Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a condition in which veins are unable to transport blood unidirectionally towards the heart. CVI usually occurs in the lower limbs. It might result in considerable discomfort, with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is the second update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered orally or topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, and CINAHL databases and the World Health Organization International Clinical Trials Registry Platform and Clinicaltrials.gov trials register up to 12 November 2019. We searched the reference lists of the articles retrieved by electronic searches for additional citations. We also contacted authors of unpublished studies. SELECTION CRITERIA: We included randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of phlebotonics (rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, French maritime pine bark extract, grape seed extract and aminaftone) in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardized mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence intervals (CIs) and percentage of heterogeneity (I2). Outcomes of interest were oedema, quality of life (QoL), assessment of CVI and adverse events. We used GRADE criteria to assess the certainty of the evidence. MAIN RESULTS: We identified three new studies for this update. In total, 69 RCTs of oral phlebotonics were included, but only 56 studies (7690 participants, mean age 50 years) provided quantifiable data for the efficacy analysis. These studies used different phlebotonics (28 on rutosides, 11 on hidrosmine and diosmine, 10 on calcium dobesilate, two on Centella asiatica, two on aminaftone, two on French maritime pine bark extract and one on grape seed extract). No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria. Moderate-certainty evidence suggests that phlebotonics probably reduce oedema slightly in the lower legs, compared with placebo (RR 0.70, 95% CI 0.63 to 0.78; 13 studies; 1245 participants); and probably reduce ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies; 2010 participants). Moderate-certainty evidence shows that phlebotonics probably make little or no difference in QoL compared with placebo (SMD -0.06, 95% CI -0.22 to 0.10; five studies; 1639 participants); and similarly, may have little or no effect on ulcer healing (RR 0.94, 95% CI 0.79 to 1.13; six studies; 461 participants; low-certainty evidence). Thirty-seven studies reported on adverse events. Pooled data suggest that phlebotonics probably increase adverse events slightly, compared to placebo (RR 1.14, 95% CI 1.02 to 1.27; 37 studies; 5789 participants; moderate-certainty evidence). Gastrointestinal disorders were the most frequently reported adverse events. We downgraded our certainty in the evidence from 'high' to 'moderate' because of risk of bias concerns, and further to 'low' because of imprecision. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that phlebotonics probably reduce oedema slightly, compared to placebo; moderate-certainty evidence of little or no difference in QoL; and low-certainty evidence that these drugs do not influence ulcer healing. Moderate-certainty evidence suggests that phlebotonics are probably associated with a higher risk of adverse events than placebo. Studies included in this systematic review provided only short-term safety data; therefore, the medium- and long-term safety of phlebotonics could not be estimated. Findings for specific groups of phlebotonics are limited due to small study numbers and heterogeneous results. Additional high-quality RCTs focusing on clinically important outcomes are needed to improve the evidence base.

Rationale and design for a cluster randomized quality-improvement trial to increase the uptake of evidence-based therapies for patients at high cardiovascular risk: The BRIDGE-Cardiovascular Prevention trial.

BACKGROUND: Translating evidence into clinical practice in the management of high cardiovascular risk patients is challenging. Few quality improvement interventions have rigorously evaluated their impact on both patient care and clinical outcomes. OBJECTIVES: The main objectives are to evaluate the impact of a multifaceted educational intervention on adherence to local guidelines for the prescription of statins, antiplatelets and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers for high cardiovascular risk patients, as well as on the incidence of major cardiovascular events. DESIGN: We designed a pragmatic two arm cluster randomized trial involving 40 clusters. Clusters are randomized to receive a multifaceted quality improvement intervention or to routine practice (control). The multifaceted intervention includes: reminders, care algorithms, training of a case manager, audit and feedback reports, and distribution of educational materials to health care providers. The primary endpoint is the adherence to combined evidence-based therapies (statins, antiplatelet therapy and angiotensin converting enzyme inhibitors or angiotensin receptor blockers) at 12 months after the intervention period in patients without contra-indications for these medications. All analyses follow the intention-to-treat principle and take the cluster design into account using linear mixed logistic regression modeling. SUMMARY: If proven effective, this multifaceted intervention would have wide utility as a means of promoting optimal usage of evidence-based interventions for the management of high cardiovascular risk patients.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: This is the second updated version of the original Cochrane review published in the Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. OBJECTIVES: To evaluate the effectiveness and safety of adjuvant platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. SEARCH METHODS: For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library 2009, Issue 1), MEDLINE, Embase, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for the first update and to September 2016 for the second update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. MAIN RESULTS: For this second updated version we identified only one small trial reporting grade 4 toxicity results, without disease-free or overall survival data with a median follow-up of 16 months.From the first updated version, we identified three trials that were ongoing, and remain so in 2016.Four trials including 401 women with evaluable results with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Three trials compared chemotherapy combined with radiotherapy versus radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy versus radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (three trials, 321 women; risk ratio (RR) 6.26, 95% CI 2.50 to 15.67). We considered the evidence for all three outcomes to be of a moderate quality, using the GRADE approach due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no difference in disease recurrence between the groups (one trial, 71 women; HR = 1.34; 95% CI 0.24 to 7.66) and overall survival was not reported. We considered this evidence to be of a low quality.No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long term due to a lack of long-term data. This evidence is limited by the small numbers and low to moderate methodological quality of the included studies. We await the results of three ongoing trials, which are likely to have an important impact on our confidence in this evidence.

