Correction: Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0128754.].

Gastroenteritis Therapies in Developed Countries: Systematic Review and Meta-Analysis.

CONTEXT: Gastroenteritis remains a leading cause of childhood morbidity. OBJECTIVE: Because prior reviews have focused on isolated symptoms and studies conducted in developing countries, this study focused on interventions commonly considered for use in developed countries. Intervention specific, patient-centered outcomes were selected. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Database of Systematic Reviews, trial registries, grey literature, and scientific meetings. STUDY SELECTION: Randomized controlled trials, conducted in developed countries, of children aged <18 years, with gastroenteritis, performed in emergency department or outpatient settings which evaluated oral rehydration therapy (ORT), antiemetics, probiotics or intravenous fluid administration rate. DATA EXTRACTION: The study was conducted in accordance with the Cochrane Handbook for Systematic Reviews of Interventions and the PRISMA guidelines. Data were independently extracted by multiple investigators. Analyses employed random effects models. RESULTS: 31 trials (4,444 patients) were included. ORT: Compared with intravenous rehydration, hospitalization (RR 0.80, 95%CI 0.24, 2.71) and emergency department return visits (RR 0.86, 95%CI 0.39, 1.89) were similar. Antiemetics: Fewer children administered an antiemetic required intravenous rehydration (RR 0.40, 95%CI 0.26, 0.60) While the data could not be meta-analyzed, three studies reported that ondansetron administration does increase the frequency of diarrhea. Probiotics: No studies reported on the primary outcome, three studies evaluated hospitalization within 7 days (RR 0.87, 95%CI 0.25, 2.98). Rehydration: No difference in length of stay was identified for rapid vs. standard intravenous or nasogastric rehydration. A single study found that 5% dextrose in normal saline reduced hospitalizations compared with normal saline alone (RR 0.70, 95% CI 0.53, 0.92). CONCLUSIONS: There is a paucity of patient-centered outcome evidence to support many interventions. Since ORT is a low-cost, non-invasive intervention, it should continue to be used. Routine probiotic use cannot be endorsed at this time in outpatient children with gastroenteritis. Despite some evidence that ondansetron administration increases diarrhea frequency, emergency department use leads to reductions in intravenous rehydration and hospitalization. No benefits were associated with ondansetron use following emergency department discharge.

Identifying items to assess methodological quality in physical therapy trials: a factor analysis.

BACKGROUND: Numerous tools and individual items have been proposed to assess the methodological quality of randomized controlled trials (RCTs). The frequency of use of these items varies according to health area, which suggests a lack of agreement regarding their relevance to trial quality or risk of bias. OBJECTIVE: The objectives of this study were: (1) to identify the underlying component structure of items and (2) to determine relevant items to evaluate the quality and risk of bias of trials in physical therapy by using an exploratory factor analysis (EFA). DESIGN: A methodological research design was used, and an EFA was performed. METHODS: Randomized controlled trials used for this study were randomly selected from searches of the Cochrane Database of Systematic Reviews. Two reviewers used 45 items gathered from 7 different quality tools to assess the methodological quality of the RCTs. An exploratory factor analysis was conducted using the principal axis factoring (PAF) method followed by varimax rotation. RESULTS: Principal axis factoring identified 34 items loaded on 9 common factors: (1) selection bias; (2) performance and detection bias; (3) eligibility, intervention details, and description of outcome measures; (4) psychometric properties of the main outcome; (5) contamination and adherence to treatment; (6) attrition bias; (7) data analysis; (8) sample size; and (9) control and placebo adequacy. LIMITATION: Because of the exploratory nature of the results, a confirmatory factor analysis is needed to validate this model. CONCLUSIONS: To the authors' knowledge, this is the first factor analysis to explore the underlying component items used to evaluate the methodological quality or risk of bias of RCTs in physical therapy. The items and factors represent a starting point for evaluating the methodological quality and risk of bias in physical therapy trials. Empirical evidence of the association among these items with treatment effects and a confirmatory factor analysis of these results are needed to validate these items.

