Bifeprunox versus placebo for schizophrenia.

BACKGROUND: Bifeprunox is a novel antipsychotic drug designed to treat schizophrenia. However, research into the drug was ceased in 2009 due to rejection of licence to go to market by the US Food and Drug Administration (FDA), who could not approve the drug for acute or long-term symptoms of schizophrenia because more research was required to demonstrate convincing effects "beyond those already achieved" with currently licenced drugs. There were also concerns expressed over one death of a person whilst on the drug. OBJECTIVES: To investigate the clinical and adverse effects of bifeprunox for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Trials Register on 23 October 2015, which is based on regular searches of MEDLINE, EMBASE, CINAHL, BIOSIS, AMED, PubMed, PsycINFO, and clinical trials registries. There are no language, date, document type, or publication status limitations for inclusion of records in the register. SELECTION CRITERIA: All randomised clinical trials focusing on bifeprunox versus placebo for schizophrenia. DATA COLLECTION AND ANALYSIS: We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE. MAIN RESULTS: We included four randomised controlled trials (RCTs). We found evidence of missing data and poor reporting. When bifeprunox 20 mg was compared with placebo for schizophrenia, the drug resulted in a reduction of the Positive and Negative Syndrome Scale (PANSS) positive subscale score regarding positive symptoms (n = 549, 2 RCTs, MD -1.89, 95% CI -2.85 to -0.92, low-quality evidence) and the PANSS negative subscale regarding negative symptoms (n = 549, 2 RCTs, MD -1.53, 95% CI -2.37 to -0.69, low-quality evidence). There was a clear improvement regarding deterioration in the bifeprunox 20 mg group (n = 231, 1 RCT, RR 0.71 95% CI, 0.54 to 0.93, very low-quality evidence). The total number of participants with equal to or greater than 7% weight increase was similar between bifeprunox and placebo (n = 483, 1 RCT, RR 1.02 95% CI 0.31 to 3.33 moderate-quality evidence). There were no useable data for quality of life, economic outcomes, and service use. AUTHORS' CONCLUSIONS: Our results showed some positive effects and a favourable adverse effect profile for bifeprunox, although there were few data overall and none were of high quality. It would seem that these data alone would not have been enough for the FDA to decide to halt progress of the drug to market. We can only assume that we are missing important data. Both the FDA and the relevant pharmaceutical companies have not made all relevant data accessible. As some of these trials also involved an additional haloperidol, olanzapine, quetiapine, or risperidone arm, these data are not only relevant to evaluation of bifeprunox. In not making all data accessible, it is hard to see how the FDA and the drug companies have fulfilled their full obligations to people with schizophrenia or their clinicians.

Evaluation of fliC-d based direct blood PCR assays for typhoid diagnosis.

BACKGROUND: Typhoid cases need to be diagnosed accurately for early antibiotic therapy and reducing mortality. Identification of Salmonella Typhi (S. Typhi) in blood culture is conclusive, but has poor sensitivity. Detection of S. Typhi by PCR from blood sample has shown promise. Real-time quantitative PCR (Q-PCR) has been widely used in diagnostics for its rapidity and reliability. In the present study, the performance of molecular methods like conventional PCR (C-PCR), nested PCR (N-PCR) and Q-PCR were investigated and compared by targeting S. Typhi specific flagellar fliC-d gene directly in blood samples for typhoid diagnosis. RESULTS: Analytical sensitivities and specificities of the PCR assays were determined under laboratory condition followed by diagnostic performances were demonstrated in 110 clinically diagnosed typhoid fever (CDTF) cases included as study subjects. The DNA detection limit of C-PCR was observed 3 × 10(4) copies/reaction; those of N-PCR and Q-PCR (cutoff Ct value, ≤37) were 3 copies/reaction. The C-PCR was not further evaluated since it showed negative results with all clinical samples due to low sensitivity. Low isolation rate (21.8 %, 24/110) of S. Typhi by blood culture did not reflect the true burden of typhoid fever among the study subjects. Hence diagnostic performances of N-PCR and Q-PCR were determined considering CDTF cases positive by any of the diagnostic assay methods (n = 81) as true positives. Laboratory confirmed non-typhoidal cases (n = 29) were included as true negatives. On comparison, although both the assays were 100 % specific; sensitivity (91.4 % vs. 81.5 %) and efficiency (93.6 % vs. 86.4 %) of Q-PCR were better, but statistically not significant (p > 0.1) than N-PCR. The positive and negative likelihood ratios of Q-PCR were ∞ and 0.09 which indicated the potential clinical utility of Q-PCR for typhoid diagnosis. Q-PCR was more rapid than N-PCR (2 h vs. 6 h) in obtaining test results. CONCLUSIONS: This study demonstrates for the first time that TaqMan-based Q-PCR assay performs more favorably than N-PCR for direct detection of S. Typhi DNA in blood samples. Direct and quantitative blood Q-PCR is a rapid and reliable method for diagnosis of typhoid fever.