Physical activity for general health benefits in disabled children and disabled young people: rapid evidence review<strong> </strong>

Executive summary: Disabled children and disabled young people are at increased risk of being typically inactive, particularly as they become older. These issues have been exacerbated by the COVID-19 pandemic. This public health-focused report provides a review of the scientific evidence of the health benefits from physical activity, specifically for disabled children and disabled young people in non-clinical settings (aged 2 to 17 years). The research responds to a gap identified in the review of evidence for the 2019 UK Chief Medical Officers’ (CMOs’) physical activity guidelines. This important adjunct report enhances the comprehensiveness of the UK’s physical activity guidelines provision. It also provides future research recommendations. Furthermore, the report will also inform the first evidence-based infographic co-produced with disabled children and disabled young people, their parents and carers, health and social care professionals, and key disability and sport organisations to communicate meaningful messages about these physical activity recommendations, especially in relation to the frequency and duration of activity.There is evidence that shows a likely relationship between engaging in physical activity and positive health outcomes for disabled children and disabled young people. This report also provides suggestions about the amount (that is, frequency, duration and intensity) of physical activity that is likely to be important for disabled children and disabled young people to undertake to benefit their health. Some physical activity is better than nothing, as small amounts can bring health benefits. For likely substantial health gains, it is important for disabled children and disabled young people to do 120 to 180 minutes of mostly aerobic physical activity per week, at a moderate-to-vigorous intensity. The evidence suggests that this may be achieved in different ways (for example, 20 minutes per day or 40 minutes 3 times per week). It is also important for disabled children and disabled young people to do challenging strength and balance-focused activities on average 3 times per week. No evidence was found to show that physical activity is unsafe for disabled children and disabled young people when it is performed at an appropriate level for their current levels of physical development, fitness, physical and mental functioning (accounting for disability classification and severity), health and physical activity.This report provides evidence that aligns in part with the 2019 UK Chief Medical Officers’ physical activity guidelines for non-disabled children and disabled young people, as well as the 2020 guidelines published by the World Health Organization (WHO) for disabled children and disabled young people. However, there are also important differences in terms of recommended frequency and time. These are made based on the available evidence to provide recommendations specific to disabled children and disabled young people. The report also aids the communication and implementation of the guidelines by providing an evidence-base for disability groups, health and social care professionals, and sport and physical activity organisations to encourage physical activity to disabled children and disabled young people.The guidelines are the first to have included a review of evidence solely focused on disabled children and disabled young people’s physical activity, and thus represent the most comprehensive guidance globally

Exploring the presence of markers of decidualisation in the fallopian tubes: a systematic review.

The Fallopian tubes (FTs) are part of the female upper genital tract. The healthy FT provides the biological environment for successful fertilisation and facilitates the subsequent movement of the conceptus to the endometrial cavity. However, when the FT is damaged, as with salpingitis, pyosalpinx and hydrosalpinx, it may increase the risk of an ectopic pregnancy, a life-threatening condition. Decidualisation refers to a multifactorial process by which the endometrium changes to permit blastocyst implantation. The decidualisation reaction is vital for endometrial receptivity during the window of implantation. To date, no comprehensive review that collates evidence on decidualisation in the human FT has been conducted. Therefore, the aim of this review is to compile the current evidence on cellular decidualisation occurring in the healthy and pathological FT in women of reproductive age. A literature search was conducted using five databases and identified 746 articles, 24 of which were analysed based on inclusion and exclusion criteria. The available evidence indicates that the FT are able to undergo decidual changes under specific circumstances, however, the exact mechanism by which this occurs is poorly understood. Further research is needed to elucidate the mechanism by which decidualisation can occur in the FT

Shwachman-Bodian-Diamond syndrome (SBDS) protein is a direct inhibitor of protein phosphatase 2A (PP2A) activity and overexpressed in acute myeloid leukaemia.

Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase inactivated in many cancers including acute myeloid leukaemia (AML). Activation of PP2A is emerging as a therapeutic strategy, however the mechanisms underpinning PP2A inhibition are not well understood. Using myeloid progenitor cells harbouring oncogenic mutant c-KIT and characterised by PP2A inhibition, we have identified the ribosome biogenesis protein SBDS, as a target of the PP2A activating drugs FTY720 and AAL(S). We show SBDS binds to PP2A complexes comprised of the B55α regulatory subunit of PP2A. shRNA mediated knockdown of SBDS increased PP2A activity and induced apoptosis. At diagnosis, AML patients expressed significantly more SBDS mRNA than healthy controls, with relapsed patients expressing significantly more SBDS mRNA than both healthy controls and patients at diagnosis. Together, our data presents a role for SBDS in the dysregulation of PP2A in AML

Expression of the Multiple Sclerosis-Associated MHC Class II Allele HLA-DRB1*1501 Is Regulated by Vitamin D

