Predictors of Persistent Post-Surgical Pain Following Total Knee Arthroplasty: A Systematic Review and Meta-Analysis of Observational Studies.

OBJECTIVE: Approximately one in four total knee replacement patients develop persistent pain. Identification of those at higher risk could help inform optimal management. METHODS: We searched MEDLINE, EMBASE, CINAHL, AMED, SPORTDiscus, and PsycINFO for observational studies that explored the association between risk factors and persistent pain (≥3 months) after total knee replacement. We pooled estimates of association for all independent variables reported by >1 study. RESULTS: Thirty studies (26,517 patients) reported the association of 151 independent variables with persistent pain after knee replacement. High certainty evidence demonstrated an increased risk of persistent pain with pain catastrophizing (absolute risk increase [ARI] 23%, 95% confidence interval [CI] 12 to 35), younger age (ARI for every 10-year decrement from age 80, 4%, 95% CI 2 to 6), and moderate-to-severe acute post-operative pain (ARI 30%, 95% CI 20 to 39). Moderate certainty evidence suggested an association with female sex (ARI 7%, 95% CI 3 to 11) and higher pre-operative pain (ARI 35%, 95% CI 7 to 58). Studies did not adjust for both peri-operative pain severity and pain catastrophizing, which are unlikely to be independent. High to moderate certainty evidence demonstrated no association with pre-operative range of motion, body mass index, bilateral or unilateral knee replacement, and American Society of Anesthesiologists score. CONCLUSIONS: Rigorously conducted observational studies are required to establish the relative importance of higher levels of peri-operative pain and pain catastrophizing with persistent pain after knee replacement surgery.

Pharmaceutical policies: effects of policies regulating drug marketing.

BACKGROUND: The costs of developing new treatments and bringing them to the market are substantial. The pharmaceutical industry uses drug promotion to gain a competitive market share, and drive sale volumes and industry profitability. This involves disseminating information about new treatments to relevant targets. However, conflicts of interest can arise when profits are prioritised over patient care and its benefits. Drug promotion regulations are complex interventions that aim to prevent potential harm associated with these activities. OBJECTIVES: To assess the effects of policies that regulate drug promotion on drug utilisation, coverage or access, healthcare utilisation, patient outcomes, adverse events and costs. SEARCH METHODS: We searched Epistemonikos for related reviews and their included studies. To find primary studies we searched MEDLINE, CENTRAL, Embase, EconLit, Global Index Medicus, Virtual Health Library, INRUD Bibliography, two trial registries and two sources of grey literature. All databases and sources were searched in January 2023. SELECTION CRITERIA: We planned to include studies that assessed policies regulating drug promotion to consumers, healthcare professionals or regulators and third-party payers, or any combination of these groups.In this review we defined policies as laws, rules, guidelines, codes of practice, and financial or administrative orders made by governments, non-government organisations or private insurers. One of the following outcomes had to be reported: drug utilisation, coverage or access, healthcare utilisation, patient health outcomes, any adverse effects (unintended consequences), and costs. The study had to be a randomised or non-randomised trial, an interrupted time series analysis (ITS), a repeated measures (RM) study or a controlled before-after (CBA) study. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed eligibility for inclusion of studies. When consensus was not reached, any disagreements were discussed with a third review author.  We planned to use the criteria suggested by Cochrane Effective Practice and Organisation of Care (EPOC) to assess the risk of bias of included studies. For randomised trials, non-randomised trials, and CBA studies, we planned to estimate relative effects, with 95% confidence intervals (CI). For dichotomous outcomes, we planned to report the risk ratio (RR) when possible and adjusted for baseline differences in the outcome measures. For ITS and RM, we planned to compute changes along two dimensions: change in level and change in slope. We planned to undertake a structured synthesis following EPOC guidance.  MAIN RESULTS: The search yielded 4593 citations, and 13 studies were selected for full-text review. No study met the inclusion criteria. AUTHORS' CONCLUSIONS: We sought to assess the effects of policies that regulate drug promotion on drug use, coverage or access, use of health services, patient outcomes, adverse events, and costs, however we did not find studies that met the review's inclusion criteria. As pharmaceutical policies that regulate drug promotion have untested effects, their impact, as well as their positive and negative influences, is currently only a matter of opinion, debate, informal or descriptive reporting. There is an urgent need to assess the effects of pharmaceutical policies that regulate drug promotion using well-conducted studies with high methodological rigour.

