Transjugular intrahepatic portosystemic shunts for adults with hepatorenal syndrome.

BACKGROUND: Hepatorenal syndrome is a condition that occurs in people with chronic liver disease (such as alcoholic hepatitis, advanced cirrhosis, or fulminant liver failure) and portal hypertension. The prognosis is dismal, often with a survival of weeks to months. Hepatorenal syndrome is characterised by the development of intense splanchnic vasodilation favouring ascites and hypotension leading to renal vasoconstriction and acute renal failure. Therefore, treatment attempts focus on improving arterial pressure through the use of vasopressors, paracentesis, and increasing renal perfusion pressure. Several authors have reported that the placement of transjugular intrahepatic portosystemic shunts (TIPS) may be a therapeutic option because it decreases portal pressure and improves arterial and renal pressures. However, the evidence is not clearly documented and TIPS may cause adverse events. Accordingly, it is necessary to evaluate the evidence of the benefits and harms of TIPS to assess its value in people with hepatorenal syndrome. OBJECTIVES: To evaluate the benefits and harms of transjugular intrahepatic portosystemic shunts (TIPS) in adults with hepatorenal syndrome compared with sham, no intervention, conventional treatment, or other treatments. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 2 June 2023. SELECTION CRITERIA: We included only randomised clinical trials with a parallel-group design, which compared the TIPS placement with sham, no intervention, conventional therapy, or other therapies, in adults aged 18 years or older, regardless of sex or ethnicity, diagnosed with chronic liver disease and hepatorenal syndrome. We excluded trials of adults with kidney failure due to causes not related to hepatorenal syndrome, and we also excluded data from quasi-randomised, cross-over, and observational study designs as we did not design a separate search for such studies. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. morbidity due to any cause, and 3. serious adverse events. Our secondary outcomes were 1. health-related quality of life, 2. non-serious adverse events, 3. participants who did not receive a liver transplant, 4. participants without improvement in kidney function, and 5. length of hospitalisation. We performed fixed-effect and random-effects meta-analyses using risk ratio (RR) or Peto odds ratio (Peto OR), with 95% confidence intervals (CI) for the dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) for the continuous outcomes. We used GRADE to assess certainty of evidence. MAIN RESULTS: We included two randomised clinical trials comparing TIPS placement (64 participants) versus conventional treatment (paracentesis plus albumin 8 g/L of removed ascites) (66 participants). The co-interventions used in the trials were dietary treatment (sodium less than 60 mmoL/day), spironolactone (300 mg/day to 400 mg/day), and furosemide (120 mg/day). Follow-up was up to 24 months. Both were multicentre trials from Spain and the USA, and Germany, conducted between 1993 and 2002. Most participants were men (aged 18 to 75 years). We are uncertain about the effect of TIPS placement compared with conventional treatment, during the first 24 months of follow-up, on all-cause mortality (RR 0.88, 95% CI 0.55 to 1.38; 2 trials, 130 participants; I2 = 58%; very low-certainty evidence) and on the development of any serious adverse event (RR 1.60, 95% CI 0.10 to 24.59; 2 trials, 130 participants; I2 = 78%; very low-certainty evidence). The use of TIPS may or may not result in a decrease in overall morbidity such as bacterial peritonitis, encephalopathy, or refractory ascites, during the first 24 months of follow-up, compared with the conventional treatment (RR 0.95, 95% CI 0.77 to 1.18; 2 trials, 130 participants; I2 = 0%; low-certainty evidence). We are uncertain about the effect of TIPS placement versus conventional treatment on the number of people who did not receive a liver transplant (RR 1.03, 95% CI 0.93 to 1.14; 2 trials, 130 participants; I2 = 0%; very low-certainty evidence) or on the length of hospitalisation (MD -20.0 days, 95% CI -39.92 to -0.08; 1 trial, 60 participants; very low-certainty evidence). Kidney function may improve in participants with TIPS placement (RR 0.53, 95% CI 0.27 to 1.02; 1 trial, 70 participants; low-certainty evidence). No trials reported health-related quality of life, non-serious adverse events, or number of participants with improvement in liver function associated with the TIPS placement. Funding No trials reported sources of commercial funding or conflicts of interest between researchers. Ongoing studies We found one ongoing trial comparing TIPS with conventional therapy (terlipressin plus albumin) and listed one study as awaiting classification as no full-text article could be found. AUTHORS' CONCLUSIONS: TIPS placement was compared with conventional treatment, with a follow-up of 24 months, in adults with hepatorenal syndrome type 2. Based on two trials with insufficient sample size and trial limitations, we assessed the overall certainty of evidence as low or very low. We are unsure if TIPS may decrease all-cause mortality, serious adverse events, the number of people who did not receive a liver transplant, and the days of hospitalisation because of the very low-certainty evidence. We are unsure if TIPS, compared with conventional treatment, has better effects on overall morbidity (bacterial peritonitis, encephalopathy, or refractory ascites). TIPS may improve kidney function, but the certainty of evidence is low. The trials included no data on health-related quality of life, non-serious adverse events, and liver function associated with the TIPS placement. We identified one ongoing trial and one study awaiting classification which may contribute to the review when information becomes available.

Total and segmental phase angle in a cohort of hospitalised patients with COVID-19: mortality prediction and changes throughout hospitalisation.

