Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Enhancing long-term survival prediction with two short-term events: Landmarking with a flexible varying coefficient model.

Patients with cardiovascular diseases who experience disease-related short-term events, such as hospitalizations, often exhibit diverse long-term survival outcomes compared to others. In this study, we aim to improve the prediction of long-term survival probability by incorporating two short-term events using a flexible varying coefficient landmark model. Our objective is to predict the long-term survival among patients who survived up to a pre-specified landmark time since the initial admission. Inverse probability weighting estimation equations are formed based on the information of the short-term outcomes before the landmark time. The kernel smoothing method with the use of cross-validation for bandwidth selection is employed to estimate the time-varying coefficients. The predictive performance of the proposed model is evaluated and compared using predictive measures: area under the receiver operating characteristic curve and Brier score. Simulation studies confirm that parameters under the landmark models can be estimated accurately and the predictive performance of the proposed method consistently outperforms existing methods that either do not incorporate or only partially incorporate information from two short-term events. We demonstrate the practical application of our model using a community-based cohort from the Atherosclerosis Risk in Communities (ARIC) study.

Factors associated with blood mercury concentrations and their interactions with three glutathione S-transferase genes (GSTT1, GSTM1, and GSTP1): an exposure assessment study of typically developing Jamaican children.

BACKGROUND: Jamaican soil is abundant in heavy metals including mercury (Hg). Due to availability and ease of access, fish is a traditional dietary component in Jamaica and a significant source of Hg exposure. Mercury is a xenobiotic and known neuro-toxicant that affects children's neurodevelopment. Human glutathione S-transferase (GST) genes, including GSTT1, GSTM1, and GSTP1, affect Hg conjugation and elimination mechanisms. METHODS: In this exposure assessment study we used data from 375 typically developing (TD) 2-8-year-old Jamaican children to explore the association between environmental Hg exposure, GST genes, and their interaction effects on blood Hg concentrations (BHgCs). We used multivariable general linear models (GLMs). RESULTS: We identified the child's age, consumption of saltwater fish, canned fish (sardine, mackerel), string beans, grain, and starches (pasta, macaroni, noodles) as the environmental factors significantly associated with BHgCs (all P < 0.05). A significant interaction between consumption of canned fish (sardine, mackerel) and GSTP1 in relation to BHgC using either a co-dominant or recessive genetic model (overall interaction P = 0.01 and P < 0.01, respectively) indicated that consumption of canned fish (sardine, mackerel) was significantly associated with higher mean BHgC only among children with the GSTP1 Ile105Val, Ile/Ile [Ratio of mean Hg (95% CI) = 1.59 (1.09, 2.32), P = 0.02] and Ile/Val [Ratio of mean Hg (95% CI) = 1.46 (1.12, 1.91), P = 0.01] genotypes. CONCLUSIONS: Since this is the first study from Jamaica to report these findings, replication in other populations is recommended.

Identifying trajectories of radiographic spinal disease in ankylosing spondylitis: a 15-year follow-up study of the PSOAS cohort.

OBJECTIVES: Little is known with certainty about the natural history of spinal disease progression in ankylosing spondylitis (AS). Our objective was to discover if there were distinct patterns of change in vertebral involvement over time and to study associated clinical factors. METHODS: Data were analysed from the Prospective Study of Outcomes in Ankylosing Spondylitis (PSOAS) observational cohort. All patients met modified New York Criteria for AS and had ≥2 sets of radiographs scored by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) by two independent readers between 2002 and 2017. Group-based trajectory modelling (GBTM) was used to classify patients into distinct groups of longitudinal mSASSS considering sociodemographic and clinical covariables. The optimal trajectory model and number of trajectories was selected using Nagin's Bayesian information criterion (BIC). RESULTS: A total of 561 patients with 1618 radiographs were analysed. The optimum number of trajectory groups identified was four (BIC -4062). These groups were subsequently categorized as: non-progressors (204 patients), late-progressors (147 patients), early-progressors (107 patients) and rapid-progressors (103 patients). Baseline predictors associated with higher spinal disease burden groups included: baseline mSASSS, male gender, longer disease duration, elevated CRP and smoking history. In addition, time-varying anti-TNF use per year was associated with decreased mSASSS progression only in the rapid-progressor group. CONCLUSIONS: GBTM identified four distinct patterns of spinal disease progression in the PSOAS cohort. Male gender, longer disease duration, elevated CRP and smoking were associated with higher spinal disease groups. Independent confirmation in other AS cohorts is needed to confirm these radiographic patterns.