Data sources for drug utilization research in Latin American countries-A cross-national study: DASDUR-LATAM study.

PURPOSE: Drug utilization research (DUR) contributes to inform policymaking and to strengthen health systems. The availability of data sources is the first step for conducting DUR. However, documents that systematize these data sources in Latin American (LatAm) countries are not known. We compiled the potential data sources for DUR in the LatAm region. METHODS: A network of DUR experts from nine LatAm countries was assembled and experts conducted: (i) a website search of the government, academic, and private health institutions; (ii) screening of eligible data sources, and (iii) liaising with national experts in pharmacoepidemiology (via an online survey). The data sources were characterized by accessibility, geographic granularity, setting, sector of the data, sources and type of the data. Descriptive analyses were performed. RESULTS: We identified 125 data sources for DUR in nine LatAm countries. Thirty-eight (30%) of them were publicly and conveniently available; 89 (71%) were accessible with limitations, and 18 (14%) were not accessible or lacked clear rules for data access. From the 125 data sources, 76 (61%) were from the public sector only; 46 (37%) were from pharmacy records; 43 (34%) came from ambulatory settings and; 85 (68%) gave access to individual patient-level data. CONCLUSIONS: Although multiple sources for DUR are available in LatAm countries, the accessibility is a major challenge. The procedures for accessing DUR data should be transparent, feasible, affordable, and protocol-driven. This inventory could permit a comparison of drug utilization between countries identifying potential medication-related problems that need further exploration.

Challenges facing drug utilization research in the Latin American region.

PURPOSE: The International Society of Pharmacoepidemiology (ISPE) in collaboration with the Latin America Drug Utilization Research Group (LatAm DURG), the Medicines Utilization Research in Africa (MURIA) group, and the Uppsala Monitoring Center, is leading an initiative to understand challenges to drug utilization research (DUR) in the Latin American (LatAm) and African regions with the goal of communicating results and proposing solutions to these challenges in four scientific publications. The purpose of this first manuscript is to identify the main challenges associated with DUR in the LatAm region. METHODS: Drug utilization (DU) researchers in the LatAm region voluntarily participated in multiple discussions, contributed with local data and reviewed successive drafts and the final manuscript. Additionally, we carried out a literature review to identify the most relevant publications related to DU studies from the LatAm region. RESULTS: Multiple challenges were identified in the LatAm region for DUR including socioeconomic inequality, access to medical care, complexity of the healthcare system, limited investment in research and development, limited institutional and organization resources, language barriers, limited health education and literacy. Further, there is limited use of local DUR data by decision makers particularly in the identification of emerging health needs coming from social and demographic transitions. CONCLUSIONS: The LatAm region faces challenges to DUR which are inherent in the healthcare and political systems, and potential solutions should target changes to the system.

Paraquat and Parkinson's disease: a systematic review and meta-analysis of observational studies.

This investigation aimed to conduct a systematic review of the literature and meta-analysis to determine whether exposure to the herbicide paraquat was associated with the development of Parkinson's disease (PD). Observational studies that enrolled adults exposed to paraquat with PD as the outcome of interest were searched in the PubMed, Embase, LILACS, TOXNET, and Web of Science databases up to May 2019. Two authors independently selected relevant studies, extracted data, and assessed methodological quality. The evidence certainty was assessed by the GRADE approach, which served as basis for a tentative causality assessment, supplemented by the Bradford Hill criteria when necessary. Results from nine case-control studies indicated that PD occurrence was 25% higher in participants exposed to paraquat. The only cohort investigation included demonstrated a non-significant OR of 1.08. Results from subgroup analyses also indicated higher PD frequency in participants that were exposed to paraquat for longer periods or individuals co-exposed with paraquat and any other dithiocarbamate. Data indicate apositive association between exposure to paraquat and PD occurrence, but the weight-of-evidence does not enable one to assume an indisputable cause-effect relationship between these two conditions. Better designed studies are needed to increase confidence in results. Systematic Review Registration: PROSPERO CRD42017069994.

