Systematic Review and Network Meta-Analysis of Treatments for Chemotherapy-Naive Patients with Asymptomatic/Mildly Symptomatic Metastatic Castration-Resistant Prostate Cancer.

OBJECTIVES: To estimate the relative effectiveness of enzalutamide in chemotherapy-naive metastatic castration-resistant prostate cancer by conducting a systematic literature review and a network meta-analysis (NMA). METHODS: A systematic literature review identified randomized controlled trials comparing enzalutamide, abiraterone/prednisone, radium-223, sipuleucel-T, or docetaxel with each other or placebo in chemotherapy-naive or mixed populations (with and without prior chemotherapy) with asymptomatic/mildly symptomatic metastatic castration-resistant prostate cancer. Feasibility assessment evaluated the trials' suitability for NMA inclusion. The main outcomes were hazard ratios (HRs) for overall survival (OS) and radiographic progression-free survival (rPFS). RESULTS: Searches of relevant bibliographic databases, trial registers, Web sites, and conference abstracts conducted in October 2014 identified 25,712 records. Ten randomized controlled trials were eligible for the NMA. Enzalutamide was superior to placebo for OS and rPFS (fixed-effects model). NMA results (fixed-effects model) showed no evidence of a difference between enzalutamide and abiraterone/prednisone (HR 0.95 [95% CrI 0.77-1.16]), sipuleucel-T (HR 1.07 [95% CrI 0.84-1.37]), or radium-223 (HR 1.10 [95% CrI 0.87-1.37]) for OS. HRs were similar for the random-effects model. Nevertheless, results (fixed-effects model) suggested that enzalutamide was superior to abiraterone/prednisone (HR 0.59 [95% CrI 0.48-0.72]) and sipuleucel-T (HR 0.32 [95% CrI 0.25-0.42]) for rPFS. Results also suggested superiority of enzalutamide versus placebo, abiraterone/prednisone, or sipuleucel-T for time to chemotherapy. CONCLUSIONS: For rPFS, the NMA suggests that enzalutamide is superior to abiraterone/prednisone and sipuleucel-T. There is no evidence of a statistically significant difference in OS between enzalutamide and abiraterone/prednisone, sipuleucel-T, or radium-223. Given the limitations in network construction and underlying assumptions made to complete these analyses, results should be interpreted with caution.

A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta-analysis of the vaptans.

International and national guidelines on the treatment of chronic nonhypovolaemic hypotonic hyponatraemia differ; therefore, we have undertaken this systematic review and meta-analysis to investigate the efficacy and safety of interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia. Following registration of the review protocol with PROSPERO, systematic literature searches were conducted to identify randomized and quasi-randomized controlled trials assessing any degree of fluid restriction or any drug treatment with the aim of increasing serum sodium concentration in patients with chronic nonhypovolaemic hypotonic hyponatraemia. Where appropriate, outcome data were synthesized in a meta-analysis. A total of 45 716 bibliographic records were identified from the searches and 18 trials (assessing conivaptan, lixivaptan, tolvaptan and satavaptan) met the eligibility criteria. Results suggest that all four vasopressin receptor agonists ("vaptans") significantly improve serum sodium concentration. Lixivaptan, satavaptan and tolvaptan were associated with greater rates of response versus placebo. There was no evidence of a difference between each of the vaptans compared with placebo for mortality, discontinuation and rates of hypernatraemia. No RCT evidence of treatments other than the vaptans for hyponatraemia such as oral urea, salt tablets, mannitol, loop diuretics demeclocycline or lithium was identified. Vaptans demonstrated superiority over placebo for outcomes relating to serum sodium correction. Few trials documented the potential benefit of vaptans on change in health-related quality of life as a result of treatment. There was also a lack of high-quality RCT evidence on the comparative efficacy of the vaptans and other treatment strategies for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia.

Comparative assessment of the efficacy of onabotulinumtoxinA and oral therapies (anticholinergics and mirabegron) for overactive bladder: a systematic review and network meta-analysis.

OBJECTIVES: To compare the efficacy of onabotulinumtoxinA, mirabegron, and anticholinergics in adults with idiopathic overactive bladder (OAB) using network meta-analysis (NMA). PATIENTS AND METHODS: Information sources were searched for blinded randomised controlled trials (RCTs), of ≥2 weeks duration, comparing any dose of onabotulinumtoxinA, eligible oral/transdermal anticholinergics, or mirabegron, with each other or placebo, in adults with OAB. Bayesian random-effects models were used to synthesise the results at week 12: NMA for responder analyses and network meta-regression (NMR) for change from baseline analyses. The NMR was used to adjust for differences in baseline severity between studies. Sensitivity analysis, excluding studies considered to be at a high risk of methodological bias, was conducted. RESULTS: In all, 56 RCTs were included in the networks. For each outcome, results are reported for all licensed treatment doses. For each NMR, results are based on patients with an average number of episodes of the outcome at baseline. After 12 weeks, all treatments were more efficacious than placebo. Patients who received onabotulinumtoxinA (100 U) had, on average, the greatest reductions in urinary incontinence episodes (UIE), urgency episodes, and micturition frequency, and the highest odds of achieving decreases of 100% and ≥50% from baseline in UIE/day. When comparing onabotulinumtoxinA with other pharmacotherapies, mean differences favoured onabotulinumtoxinA 100 U over all comparators for UIE and urgency episodes (credible intervals excluded zero) and all but two of the comparators for micturition frequency. OnabotulinumtoxinA 100 U was also associated with higher odds of achieving a 100% and ≥50% decrease in UIE/day than most other licensed treatments in the network. The exclusion of studies with a high risk of bias had little impact on the conclusions. CONCLUSION: The results indicate that, after 12 weeks, onabotulinumtoxinA 100 U provides greater relief of OAB symptoms compared with most other licensed doses of other pharmacotherapies in the network.

