Increased frequency of circulating IL-21 producing Th-cells in patients with granulomatosis with polyangiitis (GPA).

INTRODUCTION: The present study aimed to explore a possible role for IL-21 producing Th-cells in the immunopathogenesis of granulomatosis with polyangiitis (GPA). METHODS: Peripheral blood from 42 GPA patients in remission and 29 age-matched healthy controls (HCs) were stimulated in vitro, and the frequencies of IL-21 producing Th-cells were determined by flow cytometry. Since Th17-cells produce a low level of IL-21, IL-17 was also included in the analysis. Given that IL-21 is a hallmark cytokine for T follicular helper cells (T(FH)), we next evaluated the expression of their key transcription factor BCL-6 by RT-PCR and flow cytometry. To investigate the effect of IL-21 on autoantibody-production, PBMCs from GPA patients were stimulated in vitro with BAFF/IL-21 and total IgG and ANCA levels were measured in supernatants. In addition, the expression of IL-21-receptor on B-cells was analyzed. RESULTS: Percentages of IL-21 producing Th-cells were significantly elevated in GPA-patients compared to HCs, and were restricted to ANCA-positive patients. The expression of BCL-6 was significantly higher in ANCA-positive GPA-patients, as compared with ANCA-negative patients and HCs. IL-21 enhanced the production of IgG and ANCA in vitro in stimulated PBMCs from GPA patients. No difference was found in the expression of the IL-21-receptor on B-cells between ANCA-negative patients, ANCA-positive patients, and HCs. CONCLUSION: The increased frequency of circulating IL-21 producing Th-cells in ANCA-positive GPA patients and the stimulating capacity of IL-21 on ANCA-production suggest a role for these cells in the immunopathogenesis of GPA. Blockade of IL-21 could constitute a new therapeutic strategy for GPA

Field procedures in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi‐component epidemiological and neurobiological study of unprecedented size and complexity designed to generate actionable evidence‐based recommendations to reduce US Army suicides and increase basic knowledge about determinants of suicidality by carrying out coordinated component studies. A number of major logistical challenges were faced in implementing these studies. The current report presents an overview of the approaches taken to meet these challenges, with a special focus on the field procedures used to implement the component studies. As detailed in the paper, these challenges were addressed at the onset of the initiative by establishing an Executive Committee, a Data Coordination Center (the Survey Research Center [SRC] at the University of Michigan), and study‐specific design and analysis teams that worked with staff on instrumentation and field procedures. SRC staff, in turn, worked with the Office of the Deputy Under Secretary of the Army (ODUSA) and local Army Points of Contact (POCs) to address logistical issues and facilitate data collection. These structures, coupled with careful fieldworker training, supervision, and piloting, contributed to the major Army STARRS data collection efforts having higher response rates than previous large‐scale studies of comparable military samples. Copyright © 2013 John Wiley & Sons, Ltd .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102238/1/mpr1400.pd

Response bias, weighting adjustments, and design effects in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi‐component epidemiological and neurobiological study designed to generate actionable recommendations to reduce US Army suicides and increase knowledge about determinants of suicidality. Three Army STARRS component studies are large‐scale surveys: one of new soldiers prior to beginning Basic Combat Training (BCT; n  = 50,765 completed self‐administered questionnaires); another of other soldiers exclusive of those in BCT ( n  = 35,372); and a third of three Brigade Combat Teams about to deploy to Afghanistan who are being followed multiple times after returning from deployment ( n  = 9421). Although the response rates in these surveys are quite good (72.0–90.8%), questions can be raised about sample biases in estimating prevalence of mental disorders and suicidality, the main outcomes of the surveys based on evidence that people in the general population with mental disorders are under‐represented in community surveys. This paper presents the results of analyses designed to determine whether such bias exists in the Army STARRS surveys and, if so, to develop weights to correct for these biases. Data are also presented on sample inefficiencies introduced by weighting and sample clustering and on analyses of the trade‐off between bias and efficiency in weight trimming. Copyright © 2013 John Wiley & Sons, Ltd .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102203/1/mpr1399.pd

RHYTHM-AF: design of an international registry on cardioversion of atrial fibrillation and characteristics of participating centers