Opioids for Chronic Noncancer Pain: A Systematic Review and Meta-analysis.

Importance: Harms and benefits of opioids for chronic noncancer pain remain unclear. Objective: To systematically review randomized clinical trials (RCTs) of opioids for chronic noncancer pain. Data Sources and Study Selection: The databases of CENTRAL, CINAHL, EMBASE, MEDLINE, AMED, and PsycINFO were searched from inception to April 2018 for RCTs of opioids for chronic noncancer pain vs any nonopioid control. Data Extraction and Synthesis: Paired reviewers independently extracted data. The analyses used random-effects models and the Grading of Recommendations Assessment, Development and Evaluation to rate the quality of the evidence. Main Outcomes and Measures: The primary outcomes were pain intensity (score range, 0-10 cm on a visual analog scale for pain; lower is better and the minimally important difference [MID] is 1 cm), physical functioning (score range, 0-100 points on the 36-item Short Form physical component score [SF-36 PCS]; higher is better and the MID is 5 points), and incidence of vomiting. Results: Ninety-six RCTs including 26 169 participants (61% female; median age, 58 years [interquartile range, 51-61 years]) were included. Of the included studies, there were 25 trials of neuropathic pain, 32 trials of nociceptive pain, 33 trials of central sensitization (pain present in the absence of tissue damage), and 6 trials of mixed types of pain. Compared with placebo, opioid use was associated with reduced pain (weighted mean difference [WMD], -0.69 cm [95% CI, -0.82 to -0.56 cm] on a 10-cm visual analog scale for pain; modeled risk difference for achieving the MID, 11.9% [95% CI, 9.7% to 14.1%]), improved physical functioning (WMD, 2.04 points [95% CI, 1.41 to 2.68 points] on the 100-point SF-36 PCS; modeled risk difference for achieving the MID, 8.5% [95% CI, 5.9% to 11.2%]), and increased vomiting (5.9% with opioids vs 2.3% with placebo for trials that excluded patients with adverse events during a run-in period). Low- to moderate-quality evidence suggested similar associations of opioids with improvements in pain and physical functioning compared with nonsteroidal anti-inflammatory drugs (pain: WMD, -0.60 cm [95% CI, -1.54 to 0.34 cm]; physical functioning: WMD, -0.90 points [95% CI, -2.69 to 0.89 points]), tricyclic antidepressants (pain: WMD, -0.13 cm [95% CI, -0.99 to 0.74 cm]; physical functioning: WMD, -5.31 points [95% CI, -13.77 to 3.14 points]), and anticonvulsants (pain: WMD, -0.90 cm [95% CI, -1.65 to -0.14 cm]; physical functioning: WMD, 0.45 points [95% CI, -5.77 to 6.66 points]). Conclusions and Relevance: In this meta-analysis of RCTs of patients with chronic noncancer pain, evidence from high-quality studies showed that opioid use was associated with statistically significant but small improvements in pain and physical functioning, and increased risk of vomiting compared with placebo. Comparisons of opioids with nonopioid alternatives suggested that the benefit for pain and functioning may be similar, although the evidence was from studies of only low to moderate quality.

Pharmacological characterization of Solanum cernuum Vell.: 31-norcycloartanones with analgesic and anti-inflammatory properties.

Cycloeucalenone (1) and 24-oxo-31-norcycloartanone (2) obtained from Solanum cernuum Vell. were assayed to explore their pharmacologic roles. Previous studies showed that (2) has selective activity against lung tumor cell line (NCIH460) which expresses high levels of COX-2, suggesting its role in inflammatory process, and also a link between chronic inflammation and cancer-associated process. Dichloromethane crude extract (DCE) significantly reduced writhing and stretching induced by 0.8 % acetic acid at a dose of 100, 300, and 600 mg/kg, po; oral administration of different doses of (1) and (2) also displayed significant analgesic and anti-inflammatory effects in the writhing acetic acid test (p < 0.0001). Selected oral doses of both compounds (100 and 50 mg/kg) were assayed in the carrageenan-induced paw edema model. Compound (2) showed significant activity during the early phase (1.5-6 h) and also in the late phase (48 h) (p < 0.01). The anti-nociceptive activity observed for the compounds (1) and (2) and DCE was found to be related to the inhibition of different mediators involved in inflammation and nociceptive process. Both compounds decrease COX-2 protein expression, although only compound (2) reached a significant response (p < 0.05 vs control). However, in vitro Sirtuin 1 activity and TNF-α production in THP-1 macrophages were not affected.

