What Is Intensity and How Can It Benefit Exercise Intervention in People With Stroke? A Rapid Review

Background: Stroke is one of the major causes of chronic physical disability in the United Kingdom, typically characterized by unilateral weakness and a loss of muscle power and movement coordination. When combined with pre-existing comorbidities such as cardiac disease and diabetes, it results in reductions in cardiovascular (CV) fitness, physical activity levels, functional capacity, and levels of independent living. High-intensity training protocols have shown promising improvements in fitness and function for people with stroke (PwS). However, it remains unclear how intensity is defined, measured, and prescribed in this population. Further, we do not know what the optimal outcome measures are to capture the benefits of intensive exercise. Aim: To understand how intensity is defined and calibrated in the stroke exercise literature to date and how the benefits of high-intensity training in PwS are measured. Methods: A rapid review of the literature was undertaken to provide an evidence synthesis that would provide more timely information for decision-making (compared with a standard systematic review). Electronic databases were searched (including Medline, PubMed, CINAHL, and Embase for studies from 2015 to 2020). These were screened by title and abstract for inclusion if they: (a) were specific to adult PwS; and (b) were high-intensity exercise interventions. Eligible studies were critically appraised using the Mixed Method Appraisal Tool (MMAT). The data extraction tool recorded the definition of intensity, methods used to measure and progress intensity within sessions, and the outcomes measure used to capture the effects of the exercise intervention. Results: Seventeen studies were selected for review, 15 primary research studies and two literature reviews. Sixteen of the 17 studies were of high quality. Nine of the primary research studies used bodyweight-supported treadmills to achieve the high-intensity training threshold, four used static exercise bikes, and two used isometric arm strengthening. Five of the primary research studies had the aim of increasing walking speed, five aimed to increase CV fitness, three aimed to improve electroencephalogram (EEG) measured cortical evoked potentials and corticospinal excitability, and two investigated any changes in muscle strength. Although only one study gave a clear definition of intensity, all studies clearly defined the high-intensity protocol used, with most (15 out of 17 studies) clearly describing threshold periods of high-intensity activity, followed by rest or active recovery periods (of varying times). All of the studies reviewed used outcomes specific to body structure and function (International Classification of Functioning, Disability, and Health (ICF) constructs), with fewer including outcomes relating to activity and only three outcomes relating to participation. The reported effect of high-intensity training on PwS was promising, however, the underlying impact on neurological, musculoskeletal, and CV systems was not clearly specified. Conclusions: There is a clear lack of definition and understanding about intensity and how thresholds of intensity in this population are used as an intervention. There is also an inconsistency about the most appropriate methods to assess and provide a training protocol based on that assessment. It remains unclear if high-intensity training impacts the desired body system, given the diverse presentation of PwS, from a neuromuscular, CV, functional, and psychosocial perspective. Future work needs to establish a clearer understanding of intensity and the impact of exercise training on multiple body systems in PwS. Further understanding into the appropriate assessment tools to enable appropriate prescription of intensity in exercise intervention is required. Outcomes need to capture measures specific not only to the body system, but also level of function and desired goals of individuals

What Is Intensity and How Can It Benefit Exercise Intervention in People With Stroke? A Rapid Review