BACKGROUND Atrial fibrillation is a serious public health problem posing a considerable burden to not only patients, but the healthcare environment due to high rates of morbidity, mortality, and medical resource utilization. There are limited data on the variation in treatment practice patterns across different countries, healthcare settings and the associated health outcomes. METHODS/DESIGN RHYTHM-AF was a prospective observational multinational study of management of recent onset atrial fibrillation patients considered for cardioversion designed to collect data on international treatment patterns and short term outcomes related to cardioversion. We present data collected in 10 countries between May 2010 and June 2011. Enrollment was ongoing in Italy and Brazil at the time of data analysis. Data were collected at the time of atrial fibrillation episode in all countries (Australia, Brazil, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom), and cumulative follow-up data were collected at day 60 (±10) in all but Spain. Information on center characteristics, enrollment data, patient demographics, detail of atrial fibrillation episode, medical history, diagnostic procedures, acute treatment of atrial fibrillation, discharge information and the follow-up data on major events and rehospitalizations up to day 60 were collected. DISCUSSIN A total of 3940 patients were enrolled from 175 acute care centers. 70.5% of the centers were either academic (44%) or teaching (26%) hospitals with an overall median capacity of 510 beds. The sites were mostly specialized with anticoagulation clinics (65.9%), heart failure (75.1%) and hypertension clinics (60.1%) available. The RHYTHM-AF registry will provide insight into regional variability of antiarrhythmic and antithrombotic treatment of atrial fibrillation, the appropriateness of such treatments with respect to outcomes, and their cost-efficacy. Observations will help inform strategies to improve cardiovascular outcomes in patients with atrial fibrillation. TRIAL REGISTRATION Clinical trials NCT01119716Harry JGM Crijns, Lori D Bash, François Chazelle, Jean-Yves Le Heuzey, Thorsten Lewalter, Gregory YH Lip, Aldo P Maggioni, Alfonso Martín, Piotr Ponikowski, Mårten Rosenqvist, Prashanthan Sanders, Mauricio Scanavacca, Alexandra A Bernhardt, Sreevalsa Unniachan, Hemant M Phatak and Anselm K Git

Design of the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

The Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) is a multi‐component epidemiological and neurobiological study designed to generate actionable evidence‐based recommendations to reduce US Army suicides and increase basic knowledge about the determinants of suicidality. This report presents an overview of the designs of the six components of the Army STARRS. These include: an integrated analysis of the Historical Administrative Data Study (HADS) designed to provide data on significant administrative predictors of suicides among the more than 1.6 million soldiers on active duty in 2004–2009; retrospective case‐control studies of suicide attempts and fatalities; separate large‐scale cross‐sectional studies of new soldiers (i.e. those just beginning Basic Combat Training [BCT], who completed self‐administered questionnaires [SAQs] and neurocognitive tests and provided blood samples) and soldiers exclusive of those in BCT (who completed SAQs); a pre‐post deployment study of soldiers in three Brigade Combat Teams about to deploy to Afghanistan (who completed SAQs and provided blood samples) followed multiple times after returning from deployment; and a platform for following up Army STARRS participants who have returned to civilian life. Department of Defense/Army administrative data records are linked with SAQ data to examine prospective associations between self‐reports and subsequent suicidality. The presentation closes with a discussion of the methodological advantages of cross‐component coordination. Copyright © 2013 John Wiley & Sons, Ltd .Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102177/1/mpr1401.pd

Afrikaans and Dutch as closely-related languages: A comparison to West Germanic languages and Dutch dialects

Following Den Besten‟s (2009) desiderata for historical linguistics of Afrikaans, this article aims to contribute some modern evidence to the debate regarding the founding dialects of Afrikaans. From an applied perspective (i.e. human language technology), we aim to determine which West Germanic language(s) and/or dialect(s)  would be best suited for the purposes of recycling speech resources for the benefit of developing speech  technologies for Afrikaans. Being recognised as a West Germanic language, Afrikaans is first compared to  Standard Dutch, Standard Frisian and Standard German. Pronunciation distances are measured by means of  Levenshtein distances. Afrikaans is found to be closest to Standard Dutch. Secondly, Afrikaans is compared to 361 Dutch dialectal varieties in the Netherlands and North-Belgium, using material from the Reeks  Nederlandse Dialectatlassen, a series of dialect atlases compiled by Blancquaert and Pée in the period  1925-1982 which cover the Dutch dialect area. Afrikaans is found to be closest to the South-Holland dialectal variety of Zoetermeer; this largely agrees with the findings of Kloeke (1950). No speech resources are  available for Zoetermeer, but such resources are available for Standard Dutch. Although the dialect of  Zoetermeer is significantly closer to Afrikaans than Standard Dutch is, Standard Dutch speech resources might be a good substitute.Keywords: human language technologies, speech resources, Afrikaans, Dutch, acoustic distanc