Adverse effects of biologics: a network meta-analysis and Cochrane overview.

BACKGROUND: Biologics are used for the treatment of rheumatoid arthritis and many other conditions. While the efficacy of biologics has been established, there is uncertainty regarding the adverse effects of this treatment. Since serious risks such as tuberculosis (TB) reactivation, serious infections, and lymphomas may be common to the biologics but occur in small numbers across the various indications, we planned to combine the results from biologics used in many conditions to obtain the much needed risk estimates. OBJECTIVES: To compare the adverse effects of tumor necrosis factor blocker (etanercept, adalimumab, infliximab, golimumab, certolizumab), interleukin (IL)-1 antagonist (anakinra), IL-6 antagonist (tocilizumab), anti-CD28 (abatacept), and anti-B cell (rituximab) therapy in patients with any disease condition except human immunodeficiency disease (HIV/AIDS). METHODS: Randomized controlled trials (RCTs), controlled clinical trials (CCTs) and open-label extension (OLE) studies that studied one of the nine biologics for use in any indication (with the exception of HIV/AIDS) and that reported our pre-specified adverse outcomes were considered for inclusion. We searched The Cochrane Library, MEDLINE, and EMBASE (to January 2010). Identifying search results and data extraction were performed independently and in duplicate. For the network meta-analysis, we performed mixed-effects logistic regression using an arm-based, random-effects model within an empirical Bayes framework. MAIN RESULTS: We included 163 RCTs with 50,010 participants and 46 extension studies with 11,954 participants. The median duration of RCTs was six months and 13 months for OLEs. Data were limited for tuberculosis (TB) reactivation, lymphoma, and congestive heart failure. Adjusted for dose, biologics as a group were associated with a statistically significant higher rate of total adverse events (odds ratio (OR) 1.19, 95% CI 1.09 to 1.30; number needed to treat to harm (NNTH) = 30, 95% CI 21 to 60) and withdrawals due to adverse events (OR 1.32, 95% CI 1.06 to 1.64; NNTH = 37, 95% CI 19 to 190) and an increased risk of TB reactivation (OR 4.68, 95% CI 1.18 to 18.60; NNTH = 681, 95% CI 143 to 14706) compared to control.The rate of serious adverse events, serious infections, lymphoma, and congestive heart failure were not statistically significantly different between biologics and control treatment. Certolizumab pegol was associated with significantly higher risk of serious infections compared to control treatment (OR 3.51, 95% CI 1.59 to 7.79; NNTH = 17, 95% CI 7 to 68). Infliximab was associated with significantly higher risk of withdrawals due to adverse events compared to control (OR 2.04, 95% CI 1.43 to 2.91; NNTH = 12, 95% CI 8 to 28). Indirect comparisons revealed that abatacept and anakinra were associated with a significantly lower risk of serious adverse events compared to most other biologics.  Although the overall numbers are relatively small, certolizumab pegol was associated with significantly higher odds of serious infections compared to etanercept, adalimumab, abatacept, anakinra, golimumab, infliximab, and rituximab; abatacept was significantly less likely than infliximab and tocilizumab to be associated with serious infections.  Abatacept, adalimumab, etanercept and golimumab were significantly less likely than infliximab to result in withdrawals due to adverse events. AUTHORS' CONCLUSIONS: Overall, in the short term biologics were associated with significantly higher rates of total adverse events, withdrawals due to adverse events and TB reactivation. Some biologics had a statistically higher association with certain adverse outcomes compared to control, but there was no consistency across the outcomes so caution is needed in interpreting these results.There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics. National and international registries and other types of large databases are relevant sources for providing complementary evidence regarding the short- and longer-term safety of biologics. 

