Subclinical thyroid dysfunction and the risk of stroke: a systematic review and meta-analysis

Subclinical thyroid dysfunction has been associated with coronary heart disease, but the risk of stroke is unclear. Our aim is to combine the evidence on the association between subclinical thyroid dysfunction and the risk of stroke in prospective cohort studies. We searched Medline (OvidSP), Embase, Web-of-Science, Pubmed Publisher, Cochrane and Google Scholar from inception to November 2013 using a cohort filter, but without language restriction or other limitations. Reference lists of articles were searched. Two independent reviewers screened articles according to pre-specified criteria and selected prospective cohort studies with baseline thyroid function measurements and assessment of stroke outcomes. Data were derived using a standardized data extraction form. Quality was assessed according to previously defined quality indicators by two independent reviewers. We pooled the outcomes using a random-effects model. Of 2,274 articles screened, six cohort studies, including 11,309 participants with 665 stroke events, met the criteria. Four of six studies provided information on subclinical hyperthyroidism including a total of 6,029 participants and five on subclinical hypothyroidism (n = 10,118). The pooled hazard ratio (HR) was 1.08 (95 % CI 0.87-1.34) for subclinical hypothyroidism (I (2) of 0 %) and 1.17 (95 % CI 0.54-2.56) for subclinical hyperthyroidism (I (2) of 67 %) compared to euthyroidism. Subgroup analyses yielded similar results. Our systematic review provides no evidence supporting an increased risk for stroke associated with subclinical thyroid dysfunction. However, the available literature is insufficient and larger datasets are needed to perform extended analyses. Also, there were insufficient events to exclude clinically significant risk from subclinical hyperthyroidism, and more data are required for subgroup analyses.

Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV infection.

BACKGROUND Pneumocystis jiroveci pneumonia (PCP) remains the most common opportunistic infection in patients infected with the human immunodeficiency virus (HIV). Among patients with HIV infection and PCP the mortality rate is 10% to 20% during the initial infection and this increases substantially with the need for mechanical ventilation. It has been suggested that corticosteroids adjunctive to standard treatment for PCP could prevent the need for mechanical ventilation and decrease mortality in these patients. OBJECTIVES To assess the effects of adjunctive corticosteroids on overall mortality and the need for mechanical ventilation in HIV-infected patients with PCP and substantial hypoxaemia (arterial oxygen partial pressure < 70 mmHg or alveolar-arterial gradient > 35 mmHg on room air). SEARCH METHODS For the original review we searched The Cochrane Library (2004, Issue 4), MEDLINE (January 1980 to December 2004) and EMBASE (January 1985 to December 2004) without language restrictions. We further reviewed the reference lists from previously published overviews, searched UptoDate version 2005 and Clinical Evidence Concise (Issue 12, 2004), contacted experts in the field and searched the reference lists of identified publications for citations of additional relevant articles.In this update of our review, we searched the above-mentioned databases in September 2010 and April 2014 for trials published since our original review. We also searched for ongoing trials in ClinicalTrials.gov and the World Health Organization International Clinical Trial Registry Platform (ICTRP). We searched for conference abstracts via AEGIS. SELECTION CRITERIA Randomised controlled trials that compared corticosteroids to placebo or usual care in HIV-infected patients with PCP in addition to baseline treatment with trimethoprim-sulfamethoxazole, pentamidine or dapsone-trimethoprim, and reported mortality data. We excluded trials in patients with no or mild hypoxaemia (arterial oxygen partial pressure > 70 mmHg or an alveolar-arterial gradient < 35 mmHg on room air) and trials with a follow-up of less than 30 days. DATA COLLECTION AND ANALYSIS Two teams of review authors independently evaluated the methodology and extracted data from each primary study. We pooled treatment effects across studies and calculated a weighted average risk ratio of overall mortality in the treatment and control groups using a random-effects model.In this update of our review, we used the GRADE methodology to assess evidence quality. MAIN RESULTS Of 2029 screened records, we included seven studies in the review and six in the meta-analysis. Risk of bias varied: the randomisation and allocation process was often not clearly described, five of seven studies were double-blind and there was almost no missing data. The quality of the evidence for mortality was high. Risk ratios for overall mortality for adjunctive corticosteroids were 0.56 (95% confidence interval (CI) 0.32 to 0.98) at one month and 0.59 (95% CI 0.41 to 0.85) at three to four months of follow-up. In adults, to prevent one death, numbers needed to treat are nine patients in a setting without highly active antiretroviral therapy (HAART) available, and 23 patients with HAART available. The three largest trials provided moderate quality data on the need for mechanical ventilation, with a risk ratio of 0.38 (95% CI 0.20 to 0.73) in favour of adjunctive corticosteroids. One study was conducted in infants, suggesting a risk ratio for death in hospital of 0.81 (95% CI 0.51 to 1.29; moderate quality evidence). AUTHORS' CONCLUSIONS The number and size of trials investigating adjunctive corticosteroids for HIV-infected patients with PCP is small, but the evidence from this review suggests a beneficial effect for adult patients with substantial hypoxaemia. There is insufficient evidence on the effect of adjunctive corticosteroids on survival in infants.