Fungi: Friend or Foe? A Mycobiome Evaluation in Children With Autism and Gastrointestinal Symptoms.

ABSTRACT: Gastrointestinal (GI) symptoms often affect children with autism spectrum disorders (ASD) and GI symptoms have been associated with an abnormal fecal microbiome. There is limited evidence of Candida species being more prevalent in children with ASD. We enrolled 20 children with ASD and GI symptoms (ASD + GI), 10 children with ASD but no GI symptoms (ASD - GI), and 20 from typically developing (TD) children in this pilot study. Fecal mycobiome taxa were analyzed by Internal Transcribed Spacer sequencing. GI symptoms (GI Severity Index [GSI]), behavioral symptoms (Social Responsiveness Scale -2 [SRS-2]), inflammation and fungal immunity (fecal calprotectin and serum dectin-1 [ELISA]) were evaluated. We observed no changes in the abundance of total fungal species (alpha diversity) between groups. Samples with identifiable Candida spp. were present in 4 of 19 (21%) ASD + GI, in 5 of 9 (56%) ASD - GI, and in 4 of 16 (25%) TD children (overall P = 0.18). The presence of Candida spp. did not correlate with behavioral or GI symptoms (P = 0.38, P = 0.5, respectively). Fecal calprotectin was normal in all but one child. Finally, there was no significance in serum dectin-1 levels, suggesting no increased fungal immunity in children with ASD. Our data suggest that fungi are present at normal levels in the stool of children with ASD and are not associated with gut inflammation.

Role of faculty characteristics in failing to fail in clinical clerkships.

INTRODUCTION: In the context of competency-based medical education, poor student performance must be accurately documented to allow learners to improve and to protect the public. However, faculty may be reluctant to provide evaluations that could be perceived as negative, and clerkship directors report that some students pass who should have failed. Student perception of faculty may be considered in faculty promotion, teaching awards, and leadership positions. Therefore, faculty of lower academic rank may perceive themselves to be more vulnerable and, therefore, be less likely to document poor student performance. This study investigated faculty characteristics associated with low performance evaluations (LPEs). METHOD: The authors analysed individual faculty evaluations of medical students who completed the third-year clerkships over 15 years using a generalised mixed regression model to assess the association of evaluator academic rank with likelihood of an LPE. Other available factors related to experience or academic vulnerability were incorporated including faculty age, race, ethnicity, and gender. RESULTS: The authors identified 50 120 evaluations by 585 faculty on 3447 students between January 2007 and April 2021. Faculty were more likely to give LPEs at the midpoint (4.9%), compared with the final (1.6%), evaluation (odds ratio [OR] = 4.004, 95% confidence interval [CI] [3.59, 4.53]; p < 0.001). The likelihood of LPE decreased significantly during the 15-year study period (OR = 0.94 [0.90, 0.97]; p < 0.01). Full professors were significantly more likely to give an LPE than assistant professors (OR = 1.62 [1.08, 2.43]; p = 0.02). Women were more likely to give LPEs than men (OR = 1.88 [1.37, 2.58]; p 0.01). Other faculty characteristics including race and experience were not associated with LPE. CONCLUSIONS: The number of LPEs decreased over time, and senior faculty were more likely to document poor medical student performance compared with assistant professors.

Chronic inflammatory back pain commencing late in life: a neglected concept.

Chronic inflammatory back pain (CIBP) occurs in up to one-third of those with chronic back pain. Criteria for diagnosis of inflammatory back pain include an onset below 50 years. Using the US National Health and Nutrition Examination Survey data for 2009-2010, we showed that 3% of adults aged 50-69 years have features of CIBP with onset on or after 50 years. There is little information in the literature on CIBP of late onset. Patients with late onset CIBP may be falling through the cracks.

Construct validity for the self-reported competency and sub-construct associated characteristics of Romanian physicians in autism spectrum disorder.