GLP-1 and GIP receptor agonists in the treatment of Parkinson's disease: Translational systematic review and meta-analysis protocol of clinical and preclinical studies.

BACKGROUND: Parkinson's disease (PD) is a progressive multifactorial neurodegenerative condition. Epidemiological studies have shown that patients with type 2 diabetes mellitus (T2DM2) are at increased risk for developing PD, indicating a possible insulin-modulating role in this latter condition. We hypothesized that drugs similar to glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP), used in the treatment of T2DM2, may play a role in PD. OBJECTIVES: The purpose of this study is to systematically review and meta-analyze data of preclinical and clinical studies evaluating the efficacy and safety of GLP-1 and GIP drugs in the treatment of PD. METHODS: Two reviewers will independently evaluate the studies available in the Ovid Medline, Ovid Embase, Web of Science, Cochrane Central Register of Controlled Trials, Cinahl, and Lilacs databases. Preclinical rodent or non-human primate studies and randomized controlled human clinical trials will be included, without language or publication period restrictions. Outcomes of interest in preclinical studies will be primarily locomotor improvements and adverse effects in animal models of PD. For clinical trials, we will evaluate clinical improvements rated by the Movement Disorders Society Unified Parkinson's Disease Rating Scale-parts I, II, III, and IV, and adverse effects. The risk of bias of preclinical studies will be assessed by the SYRCLE tool and CAMARADES checklist and the clinical studies by the Cochrane tool; the certainty of the evidence will be rated by GRADE. DISCUSSION AND CONCLUSION: There is an urge for new PD treatments that may slow the progression of the disease rather than just restoring dopamine levels. This study will comprehensively review and update the state of the art of what is known about incretin hormones and PD and highlight the strengths and limitations of translating preclinical data to the clinic whenever possible. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number CRD42020223435.

Antineoplastic 31-norcycloartanones from Solanum cernuum vell.

Triterpenoids with 31-norcycloartanone structure were isolated for the first time from the Solanum genus. Cycloeucalenone and 24-oxo-31-norcycloartanone were the main constituents of the dichloromethane extract of Solanum cernuum Vell. leaves [7% (w/w) and 1.47% (w/w)]. Both triterpenoids were tested against human tumour cell lines, and 24-oxo-31-norcycloartanone was significantly active and selective against the lung tumour cell line NCI-H460 with total growth inhibition at 1.10 microg/mL, growth inhibition 50 at 0.19 microg/mL and lethal concentration 50 at 8.43 microg/mL, while cycloeucalenone showed poor activity. A homologous series of alkanes (C25-C34), beta-sitosterol, and the xanthophyll lutein were also identified. The antiulcer activity was assayed for the dichloromethane extract. In the gastric ulcer model induced by 95% ethanol, administration of 500, 1000 and 2000 mg/kg/po dichloromethane extract gave ulcer lesion indices of, respectively, 38.2, 61.0 and 81.9%, while carbenoxolone inhibited 88.9% at 200 mg/kg. In the gastric ulcer model induced by indomethacin the dichloromethane extract showed a small percentage of lesion inhibition. The ethanol extract was also analyzed and was mainly composed of glycoalkaloids, peptides and disaccharides.

Obesity: A New Adverse Effect of Antibiotics?

Since the introduction of antibiotics, they have been used freely, with their prescription occurring almost always when they were not necessary. The other major form of contact between humans and antibiotics, now unintentionally, is with the large amount of these drugs in the environment and in our food. The relationship between antibiotic use and the development of obesity has become increasingly evident and apparent in humans, with some authors clearly establishing the relationship between the large-scale use of antibiotics in the past 70 years and the "epidemic" of obesity that has occurred in parallel, almost as an adverse epidemiological effect. In the research effort entertained herein, a correlation between the use and abuse of antibiotics and the onset of obesity was investigated.

Policy Change and the National Essential Medicines List Development Process in Brazil between 2000 and 2014: Has the Essential Medicine Concept been Abandoned?

