Interleukin-receptor antagonist and tumour necrosis factor inhibitors for the primary and secondary prevention of atherosclerotic cardiovascular diseases.

BACKGROUND: Atherosclerotic cardiovascular disease (ACVD) is worsened by chronic inflammatory diseases. Interleukin receptor antagonists (IL-RAs) and tumour necrosis factor-alpha (TNF) inhibitors have been studied to see if they can prevent cardiovascular events. OBJECTIVES: The purpose of this study was to assess the clinical benefits and harms of IL-RAs and TNF inhibitors in the primary and secondary prevention of ACVD. SEARCH METHODS: The Cochrane Heart Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE (including In-Process & Other Non-Indexed Citations), Ovid Embase, EBSCO CINAHL plus, and clinical trial registries for ongoing and unpublished studies were searched in February 2024. The reference lists of relevant studies, reviews, meta-analyses and health technology reports were searched to identify additional studies. No limitations on language, date of publication or study type were set. SELECTION CRITERIA: RCTs that recruited people with and without pre-existing ACVD, comparing IL-RAs or TNF inhibitors versus placebo or usual care, were selected. The primary outcomes considered were all-cause mortality, myocardial infarction, unstable angina, and adverse events. DATA COLLECTION AND ANALYSIS: Two or more review authors, working independently at each step, selected studies, extracted data, assessed the risk of bias and used GRADE to judge the certainty of evidence. MAIN RESULTS: We included 58 RCTs (22,053 participants; 21,308 analysed), comparing medication efficacy with placebo or usual care. Thirty-four trials focused on primary prevention and 24 on secondary prevention. The interventions included IL-1 RAs (anakinra, canakinumab), IL-6 RA (tocilizumab), TNF-inhibitors (etanercept, infliximab) compared with placebo or usual care. The certainty of evidence was low to very low due to biases and imprecision; all trials had a high risk of bias. Primary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality(RR 0.33, 95% CI 0.01 to 7.58, 1 trial), myocardial infarction (RR 0.71, 95% CI 0.04 to 12.48, I² = 39%, 2 trials), unstable angina (RR 0.24, 95% CI 0.03 to 2.11, I² = 0%, 2 trials), stroke (RR 2.42, 95% CI 0.12 to 50.15; 1 trial), adverse events (RR 0.85, 95% CI 0.59 to 1.22, I² = 54%, 3 trials), or infection (rate ratio 0.84, 95% 0.55 to 1.29, I² = 0%, 4 trials). Evidence is very uncertain about whether anakinra and cankinumab may reduce heart failure (RR 0.21, 95% CI 0.05 to 0.94, I² = 0%, 3 trials). Peripheral vascular disease (PVD) was not reported as an outcome. IL-6 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.68, 95% CI 0.12 to 3.74, I² = 30%, 3 trials), myocardial infarction (RR 0.27, 95% CI 0.04 to1.68, I² = 0%, 3 trials), heart failure (RR 1.02, 95% CI 0.11 to 9.63, I² = 0%, 2 trials), PVD (RR 2.94, 95% CI 0.12 to 71.47, 1 trial), stroke (RR 0.34, 95% CI 0.01 to 8.14, 1 trial), or any infection (rate ratio 1.10, 95% CI: 0.88 to 1.37, I2 = 18%, 5 trials). Adverse events may increase (RR 1.13, 95% CI 1.04 to 1.23, I² = 33%, 5 trials). No trial assessed unstable angina. TNF inhibitors The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.78, 95% CI 0.63 to 4.99, I² = 10%, 3 trials), myocardial infarction (RR 2.61, 95% CI 0.11 to 62.26, 1 trial), stroke (RR 0.46, 95% CI 0.08 to 2.80, I² = 0%; 3 trials), heart failure (RR 0.85, 95% CI 0.06 to 12.76, 1 trial). Adverse events may increase (RR 1.13, 95% CI 1.01 to 1.25, I² = 51%, 13 trials). No trial assessed unstable angina or PVD. Secondary prevention: IL-1 RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 0.94, 95% CI 0.84 to 1.06, I² = 0%, 8 trials), unstable angina (RR 0.88, 95% CI 0.65 to 1.19, I² = 0%, 3 trials), PVD (RR 0.85, 95% CI 0.19 to 3.73, I² = 38%, 3 trials), stroke (RR 0.94, 95% CI 0.74 to 1.2, I² = 0%; 7 trials), heart failure (RR 0.91, 95% 0.5 to 1.65, I² = 0%; 7 trials), or adverse events (RR 0.92, 95% CI 0.78 to 1.09, I² = 3%, 4 trials). There may be little to no difference between the groups in myocardial infarction (RR 0.88, 95% CI 0.0.75 to 1.04, I² = 0%, 6 trials). IL6-RAs The evidence is very uncertain about the effects of the intervention on all-cause mortality (RR 1.09, 95% CI 0.61 to 1.96, I² = 0%, 2 trials), myocardial infarction (RR 0.46, 95% CI 0.07 to 3.04, I² = 45%, 3 trials), unstable angina (RR 0.33, 95% CI 0.01 to 8.02, 1 trial), stroke (RR 1.03, 95% CI 0.07 to 16.25, 1 trial), adverse events (RR 0.89, 95% CI 0.76 to 1.05, I² = 0%, 2 trials), or any infection (rate ratio 0.66, 95% CI 0.32 to 1.36, I² = 0%, 4 trials). No trial assessed PVD or heart failure. TNF inhibitors The evidence is very uncertain about the effect of the intervention on all-cause mortality (RR 1.16, 95% CI 0.69 to 1.95, I² = 47%, 5 trials), heart failure (RR 0.92, 95% 0.75 to 1.14, I² = 0%, 4 trials), or adverse events (RR 1.15, 95% CI 0.84 to 1.56, I² = 32%, 2 trials). No trial assessed myocardial infarction, unstable angina, PVD or stroke. Adverse events may be underestimated and benefits inflated due to inadequate reporting. AUTHORS' CONCLUSIONS: This Cochrane review assessed the benefits and harms of using interleukin-receptor antagonists and tumour necrosis factor inhibitors for primary and secondary prevention of atherosclerotic diseases compared with placebo or usual care. However, the evidence for the predetermined outcomes was deemed low or very low certainty, so there is still a need to determine whether these interventions provide clinical benefits or cause harm from this perspective. In summary, the different biases and imprecision in the included studies limit their external validity and represent a limitation to determining the effectiveness of the intervention for both primary and secondary prevention of ACVD.