Body composition and phase angle (PhA) have been used to predict mortality in multiple diseases. However, little has been studied regarding segmental measurements, which could potentially help assess subtle changes in specific tissue segments. This study aimed to identify the total PhA cut-off point associated with mortality risk and changes in body composition within a week of hospitalisation in non-critical hospitalised patients with COVID-19. A cohort study was conducted where patients underwent to a complete nutritional assessment upon admission and after seven days, and followed up until hospital discharge or death. A receiver operating characteristic curve was constructed to determine the PhA cut-off point, and the Kaplan­Meier estimator was used to determine survival analysis. Segmental and complete body compositions on admission and after 7 d were compared. We included 110 patients (60 men) with a mean age of 50·5 ± 15·0 years and a median BMI of 28·5 (IQR, 25·6­33·5) kg/m2. The median length of hospital stay was 6 (IQR, 4­9) d, and the mortality rate was 13·6 %. The PhA cut-off point obtained was 4°, with significant differences in the survival rate (P < 0·001) and mortality (HR = 5·81, 95 % CI: 1·80, 18·67, P = 0·003). Segmental and whole-body compositions were negatively affected within one week of hospitalisation, with changes in the approach by the graphical method in both sexes. Nutritional status deteriorates within a week of hospitalisation. PhA < 4° is strongly associated with increased mortality in non-critical hospitalised patients with COVID-19.

Is intradialytic oral nutritional supplementation safe and effective on clinical outcomes? A systematic review with conventional meta-analysis and network meta-analysis.

AIM: determine the effect of intradialytic oral nutrition (ION) on clinical and safety outcomes. DESIGN: Systematic Review with conventional Meta-analysis, and a Network Meta-analysis (NMA) as sensitivity analysis. We searched on MEDLINE, LILACS, CENTRAL, and EMBASE in June 2020, and the last update was until August 2022. We selected observational and randomized controlled trials with ION for at least four weeks. Primary outcomes were all-cause mortality and quality of life (QoL); adverse events, physical performance, and appetite were secondary outcomes. RESULTS: Seven clinical trials and three observational studies were selected. Even when we did not obtain significant differences in physical performance and gastrointestinal symptoms, we identified a clinical improvement in the QoL's physical role, bodily pain, and physical performance domains. After pooling the data on mortality, a protection rate trend was observed in the ION group without statistical significance. The home-prepared ION was the best nutritional supplementation when assessing the appetite outcome through NMA. CONCLUSIONS: ION seems to have a protective trend in mortality risk; the current evidence is insufficient to establish a relationship with adverse events or other clinical outcomes. The lack of homogeneity in the trials makes it difficult to generalize these results. PROSPERO REGISTRATION: CRD42020186311.

Higher versus lower protein intake in formula-fed term infants.

BACKGROUND: Many infants are fed infant formulas to promote growth. Some formulas have a high protein content (≥ 2.5 g per 100 kcal) to accelerate weight gain during the first year of life. The risk-benefit balance of these formulas is unclear. OBJECTIVES: To evaluate the benefits and harms of higher protein intake versus lower protein intake in healthy, formula-fed term infants. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, OpenGrey, clinical trial registries, and conference proceedings in October 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) of healthy formula-fed infants (those fed only formula and those given formula as a complementary food). We included infants of any sex or ethnicity who were fed infant formula for at least three consecutive months at any time from birth. We excluded quasi-randomized trials, observational studies, and infants with congenital malformations or serious underlying diseases. We defined high protein content as 2.5 g or more per 100 kcal, and low protein content as less than 1.8 g per 100 kcal (for exclusive formula feeding) or less than 1.7 g per 100 kcal (for complementary formula feeding). DATA COLLECTION AND ANALYSIS: Four review authors independently assessed the risk of bias and extracted data from trials, and a fifth review author resolved discrepancies. We performed random-effects meta-analyses, calculating risk ratios (RRs) or Peto odds ratios (Peto ORs) with 95% confidence intervals (CIs) for dichotomous outcomes, and mean differences (MDs) with 95% CIs for continuous outcomes. We used the GRADE approach to evaluate the certainty of the evidence. MAIN RESULTS: We included 11 RCTs (1185 infants) conducted in high-income countries. Seven trials (1629 infants) compared high-protein formula against standard-protein formula, and four trials (256 infants) compared standard-protein formula against low-protein formula. The longest follow-up was 11 years. High-protein formula versus standard-protein formula We found very low-certainty evidence that feeding healthy term infants high-protein formula compared to standard-protein formula has little or no effect on underweight (MD in weight-for-age z-score 0.05 SDs, 95% CI -0.09 to 0.19; P = 0.51, I2 = 61%; 7 studies, 1629 participants), stunting (MD in height-for-age z-score 0.15 SDs, 95% CI -0.05 to 0.35; P = 0.14, I2 = 73%; 7 studies, 1629 participants), and wasting (MD in weight-for-height z-score -0.12 SDs, 95% CI -0.31 to 0.07; P = 0.20, I2 = 94%; 7 studies, 1629 participants) in the first year of life. We found very low-certainty evidence that feeding healthy infants high-protein formula compared to standard-protein formula has little or no effect on the occurrence of overweight (RR 1.26, 95% CI 0.63 to 2.51; P = 0.51; 1 study, 1090 participants) or obesity (RR 1.96, 95% CI 0.59 to 6.48; P = 0.27; 1 study, 1090 participants) at five years of follow-up. No studies reported all-cause mortality. Feeding healthy infants high-protein formula compared to standard-protein formula may have little or no effect on the occurrence of adverse events such as diarrhea, vomiting, or milk hypersensitivity (RR 0.93, 95% CI 0.76 to 1.13; P = 0.44, I2 = 0%; 4 studies, 445 participants; low-certainty evidence) in the first year of life. Standard-protein formula versus low-protein formula We found very low-certainty evidence that feeding healthy infants standard-protein formula compared to low-protein formula has little or no effect on underweight (MD in weight-for-age z-score 0.0, 95% CI -0.43 to 0.43; P = 0.99, I2 = 81%; 4 studies, 256 participants), stunting (MD in height-for-age z-score -0.01, 95% CI -0.36 to 0.35; P = 0.96, I2 = 73%; 4 studies, 256 participants), and wasting (MD in weight-for-height z-score 0.13, 95% CI -0.29 to 0.56; P = 0.54, I2 = 95%; 4 studies, 256 participants) in the first year of life. No studies reported overweight, obesity, or all-cause mortality. Feeding healthy infants standard-protein formula compared to low-protein formula may have little or no effect on the occurrence of adverse events such as diarrhea, vomiting, or milk hypersensitivity (Peto OR 1.55, 95% CI 0.70 to 3.40; P = 0.28, I2 = 0%; 2 studies, 206 participants; low-certainty evidence) in the first four months of life. AUTHORS' CONCLUSIONS: We are unsure if feeding healthy infants high-protein formula compared to standard-protein formula has an effect on undernutrition, overweight, or obesity. There may be little or no difference in the risk of adverse effects between infants fed with high-protein formula versus those fed with standard-protein formula. We are unsure if feeding healthy infants standard-protein formula compared to low-protein formula has any effect on undernutrition. There may be little or no difference in the risk of adverse effects between infants fed with standard-protein formula versus those fed with low-protein formula. The findings of six ongoing studies and two studies awaiting classification studies may change the conclusions of this review.