Brazil has had a National Essential Medicines List (EML) since 1964. From 2000 to 2010, five consecutive evidence-based editions were produced, building on the essential medicine concept. In 2012, the government changed course to establish a new paradigm, introducing adoption of new medicines as the main aim within the recommendation process. The objective of the article was to report efforts to develop Brazil's national EML, policy changes from 2000 to 2014, discussing results, challenges and perspectives. Brazilian EML history and development process were collected from legislation, minutes, reports and legal ordinances, from 2000 to 2014. The Brazilian EML and the WHO Model Lists were compared using the Anatomical Therapeutic Chemical system. Overlap between lists was verified, and linear trends were produced. Type of membership, inclusion criteria, procedures, flow and listed medicines varied greatly between the selection committees acting before and after 2012. Paradigm-changing legislation aiming at linking list compliance to public financing in 2012 produced (i) greater importance given to political and administrative stakeholders, (ii) increasing trends in number of medicines over the years, (iii) decrease in use of WHO Model List as a reference and (iv) substitution of an essential medicines list review and update process by an adoption decision output. Other issues remained unchanged. Insufficient efforts for list implementation, such as lack of physician education, presented consequences to the health system. Substantial efforts were made to produce and update the list from 2000 to 2014. However, continuous and intense health litigation disproves process outcome effectiveness.

Herbal medications for surgical patients: a systematic review protocol.

INTRODUCTION: Postoperative nausea and vomiting (PONV) affect approximately 80% of surgical patients and is associated with increased length of hospital stay and systemic costs. Preoperative and postoperative pain, anxiety and depression are also commonly reported. Recent evidence regarding their safety and effectiveness has not been synthesised. The aim of this systematic review is to evaluate the efficacy and safety of herbal medications for the treatment and prevention of anxiety, depression, pain and PONV in patients undergoing laparoscopic, obstetrical/gynaecological and cardiovascular surgical procedures. METHODS AND ANALYSIS: The following electronic databases will be searched up to 1 October 2016 without language or publication status restrictions: CENTRAL, MEDLINE, EMBASE, CINAHL, Web of Science and LILACS. Randomised clinical trials enrolling adult surgical patients undergoing laparoscopic, obstetrical/gynaecological and cardiovascular surgeries and managed with herbal medication versus a control group (placebo, no intervention or active control) prophylactically or therapeutically will be considered eligible. Outcomes of interest will include the following: anxiety, depression, pain, nausea and vomiting. A team of reviewers will complete title and abstract screening and full-text screening for identified hits independently and in duplicate. Data extraction, risk of bias assessments and evaluation of the overall quality of evidence for each relevant outcome reported will be conducted independently and in duplicate using the Grading of Recommendations Assessment Development and Evaluation classification system. Dichotomous data will be summarised as risk ratios; continuous data will be summarised as standard average differences with 95% CIs. ETHICS AND DISSEMINATION: This is one of the first efforts to systematically summarise existing evidence evaluating the use of herbal medications in laparoscopic, obstetrical/gynaecological and cardiovascular surgical patients. The findings of this review will be disseminated through peer-reviewed publications and conference presentations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016042838.

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.

A systematic survey on reporting and methods for handling missing participant data for continuous outcomes in randomized controlled trials.

OBJECTIVE: To assess analytic approaches randomized controlled trial (RCT) authors use to address missing participant data (MPD) for patient-important continuous outcomes. STUDY DESIGN AND SETTING: We conducted a systematic survey of RCTs published in 2014 in the core clinical journals that reported at least one patient-important outcome analyzed as a continuous variable. RESULTS: Among 200 studies, 187 (93.5%) trials explicitly reported whether MPD occurred. In the 163 (81.5%) trials that reported the occurrence of MPD, the median and interquartile ranges of the percentage of participants with MPD were 11.4% (2.5%-22.6%).Among the 147 trials in which authors made clear their analytical approach to MPD, the approaches chosen included available data only (109, 67%); mixed-effect models (10, 6.1%); multiple imputation (9, 4.5%); and last observation carried forward (9, 4.5). Of the 163 studies reporting MPD, 16 (9.8%) conducted sensitivity analyses examining the impact of the MPD and (18, 11.1%) discussed the risk of bias associated with MPD. CONCLUSION: RCTs reporting continuous outcomes typically have over 10% of participant data missing. Most RCTs failed to use optimal analytic methods, and very few conducted sensitivity analyses addressing the possible impact of MPD or commented on how MPD might influence risk of bias.