Background: Stroke is one of the major causes of chronic physical disability in the United Kingdom, typically characterized by unilateral weakness and a loss of muscle power and movement coordination. When combined with pre-existing comorbidities such as cardiac disease and diabetes, it results in reductions in cardiovascular (CV) fitness, physical activity levels, functional capacity, and levels of independent living. High-intensity training protocols have shown promising improvements in fitness and function for people with stroke (PwS). However, it remains unclear how intensity is defined, measured, and prescribed in this population. Further, we do not know what the optimal outcome measures are to capture the benefits of intensive exercise. Aim: To understand how intensity is defined and calibrated in the stroke exercise literature to date and how the benefits of high-intensity training in PwS are measured. Methods: A rapid review of the literature was undertaken to provide an evidence synthesis that would provide more timely information for decision-making (compared with a standard systematic review). Electronic databases were searched (including Medline, PubMed, CINAHL, and Embase for studies from 2015 to 2020). These were screened by title and abstract for inclusion if they: (a) were specific to adult PwS; and (b) were high-intensity exercise interventions. Eligible studies were critically appraised using the Mixed Method Appraisal Tool (MMAT). The data extraction tool recorded the definition of intensity, methods used to measure and progress intensity within sessions, and the outcomes measure used to capture the effects of the exercise intervention. Results: Seventeen studies were selected for review, 15 primary research studies and two literature reviews. Sixteen of the 17 studies were of high quality. Nine of the primary research studies used bodyweight-supported treadmills to achieve the high-intensity training threshold, four used static exercise bikes, and two used isometric arm strengthening. Five of the primary research studies had the aim of increasing walking speed, five aimed to increase CV fitness, three aimed to improve electroencephalogram (EEG) measured cortical evoked potentials and corticospinal excitability, and two investigated any changes in muscle strength. Although only one study gave a clear definition of intensity, all studies clearly defined the high-intensity protocol used, with Church et al. Stroke Exercise Intensity Prescription Outcome most (15 out of 17 studies) clearly describing threshold periods of high-intensity activity, followed by rest or active recovery periods (of varying times). All of the studies reviewed used outcomes specific to body structure and function (International Classification of Functioning, Disability, and Health (ICF) constructs), with fewer including outcomes relating to activity and only three outcomes relating to participation. The reported effect of high-intensity training on PwS was promising, however, the underlying impact on neurological, musculoskeletal, and CV systems was not clearly specified. Conclusions: There is a clear lack of definition and understanding about intensity and how thresholds of intensity in this population are used as an intervention. There is also an inconsistency about the most appropriate methods to assess and provide a training protocol based on that assessment. It remains unclear if high-intensity training impacts the desired body system, given the diverse presentation of PwS, from a neuromuscular, CV, functional, and psychosocial perspective. Future work needs to establish a clearer understanding of intensity and the impact of exercise training on multiple body systems in PwS. Further understanding into the appropriate assessment tools to enable appropriate prescription of intensity in exercise intervention is required. Outcomes need to capture measures specific not only to the body system, but also level of function and desired goals of individuals

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

UK Joint Advisory Group consensus statements for training and certification in endoscopic retrograde cholangiopancreatography

© 2022 The Authors. Published by Thieme Open. This is an open access article available under a Creative Commons licence. The published version can be accessed at the following link on the publisher’s website: https://www.thieme-connect.de/products/ejournals/abstract/10.1055/a-1629-7540Introduction: Despite the high-risk nature of endoscopic retrograde cholangiopancreatography (ERCP), a robust and standardised credentialing process to ensure competency before independent practice is lacking worldwide. On behalf of the Joint Advisory Group (JAG), we aimed to develop evidence-based recommendations to form the framework of ERCP training and certification in the UK. Methods: Under the oversight of the JAG, a modified Delphi process was conducted with stakeholder representation from the British Society of Gastroenterology, Association of Upper Gastrointestinal Surgeons, trainees and trainers. Recommendations on ERCP training and certification were formulated after formal literature review and appraised using the GRADE tool. These were subjected to electronic voting to achieve consensus. Accepted statements were peer-reviewed by JAG and relevant Specialist Advisory Committees before incorporation into the ERCP certification pathway. Results: In total, 27 recommendation statements were generated for the following domains: definition of competence (9 statements), acquisition of competence (8 statements), assessment of competence (6 statements) and post-certification support (4 statements). The consensus process led to the following criteria for ERCP certification: 1) performing ≥300 hands-on procedures; 2) attending a JAG-accredited ERCP skills course; 3) in modified Schutz 1-2 procedures: achieving native papilla cannulation rate ≥80%, complete bile duct clearance ≥70%, successful stenting of distal biliary strictures ≥75%, physically unassisted in ≥80% of cases; 4) 30-day post-ERCP pancreatitis rates ≤5%; 5) satisfactory performance in formative and summative direct observation of procedural skills (DOPS) assessments. Conclusion: JAG certification in ERCP has been developed following evidence-based consensus to quality assure training and to ultimately improve future standards of ERCP practice