Anti-vascular endothelial growth factor for proliferative diabetic retinopathy.

BACKGROUND: Proliferative diabetic retinopathy (PDR) is an advanced complication of diabetic retinopathy that can cause blindness. It consists of the presence of new vessels in the retina and vitreous haemorrhage. Although panretinal photocoagulation (PRP) is the treatment of choice for PDR, it has secondary effects that can affect vision. Anti-vascular endothelial growth factor (anti-VEGF), which produces an inhibition of vascular proliferation, could improve the vision of people with PDR. OBJECTIVES: To assess the effectiveness and safety of anti-VEGFs for PDR and summarise any relevant economic evaluations of their use. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 6); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov, and the WHO ICTRP. We did not use any date or language restrictions. We last searched the electronic databases on 1 June 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing anti-VEGFs to another active treatment, sham treatment, or no treatment for people with PDR. We also included studies that assessed the combination of anti-VEGFs with other treatments. We excluded studies that used anti-VEGFs in people undergoing vitrectomy. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data, and assessed the risk of bias (RoB) for all included trials. We calculated the risk ratio (RR) or the mean difference (MD), and 95% confidence intervals (CI). We used GRADE to assess the certainty of evidence. MAIN RESULTS: We included 15 new studies in this update, bringing the total to 23 RCTs with 1755 participants (2334 eyes). Forty-five per cent of participants were women and 55% were men, with a mean age of 56 years (range 48 to 77 years). The mean glycosylated haemoglobin (Hb1Ac) was 8.45% for the PRP group and 8.25% for people receiving anti-VEGFs alone or in combination. Twelve studies included people with PDR, and participants in 11 studies had high-risk PDR (HRPDR). Twelve studies were of bevacizumab, seven of ranibizumab, one of conbercept, two of pegaptanib, and one of aflibercept. The mean number of participants per RCT was 76 (ranging from 15 to 305). Most studies had an unclear or high RoB, mainly in the blinding of interventions and outcome assessors. A few studies had selective reporting and attrition bias. No study reported loss or gain of 3 or more lines of visual acuity (VA) at 12 months. Anti-VEGFs ± PRP probably increase VA compared with PRP alone (mean difference (MD) -0.08 logMAR, 95% CI -0.12 to -0.04; I2 = 28%; 10 RCTS, 1172 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may increase regression of new vessels (MD -4.14 mm2, 95% CI -6.84 to -1.43; I2 = 75%; 4 RCTS, 189 eyes; low-certainty evidence) and probably increase a complete regression of new vessels (RR 1.63, 95% CI 1.19 to 2.24; I2 = 46%; 5 RCTS, 405 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP probably reduce vitreous haemorrhage (RR 0.72, 95% CI 0.57 to 0.90; I2 = 0%; 6 RCTS, 1008 eyes; moderate-certainty evidence). Anti-VEGFs ± PRP may reduce the need for vitrectomy compared with eyes that received PRP alone (RR 0.67, 95% CI 0.49 to 0.93; I2 = 43%; 8 RCTs, 1248 eyes; low-certainty evidence). Anti-VEGFs ± PRP may result in little to no difference in the quality of life compared with PRP alone (MD 0.62, 95% CI -3.99 to 5.23; I2 = 0%; 2 RCTs, 382 participants; low-certainty evidence). We do not know if anti-VEGFs ± PRP compared with PRP alone had an impact on adverse events (very low-certainty evidence). We did not find differences in visual acuity in subgroup analyses comparing the type of anti-VEGFs, the severity of the disease (PDR versus HRPDR), time to follow-up (< 12 months versus 12 or more months), and treatment with anti-VEGFs + PRP versus anti-VEGFs alone. The main reasons for downgrading the certainty of evidence included a high RoB, imprecision, and inconsistency of effect estimates. AUTHORS' CONCLUSIONS: Anti-VEGFs ± PRP compared with PRP alone probably increase visual acuity, but the degree of improvement is not clinically meaningful. Regarding secondary outcomes, anti-VEGFs ± PRP produce a regression of new vessels, reduce vitreous haemorrhage, and may reduce the need for vitrectomy compared with eyes that received PRP alone. We do not know if anti-VEGFs ± PRP have an impact on the incidence of adverse events and they may have little or no effect on patients' quality of life. Carefully designed and conducted clinical trials are required, assessing the optimal schedule of anti-VEGFs alone compared with PRP, and with a longer follow-up.

Interventions for treating leg ulcers in people with sickle cell disease.

BACKGROUND: The frequency of skin ulceration makes an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the clinical effectiveness and harms of interventions for treating leg ulcers in people with sickle cell disease. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We searched LILACS (1982 to January 2020), ISI Web of Knowledge (1985 to January 2020), and the Clinical Trials Search Portal of the World Health Organization (January 2020). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 13 January 2020; date of the last search of the Cochrane Wounds Group Trials Register: 17 February 2017. SELECTION CRITERIA: Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data. We used GRADE to assess the quality of the evidence. MAIN RESULTS: Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, arginine-glycine-aspartic acid (RGD) peptide dressing and topical antibiotics). No trials on non-pharmaceutical interventions were included in the review. All trials had an overall unclear or high risk of bias, and drug companies sponsored four of them. We were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the units of randomisation and analysis. Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, only arginine butyrate showed a reduction of ulcer size compared with a control group, mean reduction -5.10 cm² (95% CI -9.65 to -0.55), but we are uncertain whether this reduces ulcer size compared to standard care alone as the certainty of the evidence has been assessed as very low. Three trials reported on complete leg ulcer closure (isoxsuprine, arginine butyrate, RGD peptide matrix; very low quality of evidence). None reported a clinical benefit. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; incidence of amputation or harms. AUTHORS' CONCLUSIONS: Given the very low quality of the evidence identified in this updated Cochrane Review we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure in treated participants compared to controls. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having an unclear or high risk of bias. The harm profile of the all interventions remains inconclusive.

Interventions for treating intrahepatic cholestasis in people with sickle cell disease.

