Outcome measures in post-stroke arm rehabilitation trials: do existing measures capture outcomes that are important to stroke survivors, carers, and clinicians?

Objective: We sought to (1) identify the outcome measures currently used across stroke arm rehabilitation randomized trials, (2) identify and compare outcomes important to stroke survivors, carers and clinicians and (3) describe where existing research outcome measures capture outcomes that matter the most to stroke survivors, carers and clinicians and where there may be discrepancies. Methods: First, we systematically identified and extracted data on outcome measures used in trials within a Cochrane overview of arm rehabilitation interventions. Second, we conducted 16 focus groups with stroke survivors, carers and clinicians using nominal group technique, supplemented with eight semi-structured interviews, to identify these stakeholders’ most important outcomes following post-stroke arm impairment. Finally, we described the constructs of each outcome measure and indicated where stakeholders’ important outcomes were captured by each measure. Results: We extracted 144 outcome measures from 243 post-stroke arm rehabilitation trials. The Fugl-Meyer Assessment Upper Extremity section (used in 79/243 trials; 33%), Action Research Arm Test (56/243; 23%), and modified Ashworth Scale (53/243; 22%) were most frequently used. Stroke survivors (n = 43), carers (n = 10) and clinicians (n = 58) identified 66 unique, important outcomes related to arm impairment following stroke. Between one and three outcomes considered important by the stakeholders were captured by the three most commonly used assessments in research. Conclusion: Post-stroke arm rehabilitation research would benefit from a reduction in the number of outcome measures currently used, and better alignment between what is measured and what is important to stroke survivors, carers and clinicians

A Resource of Quantitative Functional Annotation for Homo sapiens Genes

The body of human genomic and proteomic evidence continues to grow at ever-increasing rates, while annotation efforts struggle to keep pace. A surprisingly small fraction of human genes have clear, documented associations with specific functions, and new functions continue to be found for characterized genes. Here we assembled an integrated collection of diverse genomic and proteomic data for 21,341 human genes and make quantitative associations of each to 4333 Gene Ontology terms. We combined guilt-by-profiling and guilt-by-association approaches to exploit features unique to the data types. Performance was evaluated by cross-validation, prospective validation, and by manual evaluation with the biological literature. Functional-linkage networks were also constructed, and their utility was demonstrated by identifying candidate genes related to a glioma FLN using a seed network from genome-wide association studies. Our annotations are presented—alongside existing validated annotations—in a publicly accessible and searchable web interface

What attributions do Australian high-performing general practices make for their success? Applying the clinical microsystems framework: a qualitative study

No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/Objectives To identify the success attributions of high-performing Australian general practices and the enablers and barriers they envisage for practices wishing to emulate them. Design Qualitative study using semi-structured interviews and content analysis of the data. Responses were recorded, transcribed verbatim and coded according to success characteristics of high-performing clinical microsystems. Setting Primary healthcare with the participating general practices representing all Australian states and territories, and representing metropolitan and rural locations. Participants Twenty-two general practices identified as high performing via a number of success criteria. The 52 participants were 19 general practitioners, 18 practice managers and 15 practice nurses. Results Participants most frequently attributed success to the interdependence of the team members, patient-focused care and leadership of the practice. They most often signalled practice leadership, team interdependence and staff focus as enablers that other organisations would need to emulate their success. They most frequently identified barriers that might be encountered in the form of potential deficits or limitations in practice leadership, staff focus and mesosystem support. Conclusions Practice leaders need to empower their teams to take action through providing inclusive leadership that facilitates team interdependence. Mesosystem support for quality improvement in general practice should focus on enabling this leadership and team building, thereby ensuring improvement efforts are converted into effective healthcare provision.The research reported in this article was funded by a grant from the Australian Government Department of Health

Developing a cluster-based approach for deciphering complexity in individuals with neurodevelopmental differences

ObjectiveIndividuals with neurodevelopmental disorders such as global developmental delay (GDD) present both genotypic and phenotypic heterogeneity. This diversity has hampered developing of targeted interventions given the relative rarity of each individual genetic etiology. Novel approaches to clinical trials where distinct, but related diseases can be treated by a common drug, known as basket trials, which have shown benefits in oncology but have yet to be used in GDD. Nonetheless, it remains unclear how individuals with GDD could be clustered. Here, we assess two different approaches: agglomerative and divisive clustering.MethodsUsing the largest cohort of individuals with GDD, which is the Deciphering Developmental Disorders (DDD), characterized using a systematic approach, we extracted genotypic and phenotypic information from 6,588 individuals with GDD. We then used a k-means clustering (divisive) and hierarchical agglomerative clustering (HAC) to identify subgroups of individuals. Next, we extracted gene network and molecular function information with regard to the clusters identified by each approach.ResultsHAC based on phenotypes identified in individuals with GDD revealed 16 clusters, each presenting with one dominant phenotype displayed by most individuals in the cluster, along with other minor phenotypes. Among the most common phenotypes reported were delayed speech, absent speech, and seizure. Interestingly, each phenotypic cluster molecularly included several (3–12) gene sub-networks of more closely related genes with diverse molecular function. k-means clustering also segregated individuals harboring those phenotypes, but the genetic pathways identified were different from the ones identified from HAC.ConclusionOur study illustrates how divisive (k-means) and agglomerative clustering can be used in order to group individuals with GDD for future basket trials. Moreover, the result of our analysis suggests that phenotypic clusters should be subdivided into molecular sub-networks for an increased likelihood of successful treatment. Finally, a combination of both agglomerative and divisive clustering may be required for developing of a comprehensive treatment

The NEMP family supports metazoan fertility and nuclear envelope stiffness.

Human genome-wide association studies have linked single-nucleotide polymorphisms (SNPs) in NEMP1 (nuclear envelope membrane protein 1) with early menopause; however, it is unclear whether NEMP1 has any role in fertility. We show that whole-animal loss of NEMP1 homologs in Drosophila, Caenorhabditis elegans, zebrafish, and mice leads to sterility or early loss of fertility. Loss of Nemp leads to nuclear shaping defects, most prominently in the germ line. Biochemical, biophysical, and genetic studies reveal that NEMP proteins support the mechanical stiffness of the germline nuclear envelope via formation of a NEMP-EMERIN complex. These data indicate that the germline nuclear envelope has specialized mechanical properties and that NEMP proteins play essential and conserved roles in fertility

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression

Ventilatory muscle strength, diaphragm thickness and pulmonary function in world-class powerlifters.

Resistance training activates the ventilatory muscles providing a stimulus similar to ventilatory muscle training. We examined the effects of elite powerlifting training upon ventilatory muscle strength, pulmonary function and diaphragm thickness in world-class powerlifters (POWER) and a control group (CON) with no history of endurance or resistance training, matched for age, height and body mass

Partial Regulatory T Cell Depletion Prior to Acute Feline Immunodeficiency Virus Infection Does Not Alter Disease Pathogenesis

Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4+CD25hiFoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4+ T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection

Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage

Hypoxanthine catabolism in vivo is potentially dangerous as it fuels production of urate and, most importantly, hydrogen peroxide. However, it is unclear whether accumulation of intracellular and supernatant hypoxanthine in stored red blood cell units is clinically relevant for transfused recipients. Leukoreduced red blood cells from glucose-6-phosphate dehydrogenase-normal or -deficient human volunteers were stored in AS-3 under normoxic, hyperoxic, or hypoxic conditions (with oxygen saturation ranging from 95%). Red blood cells from healthy human volunteers were also collected at sea level or after 1–7 days at high altitude (>5000 m). Finally, C57BL/6J mouse red blood cells were incubated in vitro with 13C1-aspartate or 13C5-adenosine under normoxic or hypoxic conditions, with or without deoxycoformycin, a purine deaminase inhibitor. Metabolomics analyses were performed on human and mouse red blood cells stored for up to 42 or 14 days, respectively, and correlated with 24 h post-transfusion red blood cell recovery. Hypoxanthine increased in stored red blood cell units as a function of oxygen levels. Stored red blood cells from human glucose-6-phosphate dehydrogenase-deficient donors had higher levels of deaminated purines. Hypoxia in vitro and in vivo decreased purine oxidation and enhanced purine salvage reactions in human and mouse red blood cells, which was partly explained by decreased adenosine monophosphate deaminase activity. In addition, hypoxanthine levels negatively correlated with post-transfusion red blood cell recovery in mice and – preliminarily albeit significantly - in humans. In conclusion, hypoxanthine is an in vitro metabolic marker of the red blood cell storage lesion that negatively correlates with post-transfusion recovery in vivo. Storage-dependent hypoxanthine accumulation is ameliorated by hypoxia-induced decreases in purine deamination reaction rates