Predictors of Shoulder Pain and Disability Index (SPADI) and work status after 1 year in patients with subacromial shoulder pain

<p>Abstract</p> <p>Background</p> <p>Shoulder pain is a common complaint in primary health care and has an unfavourable outcome in many patients. The objectives were to identify predictors for pain and disability (SPADI) and work status in patients with subacromial shoulder pain.</p> <p>Methods</p> <p>Secondary analyses of data from a randomized clinical controlled trial were performed. Outcome measures were the absolute values of the combined Shoulder Pain and Disability Index (SPADI) and work status 1 year after treatment with supervised exercises (SE) or radial extracorporeal shockwave therapy (rESWT). Predictors of outcome were investigated using multiple linear regression (SPADI) and logistic regression (work status).</p> <p>Results</p> <p>104 patients were included. Low education (≤ 12 years), previous shoulder pain, and a high baseline SPADI score predicted poor results with these variables explaining 29.9% of the variance in SPADI score at 1 year. Low education and poor self-reported health status predicted a work status of "not working": Odds Ratio, OR = 4.3(95% CI (1.3 to 14.9)), p = 0.02 for education, and OR = 1.06 (95% CI (1.0 to 1.1)), p = 0.001 for self-reported health status, respectively. Adjustments for age, gender, and treatment group were performed, but did not change the results.</p> <p>Conclusion</p> <p>Education was the most consistent predictor of pain and disability, and work status at 1 year follow-up. Also, baseline SPADI score, previous shoulder pain and self-reported health status predicted outcome.</p> <p>Trial registration</p> <p>Clinical trials NCT00653081</p

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

A multi-platform approach to identify a blood-based host protein signature for distinguishing between bacterial and viral infections in febrile children (PERFORM): a multi-cohort machine learning study

BACKGROUND: Differentiating between self-resolving viral infections and bacterial infections in children who are febrile is a common challenge, causing difficulties in identifying which individuals require antibiotics. Studying the host response to infection can provide useful insights and can lead to the identification of biomarkers of infection with diagnostic potential. This study aimed to identify host protein biomarkers for future development into an accurate, rapid point-of-care test that can distinguish between bacterial and viral infections, by recruiting children presenting to health-care settings with fever or a history of fever in the previous 72 h. METHODS: In this multi-cohort machine learning study, patient data were taken from EUCLIDS, the Swiss Pediatric Sepsis study, the GENDRES study, and the PERFORM study, which were all based in Europe. We generated three high-dimensional proteomic datasets (SomaScan and two via liquid chromatography tandem mass spectrometry, referred to as MS-A and MS-B) using targeted and untargeted platforms (SomaScan and liquid chromatography mass spectrometry). Protein biomarkers were then shortlisted using differential abundance analysis, feature selection using forward selection-partial least squares (FS-PLS; 100 iterations), along with a literature search. Identified proteins were tested with Luminex and ELISA and iterative FS-PLS was done again (25 iterations) on the Luminex results alone, and the Luminex and ELISA results together. A sparse protein signature for distinguishing between bacterial and viral infections was identified from the selected proteins. The performance of this signature was finally tested using Luminex assays and by calculating disease risk scores. FINDINGS: 376 children provided serum or plasma samples for use in the discovery of protein biomarkers. 79 serum samples were collected for the generation of the SomaScan dataset, 147 plasma samples for the MS-A dataset, and 150 plasma samples for the MS-B dataset. Differential abundance analysis, and the first round of feature selection using FS-PLS identified 35 protein biomarker candidates, of which 13 had commercial ELISA or Luminex tests available. 16 proteins with ELISA or Luminex tests available were identified by literature review. Further evaluation via Luminex and ELISA and the second round of feature selection using FS-PLS revealed a six-protein signature: three of the included proteins are elevated in bacterial infections (SELE, NGAL, and IFN-γ), and three are elevated in viral infections (IL18, NCAM1, and LG3BP). Performance testing of the signature using Luminex assays revealed area under the receiver operating characteristic curve values between 89·4% and 93·6%. INTERPRETATION: This study has led to the identification of a protein signature that could be ultimately developed into a blood-based point-of-care diagnostic test for rapidly diagnosing bacterial and viral infections in febrile children. Such a test has the potential to greatly improve care of children who are febrile, ensuring that the correct individuals receive antibiotics. FUNDING: European Union's Horizon 2020 research and innovation programme, the European Union's Seventh Framework Programme (EUCLIDS), Imperial Biomedical Research Centre of the National Institute for Health Research, the Wellcome Trust and Medical Research Foundation, Instituto de Salud Carlos III, Consorcio Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Grupos de Refeencia Competitiva, Swiss State Secretariat for Education, Research and Innovation