Clinical reappraisal of the Composite International Diagnostic Interview Screening Scales (CIDI‐SC) in the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS)

A clinical reappraisal study was carried out in conjunction with the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS) All‐Army Study (AAS) to evaluate concordance of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM‐IV) diagnoses based on the Composite International Diagnostic Interview Screening Scales (CIDI‐SC) and post‐traumatic stress disorder (PTSD) checklist (PCL) with diagnoses based on independent clinical reappraisal interviews (Structured Clinical Interview for DSM‐IV [SCID]). Diagnoses included: lifetime mania/hypomania, panic disorder, and intermittent explosive disorder; six‐month adult attention‐deficit/hyperactivity disorder; and 30‐day major depressive episode, generalized anxiety disorder, PTSD, and substance (alcohol or drug) use disorder (abuse or dependence). The sample ( n  = 460) was weighted for over‐sampling CIDI‐SC/PCL screened positives. Diagnostic thresholds were set to equalize false positives and false negatives. Good individual‐level concordance was found between CIDI‐SC/PCL and SCID diagnoses at these thresholds (area under curve [AUC] = 0.69–0.79). AUC was considerably higher for continuous than dichotomous screening scale scores (AUC = 0.80–0.90), arguing for substantive analyses using not only dichotomous case designations but also continuous measures of predicted probabilities of clinical diagnoses. Copyright © 2013 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102145/1/mpr1398.pd

Genetic loci of Staphylococcus aureus associated with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides

The proteinase 3 (PR3)-positive anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) granulomatosis with polyangiitis (GPA) has been associated with chronic nasal S. aureus carriage, which is a risk factor for disease relapse. The present study was aimed at comparing the genetic make-up of S. aureus isolates from PR3-ANCA-positive GPA patients with that of isolates from patients suffering from myeloperoxidase (MPO)-ANCA-positive AAV, and isolates from healthy controls. Based on a DNA microarray-based approach, we show that not only PR3-ANCA-positive GPA patients, but also MPO-ANCA-positive AAV patients mainly carried S. aureus types that are prevalent in the general population. Nonetheless, our data suggests that MPO-ANCA-associated S. aureus isolates may be distinct from healthy control- and PR3-ANCA-associated isolates. Furthermore, several genetic loci of S. aureus are associated with either PR3-ANCA- or MPO-ANCA-positive AAV, indicating a possible role for pore-forming toxins, such as leukocidins, in PR3-ANCA-positive GPA. Contrary to previous studies, no association between AAV and superantigens was detected. Our findings also show that a lowered humoral immune response to S. aureus is common for PR3-ANCA- and MPO-ANCA-positive AAV. Altogether, our observations imply that the presence or absence of particular virulence genes of S. aureus isolates from AAV patients contributes to disease progression and/or relapse

Lifetime Prevalence Of Dsm‐Iv Mental Disorders Among New Soldiers In The U.S. Army: Results From The Army Study To Assess Risk And Resilience In Servicemembers (Army Starrs)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110630/1/da22316.pd

Life stress and mental disorders in the South African stress and health study

Background. Although stressful life events (SLEs) are associated with psychopathology, the contribution from distal and proximal events and the specificity of their association with common mental disorders require further exploration. We examined the association of recent life events and past adversities to mood, anxiety, substance use and impulse control disorders in South Africa. Methods. Data were analysed from the South African Stress and Health study, a population-based study of mental disorders in a nationally representative sample of 4 351 adults. Psychiatric disorders were assessed with the Composite International Diagnostic Interview (CIDI). This included questions covering early and later SLEs (negative life events, relationship stress, partner violence, social strain and adverse events during childhood) and various sociodemographic variables. Logistic regression models were constructed for 3 957 respondents (2 371 female, 1 586 male) with no missing covariate data, to assess life stress and sociodemographic predictors of 12-month and lifetime disorder. Results. Recent negative life events and relationship problems were significant predictors of any 12-month disorder and any lifetime disorder. Physical partner violence predicted any lifetime disorder. There was evidence of specificity for the prediction of mood versus anxiety disorders, with childhood adversity specifically associated with mood disorders but not anxiety disorders. Single marital status was the strongest socio-demographic predictor of any 12-month and any lifetime disorder. Conclusions. Stressful life events, distal and proximal, contribute significantly and independently to the prediction of major psychiatric disorders among South Africans, underscoring the importance of screening adversities in adults with common mental disorders, and of providing appropriate adjunctive interventions