Race/Ethnicity and gender differences in health intentions and behaviors regarding exercise and diet for adults with type 2 diabetes: A cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Self-management is the cornerstone of diabetes control and prevention of complications; however, it is undetermined whether differences in intention to adopt healthy lifestyles and actual healthy behavior exist across race/ethnic groups. This study evaluated the differences across racial-ethnic groups in self-reported medical advice received and health intentions and behaviors among adults with type 2 diabetes mellitus.</p> <p>Methods</p> <p>A cross-sectional analysis of the 2007 SHIELD US survey ascertained self-reported health intentions and behaviors for regular exercise, diet, and weight management among Non-Hispanic Caucasian (n = 2526), Non-Hispanic African-American (n = 706), and Hispanic (n = 179) respondents with type 2 diabetes.</p> <p>Results</p> <p>A similar proportion of respondents from each race-gender group (43%-56%) reported receiving healthcare advice to increase their exercise (P = 0.32). Significantly more minorities reported an intention to follow the exercise recommendation compared with Non-Hispanic Caucasians (P = 0.03). More Non-Hispanic African-American (29%) and Hispanic (27%) men reported exercising regularly compared with other race-gender groups (P = 0.02). Significantly more Non-Hispanic Caucasian women (74%) and Hispanic women (79%) reported trying to lose weight compared with other groups (P < 0.0001).</p> <p>Conclusions</p> <p>Differences in health intentions and healthy behaviors were noted across race-gender groups. More Non-Hispanic African-American men reported an intention to follow advice on exercising and self-report of exercising regularly was also higher compared with other race-gender groups. More Hispanic men reported high physical activity levels than other groups. Despite an increased willingness to follow healthcare recommendations for diet, >50% of respondents were obese among all race-gender groups.</p

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

Cell-Specific “Competition for Calories� Drives Asymmetric Nutrient-Energy Partitioning, Obesity, and Metabolic Diseases in Human and Non-human Animals

The mammalian body is a complex physiologic “ecosystem� in which cells compete for calories (i.e., nutrient-energy). Axiomatically, cell-types with competitive advantages acquire a greater number of consumed calories, and when possible, increase in size and/or number. Thus, it is logical and parsimonious to posit that obesity is the competitive advantages of fat-cells (adipocytes) driving a disproportionate acquisition and storage of nutrient-energy. Accordingly, we introduce two conceptual frameworks. Asymmetric Nutrient-Energy Partitioning describes the context-dependent, cell-specific competition for calories that determines the partitioning of nutrient-energy to oxidation, anabolism, and/or storage; and Effective Caloric Intake which describes the number of calories available to constrain energy-intake via the inhibition of the sensorimotor appetitive cells in the liver and brain that govern ingestive behaviors. Inherent in these frameworks is the independence and dissociation of the energetic demands of metabolism and the neuro-muscular pathways that initiate ingestive behaviors and energy intake. As we demonstrate, if the sensorimotor cells suffer relative caloric deprivation via asymmetric competition from other cell-types (e.g., skeletal muscle- or fat-cells), energy-intake is increased to compensate for both real and merely apparent deficits in energy-homeostasis (i.e., true and false signals, respectively). Thus, we posit that the chronic positive energy balance (i.e., over-nutrition) that leads to obesity and metabolic diseases is engendered by apparent deficits (i.e., false signals) driven by the asymmetric inter-cellular competition for calories and concomitant differential partitioning of nutrient-energy to storage. These frameworks, in concert with our previous theoretic work, the Maternal Resources Hypothesis, provide a parsimonious and rigorous explanation for the rapid rise in the global prevalence of increased body and fat mass, and associated metabolic dysfunctions in humans and other mammals inclusive of companion, domesticated, laboratory, and feral animals

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Telomerecat: A ploidy-agnostic method for estimating telomere length from whole genome sequencing data.

Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human samples. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype