Prerandomization run-in periods in randomized controlled trials of chronic diseases: a methodological study.

OBJECTIVE: To systematically review the epidemiology of prerandomized run-in periods in randomized controlled trials (RCTs) of chronic diseases. STUDY DESIGN AND SETTING: Meta-epidemiologic study of all RCTs from the four highest impact medical journals from 2011 to 2016. Eligible trials included parallel RCTs that evaluated pharmacologic therapies in adults with chronic diseases with a minimum follow-up of 24 weeks. RESULTS: Of 262 eligible manuscripts, 48 (18.3%), representing 42 unique RCTs, included run-in periods. Run-in periods were most common in cardiovascular disease and diabetes trials. Of the 42 RCTs, in 22 patients received the experimental therapy, 15 placebo, 4 both (either sequentially or in combination), and one did not report the run-in period drug. The median run-in period duration was 28 days (Q1: Q3 14: 66 days). Reasons for including a run-in period included ensuring eligibility criteria were met (18, 42.9%), excluding participants with nonadherence (18, 42.9%) and intolerances to therapy (15, 35.7%), and to standardize therapy prior to randomization (8, 19.0%). The median run-in completion rate was 77.4% (Q1: Q3 62.2:87.8%). CONCLUSIONS: Run-in periods are uncommon in RCTs of chronic drug treatments and when used, their reporting is heterogeneous. Further research to improve the design, use, and reporting of run-in periods is necessary.

Screening questions for the diagnosis of restless legs syndrome in hemodialysis.

BACKGROUND: Restless legs syndrome (RLS) is common in end-stage renal disease and is associated with reduced health-related quality of life. Simple and accurate screening instruments are needed since RLS is underdiagnosed and treatable. We examined the operating characteristics of screening questions and a disease-specific measurement tool for the diagnosis of RLS in hemodialysis. METHODS: We conducted a cohort study of prevalent adult hemodialysis patients in Hamilton, Canada. The diagnosis of RLS was made using the 2012 Revised International Restless Legs Syndrome Study Group (IRLSSG) criteria. All participants received three screening instruments: (i) a single screening question for RLS derived from a nondialysis population; (ii) a single question from the Edmonton Symptom Assessment System (ESAS); and (iii) the IRLSSG Rating Scale (IRLS). All instruments were compared with the reference standard using logistic regression from which receiver operating characteristics curves were generated. Cutoffs associated with maximum performance were identified. RESULTS: We recruited 50 participants with a mean (SD) age of 64 (12.4) years, of whom 52% were male and 92% were on three times weekly hemodialysis. Using the reference standard, 14 (28%) had a diagnosis of RLS. The single screening question for RLS had an area under the receiver operating curve (AUROC) of 0.72 with a sensitivity of 85.7% and specificity of 58.3%. An ESAS cutoff of ≥1 had the highest AUROC at 0.65 with a sensitivity of 79% and specificity of 56%. An IRLS cutoff of ≥20 had the highest AUROC at 0.75 with a sensitivity of 71% and specificity of 81%. CONCLUSION: IRLS had better specificity than the single question or ESAS for the diagnosis of RLS.

Single Questions for the Screening of Anxiety and Depression in Hemodialysis.

BACKGROUND: Depression and anxiety are common and underrecognized in end-stage renal disease (ESRD), are associated with poor outcomes and reduced health-related quality of life, and are potentially treatable. Simple, accurate screening tools are needed. OBJECTIVE: We examined the operating characteristics of single questions for anxiety and depression from the Edmonton Symptom Assessment System (ESAS) in hemodialysis. DESIGN: Cross-sectional study. SETTING: Two outpatient hemodialysis units (1 tertiary, 1 community) in Hamilton, Canada. PATIENTS: Adult prevalent hemodialysis patients. MEASUREMENTS: ESAS and Hospital Anxiety and Depression Scale (HADS). METHODS: Participants were asked the degree to which they experienced anxiety and depression using the ESAS. ESAS single questions for anxiety and depression were compared with the reference standard of the HADS using dialysis population specific cutoffs (HADS anxiety subscale ≥6 and HADS depression subscale ≥7). Logistic regression was used to create receiver operating characteristics (ROC) curves. RESULTS: We recruited 50 participants with a mean age of 64 (SD = 12.4) years, of whom 52% were male and 96% were on ≥3× weekly hemodialysis. Using the reference standards, 28 (56%) had a diagnosis of anxiety and 27 (54%) had a diagnosis of depression. Areas under the ROC curves were 0.83 for anxiety and 0.81 for depression using ESAS scores of ≥2. LIMITATIONS: Sample size and the lack of a reference gold standard. CONCLUSIONS: The ESAS single questions for anxiety and depression have reasonable discrimination in a hemodialysis population. The use of more complex and time-consuming screening instruments could be reduced by adopting the ESAS questions for anxiety and depression in hemodialysis.