Effectiveness of meticillin-resistant Staphylococcus aureus decolonization in long-term haemodialysis patients: a systematic review and meta-analysis.

BACKGROUND Chronic haemodialysis patients are a high-risk population for meticillin-resistant Staphylococcus aureus (MRSA) colonization, which is a precursor of infection. AIM To summarize the effect of nasal (± whole-body wash) MRSA decolonization in haemodialysis patients by means of a systematic review and meta-analysis. METHODS We identified eligible studies using Medline, Embase, the Cochrane database, clinicaltrials.org, and conference abstracts investigating the success of MRSA decolonization in haemodialysis patients. For the statistical analysis, we used Stata 13 to express study-specific proportions with 95% confidence intervals. A likelihood ratio test was used to assess inter-study heterogeneity. FINDINGS Six published prospective cohort studies and one study described in a conference abstract met our inclusion criteria. From 1150 haemodialysis patients enrolled in these studies, MRSA was isolated from nasal swabs of 147 (12.8%) patients. Six of the trials used mupirocin nasal ointment and combined it with chlorhexidine body washes for decolonization. The most widely used protocol was a five-day course of mupirocin nasal ointment application three times a day, and chlorhexidine body wash once daily. The pooled success rate of decolonization was 0.88 (95% confidence interval: 0.75-0.95). A likelihood ratio test of the fixed versus the random-effects model showed significant inter-study heterogeneity (P = 0.047). Four of seven studies determined subsequent MRSA infections in 94 carriers overall, two (2%) of which experienced infection. CONCLUSION The use of mupirocin together with whole-body decolonization is highly effective in eradicating MRSA carriage in haemodialysis patients. The current literature, however, is characterized by a lack of comparative effectiveness studies for this intervention.

Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis.

Importance In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published. Objective To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis. Data Sources MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014. Study Selection At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo. Data Extraction and Synthesis At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting. Main Outcomes and Measures The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events. Results Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs. Conclusions and Relevance Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Diagnostic value of immunoassays for heparin-induced thrombocytopenia: a systematic review and meta-analysis.

Immunoassays are essential in the workup of patients with suspected heparin-induced thrombocytopenia. However, the diagnostic accuracy is uncertain with regard to different classes of assays, antibody specificities, thresholds, test variations, and manufacturers. We aimed to assess diagnostic accuracy measures of available immunoassays and to explore sources of heterogeneity. We performed comprehensive literature searches and applied strict inclusion criteria. Finally, 49 publications comprising 128 test evaluations in 15 199 patients were included in the analysis. Methodological quality according to the revised tool for quality assessment of diagnostic accuracy studies was moderate. Diagnostic accuracy measures were calculated with the unified model (comprising a bivariate random-effects model and a hierarchical summary receiver operating characteristics model). Important differences were observed between classes of immunoassays, type of antibody specificity, thresholds, application of confirmation step, and manufacturers. Combination of high sensitivity (>95%) and high specificity (>90%) was found in 5 tests only: polyspecific enzyme-linked immunosorbent assay (ELISA) with intermediate threshold (Genetic Testing Institute, Asserachrom), particle gel immunoassay, lateral flow immunoassay, polyspecific chemiluminescent immunoassay (CLIA) with a high threshold, and immunoglobulin G (IgG)-specific CLIA with low threshold. Borderline results (sensitivity, 99.6%; specificity, 89.9%) were observed for IgG-specific Genetic Testing Institute-ELISA with low threshold. Diagnostic accuracy appears to be inadequate in tests with high thresholds (ELISA; IgG-specific CLIA), combination of IgG specificity and intermediate thresholds (ELISA, CLIA), high-dose heparin confirmation step (ELISA), and particle immunofiltration assay. When making treatment decisions, clinicians should be a aware of diagnostic characteristics of the tests used and it is recommended they estimate posttest probabilities according to likelihood ratios as well as pretest probabilities using clinical scoring tools.