n-3 Polyunsaturated Fatty Acid Supplementation Affects Oxidative Stress Marker Levels in Patients with Type II Intestinal Failure: A Randomized Double Blind Trial.

Type II intestinal failure (IF-II) is a condition in which the gastrointestinal tract is compromised. Liver complications may occur because of the pathology and/or prolonged use of parenteral nutrition (PN); oxidative stress has been implicated as one of the causes. Lipid emulsions containing n-3 polyunsaturated fatty acids (PUFAs) have been proposed for the treatment. We aimed to evaluate the effect of 7-day n-3 PUFA supplementation on oxidative stress in IF-II patients receiving PN. This was a randomized, controlled, double-blinded, pilot trial of adult patients with IF-II, receiving either conventional PN (control) or PN enriched with n-3 PUFAs (intervention). Twenty patients were included (14 men, 49 ± 16.9 years), with the ANCOVA analysis the glucose (p = 0.003), and direct bilirubin (p = 0.001) levels reduced; whereas the high-density lipoprotein cholesterol (HDL-C) increased (p = 0.017). In the random-effect linear regression analysis, a reduction (p < 0.0001) in the malondialdehyde (MDA) level was found in the intervention group when the covariables age, HDL-C level, and alanine aminotransferase activity were considered. After 1 week of PN supplementation with n-3 PUFAs, the marker levels of some oxidative stress, blood lipids, and hepatic biomarkers improved in patients with IF-II.

Use of Fluoxetine to Reduce Weight in Adults with Overweight or Obesity: Abridged Republication of the Cochrane Systematic Review.

INTRODUCTION: Using fluoxetine is one of many weight loss strategies. A serotonin reuptake inhibitor indicated for depression believed to impact weight control by changing an individual's appetite; however, its benefit-risk ratio is unclear. The aim of this review was to assess the efficacy and safety of fluoxetine in reducing weight in adults with overweight or obesity. METHODS: We searched Cochrane Library, MEDLINE, Embase, and other databases without language restrictions. Cochrane Collaboration tool and GRADE instrument assessed the risk of bias of randomized controlled trials and certainty of their evidence. We conducted random-effects meta-analyses and calculated the risk ratio/mean difference with 95% confidence intervals for the outcomes. RESULTS: We included 19 trials (2,216 adults) and found that fluoxetine may reduce weight by -2.7 kg (95% CI -4 to -1.4; p < 0.001) and body mass index by -1.1 kg/m2 (95% CI -3.7 to 1.4), compared with placebo; however, it would cause approximately twice as many adverse events, such as dizziness, drowsiness, fatigue, insomnia, or nausea. CONCLUSIONS: Although low-certainty evidence suggests that off-label fluoxetine may reduce weight, high-certainty research is needed to be conducted in the future to determine its effects exclusively as well as whether it is useful when combined with other agents. This article is based on a Cochrane Review published in the Cochrane Database of Systematic Reviews 2019, Issue 10, DOI: 10.1002/14651858.CD011688.pub2. Cochrane Reviews are regularly updated as new evidence emerges, and in response to feedback, it should be consulted for the most recent version of the review.

Trypanocidal drugs for late-stage, symptomatic Chagas disease (Trypanosoma cruzi infection).