Phlebotonics for venous insufficiency.

BACKGROUND: Chronic venous insufficiency (CVI) is a common condition caused by valvular dysfunction with or without associated obstruction, usually in the lower limbs. It might result in considerable discomfort with symptoms such as pain, itchiness and tiredness in the legs. Patients with CVI may also experience swelling and ulcers. Phlebotonics are a class of drugs often used to treat CVI. This is an update of a review first published in 2005. OBJECTIVES: To assess the efficacy and safety of phlebotonics administered both orally and topically for treatment of signs and symptoms of lower extremity CVI. SEARCH METHODS: For this update, the Cochrane Vascular Trials Search Co-ordinator (TSC) searched the Specialised Register (August 2015), as well as the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 7). The reference lists of the articles retrieved by electronic searches were searched for additional citations. We also contacted pharmaceutical companies and searched the World Health Organization (WHO) International Clinical Trials Registry Platform Search Portal for ongoing studies (last searched in August 2015). SELECTION CRITERIA: Randomised, double-blind, placebo-controlled trials (RCTs) assessing the efficacy of rutosides, hidrosmine, diosmine, calcium dobesilate, chromocarbe, Centella asiatica, disodium flavodate, french maritime pine bark extract, grape seed extract and aminaftone in patients with CVI at any stage of the disease. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed the quality of included RCTs. We estimated the effects of treatment by using risk ratios (RRs), mean differences (MDs) and standardised mean differences (SMDs), according to the outcome assessed. We calculated 95% confidence interval (CIs) and percentage of heterogeneity (I(2)). Additionally, we performed sensitivity analyses. MAIN RESULTS: We included 66 RCTs of oral phlebotonics, but only 53 trials provided quantifiable data (involving 6013 participants; mean age 50 years) for the efficacy analysis: 28 for rutosides, 10 hidrosmine and diosmine, nine calcium dobesilate, two Centella asiatica, two aminaftone, two french maritime pine bark extract and one grape seed extract. No studies evaluating topical phlebotonics, chromocarbe, naftazone or disodium flavodate fulfilled the inclusion criteria.Moderate-quality evidence suggests that phlebotonics reduced oedema in the lower legs compared with placebo. Phlebotonics showed beneficial effects among participants including reduced oedema (RR 0.70, 95% CI 0.63 to 0.78; I(2) = 20%; 1245 participants) and ankle circumference (MD -4.27 mm, 95% CI -5.61 to -2.93 mm; I(2) = 47%; 2010 participants). Low-quality evidence reveals no difference in the proportion of ulcers cured with phlebotonics compared with placebo (RR 0.94, 95% CI 0.79 to 1.13; I(2) = 5%; 461 participants). In addition, phlebotonics showed greater efficacy for trophic disorders, cramps, restless legs, swelling and paraesthesia, when compared with placebo. We identified heterogeneity for the variables of pain, itching, heaviness, quality of life and global assessment by participants. For quality of life, it was not possible to pool the studies because heterogeneity was high. However, high-quality evidence suggests no differences in quality of life for calcium dobesilate compared with placebo (MD -0.60, 95% CI -2.15 to 0.95; I(2) = 40%; 617 participants), and low-quality evidence indicates that in the aminaftone group, quality of life was improved over that reported in the placebo group (MD -10.00, 95% CI -17.01 to - 2.99; 79 participants). Moderate-quality evidence shows that the phlebotonics group had greater risk of non-severe adverse events than the placebo group (RR 1.21, 95% CI 1.05 to 1.41; I(2) = 0; 3975 participants). Gastrointestinal disorders were the most frequently reported adverse events. AUTHORS' CONCLUSIONS: Moderate-quality evidence shows that phlebotonics may have beneficial effects on oedema and on some signs and symptoms related to CVI such as trophic disorders, cramps, restless legs, swelling and paraesthesia when compared with placebo but can produce more adverse effects. Phlebotonics showed no differences compared with placebo in ulcer healing. Additional high-quality RCTs focused on clinically important outcomes are needed to improve the evidence base.

Laparoscopy versus laparotomy for FIGO stage I ovarian cancer.

BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer. OBJECTIVES: To evaluate the benefits and harms of laparoscopy in the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic) when compared with laparotomy. SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, Embase, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For the first updated review, the search was extended to the CGCRG Specialised Register, CENTRAL, MEDLINE, Embase and LILACS to 6 December 2011. For this update we searched CENTRAL, MEDLINE, and Embase from November 2011 to September 2016. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective cohort studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO. DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion as well as important data from other meta-analyses. MAIN RESULTS: We performed no meta-analyses. AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice.