Antipsychotics in adults with schizophrenia: comparative effectiveness of first-generation versus second-generation medications: a systematic review and meta-analysis.

BACKGROUND: Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in treating schizophrenia. PURPOSE: To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality,tardive dyskinesia, and a major metabolic syndrome. DATA SOURCES: English-language studies from 10 electronic databases to March 2012, reference lists of relevant articles, and gray literature. STUDY SELECTION: Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events. DATA EXTRACTION: Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SYNTHESIS: Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Positive and Negative Syndrome Scale (PANSS) was used. Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mortality for chlorpromazine verus clozapine or haloperidol versus aripiprazole,increased incidence of the metabolic syndrome for olanzapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus. LIMITATIONS: All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measurement were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability. CONCLUSION: Clear benefits of FGAs versus SGAs for treating schizophrenia remain inconclusive because of variation in assessing outcomes and lack of clinically important differences for most comparisons. The strength of evidence on safety for major medical events is low or insufficient. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Short-term effects of ambient air pollution on stroke: who is most vulnerable?

Several studies have demonstrated positive associations between day-to-day increases in air pollution and stroke. These findings have been inconsistent, and the influence of patient characteristics has been largely ignored. In this study, we investigated the short-term effects of air pollution on stroke using a time-stratified case-crossover design. Data for hospital visits for stroke were extracted from 5927 medical charts of patients who presented to emergency departments between 2003 and 2009 in Edmonton, Canada. Daily concentrations of five air pollutants (NO(2), PM (2.5), CO, O(3), and SO(2)) were obtained from fixed-site monitors. Relative humidity and temperature were obtained from a metrological station operating at the city's airport. Chart data included: disease history, medication use, and smoking status. Conditional logistic regression was used to estimate the odds ratio (OR) of stroke in relation to an increase in the interquartile range for each pollutant. Positive associations were observed between ischemic stroke and air pollution during the 'warm' season (April through September). Specifically, the OR for an increase in 9.4 ppb in the 3-day average of NO(2) was 1.50 (95% CI: 1.12, 2.01). There were no statistically significant associations with any of the other pollutants after adjusting for NO(2) concentrations. Associations with ischemic stroke were stronger for those with a history of stroke (OR=2.31; 95% CI: 1.39, 3.83), heart disease (OR=1.99; 95% CI: 1.20, 3.28), and taking medication for diabetes (OR=2.03; 95% CI: 1.14, 3.59). Temperature was inversely associated with ischemic stroke during the 'warm' season, but no associations were evident with the other stroke subtypes. Air pollution was not associated with hemorrhagic stroke or transient ischemic attacks. The findings suggest that specific patient characteristics modify associations between air pollution and ischemic stroke.

Screening and diagnosing gestational diabetes mellitus.