Multiple sclerosis (MS) is a complex trait in which allelic variation in the MHC class II region exerts the single strongest effect on genetic risk. Epidemiological data in MS provide strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of this disease. Growing evidence implicates sunlight or vitamin D as a key environmental factor in aetiology. We hypothesised that this environmental candidate might interact with inherited factors and sought responsive regulatory elements in the MHC class II region. Sequence analysis localised a single MHC vitamin D response element (VDRE) to the promoter region of HLA-DRB1. Sequencing of this promoter in greater than 1,000 chromosomes from HLA-DRB1 homozygotes showed absolute conservation of this putative VDRE on HLA-DRB1*15 haplotypes. In contrast, there was striking variation among non–MS-associated haplotypes. Electrophoretic mobility shift assays showed specific recruitment of vitamin D receptor to the VDRE in the HLA-DRB1*15 promoter, confirmed by chromatin immunoprecipitation experiments using lymphoblastoid cells homozygous for HLA-DRB1*15. Transient transfection using a luciferase reporter assay showed a functional role for this VDRE. B cells transiently transfected with the HLA-DRB1*15 gene promoter showed increased expression on stimulation with 1,25-dihydroxyvitamin D3 (P = 0.002) that was lost both on deletion of the VDRE or with the homologous “VDRE” sequence found in non–MS-associated HLA-DRB1 haplotypes. Flow cytometric analysis showed a specific increase in the cell surface expression of HLA-DRB1 upon addition of vitamin D only in HLA-DRB1*15 bearing lymphoblastoid cells. This study further implicates vitamin D as a strong environmental candidate in MS by demonstrating direct functional interaction with the major locus determining genetic susceptibility. These findings support a connection between the main epidemiological and genetic features of this disease with major practical implications for studies of disease mechanism and prevention

Investigation of the Stationary and Transient A1·− Radical in Trp → Phe Mutants of Photosystem I

Photosystem I (PS I) contains two symmetric branches of electron transfer cofactors. In both the A- and B-branches, the phylloquinone in the A1 site is π-stacked with a tryptophan residue and is H-bonded to the backbone nitrogen of a leucine residue. In this work, we use optical and electron paramagnetic resonance (EPR) spectroscopies to investigate cyanobacterial PS I complexes, where these tryptophan residues are changed to phenylalanine. The time-resolved optical data show that backward electron transfer from the terminal electron acceptors to P700·+ is affected in the A- and B-branch mutants, both at ambient and cryogenic temperatures. These results suggest that the quinones in both branches take part in electron transport at all temperatures. The electron-nuclear double resonance (ENDOR) spectra of the spin-correlated radical pair P700·+A1·− and the photoaccumulated radical anion A1·−, recorded at cryogenic temperature, allowed the identification of characteristic resonances belonging to protons of the methyl group, some of the ring protons and the proton hydrogen-bonded to phylloquinone in the wild type and both mutants. Significant changes in PS I isolated from the A-branch mutant are detected, while PS I isolated from the B-branch mutant shows the spectral characteristics of wild-type PS I. A possible short-lived B-branch radical pair cannot be detected by EPR due to the available time resolution; therefore, only the A-branch quinone is observed under conditions typically employed for EPR and ENDOR spectroscopies

Seasonal Variation in Vitamin D3 Levels Is Paralleled by Changes in the Peripheral Blood Human T Cell Compartment

It is well-recognized that vitamin D3 has immune-modulatory properties and that the variation in ultraviolet (UV) exposure affects vitamin D3 status. Here, we investigated if and to what extent seasonality of vitamin D3 levels are associated with changes in T cell numbers and phenotypes. Every three months during the course of the entire year, human PBMC and whole blood from 15 healthy subjects were sampled and analyzed using flow cytometry. We observed that elevated serum 25(OH)D3 and 1,25(OH)2D3 levels in summer were associated with a higher number of peripheral CD4+ and CD8+ T cells. In addition, an increase in naïve CD4+CD45RA+ T cells with a reciprocal drop in memory CD4+CD45RO+ T cells was observed. The increase in CD4+CD45RA+ T cell count was a result of heightened proliferative capacity rather than recent thymic emigration of T cells. The percentage of Treg dropped in summer, but not the absolute Treg numbers. Notably, in the Treg population, the levels of forkhead box protein 3 (Foxp3) expression were increased in summer. Skin, gut and lymphoid tissue homing potential was increased during summer as well, exemplified by increased CCR4, CCR6, CLA, CCR9 and CCR7 levels. Also, in summer, CD4+ and CD8+ T cells revealed a reduced capacity to produce pro-inflammatory cytokines. In conclusion, seasonal variation in vitamin D3 status in vivo throughout the year is associated with changes in the human peripheral T cell compartment and may as such explain some of the seasonal variation in immune status which has been observed previously. Given that the current observations are limited to healthy adult males, larger population-based studies would be useful to validate these findings