Prevalence and risk factors of Hepatitis C virus infection in Brazil, 2005 through 2009: a cross-sectional study.

BACKGROUND: Hepatitis C chronic liver disease is a major cause of liver transplant in developed countries. This article reports the first nationwide population-based survey conducted to estimate the seroprevalence of HCV antibodies and associated risk factors in the urban population of Brazil. METHODS: The cross sectional study was conducted in all Brazilian macro-regions from 2005 to 2009, as a stratified multistage cluster sample of 19,503 inhabitants aged between 10 and 69 years, representing individuals living in all 26 State capitals and the Federal District. Hepatitis C antibodies were detected by a third-generation enzyme immunoassay. Seropositive individuals were retested by Polymerase Chain Reaction and genotyped. Adjusted prevalence was estimated by macro-regions. Potential risk factors associated with HCV infection were assessed by calculating the crude and adjusted odds ratios, 95% confidence intervals (95% CI) and p values. Population attributable risk was estimated for multiple factors using a case-control approach. RESULTS: The overall weighted prevalence of hepatitis C antibodies was 1.38% (95% CI: 1.12%-1.64%). Prevalence of infection increased in older groups but was similar for both sexes. The multivariate model showed the following to be predictors of HCV infection: age, injected drug use (OR = 6.65), sniffed drug use (OR = 2.59), hospitalization (OR = 1.90), groups socially deprived by the lack of sewage disposal (OR = 2.53), and injection with glass syringe (OR = 1.52, with a borderline p value). The genotypes 1 (subtypes 1a, 1b), 2b and 3a were identified. The estimated population attributable risk for the ensemble of risk factors was 40%. Approximately 1.3 million individuals would be expected to be anti-HCV-positive in the country. CONCLUSIONS: The large estimated absolute numbers of infected individuals reveals the burden of the disease in the near future, giving rise to costs for the health care system and society at large. The known risk factors explain less than 50% of the infected cases, limiting the prevention strategies. Our findings regarding risk behaviors associated with HCV infection showed that there is still room for improving strategies for reducing transmission among drug users and nosocomial infection, as well as a need for specific prevention and control strategies targeting individuals living in poverty.

Laparoscopy versus laparotomy for FIGO stage I ovarian cancer.

BACKGROUND: This is an updated version of the original review that was first published in the Cochrane Database of Systematic Reviews 2008, Issue 4. Laparoscopy has become an increasingly common approach to surgical staging of apparent early-stage ovarian tumours. This review was undertaken to assess the available evidence on the benefits and risks of laparoscopy compared with laparotomy for the management of International Federation of Gynaecology and Obstetrics (FIGO) stage I ovarian cancer. OBJECTIVES: To evaluate the benefits and risks of laparoscopy compared with laparotomy for the surgical treatment of FIGO stage I ovarian cancer (stages Ia, Ib and Ic). SEARCH METHODS: For the original review, we searched the Cochrane Gynaecological Cancer Group Trials (CGCRG) Register, Cochrane Central Register of Controlled Trials (CENTRAL 2007, Issue 2), MEDLINE, EMBASE, LILACS, Biological Abstracts and CancerLit from 1 January 1990 to 30 November 2007. We also handsearched relevant journals, reference lists of identified studies and conference abstracts. For this updated review, we extended the CGCRG Specialised Register, CENTRAL, MEDLINE, EMBASE and LILACS searches to 6 December 2011. SELECTION CRITERIA: Randomised controlled trials (RCTs), quasi-RCTs and prospective case-control studies comparing laparoscopic staging with open surgery (laparotomy) in women with stage I ovarian cancer according to FIGO. DATA COLLECTION AND ANALYSIS: There were no studies to include, therefore we tabulated data from non-randomised studies (NRS) for discussion. MAIN RESULTS: We performed no meta-analyses. AUTHORS' CONCLUSIONS: This review has found no good-quality evidence to help quantify the risks and benefits of laparoscopy for the management of early-stage ovarian cancer as routine clinical practice.

Academic detailing and adherence to guidelines for Group B streptococci prenatal screening: a randomized controlled trial.