Systematic review and network meta-analysis of tedizolid for the treatment of acute bacterial skin and skin structure infections caused by MRSA.

BACKGROUND: Tedizolid, the active moiety of tedizolid phosphate, is approved in the United States, the European Union, Canada and a number of other countries for the treatment of acute bacterial skin and skin structure infections (ABSSSI) caused by certain susceptible bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). This network meta-analysis (NMA) evaluates the comparative effectiveness of tedizolid and other antibacterials indicated for the treatment of ABSSSI caused by MRSA. METHODS: Systematic review of 10 databases was undertaken to inform an NMA to estimate the relative effectiveness of tedizolid and established monotherapy comparators (ceftaroline, daptomycin, linezolid, teicoplanin, tigecycline, vancomycin) for treating MRSA-associated ABSSSI. Randomized controlled trials enrolling adults with ABSSSI or complicated skin and skin structure infections caused by suspected/documented MRSA were eligible for inclusion. Networks were developed based on similarity of study design, patient characteristics, outcome measures and available data. Outcomes of interest included clinical response at end of therapy (EOT), post-therapy evaluation (PTE) or test-of-cure assessment and treatment discontinuations resulting from adverse events (AEs). Bayesian NMA was conducted for each outcome using fixed-effects and random effects models. RESULTS: Literature searches identified 3,618 records; 15 trials met the inclusion criteria and were considered suitable for NMA comparison. In fixed-effects models, tedizolid had higher odds of clinical response at EOT (odds ratio [OR], 1.7; credible interval, 1.0, 3.0) and PTE than vancomycin (OR, 1.6; credible interval, 1.1, 2.5). No differences in odds of clinical response at EOT or PTE were observed between tedizolid and other comparators. There was no evidence of a difference among treatments for discontinuation due to AEs. Results from random effects and fixed-effects models were generally consistent. CONCLUSIONS: Tedizolid was superior to vancomycin for clinical response at EOT and PTE. There was no evidence of a difference between tedizolid and other comparators and no evidence of a difference between tedizolid and all comparators when evaluating discontinuation due to AEs. These findings suggest that tedizolid provides an alternative option for the management of serious skin infections caused by suspected or documented MRSA. This study is subject to the limitations inherent in all NMAs, and the results should be interpreted accordingly.

The humanistic, economic and societal burden of herpes zoster in Europe: a critical review.

BACKGROUND: Herpes zoster (HZ) or "shingles" is common in persons aged 50 years or over. HZ is characterised by a painful dermatological rash which typically resolves in approximately one month. Persistent pain for months or years after rash onset, however, is a common complication of HZ; referred to as post-herpetic neuralgia (PHN). Both HZ and PHN have a significant impact on patients' lives, with considerable implications for healthcare systems and wider society. The aim of the present review is to provide comprehensive documentation and critical appraisal of published data concerning the humanistic, economic and societal burden of HZ in Europe. METHODS: Systematic literature searches were conducted in Medline, EMBASE, PsycINFO, EconLit, HEED and CRD databases. Searches were conducted in July 2014 and restricted to articles published in the past 20 years. Articles were selected for full review by two independent researchers in accordance with predefined eligibility criteria. RESULTS: From a review of 1619 abstracts, 53 eligible articles, were identified which reported data concerning healthcare resource use (n = 38), direct costs (n = 20), indirect costs (n = 16), total costs (n = 10) and impact on health-related quality of life (HRQoL) (n = 21). Findings highlight that PHN is associated with greater impairments in HRQoL and higher costs of management than HZ. For both HZ and PHN, pain severity is a significant predictor of impact on individuals, healthcare systems and society. While the incidence of HZ and PHN increase with age, age does not appear to be a key driver of overall costs for HZ and PHN. Specifically, while direct costs (e.g. GP, specialists, medications, hospitalisations) tend to be higher for older patients, indirect costs (e.g. work time missed) are higher for younger patients. CONCLUSIONS: Available evidence highlights that HZ and PHN result in significant humanistic and economic burden for patients, healthcare systems and wider societies. A tendency to focus upon healthcare resource use and the direct costs of management at the expense of other impacts (e.g. informal caregivers and formal social care) may result in an underestimation of the true burden of HZ and PHN.

Comparative efficacy of everolimus plus exemestane versus fulvestrant for hormone-receptor-positive advanced breast cancer following progression/recurrence after endocrine therapy: a network meta-analysis.