Kinesiophobia in patients with non-traumatic arm, neck and shoulder complaints: a prospective cohort study in general practice

BACKGROUND: Complaints of arm, neck and shoulder are common in Western societies. Of those consulting a general practitioner (GP) with non-traumatic arm, neck or shoulder complaints, about 50% do not recover within 6 months.Kinesiophobia (also known as fear of movement/(re)injury) may also play a role in these complaints, as it may lead to avoidance behaviour resulting in hypervigilance to bodily sensations, followed by disability, disuse and depression. However, in relation to arm, neck and shoulder complaints little is known about kinesiophobia and its associated variables.Therefore this study aimed to: describe the degree of kinesiophobia in patients with non-traumatic complaints of arm, neck and shoulder in general practice; to determine whether mean scores of kinesiophobia change over time in non-recovered patients; and to evaluate variables associated with kinesiophobia at baseline. METHODS: In this prospective cohort study set in general practice, consulters with a first or new episode of non-traumatic arm, neck or shoulder complaints (aged 18-64 years) entered the cohort. Baseline data were collected on kinesiophobia using the Tampa Scale for Kinesiophobia, the 13-item adjusted version: TSK-AV, and on patient-, complaint-, and psychosocial variables using self-administered questionnaires. The mean TSK-AV score was calculated. In non-recovered patients the follow-up TSK-AV scores at 6 and 12 months were analyzed with the general linear mixed model. Variables associated with kinesiophobia at baseline were evaluated using multivariate linear regression analyses. RESULTS: The mean TSK-AV score at baseline was 24.8 [SD: 6.2]. Among non-recovered patients the mean TSK-AV score at baseline was 26.1 [SD: 6.6], which remained unchanged over 12- months follow-up period. The strongest associations with kinesiophobia were catastrophizing, disability, and comorbidity of musculoskeletal complaints. Additionally, having a shoulder complaint, low social support, high somatization and high distress contributed to the kinesiophobia score. CONCLUSION: The mean TSK-AV score in our population seems comparable to those in other populations in primary care.In patients who did not recover during the 12- month follow-up, the degree of kinesiophobia remained unchanged during this time period.The variables associated with kinesiophobia at baseline appear to be in line with the fear-avoidance model

Loss of function NFKB1 variants are the most common monogenic cause of CVID in Europeans

BACKGROUND: The genetic etiology of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR-BioResource - Rare Disease cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n=846), a novel Bayesian method identified NFKB1 as one most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n=390) in the cohort. Amino-acid substitutions predicted to be pathogenic were assessed by analysis of structural protein data. Immunophenotyping, immunoblotting and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype co-segregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the non-infective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%) and autoimmune disease (48%), features prior studies correlate with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B lymphocyte differentiation. Detailed assessment of B lymphocyte numbers, phenotype and function identifies the presence of a raised CD21lowB cell population: combined with identification of the disease-causing variant, this distinguishes between healthy individuals, asymptomatic carriers and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID that results in a temporally progressive defect in the formation of immunoglobulin-producing B cells

Disequilibrium, adaptation and the Norse settlement of Greenland

This research was supported by the University of Edinburgh ExEDE Doctoral Training Studentship and NSF grant numbers 1202692 and 1140106.There is increasing evidence to suggest that arctic cultures and ecosystems have followed non-linear responses to climate change. Norse Scandinavian farmers introduced agriculture to sub-arctic Greenland in the late tenth century, creating synanthropic landscapes and utilising seasonally abundant marine and terrestrial resources. Using a niche-construction framework and data from recent survey work, studies of diet, and regional-scale climate proxies we examine the potential mismatch between this imported agricultural niche and the constraints of the environment from the tenth to the fifteenth centuries. We argue that landscape modification conformed the Norse to a Scandinavian style of agriculture throughout settlement, structuring and limiting the efficacy of seasonal hunting strategies. Recent climate data provide evidence of sustained cooling from the mid thirteenth century and climate variation from the early fifteenth century. Archaeological evidence suggests that the Norse made incremental adjustments to the changing sub-arctic environment, but were limited by cultural adaptations made in past environments.Publisher PDFPeer reviewe