Citations

A large cohort consisting of all children born to mothers from community provides ‘natural’ selection into different exposures and is a powerful resource for epidemiological research. A large population-based birth cohort with detailed systematic information already recorded, as part of longitudinal medical care, historical and current school data, detailed birth certificate data and all three resources available for every member of the birth cohort, are extremely rare. Our population-based birth cohort consists of all children born between 1976 and 2000 to mothers residing in Olmsted County, Minnesota, at the time of child's birth (N=39 890). In this paper, we provide a comprehensive report of the method describing the identification, the characteristics and longitudinal follow-up of each child (and family members) from the birth cohort, wealth of complementary resources of data and study measures and designs (retrospective, combined retrospective/prospective). In the last decade or so, we obtained scientific and clinically needed answers for incidence rates, potential risk/protective factors, treatment, comorbidities, outcomes, cost/usage and potential biases (that are always assessed and clinically interpreted) of many developmental learning and behavioural disorders (DLBDs) including learning and attention-deficit/hyperactivity disorders, intellectual disability, speech-language impairment and autism spectrum disorder. Many current and future questions related to DLBDs are remaining to be answered. The Olmsted County Birth Cohort (OCBC) is an example of a comprehensive, contemporary epidemiological research model for the development of similar research infrastructures, and its current and future results are important for replication and comparison with other population-based retrospective and prospective birth cohort studies.

ObjectiveTo compare the efficacy of abatacept to that of placebo for the treatment of giant cell arteritis (GCA).MethodsIn this multicenter trial, patients with newly diagnosed or relapsing GCA were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double‐blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse‐free survival rate).ResultsForty‐nine eligible patients with GCA were enrolled and treated with prednisone and abatacept; of these, 41 reached the week 12 randomization and underwent a blinded randomization to receive abatacept or placebo. Prednisone was tapered using a standardized schedule, reaching a daily dosage of 20 mg at week 12 with discontinuation in all patients at week 28. The relapse‐free survival rate at 12 months was 48% for those receiving abatacept and 31% for those receiving placebo (P = 0.049). A longer median duration of remission was seen in those receiving abatacept compared to those receiving placebo (median duration 9.9 months versus 3.9 months; P = 0.023). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms.ConclusionIn patients with GCA, the addition of abatacept to a treatment regimen with prednisone reduced the risk of relapse and was not associated with a higher rate of toxicity compared to prednisone alone.

Objective To compare the efficacy of abatacept to that of placebo for the treatment of Takayasu arteritis (TAK). Methods In this multicenter trial, patients with newly diagnosed or relapsing TAK were treated with abatacept 10 mg/kg intravenously on days 1, 15, and 29 and week 8, together with prednisone administered daily. At week 12, patients in remission underwent a double‐blinded randomization to continue to receive abatacept monthly or switch to placebo. Patients in both study arms received a standardized prednisone taper, reaching a dosage of 20 mg daily at week 12, with discontinuation of prednisone at week 28. All patients remained on their randomized assignment until meeting criteria for early termination or until 12 months after enrollment of the last patient. The primary end point was duration of remission (relapse‐free survival). Results Thirty‐four eligible patients with TAK were enrolled and treated with prednisone and abatacept; of these, 26 reached the week 12 randomization and underwent a blinded randomization to receive either abatacept or placebo. The relapse‐free survival rate at 12 months was 22% for those receiving abatacept and 40% for those receiving placebo ( P = 0.853). Treatment with abatacept in patients with TAK enrolled in this study was not associated with a longer median duration of remission (median duration 5.5 months for abatacept versus 5.7 months for placebo). There was no difference in the frequency or severity of adverse events, including infection, between the treatment arms. Conclusion In patients with TAK, the addition of abatacept to a treatment regimen with prednisone did not reduce the risk of relapse.

