Association of rs11190870 near LBX1 with adolescent idiopathic scoliosis in East Asians: a systematic review and meta-analysis

Background contextThe rs11190870 single nucleotide polymorphism in the 3'-flanking region of the LBX1 gene has been implicated in the etiology of adolescent idiopathic scoliosis (AIS). A thorough appraisal of the evidence supporting this association has not been previously attempted.PurposeTo provide a comprehensive assessment and synthesis of the currently available evidence on the association between rs11190870 and AIS.Study designA systematic review and meta-analysis.MethodsThis review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. PubMed (MEDLINE), EMBASE, Scopus, and HuGE Literature Finder databases were systematically searched through November 2013 to identify relevant studies following a sensitive strategy. Summary odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated using the fixed-effect inverse variance model for allelic (T vs. C) and genotypic comparisons.ResultsMeta-analysis of four studies conducted in East Asian populations (n=3,215 AIS cases and n=15,347 controls) found a highly statistically significant and robust association between rs11190870 and AIS. Comparison of summary ORs indicated a codominant model effect of the T allele. Carriers of the TC and TT genotypes were 69% (OR=1.69, 95% CI: 1.48–1.94, p<.001) and 162% (OR=2.62, 95% CI: 2.28–3.02, p<.001), respectively, more likely to have AIS compared with carriers of the CC genotype.ConclusionsBased on a comprehensive analysis of the currently available evidence, rs11190870 is likely a susceptibility variant for AIS in East Asians. Further investigation of this association is necessary in other populations.     

Planning and managing a complex multisite study in the age of technology

A 2‐year long, multisite research study that evaluated cardiopulmonary resuscitation skill decay among nursing students was conducted at 10 schools of nursing across the United States. The study was conducted in two phases and required carefully timed sessions for skill performance. Multisite studies in nursing education need to be carefully planned. Time delays should be anticipated with processes and Institutional Review Board protocols across sites. All team members were trained and consistently supported during the entire study. While challenges and obstacles were identified, innovative solutions were implemented that assisted the research team to successfully complete the study. The use of new and existing technology allowed the team to surmount many of the challenges encountered in this study. The purpose of this article is to describe the logistics, processes, challenges, and lessons learned related to conducting a complex multisite study.     

Predictors of Having Paid Work in Older Workers With and Without Chronic Disease: A 3-Year Prospective Cohort Study

Background As the prevalence of chronic disease amongst older workers is high and increasing, it is important to know if the large subgroup of older workers with chronic disease has specific needs when it comes to prolonging participation in paid work. Objectives To investigate differences and similarities in predictors of having paid work in workers aged 55+ with and without chronic disease. Methods Workers aged 55–62 years were selected from the 2002–2003 cohort of the Longitudinal Aging Study Amsterdam (n = 333). Potential predictors were: health, personality, work characteristics, and demographics. Per potential predictor, a logistic regression coefficient for ‘having paid work in 2005–2006’ was calculated for workers with and without chronic disease. A pooled estimate was computed and differences between the pooled estimate and the coefficients were tested. Results Follow-up data were available for 95 %, of whom 67 % still had paid work. Predictors of having paid work were similar for workers with and without chronic diseases, except for physical workload (χ² = 5.37; DF = 1) and psychosocial resources at work (χ² = 5.94; DF = 1). Having more psychosocial resources (OR = 3.57; 95 %CI 1.33–10.0) was predictive for having paid work in workers with chronic disease and not in workers without chronic disease. Lower age, more weekly working hours, no functional limitations, fewer depressive symptoms, lower neuroticism scores, and more sense of mastery were significantly associated with having paid work in all workers. Conclusions Differences between predictors of having paid work between workers with and without chronic disease should be taken into account when aiming to prevent exit from the workforce. In particular the vulnerable subgroup of older workers with chronic disease and low psychosocial resources at work is more likely to quit working.     

High pre-transplant serum nitrate levels predict risk of acute steroid-refractory graft-versus-host disease in the absence of statin therapy

Steroid-refractory graft-versus-host disease is a life-threatening complication after allogeneic stem cell transplantation. Evidence is accumulating that steroid-refractory graft-versus-host disease is associated with endothelial distress. Endothelial cell homeostasis is regulated by nitric oxide, and serum nitrates are derived from nitric oxide synthase activity or dietary sources. In this retrospective study based on 417 patients allografted at our institution we investigated whether quantification of serum nitrates could predict steroid-refractory graft-versus-host disease. Elevated pre-transplant levels of serum nitrates (>26.5 μM) predicted steroid-refractory graft-versus-host disease (P=0.026) and non-relapse mortality (P=0.028), particularly in combination with high pre-transplant angiopoietin-2 levels (P=0.0007 and P=0.021, respectively). Multivariate analyses confirmed serum nitrates as independent predictors of steroid-refractory graft-versus-host disease and non-relapse mortality. Differences in serum nitrate levels did not correlate with serum levels of tumor necrosis factor or C-reactive protein or expression of inducible nitric oxide synthase in blood cells. Patients with high pre-transplant nitrate levels had significantly reduced rates of refractory graft-versus-host disease (P=0.031) when pravastatin was taken. In summary, patients at high risk of developing steroid-refractory graft-versus-host disease could be identified prior to transplantation by serum markers linked to endothelial cell function. Retrospectively, statin medication was associated with a reduced incidence of refractory graft-versus-host disease in this endothelial high-risk cohort.     

Antileukemic effects of the novel, mutant FLT3 inhibitor NVP-AST487: effects on PKC412-sensitive and -resistant FLT3-expressing cells

An attractive target for therapeutic intervention is constitutively activated, mutant FLT3, which is expressed in a subpopulation of patients with acute myelocyic leukemia (AML) and is generally a poor prognostic indicator in patients under the age of 65 years. PKC412 is one of several mutant FLT3 inhibitors that is undergoing clinical testing, and which is currently in late-stage clinical trials. However, the discovery of drug-resistant leukemic blast cells in PKC412-treated patients with AML has prompted the search for novel, structurally diverse FLT3 inhibitors that could be alternatively used to override drug resistance. Here, we report the potent and selective antiproliferative effects of the novel mutant FLT3 inhibitor NVP-AST487 on primary patient cells and cell lines expressing FLT3-ITD or FLT3 kinase domain point mutants. NVP-AST487, which selectively targets mutant FLT3 protein kinase activity, is also shown to override PKC412 resistance in vitro, and has significant antileukemic activity in an in vivo model of FLT3-ITD(+) leukemia. Finally, the combination of NVP-AST487 with standard chemotherapeutic agents leads to enhanced inhibition of proliferation of mutant FLT3-expressing cells. Thus, we present a novel class of FLT3 inhibitors that displays high selectivity and potency toward FLT3 as a molecular target, and which could potentially be used to override drug resistance in AML.