infarction without right ventricular involvement. Early recognition allows maintenance of preload. We reviewed the diagnostic test accuracy studies for Kussmaul's sign for diagnosis of right ventricular myocardial infarction. METHODS: We conducted a librarian-assisted search using PubMed, Medline, Embase, and the Cochrane database from 1965 to October 2019. Only English language restriction was imposed. We identified studies that assessed patients presenting to a hospital with a suspected myocardial infarction who underwent an assessment for Kussmaul's sign and a diagnostic test for right ventricular myocardial infarction. Four independent reviewers extracted data from relevant studies. Study quality was assessed using the QUADAS-2 tool. A bivariate random effects meta-analysis was performed. RESULTS: We identified 122 studies; ten were selected for full review. Eight studies had comparable populations with a total of 469 consecutive patients admitted with acute inferior myocardial infarction and were included in the analysis. Prevalence of right ventricular myocardial infarction was 36% (confidence interval [CI] 95% 31.8-40.5). All reference standards were combined. Kussmaul's sign had a sensitivity of 62.5% (44.6, 77.5), specificity 90% (73.0, 96.8), negative likelihood ratio (LR) 0.2 (0.1-0.8) and positive LR 5.8 (2.5, 13.3). CONCLUSION: In the presence of acute myocardial infarction, Kussmaul's sign is specific for acute right ventricular myocardial infarction and may serve as an important clinical sign of right ventricular dysfunction requiring preload preserving management.

RéSUMé: INTRODUCTION: Le signe de Kussmaul, l'absence de baisse de la pression veineuse jugulaire ou une augmentation paradoxale de la pression veineuse jugulaire à l'inspiration, peut être évalué comme un indicateur d'infarctus du myocarde ventriculaire droit. Elle complique 30 à 50% des infarctus du myocarde inférieur et est associée à une mortalité accrue par rapport à l'infarctus du myocarde inférieur sans atteinte ventriculaire droite. Une détection précoce permet de maintenir la précharge. Nous avons examiné les études sur la précision des tests de diagnostic du signe de Kussmaul pour le diagnostic de l'infarctus du myocarde ventriculaire droit. MéTHODES: Nous avons mené une recherche assistée par un bibliothécaire à l'aide de PubMed, Medline, Embase et la base de données Cochrane de 1965 à octobre 2019. Seule la restriction de la langue anglaise a été imposée. Nous avons identifié des études qui ont évalué des patients se présentant à un hôpital avec un infarctus suspecté de myocarde et qui ont subi une évaluation du signe de Kussmaul et un test de diagnostic pour un infarctus du myocarde ventriculaire droit. Quatre examinateurs indépendants ont extrait les données d'études pertinentes. La qualité de l'étude a été évaluée à l'aide de l'outil QUADAS-2. Une méta-analyse bivariée des effets aléatoires a été réalisée. RéSULTATS: Nous avons recensé 122 études ; dix ont été sélectionnées pour un examen complet. Huit études avaient des populations comparables avec un total de 469 patients consécutifs admis avec un infarctus aigu du myocarde inférieur et ont été inclus dans l'analyse. La prévalence de l'infarctus du myocarde ventriculaire droit était de 36 % (intervalle de confiance [IC] 95 % 31,8-40,5). Toutes les normes de référence ont été combinées. Le signe de Kussmaul avait une sensibilité de 62,5 % (44,6, 77,5), de spécificité 90 % (73,0, 96,8), un rapport de vraisemblance négatif (LR) 0,2 (0,1-0,8) et de LR positif 5,8 (2,5, 13,3). CONCLUSION: En présence d'un infarctus aigu du myocarde, le signe de Kussmaul est spécifique à l'infarctus aigu du myocarde ventriculaire droit et peut constituer un signe clinique important de dysfonctionnement du ventricule droit nécessitant une gestion de la préservation de la précharge.

Correction: Lifelong aerobic exercise protects against inflammaging and cancer.

[This corrects the article DOI: 10.1371/journal.pone.0210863.].

Lifelong aerobic exercise protects against inflammaging and cancer.