Systematic survey of randomized trials evaluating the impact of alternative diagnostic strategies on patient-important outcomes.

OBJECTIVES: To provide a perspective on the current practice of randomized clinical trials (RCTs) of diagnostic strategies focusing on patient-important outcomes. STUDY DESIGN AND SETTING: We conducted a comprehensive search of MEDLINE and included RCTs published in full-text reports that evaluated alternative diagnostic strategies. RESULTS: Of 56,912 unique citations, we sampled 7,500 and included 103 eligible RCTs, therefore suggesting that MEDLINE includes approximately 781 diagnostic RCTs. The 103 eligible trials reported on: mortality (n = 41; 39.8%); morbidities (n = 63; 61.2%); symptoms/quality of life/functional status (n = 14; 13.6%); and on composite end points (n = 10; 9.7%). Of the studies that reported statistically significant results (n = 12; 11.6%), we judged 7 (58.3%) as at low risk of bias with respect to missing outcome data and 4 (33.3%) as at low risk of bias regarding blinding. Of the 41 RCTs that reported on mortality, only one (2.4%) reported statistically significant results. Of 63 RCTs addressing morbidity outcomes, 11 (17.5%) reported statistically significant results, all of which reported relative effects of greater than 20%. CONCLUSION: RCTs of diagnostic tests are not uncommon, and sometimes suggest benefits on patient-important outcomes but often suffer from limitations in sample size and conduct.

Analysis of analgesic, antipyretic, and nonsteroidal anti-inflammatory drug use in pediatric prescriptions.

OBJECTIVE: Data on clinical practice in pediatrics on the use of analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs considering the best available evidence and regulatory-agency approved use are uncertain. This study aimed to determine the frequency of prescription of these drugs according to the best scientific evidence and use approved by regulatory agencies. METHODS: This was a cross-sectional study of 150 pediatric prescriptions containing analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs, followed by interview with caregivers at 18 locations (nine private drugstores and nine Basic Health Units of the Brazilian Unified Health System). The assessed outcomes included recommended use or use with no contraindication, indications with benefit evidence, and health surveillance agency-approved use. Data were analyzed in electronic databases and the variables were summarized by simple frequency. RESULTS: A total of 164 analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs were prescribed to 150 children aged 1-4 years (38.6%). Dipyrone was included in 82 (54.6%) and ibuprofen in 40 (26.6%) prescriptions. Non-recommended uses were identified in 15% of prescriptions and contraindicated uses were observed in 13.3%. Nimesulide (1.5%) is still prescribed to children younger than 12 years. The dose was incorrect in 74.3% of prescriptions containing dipyrone. Of the 211 reported clinical indications, 56 (26.5%) had no evidence of benefit according to the best available scientific evidence and 66 (31.3%) had indications not approved by the regulatory agencies. CONCLUSION: There are significant discrepancies between clinical practice and recommended use of analgesic, antipyretic, and nonsteroidal anti-inflammatory drugs in pediatrics.

Factors Associated with the Combined Use of Antidepressants and Benzodiazepines in Major Depression: A Case-Control Study.

The aim of this study was to identify the factors associated with the combined use of antidepressants and benzodiazepines (BDZs) in patients with major depression. We conducted a case-control study in the public health service of the city of São Paulo, Brazil. The participants were all patients being treated with antidepressants, who were diagnosed with major depression. Patients who received a combination of antidepressants and BDZs were classified as cases, and those who used only antidepressants, as controls. Data were obtained from a pharmacy database, medical records and interviews with the healthcare team. The association of predisposing factors for combined therapy was analysed using logistic regression analysis, and the odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Of the 1355 users of antidepressants, 265 had major depression, of whom 138 were cases and 127 were controls. The factors associated with combined use were age older than 35 years (OR 2.2, 95% CI 1.0-4.7), absence of comorbidities (OR 2.3, 95% CI 1.4-4.1) and no use of other drugs (OR 1.9, 95% CI 1.1-3.3). Patients with combined use were more likely to exhibit inadequate prescribing, including inappropriate antidepressants (OR 4.7, 95% CI 2.2-9.9), inadequate dosages (OR 3.62, 95% CI 1.4-9.6) and/or a non-recommended duration (OR 66.6, 95% CI 18.4-240.7). The factors identified showed the groups most susceptible to combined use in this population, who in turn are more likely to receive inappropriate prescriptions.

Long-term Impact of Mode of Delivery on Stress Urinary Incontinence and Urgency Urinary Incontinence: A Systematic Review and Meta-analysis.

CONTEXT: Stress urinary incontinence (SUI) and urgency urinary incontinence (UUI) are associated with physical and psychological morbidity, and large societal costs. The long-term effects of delivery modes on each kind of incontinence remain uncertain. OBJECTIVE: To investigate the long-term impact of delivery mode on SUI and UUI. EVIDENCE ACQUISITION: We searched Medline, Scopus, CINAHL, and relevant major conference abstracts up to October 31, 2014, including any observational study with adjusted analyses or any randomized trial addressing the association between delivery mode and SUI or UUI ≥1 yr after delivery. Two reviewers extracted data, including incidence/prevalence of SUI and UUI by delivery modes, and assessed risk of bias. EVIDENCE SYNTHESIS: Pooled estimates from 15 eligible studies demonstrated an increased risk of SUI after vaginal delivery versus cesarean section (adjusted odds ratio [aOR]: 1.85; 95% confidence interval [CI], 1.56-2.19; I(2)=57%; risk difference: 8.2%). Metaregression demonstrated a larger effect of vaginal delivery among younger women (p=0.005). Four studies suggested no difference in the risk of SUI between spontaneous vaginal and instrumental delivery (aOR: 1.11; 95% CI, 0.84-1.45; I(2)=50%). Eight studies suggested an elevated risk of UUI after vaginal delivery versus cesarean section (aOR: 1.30; 95% CI, 1.02-1.65; I(2)=37%; risk difference: 2.6%). CONCLUSIONS: Compared with cesarean section, vaginal delivery is associated with an almost twofold increase in the risk of long-term SUI, with an absolute increase of 8%, and an effect that is largest in younger women. There is also an increased risk of UUI, with an absolute increase of approximately 3%. PATIENT SUMMARY: In this systematic review we looked for the long-term effects of childbirth on urinary leakage. We found that vaginal delivery is associated with an almost twofold increase in the risk of developing leakage with exertion, compared with cesarean section, with a smaller effect on leakage in association with urgency.

Reporting of IMMPACT-recommended core outcome domains among trials assessing opioids for chronic non-cancer pain.

The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) has recommended that trialists evaluating treatments for chronic pain should consider reporting 9 patient-important outcome domains. We examined the extent to which clinical trials evaluating the effect of opioids for chronic non-cancer pain (CNCP) report outcome domains recommended by IMMPACT. We systematically searched electronic databases for English-language studies that randomized patients with CNCP to receive an opioid or a non-opioid control. In duplicate and independently, reviewers established the eligibility of each identified study and recorded all reported outcome domains from eligible trials. We conducted a priori regression analyses to explore factors that may be associated with IMMPACT-recommended outcome domains. Among 156 eligible trials, reporting of IMMPACT-recommended outcome domains was highly variable, ranging from 99% for pain to 7% for interpersonal functioning. Recently published trials were more likely to report the effect of treatment on physical functioning, emotional functioning, role functioning, sleep and fatigue, and participant disposition. Trials for which the corresponding author was from North America were more likely to report treatment effects on physical functioning and participant ratings of improvement and satisfaction with treatment. Trials published in higher impact journals were more likely to report treatment effects on emotional function, but less likely to report participant ratings of improvement and satisfaction with treatment. Most IMMPACT domains showed an increased rate of reporting over time, although many patient-important outcome domains remained unreported by over half of all trials evaluating the effects of opioids for CNCP.