HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry

OBJECTIVE: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry.

OBJECTIVE To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein

No alteration of back muscle oxygenation during isometric exercise in individuals with non-specific low back pain

The aim of our study was (I) To compare back muscle oxygenation and perfusion as well as Biering-Sorensen muscle endurance (BSME) test holding times between chronic non-specific low back pain (CNSLBP) patients and asymptomatic controls matched for age, body mass index (BMI), sex and physical activity, and (II) to investigate factors associated with BSME holding times. Muscle perfusion (tHb) and oxygenation (SmO2) were measured by near-infrared spectroscopy (NIRS) based oximetry in three back muscles during the BSME. Reliability of tHb and SmO2 was assessed in a separate sample. BSME holding time and SmO2 were compared between patients (n = 45) and controls (n = 45) and factors associated with BSME holding time were assessed using multiple linear regression. Reliability for SmO2 was excellent (ICC = 0.87-0.99). THb showed poor to moderate reliability and was not further used. Groups differed for BSME holding time (P = 0.03), pain intensity (P ≤ 0.0005) and subcutaneous tissue thickness (P = 0.01) but not for NIRS measures. Physical activity and BMI were associated with BSME holding times. Insufficient muscle oxygenation does not seem to be a major factor contributing to CNSLBP. Future investigation should evaluate other determinants of BSME holding times, such as motivation and recruitment of auxiliary muscles

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: A Gradient of Severity in Cognitive Impairments.

International audienceSHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Physicians' predictions of long-term survival and functional outcomes do not influence the decision to admit patients with advanced disease to intensive care: A prospective study

Background: Long-term survival and functional outcomes should influence admission decisions to intensive care, especially for patients with advanced disease. Aim: To determine whether physicians' predictions of long-term prognosis influenced admission decisions for patients with and without advanced disease. Design: A prospective study was conducted. Physicians estimated patient survival with intensive care and with care on the ward, and the probability of 4 long-term outcomes: leaving hospital alive, survival at 6 months, recovery of functional status, and recovery of cognitive status. Patient mortality at 28 days was recorded. We built multivariate logistic regression models using admission to the intensive care unit (ICU) as the dependent variable

Physicians' Views and Agreement about Patient- and Context-Related Factors Influencing ICU Admission Decisions: A Prospective Study

Background: Single patient- and context-related factors have been associated with admission decisions to intensive care. How physicians weigh various factors and integrate them into the decision-making process is not well known. Objectives: First, to determine which patient- and context-related factors influence admission decisions according to physicians, and their agreement about these determinants; and second, to examine whether there are differences for patients with and without advanced disease. Method: This study was conducted in one tertiary hospital. Consecutive ICU consultations for medical inpatients were prospectively included. Involved physicians, i.e., internists and intensivists, rated the importance of 13 factors for each decision on a Likert scale (1 = negligible to 5 = predominant). We cross-tabulated these factors by presence or absence of advanced disease and examined the degree of agreement between internists and intensivists using the kappa statistic. Results: Of 201 evaluated patients, 105 (52.2%) had an advanced disease, and 140 (69.7%) were admitted to intensive care. The mean number of important factors per decision was 3.5 (SD 2.4) for intensivists and 4.4 (SD 2.1) for internists. Patient's comorbidities, quality of life, preferences, and code status were most often mentioned. Inter-rater agreement was low for the whole population and after stratifying for patients with and without advanced disease. Kappa values ranged from 0.02 to 0.34 for all the patients, from −0.05 to 0.42 for patients with advanced disease, and from −0.08 to 0.32 for patients without advanced disease. The best agreement was found for family preferences. Conclusion: Poor agreement between physicians about patient- and context-related determinants of ICU admission suggests a lack of explicitness during the decision-making process. The potential consequences are increased variability and inequity regarding which patients are admitted. Timely advance care planning involving families could help physicians make the decision most concordant with patient preferences

Risk factor and symptoms of burnout in physiotherapists in the canton of Bern

Abstract Background Several studies have shown that the risk of burnout is high for people working in health professions. Many physiotherapists have either suffered from burn out personally or have seen colleagues suffer from it. In Switzerland, there is a lack of evidence concerning the risk factors and symptoms for burnout among physiotherapist. The aim of this study was to empirically identify risk factors and symptoms of burnout in physiotherapists working in the canton of Bern. Method Based on interview guidelines, three semi-structured interviews with physiotherapists who experienced burn out themselves were conducted. The questions were divided into two main categories: risk factors and symptoms. For analysis, the interviews were transcribed and assigned to individual categories. Results High personal expectations and the pressure that comes with working on patients with chronic complaints were the most common answers from the participants. In this study these factors can be considered as important risk factors. In particular, emotional exhaustion and depression seem to be relevant burnout symptoms which lead to a decrease in personal performance. Conclusion In this study physiotherapists with burn out working in an acute care hospital tend to suffer from symptoms of emotional exhaustion and depersonalization. For physiotherapists, sensitization to symptoms and risk factors of burnout is essential in daily work as well as in education. The results of this study might be of interest for physiotherapist or physiotherapists students to prevent and sensitive them for burnout symptoms

ICU physicians' and internists' survival predictions for patients evaluated for admission to the intensive care unit

Background: A higher chance of survival is a key justification for admission to the intensive care unit (ICU). This implies that physicians should be able to accurately estimate a patient's prognosis, whether cared for on the ward or in the ICU. We aimed to determine whether physicians' survival predictions correlate with the admission decisions and with patients' observed survival. Consecutive ICU consultations for internal medicine patients were included. The ICU physician and the internist were asked to predict patient survival with intensive care and with care on the ward using 5 categories of probabilities ( 90%). Patient mortality at 28 days was recorded. Results: Thirty ICU physicians and 97 internists assessed 201 patients for intensive care. Among the patients, 140 (69.7%) were admitted to the ICU. Fifty-eight (28.9%) died within 28 days. Admission to intensive care was associated with predicted survival gain in the ICU, particularly for survival estimates made by ICU physicians. Observed survival was associated with predicted survival, for both groups of physicians. The discrimination of the predictions for survival with intensive care, measured by the area under the ROC curve, was 0.63 for ICU physicians and 0.76 for internists; for survival on the ward the areas under the ROC curves were 0.69 and 0.74, respectively. Conclusions: Physicians are able to predict survival probabilities when they assess patients for intensive care, albeit imperfectly. Internists are more accurate than ICU physicians. However, ICU physicians' estimates more strongly influence the admission decision. Closer collaboration between ICU physicians and internists is needed