BACKGROUND: Sickle cell disease is the most common hemoglobinopathy occurring worldwide and sickle cell intrahepatic cholestasis is a complication long recognized in this population. Cholestatic liver diseases are characterized by impaired formation or excretion (or both) of bile from the liver. There is a need to assess the clinical benefits and harms of the interventions used to treat intrahepatic cholestasis in people with sickle cell disease. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the benefits and harms of the interventions for treating intrahepatic cholestasis in people with sickle cell disease. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 21 January 2020), the WHO International Clinical Trials Registry Platform Search Portal and ClinicalTrials.gov (21 January 2020). Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 25 November 2019. SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data, assess the risk of bias of the trials by standard Cochrane methodologies and assess the quality of the evidence using the GRADE criteria; however, no trials were included in the review. MAIN RESULTS: We did not identify any randomised controlled trials. AUTHORS' CONCLUSIONS: This updated Cochrane Review did not identify any randomised controlled trials assessing interventions for treating intrahepatic cholestasis in people with sickle cell disease. Randomised controlled trials are needed to establish the optimum treatment for this condition.

Citicoline for treating people with acute ischemic stroke.

BACKGROUND: Stroke is one of the leading causes of long-lasting disability and mortality and its global burden has increased in the past two decades. Several therapies have been proposed for the recovery from, and treatment of, ischemic stroke. One of them is citicoline. This review assessed the benefits and harms of citicoline for treating patients with acute ischemic stroke. OBJECTIVES: To assess the clinical benefits and harms of citicoline compared with placebo or any other control for treating people with acute ischemic stroke. SEARCH METHODS: We searched in the Cochrane Stroke Group Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS until 29 January 2020. We searched the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. Additionally, we also reviewed reference lists of the retrieved publications and review articles, and searched the websites of the US Food and Drug Administration (FDA) and European Medicines Agency (EMA). SELECTION CRITERIA: We included randomized controlled trials (RCTs) in any setting including participants with acute ischemic stroke. Trials were eligible for inclusion if they compared citicoline versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: We selected RCTs, assessed the risk of bias in seven domains, and extracted data by duplicate. Our primary outcomes of interest were all-cause mortality and the degree of disability or dependence in daily activities at 90 days. We estimated risk ratios (RRs) for dichotomous outcomes. We measured statistical heterogeneity using the I² statistic. We conducted our analyses using the fixed-effect and random-effects model meta-analyses. We assessed the overall quality of evidence for six pre-specified outcomes using the GRADE approach. MAIN RESULTS: We identified 10 RCTs including 4281 participants. In all these trials, citicoline was given either orally, intravenously, or a combination of both compared with placebo or standard care therapy. Citicoline doses ranged between 500 mg and 2000 mg per day. We assessed all the included trials as having high risk of bias. Drug companies sponsored six trials. A pooled analysis of eight trials indicates there may be little or no difference in all-cause mortality comparing citicoline with placebo (17.3% versus 18.5%; RR 0.94, 95% CI 0.83 to 1.07; I² = 0%; low-quality evidence due to risk of bias). Four trials found no difference in the proportion of patients with disability or dependence in daily activities according to the Rankin scale comparing citicoline with placebo (21.72% versus 19.23%; RR 1.11, 95% CI 0.97 to 1.26; I² = 1%; low-quality evidence due to risk of bias). Meta-analysis of three trials indicates there may be little or no difference in serious cardiovascular adverse events comparing citicoline with placebo (8.83% versus 7.77%; RR 1.04, 95% CI 0.84 to 1.29; I² = 0%; low-quality evidence due to risk of bias). Overall, either serious or non-serious adverse events - central nervous system, gastrointestinal, musculoskeletal, etc. - were poorly reported and harms may have been underestimated. Four trials assessing functional recovery with the Barthel Index at a cut-off point of 95 points or more did not find differences comparing citicoline with placebo (32.78% versus 30.70%; RR 1.03, 95% CI 0.94 to 1.13; I² = 24%; low-quality evidence due to risk of bias). There were no differences in neurological function (National Institutes of Health Stroke Scale at a cut-off point of ≤ 1 points) comparing citicoline with placebo according to five trials (24.31% versus 22.44%; RR 1.08, 95% CI 0.96 to 1.21; I² = 27%, low-quality evidence due to risk of bias). A pre-planned Trial Sequential Analysis suggested that no more trials may be needed for the primary outcomes but no trial provided information on quality of life. AUTHORS' CONCLUSIONS: This review assessed the clinical benefits and harms of citicoline compared with placebo or any other standard treatment for people with acute ischemic stroke. The findings of the review suggest there may be little to no difference between citicoline and its controls regarding all-cause mortality, disability or dependence in daily activities, severe adverse events, functional recovery and the assessment of the neurological function, based on low-certainty evidence. None of the included trials assessed quality of life and the safety profile of citicoline remains unknown. The available evidence is of low quality due to either limitations in the design or execution of the trials.

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.

Antibiotics for treating acute chest syndrome in people with sickle cell disease.

BACKGROUND: The clinical presentation of acute chest syndrome is similar whether due to infectious or non-infectious causes, thus antibiotics are usually prescribed to treat all episodes. Many different pathogens, including bacteria, have been implicated as causative agents of acute chest syndrome. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from acute chest syndrome. This is an update of a Cochrane Review first published in 2007, and most recently updated in 2015. OBJECTIVES: To determine whether an empirical antibiotic treatment approach (used alone or in combination):1. is effective for acute chest syndrome compared to placebo or standard treatment;2. is safe for acute chest syndrome compared to placebo or standard treatment;Further objectives are to determine whether there are important variations in efficacy and safety:3. for different treatment regimens,4. by participant age, or geographical location of the clinical trials. SEARCH METHODS: We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 23 October 2017), African Index Medicus (1982 to 23 October 2017) and trial registries (23 October 2017).Date of most recent search of the Haemoglobinopathies Trials Register: 10 July 2019. SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane methodologies, but no eligible randomised controlled trials were identified. MAIN RESULTS: For this update, we were unable to find any randomised controlled trials on antibiotic treatment approaches for acute chest syndrome in people with sickle cell disease. AUTHORS' CONCLUSIONS: This update was unable to identify randomised controlled trials on efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from acute chest syndrome. While randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

Treatment for avascular necrosis of bone in people with sickle cell disease.