BACKGROUND: People with Chagas disease may develop progressive and lethal heart conditions. Drugs to eliminate the parasite Trypanosoma cruzi (T cruzi) currently carry limited therapeutic value and are used in the early stages of the disease. Extending the use of these drugs to treat chronic chagasic cardiomyopathy (CCC) has also been proposed. OBJECTIVES: To assess the benefits and harms of nitrofurans and trypanocidal drugs for treating late-stage, symptomatic Chagas disease and CCC in terms of blood parasite reduction or clearance, mortality, adverse effects, and quality of life. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS databases on 12 November 2019. We also searched two clinical trials registers, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), on 3 December 2019. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing trypanocidal drugs versus placebo or no treatment for late-stage, symptomatic Chagas disease and CCC. DATA COLLECTION AND ANALYSIS: We conducted the reporting of the review according the standard Cochrane methods. Two review authors independently retrieved articles, performed data extraction, and assessed risk of bias. Any disagreements were resolved by a third review author. We contacted study authors for additional information. MAIN RESULTS: We included two studies in this review update. One RCT randomly assigned 26 participants to benznidazole 5 mg/kg/day; 27 participants to nifurtimox 5 mg/kg/day; and 24 participants to placebo for 30 days. The second RCT, newly included in this update, randomised 1431 participants to benznidazole 300 mg/day for 40 to 80 days and 1423 participants to placebo. We also identified one ongoing study. Benznidazole compared to placebo At five-year follow-up, low quality of the evidence suggests that there may be a benefit of benznidazole when compared to placebo for clearance or reduction of antibody titres (risk ratio (RR) 1.25, 95% confidence interval (CI) 1.14 to 1.37; 1 trial; 1896 participants). We are uncertain about the effects of benznidazole for the clearance of parasitaemia demonstrated by negative xenodiagnosis, blood culture, and/or molecular assays due to very limited evidence. Low quality of the evidence suggests that when compared to placebo, benznidazole may make little to no difference in the risk of heart failure (RR 0.89, 95% CI 0.69 to 1.14; 1 trial; 2854 participants) and ventricular tachycardia (RR 0.80, 95% CI 0.51 to 1.26; 1 trial; 2854 participants). We found moderate quality of the evidence that adverse events increase with benznidazole when compared to placebo (RR 2.52, 95% CI 2.09 to 3.03; 1 trial; 2854 participants). Adverse effects were observed in 23.9% of patients in the benznidazole group compared to 9.5% in the placebo group. The most frequent adverse effects were: cutaneous rash, gastrointestinal symptoms, and peripheral polyneuropathy. No data were available for the outcomes of pathological demonstration of tissue parasites and quality of life. Nifurtimox compared to placebo Data were only available for this comparison for the outcome clearance or reduction of antibody titres, and we are uncertain about the effect due to very limited evidence. Regarding adverse events, one RCT mentioned in a general manner that nifurtimox caused intense adverse events, without any quantification. AUTHORS' CONCLUSIONS: There is insufficient evidence to support the efficacy of the trypanocidal drugs benznidazole and nifurtimox for late-stage, symptomatic Chagas disease and CCC.

A comparison of different antibiotic regimens for the treatment of infective endocarditis.

BACKGROUND: Infective endocarditis is a microbial infection of the endocardial surface of the heart. Antibiotics are the cornerstone of treatment, but due to the differences in presentation, populations affected, and the wide variety of micro-organisms that can be responsible, their use is not standardised. This is an update of a review previously published in 2016. OBJECTIVES: To assess the existing evidence about the clinical benefits and harms of different antibiotics regimens used to treat people with infective endocarditis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase Classic and Embase, LILACS, CINAHL, and the Conference Proceedings Citation Index - Science on 6 January 2020. We also searched three trials registers and handsearched the reference lists of included papers. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) assessing the effects of antibiotic regimens for treating definitive infective endocarditis diagnosed according to modified Duke's criteria. We considered all-cause mortality, cure rates, and adverse events as the primary outcomes. We excluded people with possible infective endocarditis and pregnant women. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, 'Risk of bias' assessment, and data extraction in duplicate. We constructed 'Summary of findings' tables and used GRADE methodology to assess the quality of the evidence. We described the included studies narratively. MAIN RESULTS: Six small RCTs involving 1143 allocated/632 analysed participants met the inclusion criteria of this first update. The included trials had a high risk of bias. Three trials were sponsored by drug companies. Due to heterogeneity in outcome definitions and different antibiotics used data could not be pooled. The included trials compared miscellaneous antibiotic schedules having uncertain effects for all of the prespecified outcomes in this review. Evidence was either low or very low quality due to high risk of bias and very low number of events and small sample size. The results for all-cause mortality were as follows: one trial compared quinolone (levofloxacin) plus standard treatment (antistaphylococcal penicillin (cloxacillin or dicloxacillin), aminoglycoside (tobramycin or netilmicin), and rifampicin) versus standard treatment alone and reported 8/31 (26%) with levofloxacin plus standard treatment versus 9/39 (23%) with standard treatment alone; risk ratio (RR) 1.12, 95% confidence interval (CI) 0.49 to 2.56. One trial compared fosfomycin plus imipenem 3/4 (75%) versus vancomycin 0/4 (0%) (RR 7.00, 95% CI 0.47 to 103.27), and one trial compared partial oral treatment 7/201 (3.5%) versus conventional intravenous treatment 13/199 (6.53%) (RR 0.53, 95% CI 0.22 to 1.31). The results for rates of cure with or without surgery were as follows: one trial compared daptomycin versus low-dose gentamicin plus an antistaphylococcal penicillin (nafcillin, oxacillin, or flucloxacillin) or vancomycin and reported 9/28 (32.1%) with daptomycin versus 9/25 (36%) with low-dose gentamicin plus antistaphylococcal penicillin or vancomycin; RR 0.89, 95% CI 0.42 to 1.89. One trial compared glycopeptide (vancomycin or teicoplanin) plus gentamicin with cloxacillin plus gentamicin (13/23 (56%) versus 11/11 (100%); RR 0.59, 95% CI 0.40 to 0.85). One trial compared ceftriaxone plus gentamicin versus ceftriaxone alone (15/34 (44%) versus 21/33 (64%); RR 0.69, 95% CI 0.44 to 1.10), and one trial compared fosfomycin plus imipenem versus vancomycin (1/4 (25%) versus 2/4 (50%); RR 0.50, 95% CI 0.07 to 3.55). The included trials reported adverse events, the need for cardiac surgical interventions, and rates of uncontrolled infection, congestive heart failure, relapse of endocarditis, and septic emboli, and found no conclusive differences between groups (very low-quality evidence). No trials assessed quality of life. AUTHORS' CONCLUSIONS: This first update confirms the findings of the original version of the review. Limited and low to very low-quality evidence suggests that the comparative effects of different antibiotic regimens in terms of cure rates or other relevant clinical outcomes are uncertain. The conclusions of this updated Cochrane Review were based on few RCTs with a high risk of bias. Accordingly, current evidence does not support or reject any regimen of antibiotic therapy for the treatment of infective endocarditis.