BACKGROUND: Lack of physicians' knowledge regarding mental health, including Autism Spectrum Disorder (ASD) could have adverse effects on affected individuals' health and quality of life. The purpose of this study was to provide construct validity for a modified questionnaire in order to determine the self-reported competency for underlying sub-constructs in ASD, make inferences on perceived competence in ASD based on a sample of Romanian physicians, and identify physicians' characteristics associated with these sub-domains of competency. METHODS: For this survey, we modified a questionnaire that was used in Pakistan and Turkey, and administered it to a sample of 383 practicing physicians in Romania to assess their perceived competency regarding ASD. Exploratory factor analysis on 12 knowledge questions revealed five sub-domains: stigma, potential causes, children's behavior, misconceptions, and educational needs associated with ASD knowledge. Using General Linear Models, we determined physicians' characteristics that predict the total competency score and various competency sub-scores. RESULTS: Seventy-five percent of the responding physicians were female and 30% had over 30 years practicing medicine. The majority (73-94%) of physicians have correctly responded to some basic questions regarding knowledge about ASD. We also found that younger physicians were more knowledgeable about potential causes of ASD than older physicians (Adjusted Mean Score (AMS): 2.90 vs. 2.18, P < 0.01), while older physicians knew more about the behavior of children with ASD (AMS: 0.64 vs. 0.37, P = 0.02). We found a significant interaction (P < 0.01) between television as source of ASD knowledge and city where the clinic is located in relation to knowledge of the physicians regarding stigma related to ASD. However, the total score was not associated with the variables associated with sub-domains. CONCLUSION: Using factor analysis, we demonstrated construct validity of five sub-domains related to Romanian physicians' knowledge about ASD that include stigma, potential causes, behavior in ASD children, special education needs, and misconceptions related to ASD. The lack of significant association of the knowledge of physicians on ASD neither with the Psychiatry nor the Pediatric ward rotations at medical school may support the need for improving the curriculum on ASD in Romanian medical schools.

Correlation between concentrations of four heavy metals in cord blood and childhood blood of Jamaican children.

This study investigated whether the concentrations of four metals [lead (Pb), mercury (Hg), manganese (Mn), and aluminum (Al)] are correlated in cord blood and childhood blood samples from Jamaican children. Cord blood samples were obtained from 21 pregnant women enrolled in the second Jamaican Birth Cohort Study from July 1, 2011 to September 30, 2011, and blood samples were drawn from their children who participated in a follow up study when the children were 4-8 years old. Correlations were assessed by the Pearson or the Spearman's rank correlation coefficient. The mean ages of children at the childhood visit and their mother at the child's birth were 5.5 years and 29.8 years, respectively. About 47.6% of children were male. Statistically significant correlations between cord blood and childhood blood concentrations of Pb (rSpearman =0.45; P = 0.04) and Mn (rPearson=0.48; P = 0.03) were found, and these remained significant when adjusted for the child's sex, age, or both. For Al and Hg, rSpearman=0.29 and 0.08, respectively, but the correlations were not statistically significant (both P ≥ 0.20). A significant correlation between cord blood and childhood blood Pb concentrations for children 4-8 years old has not been previously reported.

Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial.

Cellular therapy is a promising investigational modality to enhance poststroke recovery. We conducted a single-arm, phase I clinical trial to determine the safety and feasibility of intravenous (IV) administration of autologous bone marrow mononuclear cells (MNCs) after acute ischemic stroke (AIS). Patients with moderate severity of AIS underwent bone marrow harvest followed by IV reinfusion of MNCs within 24-72 hours of onset. A target dose of 10 million cells per kilogram was chosen based on preclinical data. Patients were followed up daily during hospitalization and at 1, 3, 6, 12, and 24 months for incidence of adverse events using laboratory, clinical (12 months), and radiological (24 months) parameters. The trial was powered to detect severe adverse events (SAEs) with incidences of at least 10% and planned to enroll 30 patients. Primary outcomes were study-related SAEs and the proportion of patients successfully completing study intervention. A propensity score-based matched control group was used for the estimation of effect size (ES) for day-90 modified Rankin score (mRS). There were no study-related SAEs and, based on a futility analysis, enrolment was stopped after 25 patients. All patients successfully completed study intervention and most received the target dose. Secondary analysis estimated the ES to be a reduction of 1 point (95% confidence interval: 0.33-1.67) in median day-90 mRS for treated patients as compared with the matched control group. Bone marrow harvest and infusion of MNCs is safe and feasible in patients with AIS. The estimated ES is helpful in designing future randomized controlled trials. Stem Cells 2019;37:1481-1491.

Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy (HALT-HCM): A Randomized, Placebo-Controlled, Double-Blind Pilot Study.

RATIONALE: Hypertrophic cardiomyopathy (HCM) is a genetic paradigm of cardiac hypertrophy. Cardiac hypertrophy and interstitial fibrosis are important risk factors for sudden death and morbidity in HCM. Oxidative stress is implicated in the pathogenesis of cardiac hypertrophy and fibrosis. Treatment with antioxidant N-acetylcysteine (NAC) reverses cardiac hypertrophy and fibrosis in animal models of HCM. OBJECTIVE: To determine effect sizes of NAC on indices of cardiac hypertrophy and fibrosis in patients with established HCM. METHODS AND RESULTS: HALT-HCM (Hypertrophy Regression With N-Acetylcysteine in Hypertrophic Cardiomyopathy) is a double-blind, randomized, sex-matched, placebo-controlled single-center pilot study in patients with HCM. Patients with HCM, who had a left ventricular wall thickness of ≥15 mm, were randomized either to a placebo or to NAC (1:2 ratio, respectively). NAC was titrated ≤2.4 g per day. Clinical evaluation, blood chemistry, and 6-minute walk test were performed every 3 months, and electrocardiography, echocardiography, and cardiac magnetic resonance imaging, the latter whenever not contraindicated, before and after 12 months of treatment. Eighty-five of 232 screened patients met the eligibility criteria, 42 agreed to participate; 29 were randomized to NAC and 13 to placebo groups. Demographic, echocardiographic, and cardiac magnetic resonance imaging phenotypes at the baseline between the 2 groups were similar. WSE in 38 patients identified a spectrum of 42 pathogenic variants in genes implicated in HCM in 26 participants. Twenty-four patients in the NAC group and 11 in the placebo group completed the study. Six severe adverse events occurred in the NAC group but were considered unrelated to NAC. The effect sizes of NAC on the clinical phenotype, echocardiographic, and cardiac magnetic resonance imaging indices of cardiac hypertrophy, function, and extent of late gadolinium enhancement-a surrogate for fibrosis-were small. CONCLUSIONS: Treatment with NAC for 12 months had small effect sizes on indices of cardiac hypertrophy or fibrosis. The small sample size of the HALT-HCM study hinders from making firm conclusions about efficacy of NAC in HCM. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01537926.

Dual Antiplatelet Therapy Is Associated With Coagulopathy Detectable by Thrombelastography in Acute Stroke.

BACKGROUND: Thrombelastography (TEG) provides a global, dynamic measure of coagulation. We examined the effect of antiplatelet (AP) medications on coagulation in patients with acute stroke as measured by TEG. METHODS: We reviewed prospectively collected data on patients presenting with acute ischemic stroke (AIS) and spontaneous intracerebral hemorrhage (ICH) between 2009 and 2014. Patient demographics and baseline TEG values were compared among 4 different drug use groups: aspirin only, clopidogrel only, both aspirin and clopidogrel, and no AP. Multivariable regression models were conducted to compare the differences in TEG components. RESULTS: A total of 202 patients were included, 139 with AIS and 63 with ICH. Forty-eight (24%) patients were taking aspirin alone, 12 (6%) were taking clopidogrel, 16 (8%) dual AP, and 126 (62%) no AP. Dual AP use was associated with prolonged mean R (time to initiate clotting) of 5.5 minutes as compared to no AP use (4.6 minutes, P = .04). Additionally, mean maximal amplitude (MA; final clot strength) and angle (rate of clot formation) were decreased in the dual AP group (MA = 59.3 mm, angle = 57.8°) as compared to the no AP group (MA = 64.5 mm, angle = 64.5°; P = .04 and P = .01, respectively). Patients on single AP therapy (either aspirin or clopidogrel) did not differ from those on no AP therapy in any TEG parameters measured. CONCLUSION: Dual AP therapy is associated with a detectable coagulopathy which may have implications in the management of patients with AIS and hemorrhagic stroke. The effects of single AP therapy may not be demonstrated by TEG.

A latent class based imputation method under Bayesian quantile regression framework using asymmetric Laplace distribution for longitudinal medication usage data with intermittent missing values.