Postmenopausal women with advanced breast cancer recurring/progressing on or after initial (adjuvant or first-line) endocrine therapy may be treated multiple times with one of several endocrine or combinatorial targeted treatment options before initiating chemotherapy. In the absence of direct head-to-head comparisons of these treatment options, an indirect comparison can inform treatment choice. This network meta-analysis compared the efficacy of everolimus plus exemestane with that of fulvestrant 250 and 500 mg in the advanced breast cancer setting following adjuvant or first-line endocrine therapy. The reported hazard ratios (HRs) for progression-free survival (PFS) or time to progression from six studies that formed a network to compare everolimus plus exemestane (BOLERO-2 trial) with fulvestrant were analyzed by means of a Bayesian network meta-analysis. In the primary comparison (PFS analysis based on the local review of disease progression from BOLERO-2 with the data from the other studies), everolimus plus exemestane appeared to be more efficacious than both fulvestrant 250 mg (HR = 0.47; 95 % credible interval [CrI] 0.38-0.58) and 500 mg (HR = 0.59; 95 % CrI 0.45-0.77). Similar results were obtained in an alternate comparison based on central review of disease progression from BOLERO-2 with the data from the other studies (HR = 0.40; 95 % CrI 0.31-0.51 and HR = 0.50; 95 % CrI 0.37-0.67, respectively), and in a subgroup analysis of patients who had received prior aromatase inhibitor therapy (HR = 0.47; 95 % CrI 0.38-0.58 and HR = 0.55; 95 % CrI 0.40-0.76, respectively). These results suggest that everolimus plus exemestane may be more efficacious than fulvestrant in patients with advanced breast cancer who progress on or after adjuvant or first-line therapy with a nonsteroidal aromatase inhibitor.

Interventions for drug-using offenders with co-occurring mental illness.

BACKGROUND: This is an updated version of an original Cochrane review published in Issue 3 2006 (Perry 2006). The review represents one from a family of four reviews focusing on interventions for drug-using offenders. This specific review considers interventions aimed at reducing drug use or criminal activity, or both for drug-using offenders with co-occurring mental illness. OBJECTIVES: To assess the effectiveness of interventions for drug-using offenders with co-occurring mental illness in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases (searched between 2004 and 21 March 2013) and five internet resources (searched between 2004 and 11 November 2009). We contacted experts in the field for further information. SELECTION CRITERIA: We included randomised controlled trials designed to reduce, eliminate or prevent relapse in drug-using offenders with co-occurring mental illness. We also reported data on the cost and cost effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: We identified 76 trials across the four reviews. Following a process of pre-screening, we judged eight trials to meet the inclusion criteria for this specific review (three of the five trials are awaiting classification). The five included 1502 participants. The interventions reported on case management via a mental health drugs court, a therapeutic community, and an evaluation of a motivational interviewing technique and cognitive skills in comparison to relaxation training. The methodological quality of the trials was generally difficult to rate due to a lack of clear reporting. On most risk of bias items, we rated the majority of studies as unclear. Overall, the combined interventions did not show a statistically significant reduction in self reported drug use (2 studies, 715 participants; risk ratio (RR) 0.82, 95% confidence interval (CI) 0.44 to 1.55). A statistically significantly reduction was shown for re-incarceration (4 studies, 627 participants; RR 0.40, 95% CI 0.24 to 0.67 and mean difference (MD) 28.72, 95% CI 5.89 to 51.54) but not re-arrest (2 studies, 518 participants; RR 1.00, 95% CI 0.90 to 1.12). A specific subgroup analysis combining studies using therapeutic community interventions showed a statistically significant reduction in re-incarceration (2 studies, 266 participants; RR 0.29, 95% CI 0.16 to 0.54) but not re-arrest (1 study, 428 participants; RR 0.90, 95% CI 0.61 to 1.33). Case management via a mental health court and motivational interviewing with cognitive skills did not show a statistically significant reduction in criminal activity (1 study, 235 participants; RR 1.05, 95% CI 0.90 to 1.22) or self reported drug misuse (1 study, 162 participants; MD -7.42, 95% CI -20.12 to 5.28). Due to the small number of studies, we were unable to analyse the impact of setting on outcome. Some cost information was provided in the trials but not sufficient to be able to evaluate the cost effectiveness of the interventions. AUTHORS' CONCLUSIONS: This review highlights the paucity of evidence for drug misusing offenders with co-occurring mental health problems. Two of the five trials showed some promising results for the use of therapeutic communities and aftercare, but only in relation to reducing subsequent re-incarceration. The studies overall, showed a high degree of statistical variation demonstrating a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. More evaluations are required to assess the effectiveness of interventions for drug-using offenders with co-occurring mental health problems.

Interventions for female drug-using offenders.

BACKGROUND: This is an updated version of a Cochrane review first published in Issue 3, 2006 (Perry 2006). The review represents one in a family of four reviews focusing on the effectiveness of interventions in reducing drug use and criminal activity for offenders. This specific review considers interventions for female drug-using offenders. OBJECTIVES: To assess the effectiveness of interventions for female drug-using offenders in reducing criminal activity or drug use, or both. SEARCH METHODS: We searched 14 electronic bibliographic databases (between 2004 and 21st March 2013) and five additional web resources (between 2004 and November 2011). We contacted experts in the field for further information. SELECTION CRITERIA: We include randomised controlled trials designed to reduce, eliminate or prevent relapse in female drug-using offenders. We also report data on the cost and cost effectiveness of interventions. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: We identified 76 trials across the four reviews. Following a process of prescreening, we judged that 11 trials met the inclusion criteria of the specified review; four of the 11 trials are awaiting classification in the review. The remaining seven trials cover 1236 participants. The interventions included in this review report on therapeutic communities (TCs), gender-responsive treatment (GRT), use of case management and cognitive skills, and a pharmacological intervention using buprenorphine. Trial quality and risks of bias varied across each study. The majority of studies were rated as being at 'unclear' risk of bias due to a lack of descriptive information. Overall the interventions showed statistically significant reductions in self-reported drug use, (four studies, 734 participants, risk ratio (RR) 0.68; 95% confidence interval (CI) 0.58 to 0.80) and re-incarceration, (four studies, 745 participants, RR 0.55; 95% CI 0.41 to 0.72). We found a statistically non-significant result for re-arrest (three studies, 803 participants, RR 0.80; 95% CI 0.53 to 1.19). Individual treatment results found that TCs and a GRT programme showed a statistically significant reduction in re-incarceration (one study, 509 participants, RR 0.42; 95% CI 0.29 to 0.60) but not for re-arrest, (one study, 314 participants, RR 0.73; 95% CI 0.52 to 1.03) and self-reported drug use (two studies, 825 participants, RR 0.47; 95% CI 0.14 to 1.53). Case management and cognitive skills programmes did not significantly reduce re-arrests, (one study, 183 participants RR 1.12; 95% CI 0.89 to 1.41) or self-reported drug use, (one study, 77 participants, RR 0.65; 95% CI 0.20 to 2.12), but did show a statistically significant reduction in re-incarceration, (three studies, 236 participants, RR 0.63; 95% CI 0.49 to 0.81). Buprenorphine did not significantly reduce self-reported drug use (RR 0.58; 95% CI 0.25 to 1.35), but this result came from a single study with only 36 participants. Due to the small number of studies we were unable to analyse the impact of treatment setting on outcome. No cost and cost effectiveness evidence was reported in the studies. AUTHORS' CONCLUSIONS: The seven trials show some positive results for the use of treatments to reduce self-reported drug use and subsequent re-incarceration. However, the studies overall showed a high degree of statistical variation, requiring a degree of caution in the interpretation of the magnitude of effect and direction of benefit for treatment outcomes. Descriptions of treatment modalities are required to identify the important elements for treatment success in drug-using female offenders. More trials are required to increase the confidence with which we can draw conclusions about the effectiveness of treatments for female drug-using offenders.

Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review.

BACKGROUND: Macular oedema secondary to retinal vein occlusion (RVO) can cause vision loss due to blockage of the central retinal vein (CRVO) or a branch retinal vein (BRVO). This systematic review assessed the efficacies of widely used treatments for macular oedema secondary to RVO and the feasibility of conducting indirect comparisons between these therapies. METHODS: A systematic review was undertaken in November 2010, including a literature search for trials in medical databases and relevant websites. Abstracts, conference presentations and unpublished studies were considered. Studies were data-extracted and quality assessed by two independent researchers. Outcome measures included the mean change in best corrected visual acuity (BCVA) from baseline in the study eye and/or number of patients gaining at least 10 letters from baseline to 6 months or the nearest equivalent time point. RESULTS: Fourteen unique randomized controlled trials (RCTs) were identified. Ranibizumab 0.5 mg produced greater improvements in BCVA at 6 months than sham in BRVO (mean difference 11.0 letters, 95% confidence interval [CI] 7.83, 14.17) and CRVO (mean difference 14.10 letters, 95% CI 10.51, 17.69) in two double-blind sham-controlled RCTs. Pooled data from two double-blind, sham-controlled RCTs showed that improvements in BCVA were also significantly better for dexamethasone intravitreal (IVT) implant 0.7 mg compared with sham in patients with BRVO or CRVO (mean difference 2.5 letters, 95% CI 0.7, 4.3); the difference was significant for BRVO alone, but not CRVO alone. A significantly greater proportion of patients with BRVO gained ≥15 letters with laser therapy vs. no treatment at 36 months in a large prospective RCT (odds ratio 3.16, 95% CI 1.25, 8.00), whereas no difference was observed at 9 months in a smaller study. Three studies reported no benefit for laser therapy in CRVO. No indirect comparisons with ranibizumab were feasible due to differences in study design and baseline characteristics. CONCLUSIONS: Data from RCTs for ranibizumab and dexamethasone IVT demonstrate that both new agents constitute significant improvements over the previously widely accepted standard of care (laser therapy) for the treatment of BRVO and CRVO. However, head-to-head studies are needed to assess the relative efficacies of licensed therapies for RVO.

Searching ClinicalTrials.gov and the International Clinical Trials Registry Platform to inform systematic reviews: what are the optimal search approaches?

BACKGROUND: Since 2005, International Committee of Medical Journal Editors (ICMJE) member journals have required that clinical trials be registered in publicly available trials registers before they are considered for publication. OBJECTIVES: The research explores whether it is adequate, when searching to inform systematic reviews, to search for relevant clinical trials using only public trials registers and to identify the optimal search approaches in trials registers. METHODS: A search was conducted in ClinicalTrials.gov and the International Clinical Trials Registry Platform (ICTRP) for research studies that had been included in eight systematic reviews. Four search approaches (highly sensitive, sensitive, precise, and highly precise) were performed using the basic and advanced interfaces in both resources. RESULTS: On average, 84% of studies were not listed in either resource. The largest number of included studies was retrieved in ClinicalTrials.gov and ICTRP when a sensitive search approach was used in the basic interface. The use of the advanced interface maintained or improved sensitivity in 16 of 19 strategies for Clinicaltrials.gov and 8 of 18 for ICTRP. No single search approach was sensitive enough to identify all studies included in the 6 reviews. CONCLUSIONS: Trials registers cannot yet be relied upon as the sole means to locate trials for systematic reviews. Trials registers lag behind the major bibliographic databases in terms of their search interfaces. IMPLICATIONS: For systematic reviews, trials registers and major bibliographic databases should be searched. Trials registers should be searched using sensitive approaches, and both the registers consulted in this study should be searched.

Reporting methodological search filter performance comparisons: a literature review.

BACKGROUND: Methodological search filters are tools for retrieving database records reporting studies which use a specific research method. Choosing a filter is likely to be based on filter performance data. This review examines which measures are reported, and the way that filter performance is presented, in filter comparisons. METHODS: Studies were identified from the current content and pending update (2010) of a filter website. Eligible studies compared two or more methodological search filters designed to identify randomised controlled trials, diagnostic test accuracy studies, systematic reviews or economic evaluations. RESULTS: Eighteen studies met the inclusion criteria. The number of filters compared in a single study ranged from 2 to 38. The most commonly reported measures were sensitivity/recall and precision. All studies displayed results in tables and gave results as percentages or proportions. Two studies supplemented results tables with graphical displays of data: a bar graph of the proportion of retrieved and missed gold standard references per filter; a forest plot of the overall sensitivity and specificity of each filter. CONCLUSIONS: Sensitivity/recall and precision are the most frequently reported performance measures. This review highlights the potential for presenting results in novel and innovative ways to aid filter selection.

Choosing and using methodological search filters: searchers' views.

BACKGROUND: Search filters or hedges are search strategies developed to assist information specialists and librarians to retrieve different types of evidence from bibliographic databases. The objectives of this project were to learn about searchers' filter use, how searchers choose search filters and what information they would like to receive to inform their choices. METHODS: Interviews with information specialists working in, or for, the National Institute for Health and Care Excellence (NICE) were conducted. An online questionnaire survey was also conducted and advertised via a range of email lists. RESULTS: Sixteen interviews were undertaken and 90 completed questionnaires were received. The use of search filters tends to be linked to reducing a large amount of literature, introducing focus and assisting with searches that are based on a single study type. Respondents use numerous ways to identify search filters and can find choosing between different filters problematic because of knowledge gaps and lack of time. CONCLUSIONS: Search filters are used mainly for reducing large result sets (introducing focus) and assisting with searches focused on a single study type. Features that would help with choosing filters include making information about filters less technical, offering ratings and providing more detail about filter validation strategies and filter provenance.

Renal denervation for uncontrolled hypertension: a systematic review and meta-analysis examining multiple subgroups.

This systematic review and meta-analysis was conducted to assess the randomized controlled trial (RCT) evidence available for renal denervation (RDN) in uncontrolled arterial hypertension. Twenty-five RCTs met the eligibility criteria for the systematic review, and 16 RCTs were included in the meta-analysis. The results of the random effects meta-analysis estimated a mean difference of -8.5 mmHg [95% confidence interval (CI) -13.5 to -3.6] for office SBP, -3.6 mmHg (95% CI -5.2 to -2.0) for 24 h SBP and -3.9 mmHg (95% CI -5.6 to -2.2) for ambulatory daytime SBP in favour of RDN compared with control (medication and/or sham-only) at primary follow-up. Similarly favourable results were observed across a range of prespecified subgroup analyses, including treatment-resistant hypertension. This meta-analysis suggests that the use of RDN in uncontrolled hypertension leads to consistent reductions in blood pressure. Reductions appear to be statistically consistent in the presence or absence of medications and in populations resistant to the use of three medications.

Pharmacological interventions for drug-using offenders.