Effects of Cu/Zn Superoxide Dismutase (sod1) Genotype and Genetic Background on Growth, Reproduction and Defense in Biomphalaria glabrata

Resistance of the snail Biomphalaria glabrata to the trematode Schistosoma mansoni is correlated with allelic variation at copper-zinc superoxide dismutase (sod1). We tested whether there is a fitness cost associated with carrying the most resistant allele in three outbred laboratory populations of snails. These three populations were derived from the same base population, but differed in average resistance. Under controlled laboratory conditions we found no cost of carrying the most resistant allele in terms of fecundity, and a possible advantage in terms of growth and mortality. These results suggest that it might be possible to drive resistant alleles of sod1 into natural populations of the snail vector for the purpose of controlling transmission of S. mansoni. However, we did observe a strong effect of genetic background on the association between sod1 genotype and resistance. sod1 genotype explained substantial variance in resistance among individuals in the most resistant genetic background, but had little effect in the least resistant genetic background. Thus, epistatic interactions with other loci may be as important a consideration as costs of resistance in the use of sod1 for vector manipulation

The impact of rheumatoid foot on disability in Colombian patients with rheumatoid arthritis

<p>Abstract</p> <p>Background</p> <p>Alterations in the feet of patients with rheumatoid arthritis (RA) are a cause of disability in this population. The purpose of this research was to evaluate the impact that foot impairment has on the patients' global quality of life (QOL) based on validated scales and its relationship to disease activity.</p> <p>Methods</p> <p>This was a cross-sectional study in which 95 patients with RA were enrolled. A complete physical examination, including a full foot assessment, was done. The Spanish versions of the Health Assessment Questionnaire (HAQ) Disability Index and of the Disease Activity Score (DAS 28) were administered. A logistic regression model was used to analyze data and obtain adjusted odds ratios (AORs).</p> <p>Results</p> <p>Foot deformities were observed in 78 (82%) of the patients; hallux valgus (65%), medial longitudinal arch flattening (42%), claw toe (lesser toes) (39%), dorsiflexion restriction (tibiotalar) (34%), cock-up toe (lesser toes) (25%), and transverse arch flattening (25%) were the most frequent. In the logistic regression analysis (adjusted for age, gender and duration of disease), forefoot movement pain, subtalar movement pain, tibiotalar movement pain and plantarflexion restriction (tibiotalar) were strongly associated with disease activity and disability. The positive squeeze test was significantly associated with disability risk (AOR = 6,3; 95% CI, 1.28–30.96; P = 0,02); hallux valgus, and dorsiflexion restriction (tibiotalar) were associated with disease activity.</p> <p>Conclusion</p> <p>Foot abnormalities are associated with active joint disease and disability in RA. Foot examinations provide complementary information related to the disability as an indirect measurement of quality of life and activity of disease in daily practice.</p

When research seems like clinical care: a qualitative study of the communication of individual cancer genetic research results

<p>Abstract</p> <p>Background</p> <p>Research ethicists have recently declared a new ethical imperative: that researchers should communicate the results of research to participants. For some analysts, the obligation is restricted to the communication of the general findings or conclusions of the study. However, other analysts extend the obligation to the disclosure of individual research results, especially where these results are perceived to have clinical relevance. Several scholars have advanced cogent critiques of the putative obligation to disclose individual research results. They question whether ethical goals are served by disclosure or violated by non-disclosure, and whether the communication of research results respects ethically salient differences between research practices and clinical care. Empirical data on these questions are limited. Available evidence suggests, on the one hand, growing support for disclosure, and on the other, the potential for significant harm.</p> <p>Methods</p> <p>This paper explores the implications of the disclosure of individual research results for the relationship between research and clinical care through analysis of research-based cancer genetic testing in Ontario, Canada in the late 1990s. We analyze a set of 30 interviews with key informants involved with research-based cancer genetic testing before the publicly funded clinical service became available in 2000.</p> <p>Results</p> <p>We advance three insights: First, the communication of individual research results makes research practices <it>seem </it>like clinical services for our respondents. Second, while valuing the way in which research enables a form of clinical access, our respondents experience these quasi-clinical services as inadequate. Finally, our respondents recognize the ways in which their experience with these quasi-clinical services is influenced by research imperatives, but understand and interpret the significance and appropriateness of these influences in different ways.</p> <p>Conclusion</p> <p>Our findings suggest that the hybrid state created through the disclosure of research results about individuals that are perceived to be clinically relevant may produce neither sufficiently adequate clinical care nor sufficiently ethical research practices. These findings raise questions about the extent to which research can, and <it>should</it>, be made to serve clinical purposes, and suggest the need for further deliberation regarding any ethical obligation to communicate individual research results.</p