Influence of EMS-physician presence on survival after out-of-hospital cardiopulmonary resuscitation: systematic review and meta-analysis

BACKGROUND Evidence suggests that EMS-physician-guided cardiopulmonary resuscitation (CPR) in out-of-hospital cardiac arrest (OOHCA) may be associated with improved outcomes, yet randomized controlled trials are not available. The goal of this meta-analysis was to determine the association between EMS-physician- versus paramedic-guided CPR and survival after OOHCA. METHODS AND RESULTS Studies that compared EMS-physician- versus paramedic-guided CPR in OOHCA published until June 2014 were systematically searched in MEDLINE, EMBASE and Cochrane databases. All studies were required to contain survival data. Data on study characteristics, methods, and as well as survival outcomes were extracted. A random-effects model was used for the meta-analysis due to a high degree of heterogeneity among the studies (I (2)  = 44 %). Return of spontaneous circulation [ROSC], survival to hospital admission, and survival to hospital discharge were the outcome measures. Out of 3,385 potentially eligible studies, 14 met the inclusion criteria. In the pooled analysis (n = 126,829), EMS-physician-guided CPR was associated with significantly improved outcomes compared to paramedic-guided CPR: ROSC 36.2 % (95 % confidence interval [CI] 31.0 - 41.7 %) vs. 23.4 % (95 % CI 18.5 - 29.2 %) (pooled odds ratio [OR] 1.89, 95 % CI 1.36 - 2.63, p < 0.001); survival to hospital admission 30.1 % (95 % CI 24.2 - 36.7 %) vs. 19.2 % (95 % CI 12.7 - 28.1 %) (pooled OR 1.78, 95 % CI 0.97 - 3.28, p = 0.06); and survival to discharge 15.1 % (95 % CI 14.6 - 15.7 %) vs. 8.4 % (95 % CI 8.2 - 8.5 %) (pooled OR 2.03, 95 % CI 1.48 - 2.79, p < 0.001). CONCLUSIONS This systematic review suggests that EMS-physician-guided CPR in out-of-hospital cardiac arrest is associated with improved survival outcomes.

A meta-analysis: Obesity and colorectal cancer screening

Of cancer death, colorectal cancer death ranks second in the United States. Obesity is an important risk factor for colorectal cancer (1). Early detection of colorectal cancer when it is localized can effectively reduce mortality of colorectal cancer and increase survival time of patients if they are treated. Also, previous studies showed that obese women were more likely to delay breast cancer screening and cervical cancer screening than normal weight women (2-5). However, results from prior studies demonstrating the relationship between obesity and colorectal cancer screening are not consistent. This research was done to conduct a meta-analysis of previous cross-sectional studies selected from the Medline database and to evaluate the association between obesity and colorectal cancer screening. While the odds ratio was not statistically different from one, the results from this meta-analysis under the random effects model showed that obese people are slightly less likely to have colorectal cancer screening compared to normal weight individuals (OR,0.93;95% CI 0.75-1.15). This meta-analysis was particularly sensitive to one individual study (6) and the effect of obesity on colorectal cancer screening was statistically significant (OR, 0.87; 95% CI, 0.81-0.92) after removing Heo's study. Further systematic studies focused on whether the effect of obesity on colorectal cancer screening is limited to women only are suggested. ^

A systematic review of clostridium difficile infection in patients with iatrogenic immunesuppression

Background: Incidence of C. difficile infection (CDI) has increased dramatically in the past decade and is the most frequent cause of nosocomial infectious diarrhea. The outcome of infection may range from mild diarrhea to life-threatening pseudomembranous colitis depending on the immunological response of the host, which is highly compromised in this special population that includes bone marrow transplant (BMT), solid organ transplant (SOT) and cancer patients on cytotoxic chemotherapy. ^ Objectives: We conducted a meta-analysis to assess the incidence rates of CDI and the time to onset of infection in patients with iatrogenic immune suppression. ^ Methods: Original studies were identified through an extensive search of electronic databases including PubMed, Ovid Medline (R), RefWorks and Biological Abstracts and their references. The overall incidence rate of CDI in the immune suppressed population was calculated using random effects model and their 95% confidence interval was derived. Differences in the incidence of CDI and time to onset of infection were calculated between the groups and within the groups. Publication bias was assessed using a funnel plot. Results: Twenty nine published articles involving 7,424 patients met the eligibility requirements. The overall incidence of CDI in the immune suppressed population is 11.1% (95% Confidence Interval (CI): 9.2–13.4%). The incidence of CDI was higher in SOT patients (14.2%, 95% CI: 6.8–21.5%); (p-value-0.022) and in cancer patients on cytotoxic chemotherapy (11.4%, 95% CI: 8.4–15.4%); (p = 0.042) than in BMT patients (10.5%, 95% CI: 7.9–13.1%). In a subgroup analysis of BMT population, the incidence of CDI is significantly higher in patients who received allogeneic BMT (15.1%, 95% CI: 11.2–20.0%; p value <0.0001). Similarly, in the SOT population, the incidence of CDI was higher in patients who underwent liver transplantation (11.0%, 95% CI: 5.6–20.3%); (p= 0.0672). The median time to onset of infection was shorter in BMT patients (p=0.0025). ^ Conclusions: It is evident from the combined analysis of these 29 published studies that the incidence of CDI in the immune suppressed population is higher. However, early diagnosis and treatment of CDI will help reduce the morbidity and mortality due to CDI in this special population.^