CONTEXTE: La dépression et l'anxiété sont fréquentes quoique peu reconnues chez les patients souffrant d'insuffisance rénale terminale (IRT). Ces troubles sont associés à une évolution défavorable de la maladie et à une diminution de la qualité de vie liée à l'état de santé. Cependant, ils sont potentiellement traitables. Des outils de détection simples et précis sont requis. OBJECTIF: Nous avons évalué la fonction d'efficacité de questions uniques sur l'anxiété et la dépression provenant du Système d'évaluation des symptômes d'Edmonton (ESAS) en contexte d'hémodialyse. TYPE D'ÉTUDE: Étude transversale. CADRE: Deux unités d'hémodialyse ambulatoire (une en soins tertiaires, une en milieu communautaire) à Hamilton, au Canada. SUJETS: Des patients adultes hémodialysés. MESURES: L'ESAS et l'Échelle d'anxiété et de dépression en milieu hospitalier (HADS). MÉTHODOLOGIE: Nous avons demandé aux participants, par l'entremise de l'ESAS, dans quelle mesure ils éprouvaient de l'anxiété et de la dépression. Les questions uniques de l'ESAS sur l'anxiété et la dépression ont été comparées à l'étalon de référence de la HADS en utilisant les seuils spécifiques à une population dialysée (sous-échelle de la HADS pour l'anxiété ≥ 6 et sous-échelle de la HADS pour la dépression ≥ 7). Une régression logistique a été utilisée pour établir les courbes de fonction d'efficacité de l'observateur (courbes ROC). RÉSULTATS: Nous avons recruté 50 patients (52 % d'hommes) âgés de 64 ans en moyenne (écart-type : 12,4 ans). La plupart des sujets (96 %) étaient dialysés au moins trois fois par semaine. Selon l'étalon de référence, 28 patients (56 %) vivaient de l'anxiété et 27 (54 %) souffraient de dépression. La surface sous la courbe ROC était de 0,83 pour l'anxiété et de 0,81 pour la dépression selon les scores ESAS ≥ 2. LIMITES: Le faible échantillon de sujets et le fait que l'étude ne comportait pas d'étalon-or. CONCLUSION: Les questions uniques de l'ESAS sur l'anxiété et la dépression ont discriminé adéquatement dans une population de patients hémodialysés. L'adoption du questionnaire ESAS sur l'anxiété et la dépression avec les patients hémodialysés pourrait limiter le recours à des outils de détection chronophages et complexes.

IgA Nephropathy.

IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

Normal human monocytes exposed to glioma cells acquire myeloid-derived suppressor cell-like properties.

Glioblastoma patients are immunosuppressed, yet glioblastomas are highly infiltrated by monocytes/macrophages. Myeloid-derived suppressor cells (MDSC; immunosuppressive myeloid cells including monocytes) have been identified in other cancers and correlate with tumor burden. We hypothesized that glioblastoma exposure causes normal monocytes to assume an MDSC-like phenotype and that MDSC are increased in glioblastoma patients. Healthy donor human CD14(+) monocytes were cultured with human glioblastoma cell lines. Controls were cultured alone or with normal human astrocytes. After 48 hours, glioblastoma-conditioned monocytes (GCM) were purified using magnetic beads. GCM cytokine and costimulatory molecular expression, phagocytic ability, and ability to induce apoptosis in activated lymphocytes were assessed. The frequency of MDSC was assessed by flow cytometry in glioma patients' blood and in GCM in vitro. As predicted, GCM have immunosuppressive, MDSC-like features, including reduced CD14 (but not CD11b) expression, increased immunosuppressive interleukin-10, transforming growth factor-beta, and B7-H1 expression, decreased phagocytic ability, and increased ability to induce apoptosis in activated lymphocytes. Direct contact between monocytes and glioblastoma cells is necessary for complete induction of these effects. In keeping with our hypothesis, glioblastoma patients have increased circulating MDSC compared with normal donors and MDSC are increased in glioma-conditioned monocytes in vitro. To our knowledge, this has not been reported previously. Although further study is needed to directly characterize their origin and function in glioblastoma patients, these results suggest that MDSC may be an important contributor to systemic immunosuppression and can be modeled in vitro by GCM.