Objective To identify risk alleles relevant to the causal and biologic mechanisms of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods A genome‐wide association study and subsequent replication study were conducted in a total cohort of 1,986 cases of AAV (patients with granulomatosis with polyangiitis [Wegener's] [GPA] or microscopic polyangiitis [MPA]) and 4,723 healthy controls. Meta‐analysis of these data sets and functional annotation of identified risk loci were performed, and candidate disease variants with unknown functional effects were investigated for their impact on gene expression and/or protein function. Results Among the genome‐wide significant associations identified, the largest effect on risk of AAV came from the single‐nucleotide polymorphism variants rs141530233 and rs1042169 at the HLA–DPB1 locus (odds ratio [OR] 2.99 and OR 2.82, respectively) which, together with a third variant, rs386699872, constitute a triallelic risk haplotype associated with reduced expression of the HLA–DPB1 gene and HLA–DP protein in B cells and monocytes and with increased frequency of complementary proteinase 3 (PR3)–reactive T cells relative to that in carriers of the protective haplotype. Significant associations were also observed at the SERPINA1 and PTPN22 loci, the peak signals arising from functionally relevant missense variants, and at PRTN3 , in which the top‐scoring variant correlated with increased PRTN3 expression in neutrophils. Effects of individual loci on AAV risk differed between patients with GPA and those with MPA or between patients with PR3‐ANCAs and those with myeloperoxidase‐ANCAs, but the collective population attributable fraction for these variants was substantive, at 77%. Conclusion This study reveals the association of susceptibility to GPA and MPA with functional gene variants that explain much of the genetic etiology of AAV, could influence and possibly be predictors of the clinical presentation, and appear to alter immune cell proteins and responses likely to be key factors in the pathogenesis of AAV.

BACKGROUNDTransfusion of blood products is a key component of the supportive management in patients with acute leukemia (AL). However high‐quality trial evidence and clinical outcome data to support specific transfusion goals for blood products for patients with AL remain limited leading to diverse transfusion practices. The primary objective of this study was to determine the spectrum of transfusion patterns in a variety of care settings among providers who treat AL patients.STUDY DESIGN AND METHODSA 31‐question survey queried providers caring for AL patients about the existence of institutional guidelines for transfusion of blood products, transfusion triggers for hemoglobin (Hb), platelets (PLTs), and fibrinogen in various settings including inpatient and outpatient and before procedures.RESULTSWe analyzed 130 responses and identified divergent transfusion Hb goals in hospitalized and ambulatory patients, fibrinogen goals for cryoprecipitate transfusions, and variation in practice for use of certain PLTs and red blood cell products. The least variable transfusion patterns were reported for PLT goals in thrombocytopenia and in the setting of invasive procedures such as bone marrow biopsy and lumbar punctures.CONCLUSIONSThis survey confirmed wide variations in blood product transfusion practices across several clinical scenarios in patients with AL. The findings emphasized the need for large prospective randomized trials to develop standardized evidence‐based guidelines for blood product transfusions in patients with AL with the goal of limiting unnecessary transfusions without compromising outcomes.

SummaryThe clinical course of chronic lymphocytic leukaemia (CLL) is heterogeneous, and treatment options vary considerably. The Connect® CLL registry is a multicentre, prospective observational cohort study that provides a real‐world perspective on the management of, and outcomes for, patients with CLL. Between 2010 and 2014, 1494 patients with CLL and that initiated therapy, were enrolled from 199 centres throughout the USA (179 community‐, 17 academic‐, and 3 government‐based centres). Patients were grouped by line of therapy at enrolment (LOT). We describe the clinical and demographic characteristics of, and practice patterns for, patients with CLL enrolled in this treatment registry, providing patient‐level observational data that represent real‐world experiences in the USA. Fluorescence in situ hybridization (FISH) analyses were performed on 49·3% of patients at enrolment. The most common genetic abnormalities detected by FISH were del(13q) and trisomy 12 (45·7% and 20·8%, respectively). Differences in disease characteristics and comorbidities were observed between patients enrolled in LOT1 and combined LOT2/≥3 cohorts. Important trends observed include the infrequent use of genetic prognostic testing, and differences in patient characteristics for patients receiving chemoimmunotherapy combinations. These data represent experiences of patients with CLL in the USA, which may inform treatment decisions in everyday practice.