BACKGROUND: The review represents one in a family of four reviews focusing on a range of different interventions for drug-using offenders. This specific review considers pharmacological interventions aimed at reducing drug use and/or criminal activity for illicit drug-using offenders. OBJECTIVES: To assess the effectiveness of pharmacological interventions for drug-using offenders in reducing criminal activity and/or drug use. SEARCH METHODS: Fourteen electronic bibliographic databases (searched between 2004 and 21 March 2013) and five additional Web resources (searched between 2004 and 11 November 2011) were searched. Experts in the field were contacted for further information. SELECTION CRITERIA: Randomised controlled trials assessing the efficacy of any pharmacological interventions for reducing, eliminating or preventing relapse in drug-using offenders were included. Data on the cost and cost-effectiveness of interventions were reported. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by The Cochrane Collaboration. MAIN RESULTS: A total of 76 trials across the four reviews were identified. After a process of prescreening had been completed, 17 trials were judged to meet the inclusion criteria for this specific review (six of the 17 trials are awaiting classification for the review). The remaining 11 trials contained a total of 2,678 participants. Nine of the eleven studies used samples with a majority of men. The interventions (buprenorphine, methadone and naltrexone) were compared to non pharmacological treatments (e.g., counselling) and other pharmacological drugs. The methodological trial quality was poorly described, and most studies were rated as 'unclear' by the reviewers. The biggest threats to risk of bias were generated through blinding (performance and detection bias) and incomplete outcome data (attrition bias). When combined, the results suggest that pharmacological interventions do significantly reduce subsequent drug use using biological measures, (three studies, 300 participants, RR 0.71 (95% CI 0.52 to 0.97)), self report dichotomous data (three studies, 317 participants, RR 0.42, (95% CI 0.22 to 0.81)) and continuous measures (one study, MD -59.66 (95% CI -120.60 to 1.28)) . In the subgroups analysis for community setting, (two studies, 99 participants: RR 0.62 (95% CI 0.35 to 1.09)) and for secure establishment setting, (one study, 201 participants: RR 0.76 (95% CI 0.52 to 1.10)), the results are no longer statistically significant. Criminal activity was significantly reduced favouring the dichotomous measures of re arrest, (one study, 62 participants, RR 0.60 (95% CI 0.32 to 1.14)), re-incarceration, (three studies, 142 participants, RR 0.33 (95% CI 0.19 to 0.56)) and continuous measures (one study, 51 participants, MD -74.21 (95% CI -133.53 to -14.89)). Findings on the effects of individual pharmacological interventions on drug use and criminal activity show mixed results. Buprenorphine in comparison to a non pharmacological treatment seemed to favour buprenorphine but not significantly with self report drug use, (one study, 36 participants, RR 0.58 (95% CI 0.25 to 1.35)). Methadone and cognitive behavioural skills in comparison to standard psychiatric services, did show a significant reduction for self report dichotomous drug use (one study, 253 participants, RR 0.43 (95% CI 0.33 to 0.56)) but not for self report continuous data (one study 51 participants) MD -0.52 (95% CI -1.09 to 0.05)), or re incarceration RR 1.23 (95% CI 0.53 to 2.87)). Naltrexone was favoured significantly over routine parole and probation for re incarceration (two studies 114 participants, RR 0.36 (95% CI 0.19 to 0.69)) but no data was available on drug use. Finally, we compared each pharmacological treatment to another. In each case we compared methadone to: buprenorphine, diamorphine and naltrexone. No significant differences were displayed for either treatment for self report dichotomous drug use (one study, 193 participants RR 1.23 (95% CI 0.86 to 1.76)), continuous measures of drug use MD 0.70 (95% CI -5.33 to 6.73) or criminal activity RR 1.25 (95% CI 0.83 to 1.88)) between methadone and buprenorphine. Similiar results were found for comparisons with Diamorphine with no significant differences between the drugs for self report dichotomous drug use for arrest (one study, 825 participants RR 1.25 (95% CI 1.03-1.51)) or Naltrexone for dichotomous measures of re incarceration (one study, 44 participants, RR 1.10 (95% CI 0.37 to 3.26)), and continuous outcome measure of crime MD -0.50 (95% CI -8.04 to 7.04)) or self report drug use MD 4.60 (95% CI -3.54 to 12.74)). AUTHORS' CONCLUSIONS: Pharmacological interventions for drug-using offenders do appear to reduce overall subsequent drug use and criminal activity (but to a lesser extent). No statistically significant differences were displayed by treatment setting. Individual differences are displayed between the three pharmacological interventions (buprenorphine, methadone and naltrexone) when compared to a non pharmacological intervention, but not when compared to each other. Caution should be taken when interpreting these findings, as the conclusions are based on a small number of trials, and generalisation of these study findings should be limited mainly to male adult offenders. Additionally, many studies were rated at high risk of bias because trial information was inadequately described.

Systematic literature review and network meta-analysis of lurasidone, brexpiprazole and cariprazine for schizophrenia.

A systematic review was undertaken to identify randomized controlled trials (RCTs) comparing the efficacy and safety of lurasidone, brexpiprazole and cariprazine (selected because of a shared safety profile) with each other or placebo in adult patients with schizophrenia. Key outcomes included: Positive and Negative Syndrome Scales (PANSS), Clinical Global Impression-Severity (CGI-S) scores and cardiovascular and metabolic parameters. A feasibility assessment evaluated the trials' suitability for inclusion in a Bayesian network meta-analysis (NMA). Random effects models were used. In total, 1138 records were identified and 19 RCTs contributed to the NMA. Lurasidone doses of 160 mg performed best in terms of change in PANSS and CGI-S scores at 6 weeks, with stronger evidence when compared with brexpiprazole than cariprazine. The safety outcomes were variable; for all treatments, the 95% credible intervals usually contained 'no difference'. Active treatments were associated with lower odds of discontinuation due to any cause, and higher odds of experiencing any adverse event. Lurasidone was comparable to brexpiprazole and cariprazine for efficacy and safety outcomes assessed at 6 weeks, with the 160 mg dose being superior for the change in PANSS and CGI-S outcomes. The lurasidone results were relatively consistent across doses compared with brexpiprazole and cariprazine.

A Network Meta-Analysis of Cancer Immunotherapies Versus Chemotherapy for First-Line Treatment of Patients With Non-Small Cell Lung Cancer and High Programmed Death-Ligand 1 Expression.

In the absence of head-to-head trials of first-line treatments for metastatic non-small cell lung cancer (NSCLC), synthesis of available evidence is needed. We conducted a systematic literature review and network meta-analysis of randomized controlled trials in patients with stage IV NSCLC and high programmed death-ligand 1 (PD-L1) expression. Patients with other-stage NSCLC or without PD-L1 expression and populations with < 80% stage IV NSCLC were excluded. Outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events. English records from MEDLINE and Embase published through October 2020 were eligible, supplemented by hand searches of other sources. Three evidence networks were constructed based on histology (mixed, squamous, non-squamous). OS and PFS results were analyzed applying Bayesian fractional polynomial random-effects models. Hazard ratios over time with 95% credible intervals (CrIs) and expected differences in OS and PFS between each cancer immunotherapy regimen and the chemotherapy common comparator were generated. Seventeen clinical trials were included after screening 32,527 records. Heterogeneity and risk of bias were generally low across trials. In the mixed-histology network of PD-L1-high patients, expected OS was significantly longer with atezolizumab (estimated difference: 10.4 months [95% CrI: 1.9, 18.2]), pembrolizumab (7.2 [2.2, 12.3]), and cemiplimab (13.0 [4.2, 21.0]) versus chemotherapy but not with nivolumab (3.5 [-2.5, 10.6]) or nivolumab plus ipilimumab (6.7 [-0.5, 14.2]) versus chemotherapy. OS improvements were not significant compared with chemotherapy for any regimen in the squamous and non-squamous networks, except pembrolizumab plus chemotherapy in the non-squamous network. All regimens showed significantly longer expected PFS versus chemotherapy in the non-squamous network, whereas the increases were not significant in the mixed or squamous networks. ORR was significantly higher with pembrolizumab and cemiplimab versus chemotherapy in the mixed-histology network, with sintilimab in the non-squamous network, and with combination regimens, including pembrolizumab or atezolizumab, in the squamous and non-squamous networks, except with atezolizumab plus carboplatin, paclitaxel, and bevacizumab. Survival and safety versus chemotherapy were generally similar across cancer immunotherapies and histology networks. These findings may support treatment decisions for patients with high PD-L1 status receiving first-line treatment for NSCLC.

Risk factors for carbapenem-resistant Gram-negative bacterial infections: a systematic review.

BACKGROUND: Rapid and widespread increases in carbapenem resistance (CR) necessitate identification of risk factors to guide appropriate interventions. OBJECTIVES: We aimed to identify risk factors for CR Gram-negative infection through a systematic literature review. DATA SOURCES: We searched MEDLINE (via OvidSP and PubMed) and Embase (via OvidSP) databases and the Cochrane Central Register of Controlled Trials. STUDY ELIGIBILITY CRITERIA: Prospective or retrospective cohort and case-control studies reporting quantitative data on risk factors associated with infections due to CR Gram-negative pathogens in hospitalized patients were eligible. PARTICIPANTS: Studies included hospitalized patients with CR infection caused by Gram-negative bacterial pathogens (Enterobacterales and non-fermenters). METHODS: Searches were conducted in January 2018/December 2019 to identify studies published since 2007. Risk factor data were extracted and grouped by factor. The primary metric was proportion of studies reporting a significant association with CR infection for each factor. RESULTS: In total, 92 studies were identified. Risk factors most frequently reported as significantly associated with CR infection (>10 studies) were previous antibiotic use (91.1%; 72/79 studies); previous carbapenem use (82.6%; 57/69); previous colonization (72.7%; 8/11); mechanical ventilation (66.7%; 36/54); previous intensive care unit stay (64.4%; 38/59); dialysis (61.1%; 11/18); catheter (58.0%; 40/69); length of stay in hospital (54.5%; 30/55); comorbidities (52.7%; 39/74); APACHE II (51.7%; 15/29); and intubation (51.4%; 18/35). Risk factors were mostly consistent across different species and sites of infection. CONCLUSIONS: Several variables, particularly previous antibiotic use, are strong risk factors for CR infection. Interventions to mitigate against CR infection should target these factors.

A Systematic Literature Review and Bucher Indirect Comparison: Tildrakizumab versus Guselkumab.