A systematic review of personalized therapy in patients with advanced cancer

Background: An increased understanding of the pathogenesis of cancer at the molecular level has led to the development of personalized cancer therapy based on the mutation status of the tumor. Tailoring treatments to genetic signatures has improved treatment outcomes in patients with advanced cancer. We conducted a meta-analysis to provide a quantitative summary of the response to treatment on a phase I clinical trial matched to molecular aberration in patients with advanced solid tumors. ^ Methods: Original studies that reported the results of phase I clinical trials in patients with advanced cancer treated with matched anti-cancer therapies between January 2006 and November 2011 were identified through an extensive search of Medline, Embase, Web of Science and Cochrane Library databases. Odds Ratio (OR) with 95% confidence interval (CI) was estimated for each study to assess the strength of an association between objective response rate (ORR) and mutation status. Random effects model was used to estimate the pooled OR and their 95% CI was derived. Funnel plot was used to assess publication bias. ^ Results: Thirteen studies published between January 2006 and November 2011that reported on responses to matched phase I clinical trials in patients with advanced cancer were included in the meta-analysis. Nine studies reported on the responses seen in 538 of the 835 patients with driver mutations responsive to therapy and seven studies on the responses observed in 234 of the 306 patients with mutation predictive for negative response. Random effects model was used to estimate pooled OR, which was 7.767(95% CI = 4.199 − 14.366; p-value=0.000) in patients with activating mutations that were responsive to therapy and 0.287 (95% CI = 0.119 − 0.694; p-value=0.009) in patients with mutation predictive of negative response. ^ Conclusion: It is evident from the meta-analysis that somatic mutations present in tumor tissue of patients are predictive of responses to therapy in patients with advanced cancer in phase I setting. Plethora of research and growing evidence base indicate that selection of patients based on mutation analysis of the tumor and personalizing therapy is a step forward in the war against cancer.^

A stochastic approximation algorithm with Markov chain Monte-Carlo method for incomplete data estimation problems

We propose a general procedure for solving incomplete data estimation problems. The procedure can be used to find the maximum likelihood estimate or to solve estimating equations in difficult cases such as estimation with the censored or truncated regression model, the nonlinear structural measurement error model, and the random effects model. The procedure is based on the general principle of stochastic approximation and the Markov chain Monte-Carlo method. Applying the theory on adaptive algorithms, we derive conditions under which the proposed procedure converges. Simulation studies also indicate that the proposed procedure consistently converges to the maximum likelihood estimate for the structural measurement error logistic regression model.

Confirming the Association Between Affective Disturbance and Perceived Cognitive Dysfunction Among Breast Cancer Patients: A Meta-Analysis of Available Literature

Purpose: Breast cancer is the most frequently diagnosed cancer among women worldwide. While undergoing chemotherapy treatment for breast cancer, patients often report experiencing "chemobrain." Previous literature reports correlations between psychological distress and these perceived cognitive problems. The aim of the present study was to examine the strength of the association between affective disturbance and subjective cognitive dysfunction.Methods: This study included a meta-analysis of the literature reporting a correlation between mood and subjective cognitive dysfunction. Eight studies with 1344 breast cancer patients treated with chemotherapy were selected based on stringent study inclusion criteria. Studies reporting a correlation coefficient between mood and subjective cognitive dysfunction were included.Results: In these data, there was no significant correlation between affective disturbance and subjective cognitive dysfunction. A random effects model yielded an overall weighted mean effect size of 0.12.Conclusion: Although this meta-analysis did not confirm the correlation between mood and subjective cognitive dysfunction, there was a clear association between these factors in the original disaggregated analyses, and they are clearly impactful from the time of diagnosis through long-term after care. The clinical implications of the present study and future directions for research are discussed.