Evaluating the association between diseases and the longitudinal pattern of pharmacological therapy has become increasingly important. However, in many longitudinal studies, self-reported medication usage data collected at patients' follow-up visits could be missing for various reasons. These pieces of missing or inaccurate/untenable information complicate determining the trajectory of medication use and its complete effects for patients. Although longitudinal models can deal with specific types of missing data, inappropriate handling of this issue can lead to a biased estimation of regression parameters especially when missing data mechanisms are complex and depend upon multiple sources of variation. We propose a latent class-based multiple imputation (MI) approach using a Bayesian quantile regression (BQR) that incorporates cluster of unobserved heterogeneity for medication usage data with intermittent missing values. Findings from our simulation study indicate that the proposed method performs better than traditional MI methods under certain scenarios of data distribution. We also demonstrate applications of the proposed method to data from the Prospective Study of Outcomes in Ankylosing Spondylitis (AS) cohort when assessing an association between longitudinal nonsteroidal anti-inflammatory drugs (NSAIDs) usage and radiographic damage in AS, while the longitudinal NSAID index data are intermittently missing.

Longitudinal associations between depressive symptoms and clinical factors in ankylosing spondylitis patients: analysis from an observational cohort.

OBJECTIVES: Although cross-sectional studies have shown that ankylosing spondylitis-specific factors correlate with depressive symptom severity, the association of these factors over time is unresolved. We examined the demographic and clinical factors associated with longitudinal depressive symptom severity in AS patients. METHODS: We analyzed sociodemographic, clinical, behavioral and medication data from 991 patients from the Prospective Study of Outcomes in Ankylosing spondylitis cohort, and measured depression severity with the Center for Epidemiological Studies Depression (CES-D) Scale administered at approximately 6-month visit intervals. Multivariable longitudinal negative binomial regression models were conducted using generalized estimating equation modeling to assess the demographic, clinical, and medication-related factors associated with depression severity by CES-D scores over time. RESULTS: The median baseline CES-D score (possible range 0-60) was 10.0 (interquartile range = 5, 17). In longitudinal multivariable analyses, higher CES-D scores were associated with longitudinal smoking, greater functional impairment, greater disease activity, self-reported depression, and poor global health scores. Marital status (e.g., being married) was associated with lower CES-D. Adjusted mean CES-D scores in our model decreased over time, with a significant interaction between time and gender observed. CONCLUSION: This study identified longitudinal clinical factors such as greater disease activity, greater functional impairment, and poor global health to be associated with longitudinal depression severity. These factors are potentially modifiable and may help manage depressive symptoms in AS.

Rapid Infarct Progression in Anterior Circulation Large Vessel Occlusion Ischemic Stroke Patients During Inter-Facility Transfer.

INTRODUCTION: We aimed to identify factors associated with rapid infarct progression during inter-facility transfer for endovascular thrombectomy evaluation and its impact on clinical outcomes. METHODS: Patients with anterior circulation large artery occlusion within 24 h of onset transferred within our 17 hospital tele-stroke network were retrospectively analyzed. Patients were divided into fast progressors and slow progressors. Fast progressors were defined as CT ASPECTS score of ≥6 at the referring hospital (RH) and <6 at the hub hospital. Good clinical outcomes were defined as modified Rankin Scale score (mRS) 0-2 at 90 days. Demographic, clinical and radiologic variables associated with fast progressors and good clinical outcomes were identified using multivariable regression models. RESULTS: Among the 190 patients, 44 (23%) patients underwent rapid infarct progression. Higher stroke severity at presentation [aOR, 1.096, 95% CI,1.023, 1.174; p = 0.009], presence of early ischemic changes (CT ASPECT 6-9) at the RH [aOR, 2.721, 95% CI, 1.22, 6.071; p = 0.014] were positively associated, whereas prior ischemic stroke [aOR, 0.272, 95% CI, 0.078, 0.948; p = 0.04] and higher collateral score (2,3,4) [aOR, 0.138, 95%CI, 0.059, 0.324, p=<0.0001] were negatively associated with rapid infarct progression. Fifty-eight (31%) transferred patients had good outcomes. After adjusting for reperfusion status, age [aOR, 0.96, 95% CI, 0.93, 0.98; p=<0.001], initial stroke severity [aOR, 0.87, 95% CI, 0.81, 0.93; p=<0.001], absolute rate of decrease in CT ASPECTS [aOR, 0.38, 95% CI, 0.19, 0.77; p = 0.007] and internal carotid artery (ICA) occlusion [aOR, 0.34, 95 %CI, 0.12, 0.94; p = 0.038] were negatively associated with good outcome. CONCLUSION: Higher stroke severity, presence of early ischemic changes at the referring facility, absence of prior stroke, and poor collateral scores (CS 0-1) are the factors associated with rapid infarct progression in the telemedicine transfer cohort. Increasing age, higher stroke severity, higher absolute decrease in CT ASPECTS and ICA occlusion determine poor clinical outcomes.