BACKGROUND: Psoriasis is a chronic inflammatory skin condition that impacts quality of life and requires long-term treatment and effective symptom management. Interleukin-23 (IL-23) has emerged as a key player in the pathogenesis of psoriasis and tildrakizumab and guselkumab are both immunomodulatory agents that inhibit the p19 subunit of IL-23. In its pivotal Phase III trial, tildrakizumab demonstrated greater efficacy than etanercept in moderate-to-severe psoriasis. However, there are no head-to-head trials comparing tildrakizumab with guselkumab. METHODS: We conducted a systematic literature review and Bucher indirect comparison of tildrakizumab and guselkumab, using placebo as a common comparator. We searched MEDLINE, MEDLINE In-Process, MEDLINE(R) Daily Epub Ahead of Print, and Cochrane Central Register of Controlled Trials for Phase III randomized controlled trials between 1946 and November 2018. Inclusion criteria were adult patients ≥18 years with moderate-to-severe chronic plaque psoriasis, and intervention with tildrakizumab or guselkumab compared to placebo or best supportive care. Outcomes included were severity of psoriasis as defined by the Psoriasis Area and Severity Index (PASI) 75 and PASI 90, frequency of serious adverse events (SAEs), and treatment discontinuations. Outcomes were evaluated at Weeks 12 to 16 and 24 to 28. Analysis was based on the intent-to-treat population and, for all outcomes, the number of events reported were analyzed as a proportion of the number of patients randomized to ensure consistency across trials. RESULTS: Overall, 154 unique records were identified. Five studies met the eligibility criteria and were included in the analysis; two tildrakizumab trials (reSURFACE 1 and reSURFACE 2) and three guselkumab trials (VOYAGE 1, VOYAGE 2, and a Japanese study). There was no statistically significant difference between guselkumab and tildrakizumab for PASI 75, PASI 90, SAEs, and rate of discontinuations at either timepoint. CONCLUSION: This study assessed the comparative efficacy of tildrakizumab and guselkumab for the treatment of moderate-to-severe psoriasis. Limitations included the limited number of publications, imputation of placebo arm values for Weeks 24 to 28, and limited relevance of the Japanese study. This indirect comparison does not provide evidence that one treatment is superior to the other.

Systematic review of the impact of appropriate versus inappropriate initial antibiotic therapy on outcomes of patients with severe bacterial infections.

We investigated the impact of appropriate versus inappropriate initial antimicrobial therapy on the clinical outcomes of patients with severe bacterial infections as part of a systematic review and meta-analyses assessing the impact of delay in appropriate antimicrobial therapy. Literature searches of MEDLINE and Embase, conducted on 24 July 2018, identified studies published after 2007 reporting the impact of delay in appropriate antibiotic therapy for hospitalised adult patients with bacterial infections. Results were statistically pooled for outcomes including mortality, hospital length of stay (LOS) and treatment failure. Subgroup analyses were explored by site of infection where data permitted. Inclusion criteria were met by 145 studies, of which 114 reported data on the impact of appropriate versus inappropriate initial therapy. In the pooled analysis, rates of mortality were significantly in favour of appropriate therapy [odds ratio (OR) = 0.44, 95% CI 0.38-0.50]. Across eight studies, LOS was shorter with appropriate therapy compared with inappropriate therapy [mean difference (MD) -2.54 days (95% CI -5.30 to 0.23)], but not significantly so. The incidence of treatment failure was significantly lower in patients who received appropriate therapy compared with patients who received inappropriate therapy (six studies: OR = 0.33, 95% CI 0.16-0.66) as was mean hospital costs (four studies: MD -7.38 thousand US$ or Euros, 95% CI -14.14 to -0.62). Initiation of appropriate versus inappropriate antibiotics can reduce mortality, reduce treatment failure and decrease LOS, highlighting the importance of broad­spectrum empirical therapy and rapid diagnostics for early identification of the causative pathogen. [Study registration: PROSPERO: CRD42018104669].

A Systematic Review of the Effect of Delayed Appropriate Antibiotic Treatment on the Outcomes of Patients With Severe Bacterial Infections.

BACKGROUND: Patients with severe bacterial infections often experience delay in receiving appropriate treatment. Consolidated evidence of the impact of delayed appropriate treatment is needed to guide treatment and improve outcomes. RESEARCH QUESTION: What is the impact of delayed appropriate antibacterial therapy on clinical outcomes in patients with severe bacterial infections? STUDY DESIGN AND METHODS: Literature searches of MEDLINE and Embase, conducted on July 24, 2018, identified studies published after 2007 reporting the impact of delayed appropriate therapy on clinical outcomes for hospitalized adult patients with bacterial infections. Where appropriate, results were pooled and analyzed with delayed therapy modeled three ways: delay vs no delay in receiving appropriate therapy; duration of delay; and inappropriate vs appropriate initial therapy. This article reports meta-analyses on the effect of delay and duration of delay. RESULTS: The eligibility criteria were met by 145 studies, of which 37 contributed data to analyses of effect of delay. Mortality was significantly lower in patients receiving appropriate therapy without delay compared with those experiencing delay (OR, 0.57; 95% CI, 0.45-0.72). Mortality was also lower in the no-delay group compared with the delay group in subgroups of studies reporting mortality at 20 to 30 days, during ICU stay, or in patients with bacteremia (OR, 0.57 [95% CI, 0.43-0.76]; OR, 0.47 [95% CI, 0.27-0.80]; and OR, 0.54 [95% CI, 0.40-0.75], respectively). No difference was found in time to appropriate therapy between those who died and those who survived (P = .09), but heterogeneity between studies was high. INTERPRETATION: Avoiding delayed appropriate therapy is essential to reduce mortality in patients with severe bacterial infections. CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42018104669; URL: www.crd.york.ac.uk/prospero/.