A Bayesian approach to imposing curvature on distance functions

The estimated parameters of output distance functions frequently violate the monotonicity, quasi-convexity and convexity constraints implied by economic theory, leading to estimated elasticities and shadow prices that are incorrectly signed, and ultimately to perverse conclusions concerning the effects of input and output changes on productivity growth and relative efficiency levels. We show how a Bayesian approach can be used to impose these constraints on the parameters of a translog output distance function. Implementing the approach involves the use of a Gibbs sampler with data augmentation. A Metropolis-Hastings algorithm is also used within the Gibbs to simulate observations from truncated pdfs. Our methods are developed for the case where panel data is available and technical inefficiency effects are assumed to be time-invariant. Two models-a fixed effects model and a random effects model-are developed and applied to panel data on 17 European railways. We observe significant changes in estimated elasticities and shadow price ratios when regularity restrictions are imposed. (c) 2004 Elsevier B.V. All rights reserved.

Characteristics and benefits of professional work - Assessment of their importance over a 30-year career

The Professions in Australia Study is the first longitudinal investigation of the professions in Australia; it spans 33 years. Self-administered questionnaires were distributed on at least eight occasions between 1965 and 1998 to cohorts of students and later practitioners from the professions of engineering, law and medicine. The longitudinal design of this study has allowed for an investigation of individual change over time of three archetypal characteristics of the professions, service, knowledge and autonomy and two of the benefits of professional work, financial rewards and prestige. A cumulative logit random effects model was used to statistically assess changes in the ordinal response scores for measuring importance of the characteristics and benefits through stages of the career path. Individuals were also classified by average trends in response scores over time and hence professions are described through their members' tendency to follow a particular path in attitudes either of change or constancy, in relation to the importance of the five elements (characteristics and benefits). Comparisons in trends are also made between the three professions.

Methods for Categorical Longitudinal Survey Data: Understanding Employment Status of Australian Women

Many variables that are of interest in social science research are nominal variables with two or more categories, such as employment status, occupation, political preference, or self-reported health status. With longitudinal survey data it is possible to analyse the transitions of individuals between different employment states or occupations (for example). In the statistical literature, models for analysing categorical dependent variables with repeated observations belong to the family of models known as generalized linear mixed models (GLMMs). The specific GLMM for a dependent variable with three or more categories is the multinomial logit random effects model. For these models, the marginal distribution of the response does not have a closed form solution and hence numerical integration must be used to obtain maximum likelihood estimates for the model parameters. Techniques for implementing the numerical integration are available but are computationally intensive requiring a large amount of computer processing time that increases with the number of clusters (or individuals) in the data and are not always readily accessible to the practitioner in standard software. For the purposes of analysing categorical response data from a longitudinal social survey, there is clearly a need to evaluate the existing procedures for estimating multinomial logit random effects model in terms of accuracy, efficiency and computing time. The computational time will have significant implications as to the preferred approach by researchers. In this paper we evaluate statistical software procedures that utilise adaptive Gaussian quadrature and MCMC methods, with specific application to modeling employment status of women using a GLMM, over three waves of the HILDA survey.

Efficacy of memantine on behavioral and psychological symptoms related to dementia:a systematic meta-analysis

BACKGROUND: The behavioral and psychological symptoms related to dementia (BPSD) are difficult to manage and are associated with adverse patient outcomes. OBJECTIVE: To systematically analyze the data on memantine in the treatment of BPSD. METHODS: We searched MEDLINE, EMBASE, Pharm-line, the Cochrane Centre Collaboration, www.clinicaltrials.gov, www.controlled-trials.com, and PsycINFO (1966-July 2007). We contacted manufacturers and scrutinized the reference sections of articles identified in our search for further references, including conference proceedings. Two researchers (IM and CF) independently reviewed all studies identified by the search strategy. We included 6 randomized, parallel-group, double-blind studies that rated BPSD with the Neuropsychiatric Inventory (NPI) in our meta-analysis. Patients had probable Alzheimer's disease and received treatment with memantine for at least one month. Overall efficacy of memantine on the NPI was established with a t-test for the average difference between means across studies, using a random effects model. RESULTS: Five of the 6 studies identified had NPI outcome data. In these 5 studies, 868 patients were treated with memantine and 882 patients were treated with placebo. Patients on memantine improved by 1.99 on the NPI scale (95% Cl -0.08 to -3.91; p = 0.041) compared with the placebo group. CONCLUSIONS: Initial data appear to indicate that memantine decreases NPI scores and may have a role in managing BPSD. However, there are a number of limitations with the current data; the effect size was relatively small, and whether memantine produces significant clinical benefit is not clear.