BACKGROUND: There is uncertainty as to the optimal approach for screening and diagnosis of gestational diabetes mellitus (GDM). Based on systematic reviews published in 2003 and 2008, the U.S. Preventive Services Task Force concluded that there was insufficient evidence upon which to make a recommendation regarding routine screening of all pregnant women. OBJECTIVES: (1) Identify properties of screening tests for GDM, (2) evaluate benefits and harms of screening for GDM, (3) assess the effects of different screening and diagnostic thresholds on outcomes for mothers and their offspring, and (4) determine the benefits and harms of treatment for a diagnosis of GDM. DATA SOURCES: We searched 15 electronic databases from 1995 to May 2012, including MEDLINE and Cochrane Central Register of Controlled Trials (which contains the Cochrane Pregnancy and Childbirth Group registry); gray literature; Web sites of relevant organizations; trial registries; and reference lists. METHODS: Two reviewers independently conducted study selection and quality assessment. One reviewer extracted data, and a second reviewer verified the data. We included published randomized and nonrandomized controlled trials and prospective and retrospective cohort studies that compared any screening or diagnostic test with any other screening or diagnostic test; any screening with no screening; women who met various thresholds for GDM with those who did not meet various criteria, where women in both groups did not receive treatment; any treatment for GDM with no treatment. We conducted a descriptive analysis for all studies and meta-analyses when appropriate. Key outcomes included preeclampsia, maternal weight gain, birth injury, shoulder dystocia, neonatal hypoglycemia, macrosomia, and long-term metabolic outcomes for the child and mother. RESULTS: The search identified 14,398 citations and included 97 studies (6 randomized controlled trials, 63 prospective cohort studies, and 28 retrospective cohort studies). Prevalence of GDM varied across studies and diagnostic criteria: American Diabetes Association (75 g) 2 to 19 percent; Carpenter and Coustan 3.6 to 38 percent; National Diabetes Data Group 1.4 to 50 percent; and World Health Organization 2 to 24.5 percent. Lack of a gold standard for the diagnosis of GDM and little evidence about the accuracy of screening strategies for GDM remain problematic. The 50 g oral glucose challenge test with a glucose threshold of 130 mg/dL versus 140 mg/dL improves sensitivity and reduces specificity. Both thresholds have high negative predictive values (NPV) but variable positive predictive values (PPVs) across a range of prevalence. There was limited evidence for the screening of GDM diagnosed less than 24 weeks' gestation (three studies). One study compared the International Association of Diabetes in Pregnancy Study Groups' (IADPSG) diagnostic criteria with a two-step strategy. Sensitivity was 82 percent, specificity was 94 percent. Only two studies examined the effects on health outcomes from screening for GDM. One retrospective cohort study (n=1,000) showed more cesarean deliveries in the screened group. A survey within a prospective cohort study (n=93) found the same incidence of macrosomia (≥4.3 kg) in screened and unscreened groups (7 percent each group). Thirty-eight studies examined health outcomes for women who met different criteria for GDM and did not undergo treatment. Methodologically strong studies showed a continuous positive relationship between increasing glucose levels and the incidence of primary cesarean section and macrosomia. One of these studies also found significantly fewer cases of preeclampsia, cesarean section, shoulder dystocia and/or birth injury, clinical neonatal hypoglycemia, and hyperbilirubinemia for women without GDM compared with those meeting IADPSG criteria. Among the other studies, fewer cases of preeclampsia were observed for women with no GDM and women who were false positive versus those meeting Carpenter and Coustan criteria. For maternal weight gain, few comparisons showed differences. For fetal birth trauma, single studies showed no differences for women with Carpenter and Coustan GDM and World Health Organization impaired glucose tolerance versus women without GDM. Women diagnosed based on National Diabetes Data Group GDM had more fetal birth trauma compared with women without GDM. Fewer cases of macrosomia were seen in the group without GDM compared with Carpenter and Coustan GDM, Carpenter and Coustan 1 abnormal oral glucose tolerance test, National Diabetes Data Group GDM, National Diabetes Data Group false positives, and World Health Organization impaired glucose tolerance. Fewer cases of neonatal hypoglycemia were found among patient groups without GDM compared with those meeting Carpenter and Coustan criteria. There was more childhood obesity for Carpenter and Coustan GDM versus patient groups with no GDM. Eleven studies compared diet modification, glucose monitoring, and insulin as needed with no treatment. Moderate evidence showed fewer cases of preeclampsia in the treated group. The evidence was insufficient for maternal weight gain and birth injury. Moderate evidence found less shoulder dystocia with treatment for GDM. Low evidence showed no difference for neonatal hypoglycemia between treated and untreated GDM. Moderate evidence showed benefits of treatment for reduction of macrosomia (>4,000 g). There was insufficient evidence for long-term metabolic outcomes among offspring. Five studies provided data on harms of treating GDM. No difference was found for cesarean delivery, induction of labor, small for gestational age, or admission to a neonatal intensive care unit. There were significantly more prenatal visits among those treated. CONCLUSIONS: While evidence supports a positive association with increasing plasma glucose on a 75 g or 100 g oral glucose tolerance test and macrosomia and primary cesarean section, clear thresholds for increased risk were not found. The 50 g oral glucose challenge test has high NPV but variable PPV. Treatment of GDM results in less preeclampsia and macrosomia. Current evidence does not show that treatment of GDM has an effect on neonatal hypoglycemia or future poor metabolic outcomes. There is little evidence of short-term harm from treating GDM other than an increased demand for services. Research is needed on the long-term metabolic outcome for offspring as a result of GDM and its treatment, and the "real world" effects of GDM treatment on use of care.