HLA class I and II alleles in susceptibility to ankylosing spondylitis.

OBJECTIVE: To examine associations of HLA class I and class II alleles with ankylosing spondylitis (AS) in three cohorts of patients of European, Asian and African ancestry. METHODS: HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 alleles were genotyped in 1948 unrelated white and 67 African-American patients with AS from the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, the North American Spondylitis Consortium and Australo-Anglo-American Spondyloarthritis Consortium, 990 white and 245 African-American Controls and HLA-B alleles in 442 Han Chinese patients with AS and 346 controls from Shanghai and Gansu, China. In addition to the case:control analyses, HLA-B*27-negative patients with AS were analysed separately, and logistic regression and 'relative predispositional effects' (RPE) analyses were carried out to control for the major effect of HLA-B*27 on disease susceptibility. RESULTS: Although numerous associations were seen between HLA alleles and AS in whites, among HLA-B*27-negative patients with AS , positive associations were seen with HLA-A*29, B*38, B*49, B*52, DRB1*11 and DPB1*03:01 and negative associations with HLA-B*07, HLA-B*57, HLA-DRB1*15:01, HLA-DQB1*02:01 and HLA-DQB1*06:02. Additional associations with HLA-B*14 and B*40 (B60) were observed via RPE analysis, which excludes the HLA-B*27 alleles. The increased frequency of HLA-B*40:01 and decreased frequency of HLA-B*07 was also seen in Han Chinese and African-Americans with AS. HLA-B*08 was decreased in whites with acute anterior uveitis. CONCLUSIONS: These data, analysing the largest number of patients with AS examined to date in three ethnic groups, confirm that other HLA class I and II alleles other than HLA-B*27 to be operative in AS predisposition.

A generalized weighted quantile sum approach for analyzing correlated data in the presence of interactions.

A weighted quantile sum (WQS) regression has been used to assess the associations between environmental exposures and health outcomes. However, the currently available WQS approach, which is based on additive effects, does not allow exploring for potential interactions of exposures with other covariates in relation to a health outcome. In addition, the current WQS cannot account for clustering, thus it may not be valid for analysis of clustered data. We propose a generalized WQS approach that can assess interactions by estimating stratum-specific weights of exposures in a mixture, while accounting for potential clustering effect of matched pairs of cases and controls as well as censored exposure data due to being below the limits of detection. The performance of the proposed method in identifying interactions is evaluated through simulations based on various scenarios of correlation structures among the exposures and with an outcome. We also assess how well the proposed method performs in the presence of the varying levels of censoring in exposures. Our findings from the simulation study show that the proposed method outperforms the traditional WQS, as indicated by higher power of detecting interactions. We also find no strong evidence that the proposed method falsely identifies interactions when there are no true interactive effects. We demonstrate application of the proposed method to real data from the Epidemiological Research on Autism Spectrum Disorder (ASD) in Jamaica (ERAJ) by examining interactions between exposure to manganese and glutathione S-transferase family gene, GSTP1 in relation to ASD.

A multiple imputation method based on weighted quantile regression models for longitudinal censored biomarker data with missing values at early visits.

BACKGROUND: In patient-based studies, biomarker data are often subject to left censoring due to the detection limits, or to incomplete sample or data collection. In the context of longitudinal regression analysis, inappropriate handling of these issues could lead to biased parameter estimates. We developed a specific multiple imputation (MI) strategy based on weighted censored quantile regression (CQR) that not only accounts for censoring, but also missing data at early visits when longitudinal biomarker data are modeled as a covariate. METHODS: We assessed through simulation studies the performances of developed imputation approach by considering various scenarios of covariance structures of longitudinal data and levels of censoring. We also illustrated the application of the proposed method to the Prospective Study of Outcomes in Ankylosing spondylitis (AS) (PSOAS) data to address the issues of censored or missing C-reactive protein (CRP) level at early visits for a group of patients. RESULTS: Our findings from simulation studies indicated that the proposed method performs better than other MI methods by having a higher relative efficiency. We also found that our approach is not sensitive to the choice of covariance structure as compared to other methods that assume normality of biomarker data. The analysis results of PSOAS data from the imputed CRP levels based on our method suggested that higher CRP is significantly associated with radiographic damage, while those from other methods did not result in a significant association. CONCLUSION: The MI based on weighted CQR offers a more valid statistical approach to evaluate a biomarker of disease in the presence of both issues with censoring and missing data in early visits.