BACKGROUND: Avascular necrosis of bone is a frequent and severe complication of sickle cell disease and its treatment is not standardised. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine the impact of any surgical procedure compared with other surgical interventions or non-surgical procedures, on avascular necrosis of bone in people with sickle cell disease in terms of efficacy and safety. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings. Additional trials were sought from both ongoing trial registries and the reference lists of papers identified by the search strategy. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 17 September 2019. SELECTION CRITERIA: Randomized clinical trials comparing specific therapies for avascular necrosis of bone in people with sickle cell disease. DATA COLLECTION AND ANALYSIS: Each author independently extracted data and assessed trial quality. The quality of the evidence was assessed using GRADE. Given only one trial was identified, meta-analyses were not possible. MAIN RESULTS: One trial (46 participants) was eligible for inclusion. After randomization eight participants were withdrawn, mainly because they declined to participate in the trial. Data were analysed for 38 participants at the end of the trial. After a mean follow-up of three years, hip core decompression and physical therapy did not show clinical improvement when compared with physical therapy alone using the score from the original trial (an improvement of 18.1 points for those treated with intervention therapy versus an improvement of 15.7 points with control therapy). We are very uncertain whether there is any difference between groups regarding major complications (hip pain, risk ratio 0.95 (95% confidence interval 0.56 to 1.60; vaso-occlusive crises, risk ratio 1.14 (95% confidence interval 0.72 to 1.80; very low quality of evidence); and acute chest syndrome, risk ratio 1.06 (95% confidence interval 0.44 to 2.56; very low quality of evidence)). This trial did not report results on mortality or quality of life. AUTHORS' CONCLUSIONS: We found no evidence that adding hip core decompression to physical therapy achieves clinical improvement in people with sickle cell disease with avascular necrosis of bone compared to physical therapy alone. However, we highlight that our conclusion is based on one trial with high attrition rates. Further randomized controlled trials are necessary to evaluate the role of hip-core depression for this clinical condition. Endpoints should focus on participants' subjective experience (e.g. quality of life and pain) as well as more objective 'time-to-event' measures (e.g. mortality, survival, hip longevity). The availability of participants to allow adequate trial power will be a key consideration for endpoint choice.

Antibiotics for treating osteomyelitis in people with sickle cell disease.

BACKGROUND: Osteomyelitis (both acute and chronic) is one of the most common infectious complications in people with sickle cell disease. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether an empirical antibiotic treatment approach (monotherapy or combination therapy) is effective and safe as compared to pathogen-directed antibiotic treatment and whether this effectiveness and safety is dependent on different treatment regimens, age or setting. SEARCH METHODS: We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 20 October 2016), African Index Medicus (20 October 2016), ISI Web of Knowledge (20 October 2016) and clinical trials registries (19 September 2019).Date of most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 18 September 2019. SELECTION CRITERIA: We searched for published or unpublished randomised and quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane methodologies, but no eligible randomised controlled trials were identified. MAIN RESULTS: This update was unable to find any randomised or quasi-randomised controlled trials on antibiotic treatment approaches for osteomyelitis in people with sickle cell disease. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. Randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition, however, we do not envisage further trials of this intervention will be conducted, and hence the review will no longer be regularly updated.

Acetyl-L-carnitine for patients with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy is a common and devastating neuropsychiatric complication of acute liver failure or chronic liver disease. Ammonia content in the blood seems to play a role in the development of hepatic encephalopathy. Treatment for hepatic encephalopathy is complex. Acetyl-L-carnitine is a substance that may reduce ammonia toxicity. This review assessed the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. OBJECTIVES: To assess the benefits and harms of acetyl-L-carnitine for patients with hepatic encephalopathy. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE Ovid, Embase Ovid, LILACS, and Science Citation Index Expanded for randomised clinical trials. We sought additional randomised clinical trials from the World Health Organization Clinical Trials Search Portal and ClinicalTrials.gov. We performed all electronic searches until 10 September 2018. We looked through the reference lists of retrieved publications and review articles, and we searched the FDA and EMA websites. SELECTION CRITERIA: We searched for randomised clinical trials in any setting, recruiting people with hepatic encephalopathy. Trials were eligible for inclusion if they compared acetyl-L-carnitine plus standard care (e.g. antibiotics, lactulose) versus placebo or no acetyl-L-carnitine plus standard care. We are well aware that by selecting randomised clinical trials, we placed greater focus on potential benefits than on potential harms. DATA COLLECTION AND ANALYSIS: We selected randomised clinical trials, assessed risk of bias in eight domains, and extracted data in a duplicate and independent fashion. We estimated risk ratios (RRs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes. We measured statistical heterogeneity using I² and D² statistics. We subjected our analyses to fixed-effect and random-effects model meta-analyses. We assessed bias risk domains to control systematic errors. We assessed overall quality of the data for each individual outcome by using the GRADE approach. MAIN RESULTS: We identified five randomised clinical trials involving 398 participants. All trials included only participants with cirrhosis as the underlying cause of hepatic encephalopathy. Trials included participants with covert or overt hepatic encephalopathy. All trials were conducted in Italy by a single team and assessed acetyl-L-carnitine compared with placebo. Oral intervention was the most frequent route of administration. All trials were at high risk of bias and were underpowered. None of the trials were sponsored by the pharmaceutical industry.None of the identified trials reported information on all-cause mortality, serious adverse events, or days of hospitalisation. Only one trial assessed quality of life using the Short Form (SF)-36 scale (67 participants; very low-quality evidence). The effects of acetyl-L-carnitine compared with placebo on general health at 90 days are uncertain (MD -6.20 points, 95% confidence interval (CI) -9.51 to -2.89). Results for additional domains of the SF-36 are also uncertain. One trial assessed fatigue using the Wessely and Powell test (121 participants; very low-quality evidence). The effects are uncertain in people with moderate-grade hepatic encephalopathy (mental fatigue: MD 0.40 points, 95% CI -0.21 to 1.01; physical fatigue: MD -0.20 points, 95% CI -0.92 to 0.52) and mild-grade hepatic encephalopathy (mental fatigue: -0.80 points, 95% CI -1.48 to -0.12; physical fatigue: 0.20 points, 95% CI -0.72 to 1.12). Meta-analysis showed a reduction in blood ammonium levels favouring acetyl-L-carnitine versus placebo (MD -13.06 mg/dL, 95% CI -17.24 to -8.99; 387 participants; 5 trials; very low-quality evidence). It is unclear whether acetyl-L-carnitine versus placebo increases the risk of non-serious adverse events (8/126 (6.34%) vs 3/120 (2.50%); RR 2.51, 95% CI 0.68 to 9.22; 2 trials; very low-quality evidence). Overall, adverse events data were poorly reported and harms may have been underestimated. AUTHORS' CONCLUSIONS: This Cochrane systematic review analysed a heterogeneous group of five trials at high risk of bias and with high risk of random errors conducted by only one research team. We assessed acetyl-L-carnitine versus placebo in participants with cirrhosis with covert or overt hepatic encephalopathy. Hence, we have no data on the drug for hepatic encephalopathy in acute liver failure. We found no information about all-cause mortality, serious adverse events, or days of hospitalisation. We found no clear differences in effect between acetyl-L-carnitine and placebo regarding quality of life, fatigue, and non-serious adverse events. Acetyl-L-carnitine reduces blood ammonium levels compared with placebo. We rated all evidence as of very low quality due to pitfalls in design and execution, inconsistency, small sample sizes, and very few events. The harms profile for acetyl-L-carnitine is presently unclear. Accordingly, we need further randomised clinical trials to assess acetyl-L-carnitine versus placebo conducted according to the SPIRIT statements and reported according to the CONSORT statements.