Fluoxetine for adults who are overweight or obese.

BACKGROUND: Fluoxetine is a serotonin reuptake inhibitor indicated for major depression. It is also thought to affect weight control: this seems to happen through appetite changes resulting in decreased food intake and normalisation of unusual eating behaviours. However, the benefit-risk ratio of this off-label medication is unclear. OBJECTIVES: To assess the effects of fluoxetine for overweight or obese adults. SEARCH METHODS: We searched the Cochrane Library, MEDLINE, Embase, LILACS, the ICTRP Search Portal and ClinicalTrials.gov and World Health Organization (WHO) ICTRP Search Portal. The last date of the search was December 2018 for all databases, to which we applied no language restrictions . SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the administration of fluoxetine versus placebo, other anti-obesity agents, non-pharmacological therapy or no treatment in overweight or obese adults without depression, mental illness or abnormal eating patterns. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and titles for relevance. Screening for inclusion, data extraction and risk of bias assessment was performed by one author and checked by the second. We assessed trials for the overall certainty of the evidence using the GRADE instrument. For additional information we contacted trial authors by email. We performed random-effects meta-analyses and calculated the risk ratio (RR) with 95% confidence intervals (95% CI) for dichotomous outcomes and the mean difference (MD) with 95% CI for continuous outcomes. MAIN RESULTS: We identified 1036 records, scrutinized 52 full-text articles and included 19 completed RCTs (one trial is awaiting assessment). A total of 2216 participants entered the trials, 1280 participants were randomly assigned to fluoxetine (60 mg/d, 40 mg/d, 20 mg/d and 10 mg/d) and 936 participants were randomly assigned to various comparison groups (placebo; the anti-obesity agents diethylpropion, fenproporex, mazindol, sibutramine, metformin, fenfluramine, dexfenfluramine, fluvoxamine, 5-hydroxy-tryptophan; no treatment; and omega-3 gel). Within the 19 RCTs there were 56 trial arms. Fifteen trials were parallel RCTs and four were cross-over RCTs. The participants in the included trials were followed up for periods between three weeks and one year. The certainty of the evidence was low or very low: the majority of trials had a high risk of bias in one or more of the risk of bias domains.For our main comparison group - fluoxetine versus placebo - and across all fluoxetine dosages and durations of treatment, the MD was -2.7 kg (95% CI -4 to -1.4; P < 0.001; 10 trials, 956 participants; low-certainty evidence). The 95% prediction interval ranged between -7.1 kg and 1.7 kg. The MD in body mass index (BMI) reduction across all fluoxetine dosages compared with placebo was -1.1 kg/m² (95% CI -3.7 to 1.4; 3 trials, 97 participants; very low certainty evidence). Only nine placebo-controlled trials reported adverse events. A total of 399 out of 627 participants (63.6%) receiving fluoxetine compared with 352 out of 626 participants (56.2%) receiving placebo experienced an adverse event. Random-effects meta-analysis showed an increase in the risk of having at least one adverse event of any type in the fluoxetine groups compared with placebo (RR 1.18, 95% CI 0.99 to 1.42; P = 0.07; 9 trials, 1253 participants; low-certainty evidence). The 95% prediction interval ranged between 0.74 and 1.88. Following fluoxetine treatment the adverse events of dizziness, drowsiness, fatigue, insomnia and nausea were observed approximately twice as often compared to placebo. A total of 15 out of 197 participants (7.6%) receiving fluoxetine compared with 12 out of 196 participants (6.1%) receiving placebo experienced depression. The RR across all fluoxetine doses compared with placebo was 1.20 (95% CI 0.57 to 2.52; P = 0.62; 3 trials, 393 participants; very low certainty evidence). All-cause mortality, health-related quality of life and socioeconomic effects were not reported.The comparisons of fluoxetine with other anti-obesity agents (3 trials, 234 participants), omega-3 gel (1 trial, 48 participants) and no treatment (1 trial, 60 participants) showed inconclusive results (very low certainty evidence). AUTHORS' CONCLUSIONS: Low-certainty evidence suggests that off-label fluoxetine may decrease weight compared with placebo. However, low-certainty evidence suggests an increase in the risk for dizziness, drowsiness, fatigue, insomnia and nausea following fluoxetine treatment.