Biological aging is associated with progressive damage accumulation, loss of organ reserves, and systemic inflammation ('inflammaging'), which predispose for a wide spectrum of chronic diseases, including several types of cancer. In contrast, aerobic exercise training (AET) reduces inflammation, lowers all-cause mortality, and enhances both health and lifespan. In this study, we examined the benefits of early-onset, lifelong AET on predictors of health, inflammation, and cancer incidence in a naturally aging mouse model (C57BL/J6). Lifelong, voluntary wheel-running (O-AET; 26-month-old) prevented age-related declines in aerobic fitness and motor coordination vs. age-matched, sedentary controls (O-SED). AET also provided partial protection against sarcopenia, dynapenia, testicular atrophy, and overall organ pathology, hence augmenting the 'physiologic reserve' of lifelong runners. Systemic inflammation, as evidenced by a chronic elevation in 17 of 18 pro- and anti-inflammatory cytokines and chemokines (P < 0.05 O-SED vs. 2-month-old Y-CON), was potently mitigated by lifelong AET (P < 0.05 O-AET vs. O-SED), including master regulators of the cytokine cascade and cancer progression (IL-1ß, TNF-α, and IL-6). In addition, circulating SPARC, previously known to be upregulated in metabolic disease, was elevated in old, sedentary mice, but was normalized to young control levels in lifelong runners. Remarkably, malignant tumours were also completely absent in the O-AET group, whereas they were present in the brain (pituitary), liver, spleen, and intestines of sedentary mice. Collectively, our results indicate that early-onset, lifelong running dampens inflammaging, protects against multiple cancer types, and extends healthspan of naturally-aged mice.

A systematic review of the behavioural outcomes following exercise interventions for children and youth with autism spectrum disorder.

The purpose of this review was to systematically search and critically analyse the literature pertaining to behavioural outcomes of exercise interventions for individuals with autism spectrum disorder aged ⩽16 years. This systematic review employed a comprehensive peer-reviewed search strategy, two-stage screening process and rigorous critical appraisal, which resulted in the inclusion of 13 studies. Results demonstrated that exercise interventions consisting individually of jogging, horseback riding, martial arts, swimming or yoga/dance can result in improvements to numerous behavioural outcomes including stereotypic behaviours, social-emotional functioning, cognition and attention. Horseback riding and martial arts interventions may produce the greatest results with moderate to large effect sizes, respectively. Future research with well-controlled designs, standardized assessments, larger sample sizes and longitudinal follow-ups is necessary, in addition to a greater focus on early childhood (aged 0-5 years) and adolescence (aged 12-16 years), to better understand the extent of the behavioural benefits that exercise may provide these populations.

Use of human patient simulation and validation of the Team Situation Awareness Global Assessment Technique (TSAGAT): a multidisciplinary team assessment tool in trauma education.

OBJECTIVE: Situation awareness (SA) is a vital construct for decision making in intense, dynamic environments such as trauma resuscitation. Human patient simulation (HPS) allows for a safe environment where individuals can develop these skills. Trauma resuscitation is performed by multidisciplinary teams that are traditionally difficult to globally assess. Our objective was to create and validate a novel tool to measure SA in multidisciplinary trauma teams using a HPS--the Team Situation Awareness Global Assessment Technique (TSAGAT). SETTING: Memorial University Simulation Centre. DESIGN/PARTICIPANTS: Using HPS, 4 trauma teams completed 2 separate trauma scenarios. Student, junior resident, senior resident, and attending staff teams each had 3 members (trauma team leader, nurse, and airway manager). Individual SAGATs were developed by experts in each respective field and contained shared and complimentary knowledge questions. Teams were assessed with SAGAT in real time and with traditional checklists using video review. TSAGAT was calculated as the sum of individual SAGAT scores and was compared with the traditional checklist scores. RESULTS: Shared, complimentary, and TSAGAT scores improved with increasing team experience. Differences between teams for TSAGAT and complimentary knowledge were statistically significant (p < 0.05). Mean checklist differences between teams also reached statistical significance (p < 0.05). TSAGAT scores correlated strongly with traditional checklist scores (Pearson correlation r = 0.996). Interrater reliability for the checklist tool was high (Pearson correlation r = 0.937). CONCLUSION: TSAGAT is the first valid and reliable assessment tool incorporating SA and HPS for multidisciplinary team performance in trauma resuscitation. TSAGAT could compliment or improve on current assessment methods and curricula in trauma and critical care and provides a template for team assessment in other areas of surgical education.