Antibiotic therapy for adults with neurosyphilis.

BACKGROUND: Neurosyphilis is an infection of the central nervous system, caused by Treponema pallidum, a spirochete capable of infecting almost any organ or tissue in the body causing neurological complications due to the infection. This disease is a tertiary manifestation of syphilis. The first-line treatment for neurosyphilis is aqueous crystalline penicillin. However, in cases such as penicillin allergy, other regimes of antibiotic therapy can be used. OBJECTIVES: To assess the clinical effectiveness and safety of antibiotic therapy for adults with neurosyphilis. SEARCH METHODS: We searched the Cochrane Library, CENTRAL, MEDLINE, Embase, LILACS, World Health Organization International Clinical Trials Registry Platform and Opengrey up to April 2019. We also searched proceedings of eight congresses to a maximum of 10 years, and we contacted trial authors for additional information. SELECTION CRITERIA: We included randomised clinical trials that included men and women, regardless of age, with definitive diagnoses of neurosyphilis, including HIV-seropositive patients. We compared any antibiotic regime (concentration, dose, frequency, duration), compared to any other antibiotic regime for the treatment for neurosyphilis in adults. DATA COLLECTION AND ANALYSIS: Two review authors independently selected eligible trials, extracted data, and evaluated risk of bias. We resolved disagreements by involving a third review author. For dichotomous data (serological cure, clinical cure, adverse events), we presented results as summary risk ratios (RR) with 95% confidence intervals (CI). We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: We identified one trial, with 36 participants​ diagnosed ​with syphilis and HIV. The participants were mainly men, with a median age of 34 years. This trial, ​funded by a pharmaceutical company, compared ceftriaxone in 18 participants (2 g daily for 10 days), with penicillin G, also in 18 participants (4 million/Units (MU)/intravenous (IV) every 4 hours for 10 days). The trial reported incomplete and inconclusive results. Three of 18 (16%) participants receiving ceftriaxone versus 2 of 18 (11%) receiving penicillin G achieved serological cure (RR 1.50; 95% CI: 0.28 to 7.93; 1 trial, 36 participants very low-quality evidence); and 8 of 18 (44%) participants receiving ceftriaxone versus 2 of 18 (18%) participants receiving penicillin G achieved clinical cure (RR 4.00; 95% CI: 0.98 to 16.30; 1 trial, 36 participants very low-quality evidence). Although more participants who received ceftriaxone achieved serological and clinical cure compared to those who received penicillin G, the evidence from this trial was insufficient to determine whether there was a difference between treatment with ceftriaxone or penicillin G.In this trial, the authors reported what would usually be adverse events as symptoms and signs in the follow-up of participants. Furthermore, this trial did not evaluate recurrence of neurosyphilis, time to recovery nor quality of life. We judged risk of bias in this clinical trial to be unclear for random sequence generation, allocation, ​and blinding of participants, and high for incomplete outcome data, potential conflicts of interest (funding bias), and other bias, due to the lack of a sample size calculation. We rated the quality of evidence as very low. AUTHORS' CONCLUSIONS: Due to low quality and insufficient evidence, it was not possible to determine whether there was a difference between treatment with ceftriaxone or Penicillin G. Also, the benefits to people without HIV and neurosyphilis are unknown, as is the ceftriaxone safety profile.Therefore, these results should be interpreted with caution. This conclusion does not mean that antibiotics should not be used for treating this clinical entity. This Cochrane Review has identified the need of adequately powered trials, which should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) recommendations, conducted and reported as recommended by the CONSORT statement. Furthermore, the outcomes should be based on patients' perspectives taking into account Patient-Centered Outcomes Research Institute (PCORI) recommendations.

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.

Antiplatelet agents for preventing vaso-occlusive events in people with sickle cell disease: a systematic review.