BACKGROUND: Clinical practice guidelines (CPGs) recommend universal prenatal screening for Group B Streptococcus (GBS) to identify candidates for intrapartum antibiotic prophylaxis to prevent early onset neonatal GBS infection. Interventions to promote physician adherence to these guidelines are imperative. This study examined the effectiveness of academic detailing (AD) of obstetricians, compared with CPG mailshot and no intervention, on the screening of pregnant women for GBS. METHODS: A randomized controlled clinical trial was conducted in the medical cooperative of Porto Alegre, Brazil. All obstetricians who assisted in a delivery covered by private health insurance managed by the cooperative in the 3 months preceding the study (n = 241) were invited to participate. The obstetricians were randomized to three groups: direct mail (DM, n = 76), AD (n = 76) and control (C, n = 89, no intervention). Those in the DM group were sent guidelines on GBS. The AD group received the guidelines and an educational visit detailing the guidelines, which was conducted by a trained physician. Data on obstetrician age, gender, time since graduation, whether patients received GBS screening during pregnancy, and obstetricians who requested screening were collected for all participant obstetricians for 3 months before and after the intervention, using database from the private health insurance information system. RESULTS: Three months post-intervention, the data showed that the proportion of pregnant women screened for GBS was higher in the AD group (25.4%) than in the DM (15.9%) and C (17.7%) groups (P = 0.023). Similar results emerged when the three groups were taken as a cluster (pregnant women and their obstetricians), but the difference was not statistically significant (Poisson regression, P = 0.108). Additionally, when vaginal deliveries were analyzed separately, the proportion screened was higher in the AD group (75%) than in the DM group (41.9%) and the C group (30.4%) (chi-square, P < 0.001). CONCLUSIONS: The results suggest that AD increased the prevalence of GBS screening in pregnant women in this population.

Risk of bias and certainty of evidence on the association between obesity and mortality in patients with SARS-COV-2: An umbrella review of meta-analyses.

BACKGROUND & AIMS: This umbrella review of systematic reviews with meta-analysis (SR-MAs) aimed to evaluate the risk of bias and the certainty of the evidence of SR-MAs on the association between obesity and mortality in patients with SARS-CoV-2. METHODS: We conducted a comprehensive literature search until April 22, 2022, in several databases and assessed the risk of bias of SR-MAs according to AMSTAR-2 and the certainty of evidence using the GRADE approach. The degree of overlap between meta-analyses was based on the corrected covered area (CCA) index. The results of each MA [relative risk (RR), hazard ratio (HR), or odds ratio (OR)] were extracted to evaluate the magnitude of the association between obesity and mortality. RESULTS: A total of 24 SR-MAs were eligible, and the association between obesity and mortality was not statistically significant in eight (33.3%) of them, while the OR/HR/RR ranged from 1.14 to 3.52 in the other SR-MAs. The overlap was slight (CCA = 4.82%). The majority of SR-MAs presented critically low quality according to AMSTAR-2 (66.7%), and the certainty of the evidence for most of them (83.4%) was "very low". CONCLUSIONS: Obesity was associated with an increased risk of death in patients with SARS-CoV-2 infection in most SR-MAs; however, a critical appraisal pointed to a high risk of bias, and the certainty of their evidence was not well graded. The dissemination of poor SR-MAs may limit the interpretation of findings, and we should always aspire to trustworthy scientific evidence. PROSPERO: PROSPERO 2021 CRD42021253142.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 3. Most women with early cervical cancer (stages I to IIA) are cured with surgery or radiotherapy, or both. We performed this review originally because it was unclear whether cisplatin-based chemotherapy after surgery, radiotherapy or both, in women with early stage disease with risk factors for recurrence, was associated with additional survival benefits or risks. OBJECTIVES: To evaluate the effectiveness and safety of platinum-based chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer. SEARCH METHODS: For the original 2009 review, we searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2009, Issue 1), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and CancerLit, the National Research Register and Clinical Trials register, with no language restriction. We handsearched abstracts of scientific meetings and other relevant publications. We extended the database searches to November 2011 for this update. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant cisplatin-based chemotherapy (after radical surgery, radiotherapy or both) with no adjuvant chemotherapy, in women with early stage cervical cancer (stage IA2-IIA) with at least one risk factor for recurrence. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently. Meta-analysis was performed using a random-effects model, with death and disease progression as outcomes. MAIN RESULTS: For this updated version, we identified three additional ongoing trials but no new studies for inclusion. Three trials including 368 evaluable women with early cervical cancer were included in the meta-analyses. The median follow-up period in these trials ranged from 29 to 42 months. All women had undergone surgery first. Two trials compared chemotherapy combined with radiotherapy to radiotherapy alone; and one trial compared chemotherapy followed by radiotherapy to radiotherapy alone. It was not possible to perform subgroup analyses by stage or tumour size.Compared with adjuvant radiotherapy, chemotherapy combined with radiotherapy significantly reduced the risk of death (two trials, 297 women; hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (two trials, 297 women; HR = 0.47, 95% CI 0.30 to 0.74), with no heterogeneity between trials (I² = 0% for both meta-analyses). Acute grade 4 toxicity occurred significantly more frequently in the chemotherapy plus radiotherapy group than in the radiotherapy group (risk ratio (RR) 5.66, 95% CI 2.14 to 14.98). We considered this evidence to be of a moderate quality due to small numbers and limited follow-up in the included studies. In addition, it was not possible to separate data for bulky early stage disease.In the one small trial that compared adjuvant chemotherapy followed by radiotherapy with adjuvant radiotherapy alone there was no significant difference in disease recurrence between the groups (HR = 1.34; 95% CI 0.24 to 7.66) and OS was not reported. We considered this evidence to be of a low quality.No trials compared adjuvant platinum-based chemotherapy with no adjuvant chemotherapy after surgery for early cervical cancer with risk factors for recurrence. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to adjuvant radiotherapy (chemoradiation) may improve survival in women with early stage cervical cancer (IA2-IIA) and risk factors for recurrence. Adjuvant chemoradiation is associated with an increased risk of severe acute toxicity, although it is not clear whether this toxicity is significant in the long-term due to a lack of long-term data. This evidence is limited by the small numbers and poor methodological quality of included studies. We await the results of three ongoing trials, that are likely to have an important impact on our confidence in this evidence.

PROTOCOL: Guidance for stakeholder engagement in guideline development: A systematic review.

This is the protocol for a Campbell systematic review. The objectives are as follows: to identify, describe, and summarize existing guidance and methods for multistakeholder engagement throughout the health guideline development process.

Analysis of leukocytes in medication-overuse headache, chronic migraine, and episodic migraine.

OBJECTIVE: To evaluate the number of immune cells in the peripheral blood of medication-overuse headache (MOH), chronic migraine (CM), and migraine without aura (MWA) patients, as well as from controls. BACKGROUND: Migraine has been linked to immunologic disturbances, but the role of the immune system in chronic forms of headache that evolve from migraine has not been studied. Psychiatric co-morbidity has been related to both headache chronification and immunologic alterations. METHODS: This cross-sectional study comprised 68 subjects divided in 4 groups: MOH, CM, MWA, control. Subjects were gender-matched, had no physical co-morbidity, and were taking only acetaminophen. Clinical and psychological data were recorded in a standardized protocol. Samples of peripheral blood for hematological analysis were obtained in the morning during the ictal (MOH, CM, and MWA groups) and interictal periods (MWA group), as well from control group. RESULTS: A higher lymphocyte count was measured in MOH patients relative to the MWA patients (mean ± standard deviation: 2448.7/mm3 ± 775.8 vs. 1859.7/mm3 ± 564.7; P = .027). The numbers of blood lymphocytes for CM and control subjects were 2086.1/mm3 ± 540.5 and 1961.7/mm3 ± 385.6, respectively. Multiple linear regression analysis demonstrated that only MOH and MWA groups remained associated with lymphocyte count (B = 540.7; CI 95%: 55.2-1026.1; P = .03; R2 = 19.2%). Analysis for linearity of variables in the spectrum control/MWA/CM/MOH resulted positive for body mass index (from 23.5 ± 3.25 in controls to 26.5 ± 4.49 in MOH patients; P = .034), scores on Beck Depression Inventory (from 3.29 ± 3.05 to 14.65 ± 11.21; P < 0.001) and Hamilton Anxiety Scale (from 4.29 ± 3.93 to 23.24 ± 11.01; P < 0.001), hemoglobin (from 13.7 ± 0.79 to 14.6 ± 1.31; P = .022), and lymphocyte count (from 1961.7 ± 385.6 to 2448.7 ± 775.8; P = .01), but negative for CD8+ T lymphocytes (from 34.0 ± 8.82 to 30.0 ± 6.64; P = .046). CONCLUSIONS: A higher lymphocyte count in the MOH group relative to the MWA group may indicate a chronic inflammatory state. Several clinical and laboratorial characteristics have a range along a spectrum extending from healthy subjects to patients suffering from chronic forms of migraine.

Prevalence of hepatitis A in the capitals of the States of North, Southeast and South regions of Brazil: decrease in prevalence and some consequences.

Hepatitis A virus (HAV) infection has been considered one of the leading causes of acute hepatitis. The aim of the present study was to estimate the prevalence of HAV among children and adolescents in a population-based study in the capitals of the States of the North, Southeast and South of Brazil and identify predictive factors for the infection. A multi-stage sampling was used to select subjects aged between 5-9 and 10-19 years. Individual and household levels aside from the level of variables in the areas were collected. The outcome was the total IgG antibodies to HAV levels detected using a commercial Enzyme Immuno Assay (EIA). The associations between HAV and the independent variables were assessed using the odds ratio. A multilevel analysis was performed by GLLAMM using the Stata software. The prevalence of HAV infection in the 5-9 and 10-19 age groups was 28.7% and 67.5%, respectively for the North, 20.6% and 37.7%, for the Southeast and 18.9% and 34.5% for the South Region. The prevalence of HAV increased according to age in all sites. Variables related to education at the individual level (North and South), family and area level (South and Southeast) and family income level (Southeast and South) were independently associated with HAV infection. This emphasizes the need for individualized strategies to prevent the infection.

Adherence to treatment in collective multiprofessional activities and factors associated with adherence in a specialized center for psychosocial care.

INTRODUCTION: Specialized psychosocial care centers (Centros de Atenção Psicossocial [CAPS]) are mental health services focused on social rehabilitation and reducing hospitalization of patients with severe and persistent mental illness. Collective multiprofessional activities (CMPA) are the main therapeutic tools used at CAPS. This study aimed to determine rates of adherence to CMPA and identify factors associated with adherence. METHODS: This is a cross-sectional study in which 111 CAPS users were evaluated using questionnaires covering patient characteristics, clinical status, and treatment and incorporating the Functioning Assessment Short Test (FAST), the Clinical Global Impression - Severity scale (CGI-S), and the Clinical Global Impression - Improvement scale (CGI-I). Adherence was defined as attendance at 50% or more CMPA during the previous 3 months. Data were analyzed using descriptive statistics, bivariate analysis, and Poisson logistic regression with robust variance to estimate prevalence ratios. RESULTS: CPMA adherence was 43%. Having children aged 14 years or younger was significantly associated with non-adherence (71%, p = 0.001). Poor or partial adherence to psychotropic drugs tended to be associated (p = 0.066) with poor adherence (33% higher risk), as was the number of psychiatric hospitalizations during CAPS (p = 0.076), with a cumulative association of 5% non-adherence per hospitalization. CONCLUSIONS: CMPA adherence was low in the study. It is necessary to consider the environment in which the individual lives and invest in support networks, providing patients and family members with explanations about the importance of CMPA to rehabilitation and attempting to tailor the care provided to each patient's needs. There was an association between greater number of psychiatric hospitalizations and non-adherence, suggesting that CAPS are fulfilling a preventive role.

Protocol for the development of guidance for stakeholder engagement in health and healthcare guideline development and implementation.

BACKGROUND: Stakeholder engagement has become widely accepted as a necessary component of guideline development and implementation. While frameworks for developing guidelines express the need for those potentially affected by guideline recommendations to be involved in their development, there is a lack of consensus on how this should be done in practice. Further, there is a lack of guidance on how to equitably and meaningfully engage multiple stakeholders. We aim to develop guidance for the meaningful and equitable engagement of multiple stakeholders in guideline development and implementation. METHODS: This will be a multi-stage project. The first stage is to conduct a series of four systematic reviews. These will (1) describe existing guidance and methods for stakeholder engagement in guideline development and implementation, (2) characterize barriers and facilitators to stakeholder engagement in guideline development and implementation, (3) explore the impact of stakeholder engagement on guideline development and implementation, and (4) identify issues related to conflicts of interest when engaging multiple stakeholders in guideline development and implementation. DISCUSSION: We will collaborate with our multiple and diverse stakeholders to develop guidance for multi-stakeholder engagement in guideline development and implementation. We will use the results of the systematic reviews to develop a candidate list of draft guidance recommendations and will seek broad feedback on the draft guidance via an online survey of guideline developers and external stakeholders. An invited group of representatives from all stakeholder groups will discuss the results of the survey at a consensus meeting which will inform the development of the final guidance papers. Our overall goal is to improve the development of guidelines through meaningful and equitable multi-stakeholder engagement, and subsequently to improve health outcomes and reduce inequities in health.

Day hospital versus outpatient care for people with schizophrenia.

BACKGROUND: This review considers the use of day hospitals as an alternative to outpatient care. Two types of day hospital are covered by the review: 'day treatment programmes' and 'transitional' day hospitals. Day treatment programmes offer more intense treatment for people who have failed to respond to outpatient care. Transitional day hospitals offer time-limited care to people who have just been discharged from inpatient care. OBJECTIVES: To assess effects of day hospital care as an alternative to continuing outpatient care for people with schizophrenia and and other similar severe mental illness. SEARCH STRATEGY: We searched the Cochrane Schizophrenia Group Trials Register (May 2009) and references of all identified studies for further citations. If necessary, we also contacted authors of trials for further information. SELECTION CRITERIA: Randomised controlled trials comparing day hospital care with outpatient care for those with schizophrenia and other similar severe mental illness. DATA COLLECTION AND ANALYSIS: We extracted and cross-checked data independently. We analysed dichotomous data using fixed-effect relative risk (RR) and estimated the 95% confidence interval (CI). If continuous data were included, we analysed this data using the random-effects weighted mean difference (MD) with a 95% confidence interval. MAIN RESULTS: We identified four relevant trials all dating from before 1986 (total n=309 participants); all but one of which (n=37) evaluated day treatment centres. Across time less people allocated to day hospital care tend to be admitted to hospital (beyond one year: n=242, 2 RCTs, RR 0.71 CI 0.56 to 0.89 day treatment centres) but data are heterogeneous (I(2) =74% P=0.05) and should not be taken into account. Data on time spent as an inpatient seem to support this finding but are poorly reported. We found no clear difference between day hospital and outpatient care for the outcome of 'lost to follow up' (at six months: n=147, 3 RCTs, RR 0.97 CI 0.48 to 1.95; at 12 months: n=117, 2 RCTs, RR 0.97 CI 0.48 to 1.95 day treatment centres / transitional day hospital). Scale derived findings on social functioning are equivocal (SAS: n=37, 1 RCT, MD 0.36 CI -0.07 to 0.79 transitional day hospital) but there was some suggestion from small studies that day hospital care may decrease the risk of unemployment (at 12 months: n=80, 1 RCT, RR 0.86 CI 0.69 to 1.06 day treatment centre). Different measures of mental state showed no convincing effect (Symptom Check List: n=30, 1 RCT, MD -90 0.31 CI -0.20 to 0.82 day treatment centre). Poorly reported economic data from decades ago suggested that day hospitals were more costly to establish and run than outpatient care but took no account of other costs such as inpatient stay. AUTHORS' CONCLUSIONS: Evidence is limited and dated. Day hospital care may help avoid inpatient care but data are lacking on missing on a raft of outcomes that are now considered important, such as quality of life, satisfaction, healthy days, and cost.

Laparoscopy versus laparotomy for benign ovarian tumour.

BACKGROUND: Over the last 10 years laparoscopy and minilaparotomy have become increasingly common approaches for the surgical removal of benign ovarian tumours. However, in the event that a tumour is found to be malignant, laparotomy is the appropriate procedure. Careful preoperative assessment including transvaginal ultrasound with morphological scoring, colour doppler assessment of vascular quality, and serum cancer antigen 125 (CA 125) level is desirable. OBJECTIVES: To determine the benefits, harms, and cost of laparoscopy or minilaparotomy compared with laparotomy in women with benign ovarian tumours. SEARCH STRATEGY: We searched electronic databases, trial registers, and reference lists of published trial reports. Reference lists from trials and review articles were searched. SELECTION CRITERIA: All randomised controlled trials comparing either laparoscopy or minilaparotomy with laparotomy for benign ovarian tumours. DATA COLLECTION AND ANALYSIS: Eight review authors independently assessed the eligibility and quality of each study and extracted the data. MAIN RESULTS: The results of nine randomised controlled trials (N = 482 women) showed that laparoscopic surgery was associated with fewer adverse events of surgery (surgical injury or postoperative complications including fever or infection) (OR 0.3, 95% CI 0.2 to 0.5), less postoperative pain (VAS score WMD -2.4, 95% CI -2.7 to -2.0), greater likelihood of being pain free after two days (OR 7.42, 95% CI 4.86 to 11.33), and fewer days in hospital (WMD -2.88, 95% CI -3.1 to -2.7) than with laparotomy.In one study that reported costs, laparoscopy was associated with a significant reduction in costs compared to laparotomy (WMD - USD 1045, 95% CI -1348 to -742) in 1993. Very high levels of heterogeneity made it inappropriate to pool data on duration of surgery.Three RCTs compared laparoscopy versus minilaparotomy and found that laparoscopy was associated with reduced odds of any adverse event (surgical injury or postoperative complications) (OR 0.10, 95% CI 0 to 0.8) and lower VAS scores for pain (WMD -1.0, 95% CI -1.6 to -0.45). Duration of hospital stay ranged between 1 and 2.2 days, with substantial heterogeneity. AUTHORS' CONCLUSIONS: In women undergoing surgery for benign ovarian tumours, laparoscopy was associated with a reduction in fever, urinary tract infection, postoperative complications, postoperative pain, number of days in hospital, and total cost. These findings should be interpreted with caution since only a small number of studies were identified. These included a total of only 769 women and not all of the important outcomes were reported in each study.

Adjuvant platinum-based chemotherapy for early stage cervical cancer.

BACKGROUND: Patients with early stage cervical cancer (stages IA2, IB1 or IIA) with risk factors such as lymph node metastasis, lympho vascular space invasion, depth invasion of more than 10mm, microscopic parametrial invasion, non-squamous histology and positive surgical margins have a high risk of recurrence when compared to patients with early stage cervical cancer with no risk factors for recurrence. OBJECTIVES: To evaluate the effectiveness and safety of platinum-based adjuvant chemotherapy after radical hysterectomy, radiotherapy, or both in the treatment of early stage cervical cancer (stages IA2, IB1 or IIA). SEARCH STRATEGY: We searched the Cochrane Gynaecological Cancer Group Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 1, 2009), MEDLINE, EMBASE, LILACS, BIOLOGICAL ABSTRACTS and Cancerlit, the National Research Register and Clinical Trials register, with no language restriction. Abstracts of scientific meetings and the citation lists of included studies and other relevant publications were checked through hand searching and experts in the field were contacted to identify further reports of trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing adjuvant radiotherapy with adjuvant radiotherapy and cisplatin-chemotherapy after radical surgery for early stage cervix cancer were included. DATA COLLECTION AND ANALYSIS: Two review authors extracted data independently to assess whether the studies met the specified inclusion criteria. Any discrepancies were solved by a third and a forth review author. Meta-analysis was performed using a random effects model, with death and disease progression as outcomes. MAIN RESULTS: Three trials were included. Two trials enrolling 325 participants, of whom 297 (91%) were assessed and compared radiotherapy and chemotherapy with radiotherapy alone found that adjuvant chemotherapy significantly reduced the risk of death (hazard ratio (HR) = 0.56, 95% confidence interval (CI): 0.36 to 0.87) and disease progression (HR = 0.47, 95%CI: 0.30 to 0.74), with no heterogeneity between trials (I(2) = 0% for both meta-analyses). One trial assessing 71 participants compared chemotherapy followed by radiotherapy with radiotherapy alone and found no significant difference between the two groups (HR = 1.34; 95%CI: 0.24 to 7.66). The median follow up of patients varied from 29 to 42 months. AUTHORS' CONCLUSIONS: The addition of platinum-based chemotherapy to radiotherapy may offer clinical benefit in the adjuvant treatment of early stage cervical cancer with risk factors for recurrence. However, the evidence is limited because the selected studies were quantitatively and qualitatively limited, with small number of patients and limited period of follow-up.