Interventions for preventing high altitude illness: Part 3. Miscellaneous and non-pharmacological interventions.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of mainly cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (˜ 8200 feet). Acute mountain sickness (AMS), high altitude cerebral oedema (HACE), and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude ascent. In this, the third of a series of three reviews about preventive strategies for HAI, we assessed the effectiveness of miscellaneous and non-pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of miscellaneous and non-pharmacological interventions for preventing acute HAI in people who are at risk of developing high altitude illness in any setting. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) in January 2019. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text search terms. We scanned the reference lists and citations of included trials and any relevant systematic reviews that we identified for further references to additional trials. SELECTION CRITERIA: We included randomized controlled trials conducted in any setting where non-pharmacological and miscellaneous interventions were employed to prevent acute HAI, including preacclimatization measures and the administration of non-pharmacological supplements. We included trials involving participants who are at risk of developing high altitude illness (AMS or HACE, or HAPE, or both). We included participants with, and without, a history of high altitude illness. We applied no age or gender restrictions. We included trials where the relevant intervention was administered before the beginning of ascent. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures employed by Cochrane. MAIN RESULTS: We included 20 studies (1406 participants, 21 references) in this review. Thirty studies (14 ongoing, and 16 pending classification (awaiting)) will be considered in future versions of this suite of three reviews as appropriate. We report the results for the primary outcome of this review (risk of AMS) by each group of assessed interventions.Group 1. Preacclimatization and other measures based on pressureUse of simulated altitude or remote ischaemic preconditioning (RIPC) might not improve the risk of AMS on subsequent exposure to altitude, but this effect is uncertain (simulated altitude: risk ratio (RR) 1.18, 95% confidence interval (CI) 0.82 to 1.71; I² = 0%; 3 trials, 140 participants; low-quality evidence. RIPC: RR 3.0, 95% CI 0.69 to 13.12; 1 trial, 40 participants; low-quality evidence). We found evidence of improvement of this risk using positive end-expiratory pressure (PEEP), but this information was derived from a cross-over trial with a limited number of participants (OR 3.67, 95% CI 1.38 to 9.76; 1 trial, 8 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions.Group 2. Supplements and vitaminsSupplementation of antioxidants, medroxyprogesterone, iron or Rhodiola crenulata might not improve the risk of AMS on exposure to high altitude, but this effect is uncertain (antioxidants: RR 0.58, 95% CI 0.32 to 1.03; 1 trial, 18 participants; low-quality evidence. Medroxyprogesterone: RR 0.71, 95% CI 0.48 to 1.05; I² = 0%; 2 trials, 32 participants; low-quality evidence. Iron: RR 0.65, 95% CI 0.38 to 1.11; I² = 0%; 2 trials, 65 participants; low-quality evidence. R crenulata: RR 1.00, 95% CI 0.78 to 1.29; 1 trial, 125 participants; low-quality evidence). We found evidence of improvement of this risk with the administration of erythropoietin, but this information was extracted from a trial with issues related to risk of bias and imprecision (RR 0.41, 95% CI 0.20 to 0.84; 1 trial, 39 participants; very low-quality evidence). Regarding administration of ginkgo biloba, we did not perform a pooled estimation of RR for AMS due to considerable heterogeneity between the included studies (I² = 65%). RR estimates from the individual studies were conflicting (from 0.05 to 1.03; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions.Group 3. Other comparisonsWe found heterogeneous evidence regarding the risk of AMS when ginkgo biloba was compared with acetazolamide (I² = 63%). RR estimates from the individual studies were conflicting (estimations from 0.11 (95% CI 0.01 to 1.86) to 2.97 (95% CI 1.70 to 5.21); low-quality evidence). We found evidence of improvement when ginkgo biloba was administered along with acetazolamide, but this information was derived from a single trial with issues associated to risk of bias (compared to ginkgo biloba alone: RR 0.43, 95% CI 0.26 to 0.71; 1 trial, 311 participants; low-quality evidence). Administration of medroxyprogesterone plus acetazolamide did not improve the risk of AMS when compared to administration of medroxyprogesterone or acetazolamide alone (RR 1.33, 95% CI 0.50 to 3.55; 1 trial, 12 participants; low-quality evidence). We found scarcity of evidence about the risk of adverse events for these interventions. AUTHORS' CONCLUSIONS: This Cochrane Review is the final in a series of three providing relevant information to clinicians, and other interested parties, on how to prevent high altitude illness. The assessment of non-pharmacological and miscellaneous interventions suggests that there is heterogeneous and even contradictory evidence related to the effectiveness of these prophylactic strategies. Safety of these interventions remains as an unclear issue due to lack of assessment. Overall, the evidence is limited due to its quality (low to very low), the relative paucity of that evidence and the number of studies pending classification for the three reviews belonging to this series (30 studies either awaiting classification or ongoing). Additional studies, especially those comparing with pharmacological alternatives (such as acetazolamide) are required, in order to establish or refute the strategies evaluated in this review.

Interventions for preventing high altitude illness: Part 1. Commonly-used classes of drugs.

BACKGROUND: High altitude illness (HAI) is a term used to describe a group of cerebral and pulmonary syndromes that can occur during travel to elevations above 2500 metres (8202 feet). Acute hypoxia, acute mountain sickness (AMS), high altitude cerebral oedema (HACE) and high altitude pulmonary oedema (HAPE) are reported as potential medical problems associated with high altitude. In this review, the first in a series of three about preventive strategies for HAI, we assess the effectiveness of six of the most recommended classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of commonly-used pharmacological interventions for preventing acute HAI. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), LILACS and trial registries in January 2017. We adapted the MEDLINE strategy for searching the other databases. We used a combination of thesaurus-based and free-text terms to search. SELECTION CRITERIA: We included randomized-controlled and cross-over trials conducted in any setting where commonly-used classes of drugs were used to prevent acute HAI. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as expected by Cochrane. MAIN RESULTS: We included 64 studies (78 references) and 4547 participants in this review, and classified 12 additional studies as ongoing. A further 12 studies await classification, as we were unable to obtain the full texts. Most of the studies were conducted in high altitude mountain areas, while the rest used low pressure (hypobaric) chambers to simulate altitude exposure. Twenty-four trials provided the intervention between three and five days prior to the ascent, and 23 trials, between one and two days beforehand. Most of the included studies reached a final altitude of between 4001 and 5000 metres above sea level. Risks of bias were unclear for several domains, and a considerable number of studies did not report adverse events of the evaluated interventions. We found 26 comparisons, 15 of them comparing commonly-used drugs versus placebo. We report results for the three most important comparisons: Acetazolamide versus placebo (28 parallel studies; 2345 participants)The risk of AMS was reduced with acetazolamide (risk ratio (RR) 0.47, 95% confidence interval (CI) 0.39 to 0.56; I2 = 0%; 16 studies; 2301 participants; moderate quality of evidence). No events of HAPE were reported and only one event of HACE (RR 0.32, 95% CI 0.01 to 7.48; 6 parallel studies; 1126 participants; moderate quality of evidence). Few studies reported side effects for this comparison, and they showed an increase in the risk of paraesthesia with the intake of acetazolamide (RR 5.53, 95% CI 2.81 to 10.88, I2 = 60%; 5 studies, 789 participants; low quality of evidence). Budenoside versus placebo (2 parallel studies; 132 participants)Data on budenoside showed a reduction in the incidence of AMS compared with placebo (RR 0.37, 95% CI 0.23 to 0.61; I2 = 0%; 2 studies, 132 participants; low quality of evidence). Studies included did not report events of HAPE or HACE, and they did not find side effects (low quality of evidence). Dexamethasone versus placebo (7 parallel studies; 205 participants)For dexamethasone, the data did not show benefits at any dosage (RR 0.60, 95% CI 0.36 to 1.00; I2 = 39%; 4 trials, 176 participants; low quality of evidence). Included studies did not report events of HAPE or HACE, and we rated the evidence about adverse events as of very low quality. AUTHORS' CONCLUSIONS: Our assessment of the most commonly-used pharmacological interventions suggests that acetazolamide is an effective pharmacological agent to prevent acute HAI in dosages of 250 to 750 mg/day. This information is based on evidence of moderate quality. Acetazolamide is associated with an increased risk of paraesthesia, although there are few reports about other adverse events from the available evidence. The clinical benefits and harms of other pharmacological interventions such as ibuprofen, budenoside and dexamethasone are unclear. Large multicentre studies are needed for most of the pharmacological agents evaluated in this review, to evaluate their effectiveness and safety.