Randomized, Multicenter Trial of ARTSS-2 (Argatroban With Recombinant Tissue Plasminogen Activator for Acute Stroke).

BACKGROUND AND PURPOSE: We conducted a randomized exploratory study to assess safety and the probability of a favorable outcome with adjunctive argatroban, a direct thrombin-inhibitor, administered to recombinant tissue-type plasminogen activator (r-tPA)-treated ischemic stroke patients. METHODS: Patients treated with standard-dose r-tPA, not receiving endovascular therapy, were randomized to receive no argatroban or argatroban (100 µg/kg bolus) followed by infusion of either 1 (low dose) or 3 µg/kg per minute (high dose) for 48 hours. Safety was incidence of symptomatic intracerebral hemorrhage. Probability of clinical benefit (modified Rankin Scale score 0-1 at 90 days) was estimated using a conservative Bayesian Poisson model (neutral prior probability centered at relative risk, 1.0 and 95% prior intervals, 0.33-3.0). RESULTS: Ninety patients were randomized: 29 to r-tPA alone, 30 to r-tPA+low-dose argatroban, and 31 to r-tPA+high-dose argatroban. Rates of symptomatic intracerebral hemorrhage were similar among control, low-dose, and high-dose arms: 3/29 (10%), 4/30 (13%), and 2/31 (7%), respectively. At 90 days, 6 (21%) r-tPA alone, 9 (30%) low-dose, and 10 (32%) high-dose patients were with modified Rankin Scale score 0 to 1. The relative risks (95% credible interval) for modified Rankin Scale score 0 to 1 with low, high, and either low or high dose argatroban were 1.17 (0.57-2.37), 1.27 (0.63-2.53), and 1.34 (0.68-2.76), respectively. The probability that adjunctive argatroban was superior to r-tPA alone was 67%, 74%, and 79% for low, high, and low or high dose, respectively. CONCLUSIONS: In patients treated with r-tPA, adjunctive argatroban was not associated with increased risk of symptomatic intracerebral hemorrhage and provides evidence that a definitive effectiveness trial is indicated. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique Identifier: NCT01464788.

Lactobacillus reuteri for Infants with Colic: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial.

OBJECTIVE: To assess the safety of probiotic Lactobacillus reuteri strain Deutsche Sammlung von Mikroorganismen (DSM) 17938 with daily administration to healthy infants with colic and to determine the effect of L reuteri strain DSM 17938 on crying, fussing, inflammatory, immune, and microbiome variables. STUDY DESIGN: We performed a controlled, double-blinded, phase 1 safety and tolerability trial in healthy breast-fed infants with colic, aged 3 weeks to 3 months, randomly assigned to L reuteri strain DSM 17938 (5 × 108 colony-forming units daily) or placebo for 42 days and followed for 134 days. RESULTS: Of 117 screened infants, 20 were randomized to L reuteri strain DSM 17938 or placebo (sunflower oil) (in a 2:1 ratio) with 80% retention. Eleven of the 20 (55%) presented with low absolute neutrophil counts (<1500/mm3), which resolved in all subjects by day 176. L reuteri strain DSM 17938 produced no severe adverse events and did not significantly change crying time, plasma bicarbonate, or inflammatory biomarkers. Fecal calprotectin decreased rapidly in both groups. In the infants with dominant fecal gram negatives (Klebsiella, Proteus, and Veillonella), resolution of colic was associated with marked decreases in these organisms. CONCLUSIONS: Daily administration of L reuteri strain DSM 17938 appears to be safe in newborn infants with colic, including those with neutropenia, which frequently coexists. A placebo response of 66% suggests that many infants with colic will have resolution within 3 weeks. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01849991.