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Abstract The study examined whether lateral perturbation training could improve stepping performance and balance in individuals post-stroke. Thirty-one participants with hemiparesis were randomly allocated to PERT (external perturbation) or VOL (voluntary stepping) step training. The PERT and VOL group consisted of 80 step trials predominantly in the lateral direction, with a small proportion of steps in the anterior/posterior direction. Outcome measures based on step type (medial and lateral) included step initiation time, step length, step clearance, step velocity during an induced waist pull perturbation and voluntary step, and clinical balance assessments. The PERT group initiated a lateral step faster with the non-paretic leg during the induced waist pull perturbation step (P = 0.044) than the VOL group after training. Both groups improved the non-paretic step length and step velocity during lateral steps. During the voluntary steps, the PERT group significantly initiated a voluntary step faster. No significant changes were observed in the paretic leg. Both groups significantly improved on the Community Balance & Mobility Scale and Activities Specific Balance Confidence Scale. Overall, we demonstrated that an exercise to improve stepping performance with external perturbations might provide more benefits in protective stepping responses than training with voluntary steps for individuals with a stroke.

Background: Deinstitutionalisation refers to the transition of individuals with intellectual and developmental disabilities from large institutions to smaller homes in the community. The purpose of this study was to explore how family members of persons with intellectual and developmental disabilities perceived their loved ones' community transition process. Method: Eight family members of persons with severe or profound intellectual and developmental disabilities formerly residing at the complex care facility of St.Amant participated in semi-structured interviews. Interview transcripts were analysed thematically using an iterative inductive process and constant comparative method. Results: Three main themes emerged from the family members' accounts of their loved ones' community transitions process: 1) families' initial reactions, 2) strengths, and 3) challenges. Conclusions: Initial reactions of family members to learning about the community transitions process were varied. Family members' perspectives inform deinstitutionalisation efforts by highlighting facilitators such as adequate involvement, and barriers such as, unanticipated delays, to the community transitions process.

Abstract Oral epithelial dysplasia (OED) is a premalignant histopathological diagnosis given to lesions of the oral cavity. Its grading suffers from significant inter-/intra-observer variability, and does not reliably predict malignancy progression, potentially leading to suboptimal treatment decisions. To address this, we developed an artificial intelligence (AI) algorithm, that assigns an Oral Malignant Transformation (OMT) risk score based on the Haematoxylin and Eosin (H&E) stained whole slide images (WSIs). Our AI pipeline leverages an in-house segmentation model to detect and segment both nuclei and epithelium. Subsequently, a shallow neural network utilises interpretable morphological and spatial features, emulating histological markers, to predict progression. We conducted internal cross-validation on our development cohort (Sheffield; n = 193 cases) and independent validation on two external cohorts (Birmingham and Belfast; n = 89 cases). On external validation, the proposed OMTscore achieved an AUROC = 0.75 (Recall = 0.92) in predicting OED progression, outperforming other grading systems (Binary: AUROC = 0.72, Recall = 0.85). Survival analyses showed the prognostic value of our OMTscore (C-index = 0.60, p = 0.02), compared to WHO (C-index = 0.64, p = 0.003) and binary grades (C-index = 0.65, p

Judith M Greer, Pamela A McCombeThe University of Queensland, UQ Centre for Clinical Research, Brisbane, Queensland, AustraliaAbstract: The lack of complete concordance of autoimmune disease in identical twins suggests that nongenetic factors play a major role in determining disease susceptibility. In this review, we consider how epigenetic mechanisms could affect the immune system and effector mechanisms in autoimmunity and/or the target organ of autoimmunity and thus affect the development of autoimmune diseases. We also consider the types of stimuli that lead to epigenetic modifications and how these relate to the epidemiology of autoimmune diseases and the biological pathways operative in different autoimmune diseases. Increasing our knowledge of these epigenetic mechanisms and processes will increase the prospects for controlling or preventing autoimmune diseases in the future through the use of drugs that target the epigenetic pathways.Keywords: twins, concordance, autoimmune disease, nongenetic factors, immune system, epigenetic modifications

Worldwide, the community transition process away from institutions has increased in the past 30–50 years among persons with severe intellectual and developmental disabilities. This process, also known as “deinstitutionalization”, could potentially impact problem behaviors and communication. This study examined the impacts of community transitions on behavioural and communication outcomes in Canadians with intellectual and developmental disabilities. Data were collected using the Comprehensive Health Assessment Program and medical chart reviews. Descriptive, aggregate-level, and individual-level analyses were conducted for 32 adults who transitioned to community living. Descriptive analyses and the McNemar Chi-Square Test were conducted. Following community transitions, the study group experienced a significant decrease in problem behaviours and changes in communication. The study findings suggest that deinstitutionalization could provide effective strategies for addressing problem behaviors and fostering improvements in communication, promoting the well-being and quality of life of persons with intellectual and developmental disabilities.

Abstract Background Klippel–Feil syndrome is a rare congenital bone disorder characterized by an abnormal fusion of two or more cervical spine vertebrae. Individuals with Klippel–Feil syndrome exhibit diverse clinical manifestations, including skeletal irregularities, visual and hearing impairments, orofacial anomalies, and anomalies in various internal organs, such as the heart, kidneys, genitourinary system, and nervous system. Case presentation This case report describes a 12-year-old Pashtun female patient who presented with acute bilateral visual loss. The patient had Klippel–Feil syndrome, with the typical clinical triad symptoms of Klippel–Feil syndrome, along with Sprengel’s deformity. She also exhibited generalized hypoalgesia, which had previously resulted in widespread burn-related injuries. Upon examination, bilateral optic disc swelling was observed, but intracranial pressure was found to be normal. Extensive investigations yielded normal results, except for hypocalcemia and low vitamin D levels, while parathyroid function remained within the normal range. Visual acuity improved following 2 months of calcium and vitamin D supplementation, suggesting that the visual loss and optic nerve swelling were attributed to hypocalcemia. Given the normal parathyroid function, it is possible that hypocalcemia resulted from low vitamin D levels, which can occur after severe burn scarring. Furthermore, the patient received a provisional diagnosis of congenital insensitivity to pain on the basis of the detailed medical history and the findings of severe and widespread loss of the ability to perceive painful stimuli, as well as impaired temperature sensation. However, due to limitations in genetic testing, confirmation of the congenital insensitivity to pain diagnosis could not be obtained. Conclusion This case highlights a rare presentation of transient binocular vision loss and pain insensitivity in a patient with Klippel–Feil syndrome, emphasizing the importance of considering unusual associations in symptom interpretation.

Background The ‘High-Risk Prevention Programme’ (HRPP) involved a six-week health behaviour change programme based in general practices and aimed to address cardiovascular disease (CVD) risk in disadvantaged Irish communities.Objectives This pilot study aimed to establish the HRPP’s likely effectiveness and acceptability to inform the development of a future definitive trial.Methods The HRPP was conducted at six general practices in disadvantaged areas in the Ireland East region. Patients with high CVD risk were recruited by participating practices and were allocated to either a General Practice Nurse (GPN) or Health Promotion Professional (HPP) led programme focusing on positive health behavioural change. Baseline and 12-month follow-up data were collected to capture the HRPP’s likely effectiveness in promoting health outcomes and health behavioural change.Results The HRPP programme was completed by 270 patients. Out of these 270 patients, 245 (90.74%) completed baseline assessments, and 176 (65.19%) completed follow-up assessments at 12 months. Baseline data indicated a high level of CVD risk among patients and follow-up demonstrated positive change in several areas, especially weight (−1.95 kg, [Formula: see text] < 0.001), BMI (−0.72, [Formula: see text] < 0.001), exercise during the last week ([Formula: see text]

BackgroundAmyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this.MethodsThe Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with 'omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO).ResultsSMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10-6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10-3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. Clinical heterogeneity and complex genetics pose challenges to understanding disease mechanisms and producing effective cures. To model clinical heterogeneity, we generated human induced pluripotent stem cells (iPSCs) from two sporadic ALS patients (sporadic ALS and sporadic ALS with frontotemporal dementia), two familial ALS patients (familial SOD1 mutation positive and familial C9orf72 repeat expansion positive), and four age- and sex-matched healthy controls. These iPSCs can be used to generate 2D and 3D in vitro models of ALS to investigate mechanisms of disease and screen for therapeutics.

IntroductionShort-term clinical outcomes from SARS-CoV-2 infection are generally favorable. However, 15–20% of patients report persistent symptoms of at least 12 weeks duration, often referred to as long COVID. Population studies have also demonstrated an increased risk of incident diabetes and cardiovascular disease at 12 months following infection. While imaging studies have identified multi-organ injury patterns in patients with recovered COVID-19, their respective contributions to the disability and morbidity of long COVID is unclear.MethodsA multicenter, observational study of 215 vaccine-naïve patients with clinically recovered COVID-19, studied at 3–6 months following infection, and 133 healthy volunteers without prior SARS-CoV-2 infection. Patients with recovered COVID-19 were screened for long COVID related symptoms and their impact on daily living. Multi-organ, multi-parametric magnetic resonance imaging (MRI) and circulating biomarkers were acquired to document sub-clinical organ pathology. All participants underwent pulmonary function, aerobic endurance (6 min walk test), cognition testing and olfaction assessment. Clinical outcomes were collected up to 1 year from infection. The primary objective of this study is to identify associations between organ injury and disability in patients with long-COVID symptoms in comparison to controls. As a secondary objective, imaging and circulating biomarkers with the potential to exacerbate cardiovascular health were characterized.DiscussionLong-term sequelae of COVID-19 are common and can result in significant disability and cardiometabolic disease. The overall goal of this project is to identify novel targets for the treatment of long COVID including mitigating the risk of incident cardiovascular disease.Study registrationclinicaltrials.gov (MOIST late cross-sectional study; NCT04525404).

People with intellectual and developmental disabilities sometimes engage in challenging behaviours. When behaviours escalate to the point where they pose imminent risk to the safety of people and environments, a crisis occurs that jeopardises community living and participation. In these situations, timely access to crisis stabilisation services is required. We conducted a systematic review of the literature to synthesise evidence on effective crisis stabilisation service models for challenging behaviours. A total of 46 publications met the inclusion criteria. The literature describes a spectrum of crisis stabilisation services of varying intensities including: outreach, outpatient, inpatient, respite, and capacity building through education and training. However, there is limited guidance on how to best structure service models. This review highlights the need for comprehensive and person-centred programme evaluations.

Background: Evidence from network meta-analyses (NMAs) and real-world propensity score (PS) analyses suggest monoclonal antibodies (mAbs) offer a therapeutic advantage over currently available oral therapies and, therefore, warrant consideration as a distinct group of high-efficacy disease-modifying therapies (DMTs) for patients with relapsing multiple sclerosis (RMS). This is counter to the current perception of these therapies by some stakeholders, including payers. Objectives: A multifaceted indirect treatment comparison (ITC) approach was undertaken to clarify the relative efficacy of mAbs and oral therapies. Design: Two ITC methods that use individual patient data (IPD) to adjust for between-trial differences, PS analyses and simulated treatment comparisons (STCs), were used to compare the mAb ofatumumab versus the oral therapies cladribine, fingolimod, and ozanimod. Data sources and methods: As IPD were available for trials of ofatumumab and fingolimod, PS analyses were conducted. Given summary-level data were available for cladribine, fingolimod, and ozanimod trials, STCs were conducted between ofatumumab and each of these oral therapies. Three efficacy outcomes were compared: annualized relapse rate (ARR), 3-month confirmed disability progression (3mCDP), and 6-month CDP (6mCDP). Results: The PS analyses demonstrated ofatumumab was statistically superior to fingolimod for ARR and time to 3mCDP but not time to 6mCDP. In STCs, ofatumumab was statistically superior in reducing ARR and decreasing the proportion of patients with 3mCDP compared with cladribine, fingolimod, and ozanimod and in decreasing the proportion with 6mCP compared with fingolimod and ozanimod. These findings were largely consistent with recently published NMAs that identified mAb therapies as the most efficacious DMTs for RMS. Conclusion: Complementary ITC methods showed ofatumumab was superior to cladribine, fingolimod, and ozanimod in lowering relapse rates and delaying disability progression among patients with RMS. Our study supports the therapeutic superiority of mAbs over currently available oral DMTs for RMS and the delineation of mAbs as high-efficacy therapies.

Plant pathogens secrete proteins, known as effectors, that function in the apoplast or inside plant cells to promote virulence. Effector recognition by cell-surface or cytosolic receptors results in the activation of defence pathways and plant immunity. Despite their importance, our general understanding of fungal effector function and recognition by immunity receptors remains poor. One complication often associated with effectors is their high sequence diversity and lack of identifiable sequence motifs precluding prediction of structure or function. In recent years, several studies have demonstrated that fungal effectors can be grouped into structural classes, despite significant sequence variation and existence across taxonomic groups. Using protein X-ray crystallography, we identify a new structural class of effectors hidden within the secreted in xylem (SIX) effectors from Fusarium oxysporum f. sp. lycopersici (Fol). The recognised effectors Avr1 (SIX4) and Avr3 (SIX1) represent the founding members of the Fol dual-domain (FOLD) effector class, with members containing two distinct domains. Using AlphaFold2, we predicted the full SIX effector repertoire of Fol and show that SIX6 and SIX13 are also FOLD effectors, which we validated experimentally for SIX6. Based on structural prediction and comparisons, we show that FOLD effectors are present within three divisions of fungi and are expanded in pathogens and symbionts. Further structural comparisons demonstrate that Fol secretes effectors that adopt a limited number of structural folds during infection of tomato. This analysis also revealed a structural relationship between transcriptionally co-regulated effector pairs. We make use of the Avr1 structure to understand its recognition by the I receptor, which leads to disease resistance in tomato. This study represents an important advance in our understanding of Fol-tomato, and by extension plant–fungal interactions, which will assist in the development of novel control and engineering strategies to combat plant pathogens.

IntroductionResearch suggests that general practice can play an important role in managing long COVID. However, studies investigating the perspectives of general practitioners (GPs) and patients are lacking and knowledge regarding optimal long COVID care in general practice is therefore limited.AimTo investigate GPs' and patients' perspectives on the topic of long COVID and its management in general practice.MethodsBrief questionnaires (GP n = 11, Patient n = 7) and in-depth semi-structured interviews (GP n = 10, Patient n = 7) were conducted with GPs and patients from Irish general practices during July 2022-January 2023. Interviews were conducted via telephone and audio recordings were transcribed. A phenomenological analysis involving reflexive thematic analysis and constant comparison techniques was adopted.ResultsAnalysis of interviews with GPs (male = 7, female = 3; median age = 50yrs (IQR = 39.5-56)) and patients (males = 2, female = 5; median age = 58yrs (IQR = 45-62yrs) generated four themes. These were (1) Complex presentations (2) the value of standardising care, (3) choosing the right path, and (4) supportive and collaborative doctor-patient relationships. Strong agreement was observed among GPs and patients regarding the need for holistic and integrated multidisciplinary care. Supportive and collaborative doctor-patient relationships were largely well received by GPs and patients also. GPs strongly endorsed standardising long COVID care operations.ConclusionGPs and patients indicated that structured, integrated, and collaborative care can help optimise long COVID management in general practice. GPs are advised to incorporate these elements into their long COVID care practices going forward. Future research examining stakeholder's perspectives using larger and longitudinal samples is advised to enhance the generalisability of evidence in this area.

BackgroundTreatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods.ObjectiveThe objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry.MethodsIn this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect.ResultsEvery one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07–1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08–1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48–2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79–8.41; reference = 1996–2006).ConclusionSwitching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices.

Abstract Background There is reported to be a decline in immune function and an alteration in the frequency of circulating lymphocytes with advancing age. There are also differences in ageing and lifespan between males and females. We performed this study to see if there were differences between males and females in the frequency of the different lymphocyte subsets with age. Results Using flow cytometry we have examined different populations of peripheral blood leukocytes purified from healthy subjects with age ranging from the third to the tenth decade. We used linear regression analysis to determine if there is a linear relationship between age and cell frequencies. For the whole group, we find that with age there is a significant decline in the percentage of naïve T cells and CD8+ T cells, and an increase in the percentage of effector memory cells, CD4+foxp3+ T cells and NK cells. For all cells where there was an effect of ageing, the slope of the curve was greater for men than for women and this was statistically significant for CD8+αβ+ T cells and CD3+CD45RA-CCR7- effector memory cells. There was also a difference for naïve cells but this was not significant. Conclusion The cause of the change in percentage of lymphocyte subsets with age, and the different effects on males and females is not fully understood but warrants further study.

Preserving natural genetic diversity and ecological function of wild species is a central goal in conservation biology. As such, anthropogenic hybridization is considered a threat to wild populations, as it can lead to changes in the genetic makeup of wild species and even to the extinction of wild genomes. In European wildcats, the genetic and ecological impacts of gene flow from domestic cats are mostly unknown at the species scale. However, in small and isolated populations, it is known to include genetic swamping of wild genomes. In this context, it is crucial to better understand the dynamics of hybridization across the species range, to inform and implement management measures that maintain the genetic diversity and integrity of the European wildcat. In the present paper, we aim to provide an overview of the current scientific understanding of anthropogenic hybridization in European wildcats, to clarify important aspects regarding the evaluation of hybridization given the available methodologies, and to propose guidelines for management and research priorities.

Abstract Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer‐related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry‐based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p‐cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2 = 53.183, p

Background: Spinal cord lesions in multiple sclerosis (MS) have considerable impact on disability. High-efficacy disease-modifying treatments (hDMTs) are associated with greater reduction of relapses and new brain lesions compared to low-efficacy treatments (lDMTs). Knowledge on the impact of DMTs on cord lesion formation is limited as these outcome measures were not included in MS treatment trials. This study aims to investigate whether hDMTs reduce the formation of cord lesions more effectively than lDMTs. Methods: Patients with relapse-onset MS, a cord magnetic resonance imaging (MRI) within 6 months before/after initiation of their first DMT and ≥1 cord MRI at follow-up (interval > 6 months) were extracted from the MSBase registry (ACTRN12605000455662). Patients treated with hDMTs ≥90% or lDMTs ≥90% of follow-up duration were considered the hDMT and lDMT groups, respectively. Matching was performed using propensity scores. Cox proportional hazards models were used to estimate the hazards of new cord lesions, brain lesions and relapses. Results: Ninety-four and 783 satisfied hDMT and lDMT group criteria, respectively. Seventy-seven hDMT patients were matched to 184 lDMT patients. In the hDMT group there was no evidence of reduction of new cord lesions (hazard ratio [HR] 0.99 [95% CI 0.51, 1.92], p = 0.97), while there were fewer new brain lesions (HR 0.22 [95% CI 0.10, 0.49], p < 0.001) and fewer relapses (HR 0.45 [95% CI 0.28, 0.72], p = 0.004). Conclusion: A potential discrepancy exists in the effect of hDMTs over lDMTs in preventing spinal cord lesions versus brain lesions and relapses. While hDMTs provided a significant reduction for the latter when compared to lDMTs, there was no significant reduction in new spinal cord lesions. [ABSTRACT FROM AUTHOR]

BackgroundThere is an increased need for home-based, self-managed, and low maintenance stroke rehabilitation as well as interest in targeting the arm, which often lags behind leg recovery. Previous reviews have not controlled for concurrent standard of care and the ratio of self-managed care to therapist input.ObjectivesTo determine the effectiveness of home-based, self-managed and low maintenance programs for upper-limb motor recovery in individuals after stroke. A secondary objective explored the adherence to home-based self-managed programs.Data sourcesWe searched PubMed (1809-present), Embase (embase.com, 1974-present), Cochrane CENTRAL Register of Controlled Trials (Wiley), CINAHL (EBSCOhost, 1937-present), Physiotherapy Evidence Database (pedro.org.au), OTseeker (otseeker.com), and REHABDATA (National Rehabilitation Information Center). All searches were completed on June 9, 2022. Bibliographic references of included articles also were searched.Eligibility criteriaRandomized controlled trials (RCT) in adults after stroke, where both intervention and control were home-based, at least 75% self-managed and did not involve concurrent therapy as a confounding factor. Primary outcome was performance in functional motor activities after training. Secondary outcome was sensorimotor impairment. All outcomes after a retention period were also considered secondary outcomes.Data collection and analysisTwo review authors independently screened titles/abstracts, three review authors screened full papers and extracted data, and two review authors undertook assessment of risk of bias (i.e., allocation bias, measurement bias, confounding factors) using the NHLBI Study Quality Assessment Tool.Main resultsWe identified seven heterogenous studies, including five with fair to good quality. All studies had an alternative treatment, dose-equivalent control. Only one trial reported a positive, sustained, between-group effect on activity for the experimental group. The remaining studies reported seven interventions having a within-group training effect with three interventions having sustained effects at follow up. One study reported a between group effect on an impairment measure with no follow-up. Overall adherence rates were high, but three studies reported differential group rates. Compliance with daily logs was higher when the logs were collected on a weekly basis.LimitationsBy excluding studies that allowed concurrent therapy, we likely minimized the number of studies that included participants in the early sub-acute post-stroke stage. By focusing on RCTs, we are unable to comment on other potentially promising home-based, self-managed single cohort programs. By including only published and English language studies, we may have included publication bias.Conclusions and implicationsThere is some evidence that a variety of home-based, self-managed training program can be beneficial after stroke. Future research could compare such programs with natural history controls. Clinicians might utilize home exercise programs with explicit directions and some form of weekly contact to aid compliance.

BackgroundDirect access to diagnostic imaging in General Practice provides an avenue to reduce referrals to hospital-based specialities and emergency departments, and to ensure timely diagnosis. Enhanced GP access to radiology imaging could potentially reduce hospital referrals, hospital admissions, enhance patient care, and improve disease outcomes. This scoping review aims to demonstrate the value of direct access to diagnostic imaging in General Practice and how it has impacted on healthcare delivery and patient care.MethodsA search was conducted of 'PubMed', 'Cochrane Library', 'Embase' and 'Google Scholar' for papers published between 2012-2022 using Arksey and O'Malley's scoping review framework. The search process was guided by the PRISMA extension for Scoping Reviews checklist (PRISMA-ScR).ResultsTwenty-three papers were included. The studies spanned numerous geographical locations (most commonly UK, Denmark, and Netherlands), encompassing several study designs (most commonly cohort studies, randomised controlled trials and observational studies), and a range of populations and sample sizes. Key outcomes reported included the level of access to imaging serves, the feasibility and cost effectiveness of direct access interventions, GP and patient satisfaction with direct access initiatives, and intervention related scan waiting times and referral process.ConclusionDirect access to imaging for GPs can have many benefits for healthcare service delivery, patient care, and the wider healthcare ecosystem. GP focused direct access initiatives should therefore be considered as a desirable and viable health policy directive. Further research is needed to more closely examine the impacts that access to imaging studies have on health system operations, especially those in General Practice. Research examining the impacts of access to multiple imaging modalities is also warranted.

Recessive pathogenic variants in the laminin subunit alpha 2 (LAMA2) gene cause a spectrum of disease ranging from severe congenital muscular dystrophy to later-onset limb girdle muscular dystrophy (LGMDR23). The phenotype of LGMDR23 is characterized by slowly progressive proximal limb weakness, contractures, raised creatine kinase, and sometimes distinctive cerebral white matter changes and/or epilepsy. We present two siblings, born to consanguineous parents, who developed adult-onset LGMDR23 associated with typical cerebral white matter changes and who both later developed dementia. The male proband also had epilepsy and upper motor neuron signs when he presented at age 72. Merosin immunohistochemistry and Western blot on muscle biopsies taken from both subjects was normal. Whole exome sequencing revealed a previously unreported homozygous missense variant in LAMA2 [Chr6(GRCh38):g.129297734G>A; NM_000426.3:c.2906G>A; p.(Cys969Tyr)] in the proband. The same homozygous LAMA2 variant was confirmed by Sanger sequencing in the proband's affected sister. These findings expand the genotypic and phenotypic spectrum of LGMDR23.

The DES gene encodes desmin, a key intermediate filament of skeletal, cardiac and smooth muscle. Pathogenic DES variants produce a range of skeletal and cardiac muscle disorders collectively known as the desminopathies. We report three desminopathy cases which highlight the phenotypic heterogeneity of this disorder and discuss various factors that may contribute to the clinical differences seen between patients with different desmin variants and also between family members with the same variant.