A retrospective cohort study of stroke onset: implications for characterizing short term effects from ambient air pollution.

BACKGROUND: Case-crossover studies used to investigate associations between an environmental exposure and an acute health response, such as stroke, will often use the day an individual presents to an emergency department (ED) or is admitted to hospital to infer when the stroke occurred. Similarly, they will use patient's place of residence to assign exposure. The validity of using these two data elements, typically extracted from administrative databases or patient charts, to define the time of stroke onset and to assign exposure are critical in this field of research as air pollutant concentrations are temporally and spatially variable. Our a priori hypotheses were that date of presentation differs from the date of stroke onset for a substantial number of patients, and that assigning exposure to ambient pollution using place of residence introduces an important source of exposure measurement error. The objective of this study was to improve our understanding on how these sources of errors influence risk estimates derived using a case-crossover study design. METHODS: We sought to collect survey data from stroke patients presenting to hospital EDs in Edmonton, Canada on the date, time, location and nature of activities at onset of stroke symptoms. The daily mean ambient concentrations of NO2 and PM(2.5) on the self-reported day of stroke onset was estimated from continuous fixed-site monitoring stations. RESULTS: Of the 336 participating patients, 241 were able to recall when their stroke started and 72.6% (95% confidence interval [CI]: 66.9-78.3%) experienced stroke onset the same day they presented to the ED. For subjects whose day of stroke onset differed from the day of presentation to the ED, this difference ranged from 1 to 12 days (mean = 1.8; median = 1). In these subjects, there were no systematic differences in assigned pollution levels for either NO2 or PM(2.5) when day of presentation rather than day of stroke onset was used. At the time of stroke onset, 89.9% (95% CI: 86.6-93.1%) reported that they were inside, while 84.5% (95% CI: 80.6 - 88.4%) reported that for most of the day they were within a 15 minute drive from home. We estimated that due to the mis-specification of the day of stroke onset, the risk of hospitalization for stroke would be understated by 15% and 20%, for NO2 and PM(2.5), respectively. CONCLUSIONS: Our data suggest that day of presentation and residential location data obtained from administrative records reasonably captures the time and location of stroke onset for most patients. Under these conditions, any associated errors are unlikely to be an important source of bias when estimating air pollution risks in this population.

Granule-derived granzyme B mediates the vulnerability of human neurons to T cell-induced neurotoxicity.

Multiple sclerosis (MS) is considered an autoimmune disease of the CNS and is characterized by inflammatory cells infiltrating the CNS and inducing demyelination, axonal loss, and neuronal death. Recent evidence strongly suggests that axonal and neuronal degeneration underlie the progression of permanent disability in MS. In this study, we report that human neurons are selectively susceptible to the serine-protease granzyme B (GrB) isolated from cytotoxic T cell granules. In vitro, purified human GrB induced neuronal death to the same extent as the whole activated T cell population. On the contrary, activated T cells isolated from GrB knockout mice failed to induce neuronal injury. We found that following internalization through various parts of neurons, GrB accumulated in the neuronal soma. Within the cell body, GrB diffused out of endosomes possibly through a perforin-independent mechanism and induced subsequent activation of caspases and cleavage of α-tubulin. Inhibition of caspase-3, a well-known substrate for GrB, significantly reduced GrB-mediated neurotoxicity. We demonstrated that treatment of neurons with mannose-6-phosphate prevented GrB entry and inhibited GrB-mediated neuronal death, suggesting mannose-6-phosphate receptor-dependent endocytosis. Together, our data unveil a novel mechanism by which GrB induces selective neuronal injury and suggest potential new targets for the treatment of inflammatory-mediated neurodegeneration in diseases such as MS.