Influence of depression and early adverse experiences on illicit drug dependence: a case-control study.

OBJECTIVE: The purpose of this study was to investigate the association between depression and illicit drug dependence among a Latin-American population. METHOD: illicit drug dependent patients (n = 137) and controls (n = 274) were interviewed using the Diagnostic Interview for Genetic Studies, in order to detect lifetime and current depressive disorder and illicit (cocaine, cannabis or inhalants) substance dependence. A regression analysis was used to estimate the odds ratio for drug dependence according to the diagnosis of depression. RESULTS: The lifetime diagnosis of depression (p = 0.001; OR = 4.9; 95% CI, 1.9-12.7) predicts illegal drugs dependence. Sociodemographic variables such as male gender (p < 0.001; OR = 36.8; 95% CI, 11.8-114) and occupational situation (p = 0.002; OR = 5.0; 95% CI, 1.8-13) as well as alcohol dependence (p = 0.01; OR = 3.4; 95% CI, 1.3-8.7) significantly influenced depression and drug dependence. Additional influent factors detected were having parents (p = 0.006; OR = 18.9; 95% CI, 2.3-158) or friends (p < 0.001; OR = 64.4; 95% CI, 6.5-636) who are illicit drugs dependents. CONCLUSION: although a causal relationship between dependence on illicit drugs and depression cannot be determined, comparison of the sequence of events point to the occurrence of depression later in life than dependence. It remains to be determined whether depression is a comorbidity of dependence, sharing etiological factors, or a consequence of drug abuse and/or abstinence.

Effect of a Multifaceted Quality Improvement Intervention on the Prescription of Evidence-Based Treatment in Patients at High Cardiovascular Risk in Brazil: The BRIDGE Cardiovascular Prevention Cluster Randomized Clinical Trial.

Importance: Studies have found that patients at high cardiovascular risk often fail to receive evidence-based therapies in community practice. Objective: To evaluate whether a multifaceted quality improvement intervention can improve the prescription of evidence-based therapies. Design, Setting, and Participants: In this 2-arm cluster randomized clinical trial, patients with established atherothrombotic disease from 40 public and private outpatient clinics (clusters) in Brazil were studied. Patients were recruited from August 2016 to August 2017, with follow-up to August 2018. Data were analyzed in September 2018. Interventions: Case management, audit and feedback reports, and distribution of educational materials (to health care professionals and patients) vs routine practice. Main Outcomes and Measures: The primary end point was prescription of evidence-based therapies (ie, statins, antiplatelet therapy, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) using the all-or-none approach at 12 months after the intervention period in patients without contraindications. Results: Of the 1619 included patients, 1029 (63.6%) were male, 1327 (82.0%) had coronary artery disease (843 [52.1%] with prior acute myocardial infarction), 355 (21.9%) had prior ischemic stroke or transient ischemic attack, and 197 (12.2%) had peripheral vascular disease, and the mean (SD) age was 65.6 (10.5) years. Among randomized clusters, 30 (75%) were cardiology sites, 6 (15%) were primary care units, and 26 (65%) were teaching institutions. Among eligible patients, those in intervention clusters were more likely to receive a prescription of evidence-based therapies than those in control clusters (73.5% [515 of 701] vs 58.7% [493 of 840]; odds ratio, 2.30; 95% CI, 1.14-4.65). There were no differences between the intervention and control groups with regards to risk factor control (ie, hyperlipidemia, hypertension, or diabetes). Rates of education for smoking cessation were higher among current smokers in the intervention group than in the control group (51.9% [364 of 701] vs 18.2% [153 of 840]; odds ratio, 11.24; 95% CI, 2.20-57.43). The rate of cardiovascular mortality, acute myocardial infarction, and stroke was 2.6% for patients from intervention clusters and 3.4% for those in the control group (hazard ratio, 0.76; 95% CI, 0.43-1.34). Conclusions and Relevance: Among Brazilian patients at high cardiovascular risk, a quality improvement intervention resulted in improved prescription of evidence-based therapies. Trial Registration: ClinicalTrials.gov identifier: NCT02851732.