BACKGROUND: Sickle cell disease (SCD) is the most common hemoglobinopathy, occurring worldwide, and vaso-occlusive events (VOEs) are its paramount, hallmark clinical manifestation. Evidence exists that platelets play an important role in generating VOEs. OBJECTIVE: To assess the clinical benefits and harms of antiplatelet agents for preventing VOEs in patients with SCD. METHODS: We conducted searches of the Cochrane Central Register of Controlled Trials (CENTRAL; up to 2018, issue 3 of 12), PubMed/MEDLINE (up to April 20, 2018), and the Excerpta Medica database (EMBASE; from 1980 to week 16 of 2018). We also searched the Latin American and Caribbean Health Sciences Literature (LILACS) database, the US Food and Drug Administration (FDA) website, the European Medicines Agency (EMA) website, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), and www.ClinicalTrials.gov. We checked the bibliographies of included studies and any relevant systematic reviews. Our systematic review included randomized clinical trials (RCTs) conducted in people who had SCD without VOEs at trial entry. Eligible trials compared a single or combination treatment regimen (with each treatment classified as a conventional or nonconventional antiplatelet agent) with conventional care, placebo, or another regimen. No restrictions were placed on the route of administration, dose, frequency, or duration of treatment. We selected RCTs, assessed the risk for bias, and extracted data in a duplicate and independent fashion. We estimated risk ratios for dichotomous outcomes and mean differences for continuous outcomes. We also subjected our analyses to a random-effects model, and Trial Sequential Analysis (TSA) was used. We used the grading of recommendations, assessment, development, and evaluation (GRADE) approach to assess the overall quality of data for each individual outcome. RESULTS: We identified 5 RCTs (N=747) that met our criteria. Of these, 4 trials were multicenter and multinational. The trials included patients of all ages and assessed prasugrel, ticagrelor, crizanlizumab, and aspirin vs either placebo or no intervention. The most frequent route of administration was oral. The trials were small and carried a high risk for bias, given that pharmaceutical companies sponsored 4 of them. None of the trials reported information on quality of life. No meta-analysis was performed owing to heterogeneity in the ages of the participants and in the interventions. No single trial showed evidence of certainty regarding all-cause mortality. One trial showed uncertainty in comparing prasugrel vs placebo for preventing VOEs in patients younger than 18 years (relative risk [RR], 0.92; 95% CI, 0.80 to 1.06; low quality of evidence). TSA for this outcome suggested that a new trial should be conducted. One trial found a difference in the size effect of uncomplicated VOEs, favoring high-dose crizanlizumab vs placebo (mean difference, -1.50; 95% CI, -2.61 to -0.39; very low quality of evidence). No difference in VOEs was found in studies that compared either ticagrelor in children or prasugrel in adults vs placebo. The overall incidence of harms in any intervention did not differ from that in the control. CONCLUSIONS: The current evidence does not support or reject the use of any antiplatelet agent for preventing VOEs in people with SCD. This conclusion was based on small RCTs that carried a high risk for bias. No conclusive evidence exists regarding relevant clinical outcomes because the evidence is limited and of very low quality.

Antibiotics for treating gonorrhoea in pregnancy.

BACKGROUND: Gonorrhoea is a sexually transmitted infection that is caused by Neisseria gonorrhoeae, and is a major public health challenge today. N gonorrhoeae can be transmitted from the mother's genital tract to the newborn during birth, and can cause gonococcal ophthalmia neonatorum as well as systemic neonatal infections. It can also cause endometritis and pelvic sepsis in the mother. This review updates and replaces an earlier Cochrane Review on antibiotics for treating this infectious condition. OBJECTIVES: To assess the clinical effectiveness and harms of antibiotics for treating gonorrhoea in pregnant women. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2017), LILACS database (1982 to April 5, 2017), the WHO International Clinical Trials Registry Platform (ICTRP; April 5, 2017), ClinicalTrials.gov (April 5, 2017), the ISRCTN Registry (April 5, 2017), and Epistemonikos (April 5, 2017). We also searched reference lists of all retrieved articles. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the use of antibiotics for treating gonorrhoea in pregnancy. The antibiotics could have been used alone or in combination, were administered parenterally, orally, or both, and were compared with another antibiotic.We included RCTs regardless of their publication status (published, unpublished, published as an article, an abstract, or a letter), language, or country. We applied no limits on the length of follow-up.We excluded RCTs using a cluster- or cross-over design, or quasi-RCTs. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed trials for inclusion and risk of bias, extracted data, and checked them for accuracy. MAIN RESULTS: We included two RCTs, that randomised 514 pregnant women (347 women analysed) at a mean gestational age of 22 weeks. Both trials were conducted in the outpatient department of the same two hospitals in the USA between 1993 and 2001, and had a follow-up of 14 days. One of the trials was sponsored by a drug company. We considered both trials to be at a high risk of bias.One trial compared ceftriaxone (125 mg, intramuscular) with cefixime (400 mg, oral); the other trial had three arms, and assessed ceftriaxone (250 mg, intramuscular) versus either amoxicillin (3 g, oral) plus probenecid (1 g, oral) or spectinomycin (2 g, intramuscular). We did not include the spectinomycin data because this medication is no longer produced. We were unable to conduct meta-analysis because the trials compared different medications.We found inconclusive evidence that there were clear differences in the cure of gonococcal infections (genital, extragenital, or both) between intramuscular ceftriaxone versus oral amoxicillin plus oral probenecid (risk ratio (RR) 1.07, 95% confidence interval (CI) 0.98 to 1.16; one RCT; 168 women; very low-quality evidence) or intramuscular ceftriaxone versus oral cefixime (RR 0.99, 95% CI 0.91 to 1.08; one RCT; 95 women; very low-quality evidence).Neither of the trials reported on two of this review's primary maternal outcomes: incidence of obstetric complications (miscarriage, premature rupture of membranes, preterm delivery, or fetal death), or disseminated gonococcal infection, or on the incidence of neonatorum ophthalmia in the neonates.One trial reported one case of vomiting in the oral amoxacillin plus probenecid group. Trials reported pain at the injection sites, but did not quantify it. Hyperberbilurrubinemia was more frequent in neonates whose mothers were exposed to ceftriaxone. There were no clear differences between groups for neonatal malformation. AUTHORS' CONCLUSIONS: This Cochrane Review found high levels of cure of gonococcal infections in pregnancy with the given antibiotic regimens. However, the evidence in this review is inconclusive as it does not support one particular regimen over another. This conclusion was based on very low-quality evidence (downgraded for poor trial design, imprecision) from two trials (involving 514 women), which we assessed to be at a high risk of bias for a number of domains. The harm profiles of the antibiotic regimes featured in this review remain unknown.High-quality RCTs are needed, with sufficient power to assess the clinical effectiveness and potential harms of antibiotics in pregnant women with gonorrhoea. These should be planned according to Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT),conducted following CONSORT recommendations, and based on Patient-Centered Outcomes Research Institute (PCORI) outcomes.

Interventions for preventing high altitude illness: Part 2. Less commonly-used drugs.

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 second review, in a series of three about preventive strategies for HAI, we assessed the effectiveness of five of the less commonly used classes of pharmacological interventions. OBJECTIVES: To assess the clinical effectiveness and adverse events of five of the less commonly used pharmacological interventions for preventing acute HAI in participants 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 May 2017. 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 one of five classes of drugs was employed to prevent acute HAI: selective 5-hydroxytryptamine(1) receptor agonists; N-methyl-D-aspartate (NMDA) antagonist; endothelin-1 antagonist; anticonvulsant drugs; and spironolactone. 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 medication was administered before the beginning of ascent. We excluded trials using these drugs during ascent or after ascent. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures employed by Cochrane. MAIN RESULTS: We included eight studies (334 participants, 9 references) in this review. Twelve studies are ongoing and will be considered in future versions of this review as appropriate. We have been unable to obtain full-text versions of a further 12 studies and have designated them as 'awaiting classification'. Four studies were at a low risk of bias for randomization; two at a low risk of bias for allocation concealment. Four studies were at a low risk of bias for blinding of participants and personnel. We considered three studies at a low risk of bias for blinding of outcome assessors. We considered most studies at a high risk of selective reporting bias.We report results for the following four main comparisons.Sumatriptan versus placebo (1 parallel study; 102 participants)Data on sumatriptan showed a reduction of the risk of AMS when compared with a placebo (risk ratio (RR) = 0.43, CI 95% 0.21 to 0.84; 1 study, 102 participants; low quality of evidence). The one included study did not report events of HAPE, HACE or adverse events related to administrations of sumatriptan.Magnesium citrate versus placebo (1 parallel study; 70 participants)The estimated RR for AMS, comparing magnesium citrate tablets versus placebo, was 1.09 (95% CI 0.55 to 2.13; 1 study; 70 participants; low quality of evidence). In addition, the estimated RR for loose stools was 3.25 (95% CI 1.17 to 8.99; 1 study; 70 participants; low quality of evidence). The one included study did not report events of HAPE or HACE.Spironolactone versus placebo (2 parallel studies; 205 participants)Pooled estimation of RR for AMS was not performed due to considerable heterogeneity between the included studies (I² = 72%). RR from individual studies was 0.40 (95% CI 0.12 to 1.31) and 1.44 (95% CI 0.79 to 2.01; very low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated.Acetazolamide versus spironolactone (1 parallel study; 232 participants)Data on acetazolamide compared with spironolactone showed a reduction of the risk of AMS with the administration of acetazolamide (RR = 0.36, 95% CI 0.18 to 0.70; 232 participants; low quality of evidence). No events of HAPE or HACE were reported. Adverse events were not evaluated. AUTHORS' CONCLUSIONS: This Cochrane Review is the second in a series of three providing relevant information to clinicians and other interested parties on how to prevent high altitude illness. The assessment of five of the less commonly used classes of drugs suggests that there is a scarcity of evidence related to these interventions. Clinical benefits and harms related to potential interventions such as sumatriptan are still unclear. Overall, the evidence is limited due to the low number of studies identified (for most of the comparison only one study was identified); limitations in the quality of the evidence (moderate to low); and the number of studies pending classification (24 studies awaiting classification or ongoing). We lack the large and methodologically sound studies required to establish or refute the efficacy and safety of most of the pharmacological agents evaluated in this review.

Interventions for treating intrahepatic cholestasis in people with sickle cell disease.

BACKGROUND: Sickle cell disease is the most common hemoglobinopathy occurring worldwide and sickle cell intrahepatic cholestasis is a complication long recognized in this population. Cholestatic liver diseases are characterized by impaired formation or excretion (or both) of bile from the liver. There is a need to assess the clinical benefits and harms of the interventions used to treat intrahepatic cholestasis in people with sickle cell disease. This is an update of a previously published Cochrane Review. OBJECTIVES: To assess the benefits and harms of the interventions for treating intrahepatic cholestasis in people with sickle cell disease. SEARCH METHODS: We searched the Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 23 May 2017), the WHO International Clinical Trials Registry Platform Search Portal (23 May 2017) and ClinicalTrials.gov.Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 12 April 2017. SELECTION CRITERIA: We searched for published or unpublished randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess the risk of bias of the trials by standard Cochrane methodologies; however, no trials were included in the review. MAIN RESULTS: There were no randomised controlled trials identified. AUTHORS' CONCLUSIONS: This updated Cochrane Review did not identify any randomised controlled trials assessing interventions for treating intrahepatic cholestasis in people with sickle cell disease. Randomised controlled trials are needed to establish the optimum treatment for this condition.

Homocysteine-lowering interventions for preventing cardiovascular events.