A comparison of different antibiotic regimens for the treatment of infective endocarditis.

BACKGROUND: Infective endocarditis is a microbial infection of the endocardial surface of the heart. Antibiotics are the cornerstone of treatment, but their use is not standardised, due to the differences in presentation, populations affected and the wide variety of micro-organisms that can be responsible. OBJECTIVES: To assess the existing evidence about the clinical benefits and harms of different antibiotics regimens used to treat people with infective endocarditis. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE Classic and EMBASE, LILACS, CINAHL and the Conference Proceedings Citation Index on 30 April 2015. We also searched three trials registers and handsearched the reference lists of included papers. We applied no language restrictions. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of antibiotic regimens for treating possible infective endocarditis diagnosed according to modified Duke's criteria. We considered all-cause mortality, cure rates and adverse events as the primary outcomes. We excluded people with possible infective endocarditis and pregnant women. DATA COLLECTION AND ANALYSIS: Three review authors independently performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We constructed 'Summary of findings' tables and used GRADE methodology to assess the quality of studies. We described the included studies narratively. MAIN RESULTS: Four small randomised controlled trials involving 728 allocated/224 analysed participants met our inclusion criteria. These trials had a high risk of bias. Drug companies sponsored two of the trials. We were unable to pool the data due to the heterogeneity in outcome definitions and the different antibiotics used.The included trials compared the following antibiotic schedules. The first trial compared quinolone (levofloxacin) plus standard treatment (anti-staphylococcal penicillin (cloxacillin or dicloxacillin), aminoglycoside (tobramycin or netilmicin) and rifampicin) versus standard treatment alone reporting uncertain effects on all-cause mortality (8/31 (26%) with levofloxacin plus standard treatment versus 9/39 (23%) with standard treatment alone; RR 1.12, 95% CI 0.49 to 2.56, very low quality evidence). The second trial compared daptomycin versus low-dose gentamicin plus an anti-staphylococcal penicillin (nafcillin, oxacillin or flucloxacillin) or vancomycin. This showed uncertain effects in terms of cure rates (9/28 (32.1%) with daptomycin versus 9/25 (36%) with low-dose gentamicin plus anti-staphylococcal penicillin or vancomycin, RR 0.89 95% CI 0.42 to 1.89; very low quality evidence). The third trial compared cloxacillin plus gentamicin with a glycopeptide (vancomycin or teicoplanin) plus gentamicin. In participants receiving gentamycin plus glycopeptide only 13/23 (56%) were cured versus 11/11 (100%) receiving cloxacillin plus gentamicin (RR 0.59, 95% CI 0.40 to 0.85; very low quality evidence). The fourth trial compared ceftriaxone plus gentamicin versus ceftriaxone alone and found no conclusive differences in terms of cure (15/34 (44%) with ceftriaxone plus gentamicin versus 21/33 (64%) with ceftriaxone alone, RR 0.69, 95% CI 0.44 to 1.10; very low quality evidence).The trials reported adverse events, need for cardiac surgical interventions, uncontrolled infection and relapse of endocarditis and found no conclusive differences between comparison groups (very low quality evidence). No trials assessed septic emboli or quality of life. AUTHORS' CONCLUSIONS: Limited and very low quality evidence suggested that there were no conclusive differences between antibiotic regimens in terms of cure rates or other relevant clinical outcomes. However, because of the very low quality evidence, this needs confirmation. The conclusion of this Cochrane review was based on randomised controlled trials with high risk of bias. Accordingly, current evidence does not support or reject any regimen of antibiotic therapy for treatment of infective endocarditis.

Ambroxol for women at risk of preterm birth for preventing neonatal respiratory distress syndrome.

