Ivan D. Florez

The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: A systematic review and meta‐analysis

We aimed to assess the effectiveness of adding metformin to insulin in type 1 diabetes mellitus (T1DM) children for improving metabolic outcomes. We performed a systematic review and meta‐analysis of randomized controlled trials (RCTs) conducted on children age 6 to 19 years who are diagnosed with T1DM, and examined the effect of adding Metformin to standard insulin therapy. We performed literature searches on Ovid Midline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from the date of inception of the database to February 15, 2016. Two reviewers screened titles and abstracts independently, assessed full text eligibility, and extracted information from eligible trials. The primary outcome is glycated hemoglobin (HbA1c), and the secondary outcomes are health‐related quality of life, body mass index (BMI), lipid profile, total insulin daily dose, hypoglycaemia, and diabetes ketoacidosis. We screened 736 studies, and included 6 RCTs with 325 patients. All RCTs were of low risk of bias, and included adolescents (mean age 15 years). The meta‐analysis showed that the addition of Metformin resulted in decreased total insulin daily dose (TIDD) (unit/kg/d) (mean difference [MD] = −0.15, 95%CI, −0.24, −0.06), and reduced BMI kg/m2 (MD −1.46, 95%CI −2.54, 0.38), and BMI z‐score (MD= − 0.11, 95%CI −0.21, −0.01), and similar HbA1c (%) (MD= − 0.05, 95%CI, −0.19, 0.29). The overall evidence quality was high to moderate. Current evidence does not support use of Metformin in T1DM adolescents to improve HbA1c. However, Metformin may provide modest reduction in TIDD and BMI.

Metformin or Oral Contraceptives for Adolescents With Polycystic Ovarian Syndrome: A Meta-analysis.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is a common disease. There is limited evidence to support various treatment choices. This leads to variable treatment practices. OBJECTIVES: To conduct a systematic review and meta-analysis of randomized controlled trials (RCTs) to evaluate the use of metformin versus oral contraceptive pills (OCPs) for the treatment of PCOS in adolescents aged 11 to 19 years. DATA SOURCES: We performed literature searches through Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials, and gray literature resources, up to January 29, 2015. STUDY SELECTION AND DATA EXTRACTION: Two reviewers screened titles and abstracts of identified citations, assessed full text eligibility, and extracted information from eligible trials. RESULTS: Four RCTs met the inclusion and exclusion criteria. The reviewed evidence came from 170 patients. Overall, OCP treatment resulted in modest improvement in menstrual cycle frequency (weighted mean difference [WMD] = 0.27, P < .01, 95% confidence interval [CI] −0.33 to −0.21) and mild reduction of acne scores (WMD = 0.3, P = .02, 95% CI 0.05 to 0.55). While metformin resulted in greater BMI reduction (WMD = −4.02, P < .01, 95% CI −5.23 to −2.81) it was associated with decreased dysglycemia prevalence (risk ratio: 0.41, P = .02, 95% CI 0.19 to 0.86) and improved total cholesterol and low-density lipoprotein levels. Metformin and OCPs were similar in terms of impact on hirsutism. CONCLUSIONS AND LIMITATIONS: Current evidence is derived from very low to low quality evidence. Therefore, treatment choice should be guided by patient values and preferences while balancing potential side effects. Future high quality RCTs are needed to address several questions for the treatment of adolescents with PCOS.

Use of heparins in patients with cancer: individual participant data meta-analysis of randomised trials study protocol.

Introduction Parenteral anticoagulants may improve outcomes in patients with cancer by reducing risk of venous thromboembolic disease and through a direct antitumour effect. Study-level systematic reviews indicate a reduction in venous thromboembolism and provide moderate confidence that a small survival benefit exists. It remains unclear if any patient subgroups experience potential benefits. Methods and analysis First, we will perform a comprehensive systematic search of MEDLINE, EMBASE and The Cochrane Library, hand search scientific conference abstracts and check clinical trials registries for randomised control trials of participants with solid cancers who are administered parenteral anticoagulants. We anticipate identifying at least 15 trials, exceeding 9000 participants. Second, we will perform an individual participant data meta-analysis to explore the magnitude of survival benefit and address whether subgroups of patients are more likely to benefit from parenteral anticoagulants. All analyses will follow the intention-to-treat principle. For our primary outcome, mortality, we will use multivariable hierarchical models with patient-level variables as fixed effects and a categorical trial variable as a random effect. We will adjust analysis for important prognostic characteristics. To investigate whether intervention effects vary by predefined subgroups of patients, we will test interaction terms in the statistical model. Furthermore, we will develop a risk-prediction model for venous thromboembolism, with a focus on control patients of randomised trials. Ethics and dissemination Aside from maintaining participant anonymity, there are no major ethical concerns. This will be the first individual participant data meta-analysis addressing heparin use among patients with cancer and will directly influence recommendations in clinical practice guidelines. Major cancer guideline development organisations will use eventual results to inform their guideline recommendations. Several knowledge users will disseminate results through presentations at clinical rounds as well as national and international conferences. We will prepare an evidence brief and facilitate dialogue to engage policymakers and stakeholders in acting on findings. Trial registration number PROSPERO CRD42013003526.

