Increasing FDA-accelerated approval of single-arm trials in oncology (1992 to 2020).

OBJECTIVES: We aimed to map the characteristics of single-arm trials (SAT), report the Food and Drug Administration (FDA) transparency in presenting historical control, and to assess the confirmatory randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: This metaresearch included a review of all oncology indication approved using SAT by FDA-AA (FDA-Accelerated Approval) from 1992 to 2020. Two independent reviewers identified SAT, extracted data from FDA full medical reviews for historical controls reported and MEDLINE for searching for confirmatory RCT published. RESULTS: Of 254 FDA-AA approvals, 119 (47%) were approved for oncologic indications using SAT. Fifty-four drugs for 72 oncology indications were for leukemia, lymphoma, lung cancer, urothelial cancer, multiple myeloma, and thyroid cancer. Overall, 37 (52%) treatments were converted into regular approval. Of these, 17 (46%) were based on confirmatory RCTs using overall survival (OS) as an outcome. Five indications were withdrawn from the market. Most trials outcomes were blindly assessed by independent research committees. Median trial sample size was 105 patients (min:8 to max:532). The FDA did not fully specify historical control selection in 75% of cases. CONCLUSION: The granting of FDA-AAs based on SAT in oncology is increasing with more target drugs approved over time. Transparency in historical control reporting is necessary.

Shorter versus longer durations of antibiotic treatment for patients with community-acquired pneumonia: a protocol for a systematic review and meta-analysis.

INTRODUCTION: Community-acquired pneumonia (CAP), frequently encountered in both outpatient and inpatient settings, is the leading cause of infectious disease-related mortality. While equipoise regarding the optimal duration of antimicrobial therapy to treat CAP remains, recent studies suggest shorter durations of therapy may achieve optimal outcomes. We have therefore planned a systematic review and meta-analysis evaluating the impact of shorter versus longer durations of antibiotic therapy for patients with CAP. METHODS AND ANALYSIS: We searched Ovid MEDLINE, Embase, CINAHL and Cochrane Central Register of Controlled Trials from inception to September 2021 for randomised controlled trials evaluating shorter versus longer duration of antibiotics. Eligible studies will compare durations with a minimum difference of two days of antibiotic therapy, irrespective of antibiotic agent, class, route, frequency or dosage, and will report on any patient-important outcome of benefit or harm. Paired reviewers working independently will conduct title and abstract screening, full-text screening, data extraction and risk of bias (RoB) evaluation using a modified Cochrane RoB 2.0 tool. We will perform random-effects modelling for meta-analyses, with study weights generated using the inverse variance method, and will assess certainty in effect estimates using Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. The Instrument for assessing the Credibility of Effect Modification Analyses (ICEMAN) tool will inform assessments of credibility of subgroup effects based on severity of illness, drug class, duration of therapy, setting of CAP acquisition and RoB. ETHICS AND DISSEMINATION: The results will be of importance to general practitioners and internists managing CAP, and may directly inform international clinical guidance. Where concerns regarding antimicrobial resistance continue to grow internationally, this evidence summary may motivate new recommendations regarding shorter durations of therapy. We intend to disseminate our findings via national and international conferences, and publication in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42021283990.

Less intensive antileukemic therapies (monotherapy and/or combination) for older adults with acute myeloid leukemia who are not candidates for intensive antileukemic therapy: A systematic review and meta-analysis.

INTRODUCTION: Elderly patients with acute myeloid leukemia not eligible for intensive antileukemic therapy are treated with less intensive therapies, uncertainty remains regarding their relative merits. OBJECTIVES: To compare the effectiveness and safety of less intensive antileukemic therapies for older adults with newly diagnosed AML not candidates for intensive therapies. METHODS: We included randomized controlled trials (RCTs) and non-randomized studies (NRS) comparing less intensive therapies in adults over 55 years with newly diagnosed AML. We searched MEDLINE and EMBASE from inception to August 2021. We assessed risk of bias of RCTs with a modified Cochrane Risk of Bias tool, and NRS with the Non-Randomized Studies of Interventions tool (ROBINS-I). We calculated pooled hazard ratios (HRs), risk ratios (RRs), mean differences (MD) and their 95% confidence intervals (CIs) using a random-effects pairwise meta-analyses and assessed the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: We included 27 studies (17 RCTs, 10 NRS; n = 5,698), which reported 9 comparisons. Patients were treated with azacitidine, decitabine, and low-dose cytarabine (LDAC), as monotherapies or in combination with other agents. Moderate certainty of evidence suggests no convincing difference in overall survival of patients who receive azacitidine monotherapy compared to LDAC monotherapy (HR 0.69; 95% CI, 0.31-1.53), fewer febrile neutropenia events occurred between azacitidine monotherapy to azacitidine combination (RR 0.45; 95% CI, 0.31-0.65), and, fewer neutropenia events occurred between LDAC monotherapy to decitabine monotherapy (RR 0.62; 95% CI 0.44-0.86). All other comparisons and outcomes had low or very low certainty of evidence. CONCLUSION: There is no convincing superiority in OS when comparing less intensive therapies. Azacitidine monotherapy is likely to have fewer adverse events than azacitidine combination (febrile neutropenia), and LDAC monotherapy is likely to have fewer adverse events than decitabine monotherapy (neutropenia).

Single-arm clinical trials that supported FDA accelerated approvals have modest effect sizes and were at high risk of bias.

OBJECTIVE: To describe effect sizes of single-arm clinical trials that supported AA approvals. STUDY DESIGN AND SETTING: We reviewed all the single-arm approvals granted by the FDA-AA pathway between June1992 to December2020. Two independent reviewers identified single-arm studies and extracted data from FDA Full-Medical Reviews. We performed a meta-analysis to estimate the effect sizes and compared it between studies that met post-approval FDA requirements for RCTs with those that did not. RESULTS: From the total of 254 approvals, single arm clinical trials describing effects of 54 drugs for 72 clinical indications were evaluated. The effect size estimated was OR:2.22(CI95%:1.76-2.81) [relative risk (RR) = 1.63(95CI% 1.38-1.92)]; 53% of treatments had a lower 95% CI bound crossing the null effect. Effect size did not differ between the treatments that met the FDA requirement for conducting post-approval RCTs. CONCLUSIONS AND RELEVANCE: Treatment effects observed in the FDA AA single-arm studies was modest and can be to ascribed to bias.

Methodological assessment of Mexican Clinical Practice Guidelines: GRADE framework adherence and critical appraisal.

BACKGROUND AND OBJECTIVE: Clinical Practice Guidelines (CPGs) provide evidence-based recommendations to healthcare professionals, policy makers, patients and other stakeholders. Mexico is the biggest producer of CPGs in Latin America and Caribbean countries. The National Healthcare Technology Excellence Center (acronym in Spanish: CENETEC) is responsible for the CPG development, adaptation and update. The aim of this study was to assess the adherence to the GRADE framework and to critically appraise the Mexican CPGs with the AGREE-II tool. STUDY DESIGN: We conducted a descriptive cross-sectional study with a random sample of 86 CPGs produced by CENETEC between 2015 and 2017 and published in an online database called "Catalogo Maestro". We assessed the adherence to the GRADE framework and performed a critical appraisal with the AGREE II tool. RESULTS: Of the 86 CPGs, 34 were published in 2015, 21 in 2016 and 31 in 2017. Of the 86 CPGs, 25 (29%) used the GRADE framework; adherence to GRADE standards was, however, inconsistent and generally poor. The overall methodological quality by AGREE II proved a median of 16.6% (Min 16.6%, Max 50%). CONCLUSION: CPGs produced by CENETEC during this period had a poor adherence to the GRADE framework and low score by AGREE II standards. A concerted initiative could rapidly improve CENETEC guidelines.

Efficacité et innocuité des corticostéroïdes dans le traitement de la COVID-19 selon des données pour la COVID-19, d'autres infections aux coronavirus, l'influenza, la pneumonie extrahospitalière et le syndrome de détresse respiratoire aiguë : revue systématique et méta-analyse.

CONTEXTE: Il existe très peu de données directes sur l'administration de corticostéroïdes aux patients atteints de la maladie à coronavirus 2019 (COVID-19). Les données indirectes sur des maladies associées devront donc guider les conclusions quant aux bénéfices et aux préjudices associés à cette pratique. Dans le but d'appuyer la rédaction d'une ligne directrice sur la prise en charge de la COVID-19, nous avons réalisé des revues systématiques sur les effets des corticostéroïdes dans le traitement de la COVID-19 et de maladies respiratoires aiguës sévères associées. MÉTHODES: Dans des bases de données biomédicales chinoises et internationales et des sources de prépublications, nous avons cherché les essais randomisés et contrôlés (ERC) et les études d'observation comparant des patients atteints de la COVID-19, du syndrome respiratoire aigu sévère (SRAS) ou du syndrome respiratoire du Moyen-Orient (SRMO) ayant reçu des corticostéroïdes à des patients semblables n'ayant pas reçu ce type de médicaments. Pour le syndrome de détresse respiratoire aiguë (SDRA), l'influenza et la pneumonie extrahospitalière (PEH), nous avons mis à jour les revues systématiques rigoureuses les plus récentes. Nous avons réalisé des méta-analyses à effets aléatoires pour cerner les risques relatifs, puis nous avons utilisé le risque de référence des patients atteints de la COVID-19 pour calculer les effets absolus. RÉSULTATS: Pour le SDRA, selon 1 petite étude de cohorte sur des patients atteints de la COVID-19 et 7 ERC sur des patients atteints d'une autre maladie (risque relatif : 0,72, intervalle de confiance [IC] de 95 % 0,55­0,93, différence entre les moyennes [DM] 17,3 % plus faible, données de faible qualité), les corticostéroïdes pourraient réduire le risque de mortalité. Chez les patients atteints d'une forme grave de COVID-19 sans SDRA, 2 études d'observation ont généré des données directes de très faible qualité montrant une augmentation du risque de mortalité avec l'administration de corticostéroïdes (rapport de risques 2,30, IC de 95 % 1,00­5,29, DM 11,9 % plus élevé). C'est aussi le cas de données observationnelles sur l'influenza. Des données observationnelles de très faible qualité sur le SRAS et le SRMO montrent peu ou pas de réduction dans le risque de mortalité. Des essais randomisés et contrôlés sur la PEH suggèrent que les corticostéroïdes pourraient réduire le risque de mortalité (risque relatif 0,70, IC de 95 % 0,50­0,98, DM 3,1 % plus faible, données de très faible qualité), et augmenter le risque d'hyperglycémie. INTERPRÉTATION: Les corticostéroïdes pourraient réduire le risque de mortalité pour les patients atteints de la COVID-19 avec SDRA. Pour les patients atteints d'une forme grave de COVID-19 sans SDRA, les données sur les bénéfices provenant de différentes sources sont incohérentes et de très faible qualité.

Electrophysiological subtypes and associated prognosis factors of Mexican adults diagnosed with Guillain-Barré syndrome, a single center experience.

BACKGROUND: The clinical characteristics of electrophysiological subtypes and prognostic factors of Mexican adults diagnosed with Guillain-Barré Syndrome (GBS) have not been described. MATERIALS AND METHODS: A single center, ambispective, cohort study was performed (2015-2019). GBS was defined following the Asbury and Cornblath criteria. Electrodiagnosis was made according to Hadden criteria. Clinical, biochemical and electrodiagnostic parameters were described, compared and analyzed using a multivariate model. Only patients who completed a 3-month follow-up were included. RESULTS: 137 GBS patients (92 males; mean age 46.6 ± 16.6).132 (96.3%) underwent an electrodiagnostic assessment.68 (51.5%) were classified as axonal GBS, with further classified into two groups: acute motor axonal neuropathy (AMAN) 45.4%, and acute motor and sensory axonal neuropathy (AMSAN) 8,6%. The following characteristics were lower in the AMAN group: Medical Research Counsel sumscore (MRC) 30.1 ± 16.3 vs 36.4 ± 14.4, unilateral facial palsy 10% vs 25.9% and albuminocytologic dissociation 41.3% vs. 71.7%.Multivariate analysis found AMAN as an independent predictor of an unfavorable outcome OR: 3.34 (p = 0.03) CONCLUSIONS: AMAN subtype is the most frequent presentation of GBS in Mexican adult patients and an independent predictor of inability to walk independently at 3 months after discharge.

Pharmacologic thromboprophylaxis in adult patients undergoing neurosurgical interventions for preventing venous thromboembolism.

The impact of pharmacologic prophylaxis for venous thromboembolism in patients undergoing neurosurgical intervention remains uncertain. We reviewed the efficacy and safety of pharmacologic compared with nonpharmacologic thromboprophylaxis in neurosurgical patients. Three databases were searched through April 2018, including those for randomized controlled trials (RCTs) and for nonrandomized controlled studies (NRSs). Independent reviewers assessed the certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Seven RCTs and 3 NRSs proved eligible. No studies reported on symptomatic proximal and distal deep vein thrombosis (DVT). Two RCTs reported on screening-detected proximal and distal DVTs. We used the findings of these 2 RCTs as the closest surrogate outcomes to inform the proximal and distal DVT outcomes. These 2 RCTs suggest that pharmacologic thromboprophylaxis may decrease the risk of developing asymptomatic proximal DVT (relative risk [RR], 0.50; 95% confidence interval [CI], 0.30-0.84; low certainty). Findings were uncertain for mortality (RR, 1.27; 95% CI, 0.57-2.86; low certainty), symptomatic pulmonary embolism (PE) (RR, 0.84; 95% CI, 0.03-27.42; very low certainty), asymptomatic distal DVT (RR, 0.54; 95% CI, 0.27-1.08; very low certainty), and reoperation (RR, 0.43; 95% CI, 0.06-2.84; very low certainty) outcomes. NRSs also reported uncertain findings for whether pharmacologic prophylaxis affects mortality (RR, 0.72; 95% CI, 0.46-1.13; low certainty) and PE (RR, 0.18; 95% CI, 0.01-3.76). For risk of bleeding, findings were uncertain in both RCTs (RR, 1.57; 95% CI, 0.70-3.50; low certainty) and NRSs (RR, 1.45; 95% CI, 0.30-7.12; very low certainty). In patients undergoing neurosurgical procedures, low certainty of evidence suggests that pharmacologic thromboprophylaxis confers benefit for preventing asymptomatic (screening-detected) proximal DVT with very low certainty regarding its impact on patient-important outcomes.

Efficacy and safety of corticosteroids in COVID-19 based on evidence for COVID-19, other coronavirus infections, influenza, community-acquired pneumonia and acute respiratory distress syndrome: a systematic review and meta-analysis.

BACKGROUND: Very little direct evidence exists on use of corticosteroids in patients with coronavirus disease 2019 (COVID-19). Indirect evidence from related conditions must therefore inform inferences regarding benefits and harms. To support a guideline for managing COVID-19, we conducted systematic reviews examining the impact of corticosteroids in COVID-19 and related severe acute respiratory illnesses. METHODS: We searched standard international and Chinese biomedical literature databases and prepublication sources for randomized controlled trials (RCTs) and observational studies comparing corticosteroids versus no corticosteroids in patients with COVID-19, severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS). For acute respiratory distress syndrome (ARDS), influenza and community-acquired pneumonia (CAP), we updated the most recent rigorous systematic review. We conducted random-effects meta-analyses to pool relative risks and then used baseline risk in patients with COVID-19 to generate absolute effects. RESULTS: In ARDS, according to 1 small cohort study in patients with COVID-19 and 7 RCTs in non-COVID-19 populations (risk ratio [RR] 0.72, 95% confidence interval [CI] 0.55 to 0.93, mean difference 17.3% fewer; low-quality evidence), corticosteroids may reduce mortality. In patients with severe COVID-19 but without ARDS, direct evidence from 2 observational studies provided very low-quality evidence of an increase in mortality with corticosteroids (hazard ratio [HR] 2.30, 95% CI 1.00 to 5.29, mean difference 11.9% more), as did observational data from influenza studies. Observational data from SARS and MERS studies provided very low-quality evidence of a small or no reduction in mortality. Randomized controlled trials in CAP suggest that corticosteroids may reduce mortality (RR 0.70, 95% CI 0.50 to 0.98, 3.1% lower; very low-quality evidence), and may increase hyperglycemia. INTERPRETATION: Corticosteroids may reduce mortality for patients with COVID-19 and ARDS. For patients with severe COVID-19 but without ARDS, evidence regarding benefit from different bodies of evidence is inconsistent and of very low quality.

Modafinil for people with schizophrenia or related disorders.

BACKGROUND: People with schizophrenia have a range of different symptoms, including positive symptoms (hallucinations and delusions), negative symptoms (such as social withdrawal and lack of affect), and cognitive impairment. The standard medication for people with schizophrenia is antipsychotics. However, these medications may not be effective for all symptoms of schizophrenia, as cognitive and negative symptoms are usually hard to treat. Additional therapies or medications are available for the management of these symptoms. Modafinil, a wakefulness-promoting agent most frequently used in narcolepsy or shift work sleep disorder, is one intervention that is theorised to have an effect of these symptoms. OBJECTIVES: The primary objective of this review was to assess the effects of modafinil for people with schizophrenia or related disorders. SEARCH METHODS: On 27 April 2015, 24 May 2017, and 31 October 2019, we searched the Cochrane Schizophrenia Group's register of trials, which is based on regular searches of CENTRAL, MEDLINE, Embase, AMED, BIOSIS, CINAHL, PsycINFO, PubMed, and registries of clinical trials. There are no language, time, document type, or publication status limitations for the inclusion of records in the register. SELECTION CRITERIA: We selected all randomised controlled trials comparing modafinil with placebo or other treatments for people with schizophrenia or schizophrenia-spectrum disorders. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CI. We used a random-effects model for the meta-analysis. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for the included studies. MAIN RESULTS: Eleven studies including a total of 422 participants contributed to data analyses. Most studies had a small population size (average 38 people per study) and were of short duration. We also detected a high risk of bias for selective outcome reporting in just under 50% of the trials. We therefore rated the overall methodological quality of the included studies as low. We considered seven main outcomes of interest: clinically important change in overall mental state, clinically important change in cognitive functioning, incidence of a clinically important adverse effect/event, clinically important change in global state, leaving the study early for any reason, clinically important change in quality of life, and hospital admission. All studies assessed the effects of adding modafinil to participants' usual antipsychotic treatment compared to adding placebo to usual antipsychotic treatment. Six studies found that adding modafinil to antipsychotic treatment may have little or no effect on overall mental state of people with schizophrenia, specifically the risk of worsening psychosis (RR 0.91, 95% CI 0.28 to 2.98; participants = 209; studies = 6, low-quality evidence). Regarding the effect of modafinil on cognitive function, the trials did not report clinically important change data, but one study reported endpoint scores on the MATRICS Consensus Cognitive Battery (MCCB): in this study we found no clear difference in scores between modafinil and placebo treatment groups (MD -3.10, 95% CI -10.9 to 4.7; participants = 48; studies = 1, very low-quality evidence). Only one study (N = 35) reported adverse effect/event data. In this study one serious adverse event occurred in each group (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). One study measured change in global state using the Clinical Global Impression - Improvement Scale. This study found that adding modafinil to antipsychotic treatment may have little or no effect on global state (RR 6.36, 95% CI 0.94 to 43.07, participants = 21; studies = 1, very low-quality evidence). Nine studies found that modafinil has no effect on numbers of participants leaving the study early (RR 1.26, 95% CI 0.63 to 2.52 participants = 357; studies = 9, moderate-quality evidence). None of the trials reported clinically important change in quality of life, but one study did report quality of life using endpoint scores on the Quality of Life Inventory, finding no clear difference between treatment groups (MD -0.2, 95% CI -1.18 to 0.78; participants = 20; studies = 1, very low-quality evidence). Finally, one study reported data for number of participants needing hospitalisation: one participant in each group was hospitalised (RR 0.84, 95% CI 0.06 to 12.42; participants = 35; studies = 1, very low-quality evidence). AUTHORS' CONCLUSIONS: Due to methodological issues, low sample size, and short duration of the clinical trials as well as high risk of bias for outcome reporting, most of the evidence available for this review is of very low or low quality. For results where quality is low or very low, we are uncertain or very uncertain if the effect estimates are true effects, limiting our conclusions. Specifically, we found that modafinil is no better or worse than placebo at preventing worsening of psychosis; however, we are uncertain about this result. We have more confidence that participants receiving modafinil are no more likely to leave a trial early than participants receiving placebo. However, we are very uncertain about the remaining equivocal results between modafinil and placebo for outcomes such as improvement in global state or cognitive function, incidence of adverse events, and changes in quality of life. More high-quality data are needed before firm conclusions regarding the effects of modafinil for people with schizophrenia or related disorders can be made.

Sliding scale insulin for non-critically ill hospitalised adults with diabetes mellitus.

BACKGROUND: Diabetes mellitus is a metabolic disorder resulting from a defect in insulin secretion, function, or both. Hyperglycaemia in non-critically ill hospitalised people is associated with poor clinical outcomes (infections, prolonged hospital stay, poor wound healing, higher morbidity and mortality). In the hospital setting people diagnosed with diabetes receive insulin therapy as part of their treatment in order to achieve metabolic control. However, insulin therapy can be provided by different strategies (sliding scale insulin (SSI), basal-bolus insulin, and other modalities). Sliding scale insulin is currently the most commonly used method, however there is uncertainty about which strategy provides the best patient outcomes. OBJECTIVES: To assess the effects of SSI for non-critically ill hospitalised adults with diabetes mellitus. SEARCH METHODS: We identified eligible trials by searching MEDLINE, Embase, LILACS, and the Cochrane Library. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov trial registers. The date of the last search for all databases was December 2017. We also examined reference lists of identified randomised controlled trials (RCTs) and systematic reviews, and contacted trial authors. SELECTION CRITERIA: We included RCTs comparing SSI with other strategies for glycaemic control in non-critically ill hospitalised adult participants of any sex with diabetes mellitus. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed trials for risk of bias, and evaluated the overall certainty of evidence utilising the GRADE instrument. We synthesised data using a random-effects model meta-analysis with 95% prediction intervals, if possible, or descriptive analysis, as appropriate. MAIN RESULTS: Of 720 records screened, we included eight trials that randomised 1048 participants with type 2 diabetes (387 SSI participants and 615 participants in comparator groups were available for final analysis). We included non-critically ill medical and surgical adults with the diagnosis of diabetes mellitus. The mean follow-up time was measured by the mean length of hospital stay and ranged between five and 24 days. The mean age of participants was 44.5 years to 71 years.Overall, we judged the risk of bias on the trial level as unclear for selection bias, high for outcome-related performance and detection bias with regard to hypoglycaemic episodes, other adverse events, and mean glucose levels, and low for all-cause mortality and length of hospital stay. Attrition bias was low for all outcome measures.Six trials compared SSI with a basal-bolus insulin scheme, three of which investigating 64% of all participants in this category also applying an SSI approach in the bolus comparator part. One trial had a basal insulin-only comparator arm, and the remaining trial used continuous insulin infusion as the comparator. For our main comparison of SSI versus basal-bolus insulin, the results were as follows. Four trials reported mortality data. One out of 268 participants in the SSI group (0.3%) compared with two out of 334 participants in the basal-bolus group (0.6%) died (low-certainty evidence). Severe hypoglycaemic episodes, defined as blood glucose levels below 40 mg/dL (2.2 mmol/L), showed a risk ratio (RR) of 0.22, 95% confidence interval (CI) 0.05 to 1.00; P = 0.05; 5 trials; 667 participants; very low-certainty evidence. The 95% prediction interval ranged between 0.02 and 2.57. All nine severe hypoglycaemic episodes were observed among the 369 participants on basal-bolus insulin (2.4%). The mean length of hospital stay was 0.5 days longer for the SSI group, 95% CI -0.5 to 1.4; P = 0.32; 6 trials; 717 participants; very low-certainty evidence. The 95% prediction interval ranged between -1.7 days and 2.7 days. Adverse events other than hypoglycaemic episodes, such as postoperative infections, showed a RR of 1.16, 95% CI 0.25 to 5.37; P = 0.85; 3 trials; 481 participants; very low-certainty evidence. The mean blood glucose levels ranged across basal-bolus groups from 156 mg/dL (8.7 mmol/L) to 221 mg/dL (12.3 mmol/L). The mean blood glucose level in the SSI groups was 14.8 mg/dL (0.8 mmol/L) higher (95% CI 7.8 (0.4) to 21.8 (1.2); P < 0.001; 6 trials; 717 participants; low-certainty evidence). The 95% prediction interval ranged between -3.6 mg/dL (-0.2 mmol/L) and 33.2 mg/dL (1.8 mmol/L). No trial reported on diabetes-related mortality or socioeconomic effects. AUTHORS' CONCLUSIONS: We are uncertain which insulin strategy (SSI or basal-bolus insulin) is best for non-critically hospitalised adults with diabetes mellitus. A basal-bolus insulin strategy in these patients might result in better short-term glycaemic control but could increase the risk for severe hypoglycaemic episodes. The certainty of the body of evidence comparing SSI with basal-bolus insulin was low to very low and needs to be improved by adequately performed, well-powered RCTs in different hospital environments with well-educated medical staff using identical short-acting insulins in both intervention and comparator arms to compare the rigid SSI approach with flexible insulin application strategies.

Antipsychotic combinations for schizophrenia.

BACKGROUND: Many people with schizophrenia do not achieve a satisfactory treatment response with their initial antipsychotic drug treatment. Sometimes a second antipsychotic, in combination with the first, is used in these situations. OBJECTIVES: To examine whether:1. treatment with antipsychotic combinations is effective for schizophrenia; and2. treatment with antipsychotic combinations is safe for the same illness. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register which is based on regular searches of CINAHL, BIOSIS, AMED, Embase, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. There are no language, time, document type, or publication status limitations for inclusion of records in the register. We ran searches in September 2010, August 2012 and January 2016. We checked for additional trials in the reference lists of included trials. SELECTION CRITERIA: We included all randomised and quasi-randomised controlled trials comparing antipsychotic combinations with antipsychotic monotherapy for the treatment of schizophrenia and/or schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We independently extracted data from the included studies. We analysed dichotomous data using risk ratios (RR) and the 95% confidence intervals (CI). We analysed continuous data using mean difference (MD) with a 95% CIs. For the meta-analysis we used a random-effects model. We used GRADE to complete a 'Summary of findings' table and assessed risk of bias for included studies. MAIN RESULTS: Sixty-two studies are included in the review, 31 of these compared clozapine monotherapy with clozapine combination. We considered the risk of bias in the included studies to be moderate to high. The majority of trials had unclear allocation concealment, method of randomisation and blinding, and were not free of selective reporting.There is some limited evidence that combination therapy is superior to monotherapy in improving clinical response (RR 0.73, 95% CI 0.63 to 0.85; participants = 2364; studies = 29, very low-quality evidence), although subgroup analyses show that the positive result was due to the studies with clozapine in both the monotherapy and combination groups (RR 0.66, 95% CI 0.53 to 0.83; participants = 1127; studies = 17). Few studies reported on rate of relapse, most likely due to the short length of the studies. Overall, a combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in preventing relapse (RR 0.63, 95% CI 0.31 to 1.29; participants = 512; studies = 3, very low-quality evidence), but the pooled data showed high heterogeneity (I² = 82%). A combination of antipsychotics was not superior or inferior to antipsychotic monotherapy in reducing the number of participants discontinuing treatment early (RR 0.89, 95% CI 0.73 to 1.07; participants = 3103; studies = 43, low-quality evidence). No difference was found between treatment groups in the number of participants hospitalised (RR 0.96, 95% CI 0.36 to 2.55; participants = 202; studies = 3, low-quality evidence) . We did not find evidence of a difference between treatment groups in serious adverse events or those requiring discontinuation (RR 1.05, 95% CI 0.65 to 1.69; participants = 2398; studies = 30, very low-quality evidence). There is as lack of evidence on clinically important change in quality of life, with only four studies reporting average endpoint or change data for this outcome on three different scales, none of which showed a difference between treatment groups. AUTHORS' CONCLUSIONS: Currently, most evidence regarding the use of antipsychotic combinations comes from short-term trials, limiting the assessment of long-term efficacy and safety. We found very low-quality evidence that a combination of antipsychotics may improve the clinical response. We also found low-quality evidence that a combination of antipsychotics is may make no difference at preventing participants from leaving the study early, preventing relapse and/or causing more serious adverse events than monotherapy.

Efecto de la ingesta de tortilla con inulina sobre perfil metabólico en pacientes con dislipidemia e IMC > 25 / Effect of consumption of tortilla with inulin on metabolic profile in patients with dyslipidemia and BMI > 25

Introducción: La inulina es un prebiótico usado como tratamiento alternativo o preventivo de enfermedades como la obesidad, la hiperglucemia o diabetes mellitus y la dislipidemia, una estrategia para su consumo es ofrecerla en un alimento de consumo diario como lo es la tortilla. Objetivo: Evaluar la ingesta de tortillas de maíz enriquecidas con inulina sobre perfil metabólico en pacientes con dislipidemia e IMC >25. Métodos: Ensayo clínico de 1 brazo, se incluyeron 22 pacientes con sobrepeso u obesidad (IMC ≥25) y dislipidemia; que reportaron ingesta de al menos 5 tortillas diarias, las cuales se cambiaron por tortillas enriquecidas con 1 gr de inulina por 90 días. Resultados: Se mostraron cambios en la glucosa sérica, al disminuir 10% en comparación con cifras basales (p>0.016). Se mostró tendencia clínica a disminución de insulina y colesterol total, resto sin cambios significativos. Discusión: Se encontraron diferencias clínicas con reducción de cifras de colesterol total de 40 mg en promedio, aunque no resultó estadísticamente significativo, lo que contrasta con estudios anteriores con ingesta de inulina en los cuales se reporta disminución estadísticamente significativa de los lípidos séricos como LDL y/o colesterol total, cabe señalar que la inulina utilizada fue de Agave Tequilana Weber, que presenta cambios en su estructura molecular con otras inulinas, además que en el presente estudio el consumo promedio fue de 4.32 g/día contra 7.4 g y hasta 30 g/día en otros estudios. El efecto hipoglucemiante resultante fue estadísticamente significativo para pacientes sin hiperglucemia ni diabetes, el probable mecanismo de acción es por aumento del péptido similar al glucagón tipo 1, por otra parte no hubo cambios en el peso corporal aunque la inulina suele hacer cambios en la microbiota intestinal que suele generar disminución del sobrepeso o la obesidad. Conclusiónes: El consumo diario de tortillas de maíz adicionadas de 1 g de inulina disminuye la glucemia y muestra una tendencia no estadística a disminuir los niveles de insulina sérica y colesterol total (AU)

Introduction: Inulin is a prebiotic that could help as an alternative or preventive treatment of diseases such as obesity, hyperglycemia or diabetes mellitus and dyslipidemia, a strategy for its consumption is to offer it in a food of daily consumption as is the tortilla. Objective: To evaluate the intake of corn tortillas enriched with inulin on a metabolic profile in patients with dyslipidemia and BMI> 25. Methods: One arm clinical trial included 22 patients with overweight or obesity (BMI ≥25) and dyslipidemia; That they present an ingestion of at least 5 tortillas daily, which were changed by tortillas enriched with 1 gr of inulin for 90 days. Results: Changes in serum glucose were shown, decreasing 10% compared to baseline (p> 0.016). Clinical tendency to decrease insulin and total cholesterol, rest without significant changes. Discussion: Clinical differences were found with a reduction in total cholesterol levels of 40 mg on average, but not statistically significant, which contrasts with previous inulin intake studies in which a statistically significant decrease in serum lipids such as LDL and / or Total cholesterol, it should be noted that the inulin used was Agave Tequilana Weber, which presents changes in its molecular structure versus other inulins, and in the present study the average consumption was 4.32 g / day against 7.4 g and up to 30 g / day in other studies. The resulting hypoglycaemic effect was statistically significant for patients without hyperglycemia or diabetes, the mechanism of action is by increased glucagon-like peptide type 1, on the other hand there were no changes in body weight although inulin usually makes changes in the intestinal microbiota, which usually leads to a decrease in overweight or obesity. Conclusion: The daily consumption of corn tortillas added with 1 g of inulin lowers glycemia and shows a non-statistical tendency to decrease serum insulin and total cholesterol levels (AU)

[Systematic review with meta-analysis: Subcutaneous insulin glargine coadministration for diabetic ketoacidosis]. / Revisión sistemática con metaanálisis. Coadministración de insulina glargina en el manejo de la cetoacidosis diabética (CAD).

BACKGROUND: The standard treatment of diabetic ketoacidosis involves intravenous infusion of regular insulin until recovery of the episode: this is associated with high costs. Coadministration of insulin glargine from the onset of management may prove beneficial, potentially avoiding rebound hyperglycemia, and hopefully improving the time to resolution of the disease. METHODS: We searched MEDLINE, EMBASE, and CENTRAL for randomized controlled trials comparing coadministration of insulin glargine versus standard treatment in patients with diabetic ketoacidosis. To be eligible, studies must assess the efficacy of insulin glargine and report clinically important outcomes. Two reviewers extracted data, assessed risk of bias and summarized strength of evidence using the GRADE approach. RESULTS: Four studies (135 participants during hospital follow-up) were included in this review. Low-quality evidence from three trials suggested that subcutaneously administered insulin glargine, in addition to the standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis (MD -4.19 hours; 95% CI: -7.81 to 0.57; p = 0.02). There was neutral difference between the two groups regarding length of hospital stay and hypoglycemic episodes. CONCLUSIONS: subcutaneously administered insulin glargine, in addition to standard treatment, significantly reduces the time to resolution of diabetic ketoacidosis, with neutral effects on hypoglycemic episodes.

Subcutaneous rapid-acting insulin analogues for diabetic ketoacidosis.

BACKGROUND: Diabetic ketoacidosis (DKA) is an acute, life-threatening complication of uncontrolled diabetes that mainly occurs in individuals with autoimmune type 1 diabetes, but it is not uncommon in some people with type 2 diabetes. The treatment of DKA is traditionally accomplished by the administration of intravenous infusion of regular insulin that is initiated in the emergency department and continued in an intensive care unit or a high-dependency unit environment. It is unclear whether people with DKA should be treated with other treatment modalities such as subcutaneous rapid-acting insulin analogues. OBJECTIVES: To assess the effects of subcutaneous rapid-acting insulin analogues for the treatment of diabetic ketoacidosis. SEARCH METHODS: We identified eligible trials by searching MEDLINE, PubMed, EMBASE, LILACS, CINAHL, and the Cochrane Library. We searched the trials registers WHO ICTRP Search Portal and ClinicalTrials.gov. The date of last search for all databases was 27 October 2015. We also examined reference lists of included randomised controlled trials (RCTs) and systematic reviews, and contacted trial authors. SELECTION CRITERIA: We included trials if they were RCTs comparing subcutaneous rapid-acting insulin analogues versus standard intravenous infusion in participants with DKA of any age or sex with type 1 or type 2 diabetes, and in pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data, assessed studies for risk of bias, and evaluated overall study quality utilising the GRADE instrument. We assessed the statistical heterogeneity of included studies by visually inspecting forest plots and quantifying the diversity using the I² statistic. We synthesised data using random-effects model meta-analysis or descriptive analysis, as appropriate. MAIN RESULTS: Five trials randomised 201 participants (110 participants to subcutaneous rapid-acting insulin analogues and 91 to intravenous regular insulin). The criteria for DKA were consistent with the American Diabetes Association criteria for mild or moderate DKA. The underlying cause of DKA was mostly poor compliance with diabetes therapy. Most trials did not report on type of diabetes. Younger diabetic participants and children were underrepresented in our included trials (one trial only). Four trials evaluated the effects of the rapid-acting insulin analogue lispro, and one the effects of the rapid-acting insulin analogue aspart. The mean follow-up period as measured by mean hospital stay ranged between two and seven days. Overall, risk of bias of the evaluated trials was unclear in many domains and high for performance bias for the outcome measure time to resolution of DKA.No deaths were reported in the included trials (186 participants; 3 trials; moderate- (insulin lispro) to low-quality evidence (insulin aspart)). There was very low-quality evidence to evaluate the effects of subcutaneous insulin lispro versus intravenous regular insulin on the time to resolution of DKA: mean difference (MD) 0.2 h (95% CI -1.7 to 2.1); P = 0.81; 90 participants; 2 trials. In one trial involving children with DKA, the time to reach a glucose level of 250 mg/dL was similar between insulin lispro and intravenous regular insulin. There was very low-quality evidence to evaluate the effects of subcutaneous insulin aspart versus intravenous regular insulin on the time to resolution of DKA: MD -1 h (95% CI -3.2 to 1.2); P = 0.36; 30 participants; 1 trial. There was low-quality evidence to evaluate the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin on hypoglycaemic episodes: 6 of 80 insulin lispro-treated participants compared with 9 of 76 regular insulin-treated participants reported hypoglycaemic events; risk ratio (RR) 0.59 (95% CI 0.23 to 1.52); P = 0.28; 156 participants; 4 trials. For insulin aspart compared with regular insulin, RR for hypoglycaemic episodes was 1.00 (95% CI 0.07 to 14.55); P = 1.0; 30 participants; 1 trial; low-quality evidence. Socioeconomic effects as measured by length of mean hospital stay for insulin lispro compared with regular insulin showed a MD of -0.4 days (95% CI -1 to 0.2); P = 0.22; 90 participants; 2 trials; low-quality evidence and for insulin aspart compared with regular insulin 1.1 days (95% CI -3.3 to 1.1); P = 0.32; low-quality evidence. Data on morbidity were limited, but no specific events were reported for the comparison of insulin lispro with regular insulin. No trial reported on adverse events other than hypoglycaemic episodes, and no trial investigated patient satisfaction. AUTHORS' CONCLUSIONS: Our review, which provided mainly data on adults, suggests on the basis of mostly low- to very low-quality evidence that there are neither advantages nor disadvantages when comparing the effects of subcutaneous rapid-acting insulin analogues versus intravenous regular insulin for treating mild or moderate DKA.