BACKGROUND: Respiratory distress syndrome (RDS) is caused by a deficiency of pulmonary surfactant (an active agent that keeps pulmonary alveoli open and facilitates the entry of air to the lungs, thus improving the oxygenation of the newborn).A number of interventions such as pulmonary surfactant and prenatal corticosteroids are used to prevent RDS. Ambroxol has been studied as a potential agent to prevent RDS, but effectiveness and safety has yet to be evaluated. OBJECTIVES: To evaluate the efficacy and safety of giving ambroxol to pregnant women who are at risk of preterm birth, for preventing neonatal RDS. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (29 November 2013), CENTRAL (The Cochrane Library 2013, Issue 11),Embase (1988 to November 2013), MEDLINE (PubMed 1970 to November 2013), LILACS (1982 to November 2013), the WHO International Clinical Trials Registry Platform (ICTRP) (November 2013) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing the administration of ambroxol given to pregnant women at risk of preterm birth versus placebo, antenatal corticosteroids (betamethasone or dexamethasone), or no treatment.We did not identify any trials comparing ambroxol with dexamethasone (corticosteroid) in this review. Nor did we identify any trials comparing ambroxol combined with corticosteroid versus corticosteroid alone, or placebo/no treatment. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and trial quality. Two review authors independently extracted data. Data were checked for accuracy. MAIN RESULTS: We included 14 studies (in 18 trial reports), involving 1047 pregnant women at risk of preterm birth with 1077 newborns. However, three of the included studies did not report on this review's outcomes of interest. We carried out two main comparisons: ambroxol versus antenatal corticosteroids (betamethasone); and ambroxol versus placebo or no treatment. Seven RCTs provided data for our comparison of ambroxol versus corticosteroid (betamethasone) and two trials contributed data to our comparison of ambroxol compared to placebo or no treatment.The included studies were generally judged as having either 'low' risk of bias or 'unclear' risk of bias (because the trial reports provided insufficient details about methods of sequence generation, allocation concealment and blinding). Primary outcomesThere was no clear evidence of a difference in the incidence of RDS among newborns born to women who received ambroxol when compared to newborns of women who were given the corticosteroid, betamethasone (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.59 to 1.07, seven RCTs, 728 women/758 newborns, moderate quality evidence) or placebo/no treatment (average RR 0.74; 95% CI 0.46 to 1.20, two studies, 204 women/204 newborns,T2= 0.07; I(2)= 53%, low-quality evidence). Results were imprecise and consistent with appreciable benefit as well as negligible effect.Similarly, there was no clear evidence of a difference in the rates of perinatal mortality between the group of women who received ambroxol and women in the corticosteroid (betamethasone) group (RR 0.51, 95% CI 0.23 to 1.12, six studies, 648 women/657 newborns, moderate quality evidence) or the placebo/no treatment group (RR 0.61; 95% CI 0.19 to 1.98, one study, 116 women/116 newborns, low-quality evidence).In terms of maternal adverse effects, there was no clear differences (in nausea or vomiting) between those women who received ambroxol compared to either those women who received corticosteroids (betamethasone) (average RR 3.45; 95% CI 0.34 to 35.51, three studies, 305 women, T(2)= 2.82; I(2)= 67%, very low-quality evidence), or women who received placebo or no treatment (RR 1.79; 95% CI 0.45 to 7.13, one study, 116 women, low-quality evidence). No other adverse effects (e.g. diarrhoea, gastric irritation and headache) were reported in the included studies. Secondary outcomesFor the review's secondary outcomes, none of the included studies reported on the incidence of bronchopulmonary dysplasia, periventricular haemorrhage, necrotising enterocolitis or rate of maternal mortality.One small trial (involving 88 women) comparing ambroxol with placebo or no treatment, reported no difference between groups in terms of the need for mechanical ventilation in the neonate (RR 0.94; 95% CI 0.73 to 1.21, 88 women/88 babies, low-quality evidence) or the administration of pulmonary surfactant (RR 1.19; 95% CI 0.61 to 2.30, one RCT, 88 women/88 babies, low-quality evidence). AUTHORS' CONCLUSIONS: This review is based on very low to moderate quality evidence from 14 small trials (many are published in the form of conference abstracts with minimal methodological details provided). There is insufficient evidence to support or refute the practice of giving ambroxol to women at risk of preterm birth for preventing neonatal RDS, perinatal mortality and adverse effects. More research is needed in order to fully evaluate the benefits and risks of this intervention.

Bone mineral density after bariatric surgery. A systematic review.

PURPOSE: Bone regulation system may be affected after bariatric surgeries, but procedures impact differently to bone mineral density (BMD) and measures restraining bone loss are frequently neglected until clinical consequences become manifest. This is a systematic review aimed to elucidate whether BMD loss is comparable after different bariatric surgeries. MATERIALS AND METHODS: A search of morbid obese adults, undergone to bariatric surgery, with BMD measured by dual-energy X-ray absorptiometry at baseline and after surgery studies was performed in several databases. Studies were assessed using the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement and COCHRANE Risk of Bias tool. The random model was selected for meta-analysis; heterogeneity was analyzed with T(2), inconsistency (I(2) > 50%) and Chi(2) (p < 0.10). Level of evidence and strength of recommendations were summarized using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE System). RESULTS: Twelve studies met the selection criteria. After one year, reduction in total BMD in patients with mixed surgical procedures was significant: -0.03 g/cm(2) (CI 95% 0.00 to -0.06, p < 0.05). BMD was reduced by -0.12 g/cm(2) (CI 95% -0.10 to -0.15, p < 0.001) in the hip, -0.07 g/cm(2) (CI 95% -0.03 to -0.11, p < 0.001) in the column, and -0.03 g/cm(2) (IC 95% -0.02 to -0.04, p < 0.001) in the forearm, but not in restrictive surgeries. Studies included showed high heterogeneity and low quality of evidence. CONCLUSIONS: Patients undergone to mixed bariatric surgery had significant higher BMD deterioration as demonstrated in this review, suggesting that more attention for preventing fractures is required.