BACKGROUND: Cardiovascular disease, which includes coronary artery disease, stroke and peripheral vascular disease, is a leading cause of death worldwide. Homocysteine is an amino acid with biological functions in methionine metabolism. A postulated risk factor for cardiovascular disease is an elevated circulating total homocysteine level. The impact of homocysteine-lowering interventions, given to patients in the form of vitamins B6, B9 or B12 supplements, on cardiovascular events has been investigated. This is an update of a review previously published in 2009, 2013, and 2015. OBJECTIVES: To determine whether homocysteine-lowering interventions, provided to patients with and without pre-existing cardiovascular disease are effective in preventing cardiovascular events, as well as reducing all-cause mortality, and to evaluate their safety. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 5), MEDLINE (1946 to 1 June 2017), Embase (1980 to 2017 week 22) and LILACS (1986 to 1 June 2017). We also searched Web of Science (1970 to 1 June 2017). We handsearched the reference lists of included papers. We also contacted researchers in the field. There was no language restriction in the search. SELECTION CRITERIA: We included randomised controlled trials assessing the effects of homocysteine-lowering interventions for preventing cardiovascular events with a follow-up period of one year or longer. We considered myocardial infarction and stroke as the primary outcomes. We excluded studies in patients with end-stage renal disease. DATA COLLECTION AND ANALYSIS: We performed study selection, 'Risk of bias' assessment and data extraction in duplicate. We estimated risk ratios (RR) for dichotomous outcomes. We calculated the number needed to treat for an additional beneficial outcome (NNTB). We measured statistical heterogeneity using the I2 statistic. We used a random-effects model. We conducted trial sequential analyses, Bayes factor, and fragility indices where appropriate. MAIN RESULTS: In this third update, we identified three new randomised controlled trials, for a total of 15 randomised controlled trials involving 71,422 participants. Nine trials (60%) had low risk of bias, length of follow-up ranged from one to 7.3 years. Compared with placebo, there were no differences in effects of homocysteine-lowering interventions on myocardial infarction (homocysteine-lowering = 7.1% versus placebo = 6.0%; RR 1.02, 95% confidence interval (CI) 0.95 to 1.10, I2 = 0%, 12 trials; N = 46,699; Bayes factor 1.04, high-quality evidence), death from any cause (homocysteine-lowering = 11.7% versus placebo = 12.3%, RR 1.01, 95% CI 0.96 to 1.06, I2 = 0%, 11 trials, N = 44,817; Bayes factor = 1.05, high-quality evidence), or serious adverse events (homocysteine-lowering = 8.3% versus comparator = 8.5%, RR 1.07, 95% CI 1.00 to 1.14, I2 = 0%, eight trials, N = 35,788; high-quality evidence). Compared with placebo, homocysteine-lowering interventions were associated with reduced stroke outcome (homocysteine-lowering = 4.3% versus comparator = 5.1%, RR 0.90, 95% CI 0.82 to 0.99, I2 = 8%, 10 trials, N = 44,224; high-quality evidence). Compared with low doses, there were uncertain effects of high doses of homocysteine-lowering interventions on stroke (high = 10.8% versus low = 11.2%, RR 0.90, 95% CI 0.66 to 1.22, I2 = 72%, two trials, N = 3929; very low-quality evidence).We found no evidence of publication bias. AUTHORS' CONCLUSIONS: In this third update of the Cochrane review, there were no differences in effects of homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo on myocardial infarction, death from any cause or adverse events. In terms of stroke, this review found a small difference in effect favouring to homocysteine-lowering interventions in the form of supplements of vitamins B6, B9 or B12 given alone or in combination comparing with placebo.There were uncertain effects of enalapril plus folic acid compared with enalapril on stroke; approximately 143 (95% CI 85 to 428) people would need to be treated for 5.4 years to prevent 1 stroke, this evidence emerged from one mega-trial.Trial sequential analyses showed that additional trials are unlikely to increase the certainty about the findings of this issue regarding homocysteine-lowering interventions versus placebo. There is a need for additional trials comparing homocysteine-lowering interventions combined with antihypertensive medication versus antihypertensive medication, and homocysteine-lowering interventions at high doses versus homocysteine-lowering interventions at low doses. Potential trials should be large and co-operative.

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.

Antibiotics for treating osteomyelitis in people with sickle cell disease.

BACKGROUND: Osteomyelitis (both acute and chronic) is one of the most common infectious complications in people with sickle cell disease. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine whether an empirical antibiotic treatment approach (monotherapy or combination therapy) is effective and safe as compared to pathogen-directed antibiotic treatment and whether this effectiveness and safety is dependent on different treatment regimens, age or setting. SEARCH METHODS: We searched The Group's Haemoglobinopathies Trials Register, which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched the LILACS database (1982 to 20 October 2016), African Index Medicus (20 October 2016), ISI Web of Knowledge (20 October 2016) and World Health Organization International Clinical Trials Registry Platform (20 October 2016).Date of most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 18 August 2016. SELECTION CRITERIA: We searched for published or unpublished randomised and quasi-randomised controlled trials. DATA COLLECTION AND ANALYSIS: Each author intended to independently extract data and assess trial quality by standard Cochrane methodologies, but no eligible randomised controlled trials were identified. MAIN RESULTS: This update was unable to find any randomised or quasi-randomised controlled trials on antibiotic treatment approaches for osteomyelitis in people with sickle cell disease. AUTHORS' CONCLUSIONS: We were unable to identify any relevant trials on the efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from osteomyelitis. Randomised controlled trials are needed to establish the optimum antibiotic treatment for this condition.

Antibiotics for treating community-acquired pneumonia in people with sickle cell disease.

BACKGROUND: As a consequence of their condition, people with sickle cell disease are at high risk of developing an acute infection of the pulmonary parenchyma called community-acquired pneumonia. Many different bacteria can cause this infection and antibiotic treatment is generally needed to resolve it. There is no standardized approach to antibiotic therapy and treatment is likely to vary from country to country. Thus, there is a need to identify the efficacy and safety of different antibiotic treatment approaches for people with sickle cell disease suffering from community-acquired pneumonia. This is an update of a previously published Cochrane Review. OBJECTIVES: To determine the efficacy and safety of the antibiotic treatment approaches (monotherapy or combined) for people with sickle cell disease suffering from community-acquired pneumonia. SEARCH METHODS: We searched The Group's Haemoglobinopathies Trials Register (01 September 2016), which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings. We also searched LILACS (1982 to 01 September 2016), African Index Medicus (1982 to 20 October 2016) and WHO ICT Registry (20 October 2016). SELECTION CRITERIA: We searched for published or unpublished randomized controlled trials. DATA COLLECTION AND ANALYSIS: We intended to summarise data by standard Cochrane methodologies, but no eligible randomized controlled trials were identified. MAIN RESULTS: We were unable to find any randomized controlled trials on antibiotic treatment approaches for community-acquired pneumonia in people with sickle cell disease. AUTHORS' CONCLUSIONS: The updated review was unable to identify randomized controlled trials on efficacy and safety of the antibiotic treatment approaches for people with sickle cell disease suffering from community-acquired pneumonia. Randomized controlled trials are needed to establish the optimum antibiotic treatment for this condition. The trials regarding this issue should be structured and reported according to the CONSORT statement for improving the quality of reporting of efficacy and improved reports of harms in clinical research. Triallists should consider including the following outcomes in new trials: number of days to become afebrile; mortality; onset of pain crisis or complications of sickle cell disease following community-acquired pneumonia; diagnosis; hospitalization (admission rate and length of hospital stay); respiratory failure rate; and number of participants receiving a blood transfusion.There are no trials included in the review and we have not identified any relevant trials up to September 2016. We therefore do not plan to update this review until new trials are published.