Association of Placebo, Indomethacin, Ibuprofen, and Acetaminophen With Closure of Hemodynamically Significant Patent Ductus Arteriosus in Preterm Infants: A Systematic Review and Meta-analysis

Importance Despite increasing emphasis on conservative management of patent ductus arteriosus (PDA) in preterm infants, different pharmacotherapeutic interventions are used to treat those developing a hemodynamically significant PDA. Objectives To estimate the relative likelihood of hemodynamically significant PDA closure with common pharmacotherapeutic interventions and to compare adverse event rates. Data Sources and Study Selection The databases of MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials were searched from inception until August 15, 2015, and updated on December 31, 2017, along with conference proceedings up to December 2017. Randomized clinical trials that enrolled preterm infants with a gestational age younger than 37 weeks treated with intravenous or oral indomethacin, ibuprofen, or acetaminophen vs each other, placebo, or no treatment for a clinically or echocardiographically diagnosed hemodynamically significant PDA. Data Extraction and Synthesis Data were independently extracted in pairs by 6 reviewers and synthesized with Bayesian random-effects network meta-analyses. Main Outcomes and Measures Primary outcome: hemodynamically significant PDA closure; secondary: included surgical closure, mortality, necrotizing enterocolitis, and intraventricular hemorrhage. Results In 68 randomized clinical trials of 4802 infants, 14 different variations of indomethacin, ibuprofen, or acetaminophen were used as treatment modalities. The overall PDA closure rate was 67.4% (2867 of 4256 infants). A high dose of oral ibuprofen was associated with a significantly higher odds of PDA closure vs a standard dose of intravenous ibuprofen (odds ratio [OR], 3.59; 95% credible interval [CrI], 1.64-8.17; absolute risk difference, 199 [95% CrI, 95-258] more per 1000 infants) and a standard dose of intravenous indomethacin (OR, 2.35 [95% CrI, 1.08-5.31]; absolute risk difference, 124 [95% CrI, 14-188] more per 1000 infants). Based on the ranking statistics, a high dose of oral ibuprofen ranked as the best pharmacotherapeutic option for PDA closure (mean surface under the cumulative ranking [SUCRA] curve, 0.89 [SD, 0.12]) and to prevent surgical PDA ligation (mean SUCRA, 0.98 [SD, 0.08]). There was no significant difference in the odds of mortality, necrotizing enterocolitis, or intraventricular hemorrhage with use of placebo or no treatment compared with any of the other treatment modalities. Conclusions and Relevance A high dose of oral ibuprofen was associated with a higher likelihood of hemodynamically significant PDA closure vs standard doses of intravenous ibuprofen or intravenous indomethacin; placebo or no treatment did not significantly change the likelihood of mortality, necrotizing enterocolitis, or intraventricular hemorrhage. Trial Registration PROSPERO Identifier: CRD42015015797

Effectiveness and safety of treatments used for the management of patent ductus arteriosus (PDA) in preterm infants: a protocol for a systematic review and network meta-analysis

Introduction Management of patent ductus arteriosus (PDA) in preterm infants is one of the most controversial topics in neonatal medicine. The availability of different pharmacotherapeutic options often poses a practical challenge to the practising neonatologist as to which one to choose as a therapeutic option. Our objectives are to determine the relative merits of the available pharmacotherapeutic options for the management of PDA. Methods and Analysis We will conduct a systematic review of all randomised controlled trials evaluating the use of intravenous or oral: indomethacin, ibuprofen and acetaminophen for the treatment of PDA in preterm infants. The primary outcome is failure of closure of the PDA. Secondary outcomes are neonatal mortality, need for surgical closure, duration of ventilator support, chronic lung disease, intraventricular haemorrhage, periventricular leukomalacia, necrotising enterocolitis, gastrointestinal bleeding, time to full enteral feeds and oliguria. We will search Medline, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) as well as grey literature resources. Two reviewers will independently screen titles and abstracts, review full texts, extract information, and assess the risk of bias (ROB) and the confidence in the estimate (with Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach). Subgroup analysis according to gestational age, birth weight, different doses of interventions, time of administration of the first dose of the intervention, and echocardiographic definition of haemodynamically significant PDA and ROB are planned. We will perform a Bayesian network meta-analysis to combine the pooled direct and indirect treatment effect estimates for each outcome, if adequate data are available. Ethics and Dissemination The results will help to reduce the uncertainty about the safety and effectiveness of the interventions, will identify knowledge gaps or will encourage further research for other therapeutic options. Therefore, its results will be disseminated through peer-reviewed publications and conference presentations. On the basis of the nature of its design, no ethics approval is necessary for this study. Trial registration number CRD42015015797.

A critical appraisal of chronic kidney disease mineral and bone disorders clinical practice guidelines using the AGREE II instrument

BackgroundPatients with chronic kidney disease mineral and bone disorders (CKD-MBD) suffer high rates of morbidity and mortality, in particular related to bone and cardiovascular outcomes. The management of CKD-MBD remains challenging. The objective of this systematic survey is to critically appraise clinical practice guidelines (CPGs) addressing CKD-MBD.Methods/designData sources included MEDLINE, EMBASE, the National Guideline Clearinghouse, Guideline International Network and Turning Research into Practice up to May 2016. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility and subsequently appraised the guidelines using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE).ResultsSixteen CPGs published from 2003 to 2015 addressing the diagnosis and management of CKD-MBD in adult patients (11 English, two Spanish, one Italian, one Portuguese and one Slovak) proved eligible. The National Institute for Health and Care Excellence guideline performed best with respect to AGREE II criteria; only three other CPGs warranted high scores on all domains. All other guidelines received scores of under 60% on one or more domains. Major discrepancies in recommendations were not, however, present, and we found no association between quality of CPGs which was not associated with resulting recommendations.ConclusionsMost guidelines assessing CKD-MBD suffer from serious shortcomings using AGREE criteria although limitations with respect to AGREE criteria do not necessarily lead to inappropriate recommendations.

Incidence of Nutrition Deterioration in Nonseriously Ill Hospitalized Children Younger Than 5 Years

BACKGROUND The concept of deterioration of nutrition status in inpatient children, also called nutrition deterioration (ND), has gained widespread importance and is described as significant weight loss during hospitalization periods. Our main purpose was to determine the incidence of ND in nonseriously ill children younger than age 5 years admitted as inpatients and explore the presence of associated factors. MATERIALS AND METHODS This descriptive study analyzed a prospective cohort of hospitalized children. We considered a significant weight loss of >2% or >0.25 SD in body mass index with respect to the admission weight. The correspondence between the 2 methods was assessed. The frequency of some clinical variables and its association with the outcome was explored. RESULTS The incidence of ND was 28.5% with at least 1 of the 2 methods of detection and was 20% with both definitions. The correlation between both methods was high (κ = 0.79). In children with ND, results were statistically significant in those with 5 or more stools a day, those hospitalized 5 or more days, and patients with lower respiratory tract disease. CONCLUSIONS The incidence of ND was higher than that reported in the literature in children with nonserious disease. Diarrhea, lower respiratory tract disease, and hospital length of stay seem to be associated with these results. More studies are required to establish associations with those factors for an early detection of children at risk and for early interventions.

Development of rapid guidelines: 2. A qualitative study with WHO guideline developers

BackgroundSituations such as public health emergencies and outbreaks necessitate the development and publication of high-quality recommendations within a condensed timeframe. For example, WHO has produced examples of and guidance for the development of rapid guidelines (RGs). However, more information is needed to understand the experiences and perceptions of guideline developers. This is the second of a series of three articles addressing methodological issues around RGs. This study describes the perceptions and experiences of guideline developers at WHO about RGs.MethodsWe conducted interviews consisting of open- and closed-ended questions with guideline developers at WHO. Our analysis described the definition and rationale of RGs, the differences from regular guidelines with regard to timelines from topic definition until publication, barriers to identifying the evidence and the lack of a standard methodology to develop RGs.ResultsWe interviewed 10 participants, the majority of whom were comfortable with the current WHO definition of RGs. Most stated that the rationale for developing RGs should be in response to new evidence about efficacy, cost-effectiveness or safety. Respondents differed with regards to the amount of time RGs should take. While the majority of participants agreed that guidelines should be based on a systematic review, this step in the process was considered the most time and resource intensive. Challenges for developing RGs included limited personnel and financial resources as well as the lack of evidence. Facilitators, in turn, that may improve RG development include additional financial and personnel resources as well as the use of virtual meetings.ConclusionsWhile our study suggests a strong need and rationale for the development of RGs, standardisation of timelines and guidance on panel composition, peer-review process, conduct of meetings and sources of permissible evidence require further research.

A systematic survey of the methods literature on the reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials

OBJECTIVE To conduct (1) a systematic survey of the reporting quality of simulation studies dealing with how to handle missing participant data (MPD) in randomized control trials and (2) summarize the findings of these studies. STUDY DESIGN AND SETTING We included simulation studies comparing statistical methods dealing with continuous MPD in randomized controlled trials addressing bias, precision, coverage, accuracy, power, type-I error, and overall ranking. For the reporting of simulation studies, we adapted previously developed criteria for reporting quality and applied them to eligible studies. RESULTS Of 16,446 identified citations, the 60 eligible generally had important limitations in reporting, particularly in reporting simulation procedures. Of the 60 studies, 47 addressed ignorable and 32 addressed nonignorable data. For ignorable missing data, mixed model was most frequently the best on overall ranking (9 times best, 34.6% of times tested) and bias (10, 55.6%). Multiple imputation was also performed well. For nonignorable data, mixed model was most frequently the best on overall ranking (7, 46.7%) and bias (8, 57.1%). Mixed model performance varied on other criteria. Last observation carried forward (LOCF) was very seldom the best performing, and for nonignorable MPD frequently the worst. CONCLUSION Simulation studies addressing methods to deal with MPD suffered from serious limitations. The mixed model approach was superior to other methods in terms of overall performance and bias. LOCF performed worst.Please cite this article as: Zhang Y, Alyass A, Vanniyasingam T, Sadeghirad B, Flórez ID, Pichika SC, Kennedy SA, Abdulkarimova U, Zhang Y, Iljon T, Morgano GP, Colunga Lozano LE, Aloweni FAB, Lopes LC, Yepes-Nuñez JJ, Fei Y, Wang L, Kahale LA, Meyre D, Akl EA, Thabane L, Guyatt G, Reporting quality and optimal methods of handling participants with missing outcome data for continuous outcomes in randomized controlled trials: a systematic survey of the methods literature, Journal of Clinical Epidemiology (2017), doi: 10.1016/j.jclinepi.2017.05.016.

Knowledge translation in transfusion medicine. Part 1: The basics and the frameworks: BASICS OF KNOWLEDGE TRANSLATION

C linical research provides new knowledge with the goal not only to inform, but also to impact patient health so that the most effective and safe care approaches are adopted. Clinical research can elucidate which clinical care options are appropriate for implementation and which ones are not effective or potentially harmful. For example, in transfusion medicine the historical teaching of transfusing 2 units of red blood cells (RBCs) at a time is not supported by evidence; liberal transfusion does not benefit patients or confer good quality care. Indeed, the Choosing Wisely program identifies several common care options—some that are costly—that should be “deimplemented” or avoided because there is a lack of evidence of effectiveness. Despite considerable resources used in the creation and interpretation of research results, only 14% of medical research findings are implemented to benefit patients. Often, implementation of clinical research evidence is arbitrary and unsystematic, and it may take a mean of 17 years from the time of discovery to effective application. This significant delay denies the patient treatments of proven benefit. Thus, while knowing the best care options is an important first step, knowledge alone is insufficient in ensuring that clinicians and the health system act on this knowledge. This is a phenomenon known as the knowledge-to-action (KtoA) gap. To bridge this gap, an evidence-based process to facilitate the uptake of that clinical evidence is required. Knowledge translation (KT) is a set of methods that can help address KtoA gaps and maximize the extent to which patients receive evidencebased therapies in a timely fashion. Individualized hospital-based or team-based KT intervention plans that account for context may be needed. Upholding ethical principles and social values in health care delivery should result in deliberate actions to question current practice and get evidence in use.