Prevalence of antibiotic prescribing in COVID-19 patients in China and other low- and middle-income countries during the pandemic (December 2019-March 2021): a systematic review and meta-analysis.

OBJECTIVES: Low- and middle-income countries (LMICs) are particularly vulnerable to the threat of antimicrobial resistance (AMR). Use of antibiotics to treat COVID-19 patients during the pandemic may have contributed to increasing the AMR burden, but systematic evidence is lacking. METHODS: We searched Web of Science, EMBASE, PubMed, China National Knowledge Infrastructure (CNKI) and VIP databases from 1 December 2019 to 31 March 2021. Interventional and observation studies across all settings that reported antibiotic use in at least 10 COVID-19 patients were included. We restricted publications to English and Chinese languages. Screening and data extraction were undertaken by at least two independent reviewers. Results were synthesized using random-effects meta-analyses. Subgroup analyses and meta-regression were used to explore heterogeneities. This review was registered with PROSPERO (CRD42021288291). RESULTS: We included 284 studies involving 210 611 participants in 19 countries. The antibiotic prescribing rates (APRs) in COVID-19 inpatients were 71.7% (95% CI 66.7%-76.5%) in China and 86.5% (77.1%-93.9%) in other LMICs, respectively. APR was lower in mild/moderate cases in China [66.9% (57.9%-75.4%) compared with 91.8% (71.4%-100%) in other LMICs]. High APRs were found among pregnant women and the elderly in China. Disparities in APRs of other patient groups were identified. In studies reporting bacterial infections, the prevalence was 17.3% (10.0%-25.9%) in China and 24.9% (0.1%-68.8%) in other LMICs. Several antibiotics on the WHO 'Watch' and 'Reserve' lists were prescribed frequently in LMICs. CONCLUSIONS: Inappropriate antibiotic use and high prevalence of antibiotic prescribing were found in COVID-19 inpatients in many LMICs.

Lack of Evidence for Ribavirin Treatment of Lassa Fever in Systematic Review of Published and Unpublished Studies1.

Ribavirin has been used widely to treat Lassa fever in West Africa since the 1980s. However, few studies have systematically appraised the evidence for its use. We conducted a systematic review of published and unpublished literature retrieved from electronic databases and gray literature from inception to March 8, 2022. We identified 13 studies of the comparative effectiveness of ribavirin versus no ribavirin treatment on mortality outcomes, including unpublished data from a study in Sierra Leone provided through a US Freedom of Information Act request. Although ribavirin was associated with decreased mortality rates, results of these studies were at critical or serious risk for bias when appraised using the ROBINS-I tool. Important risks for bias related to lack of control for confounders, immortal time bias, and missing outcome data. Robust evidence supporting the use of ribavirin in Lassa fever is lacking. Well-conducted clinical trials to elucidate the effectiveness of ribavirin for Lassa fever are needed.

Systematic review and narrative synthesis of surveillance practices after endovascular intervention for lower limb peripheral arterial disease.

OBJECTIVE: The optimal timing and modality of surveillance after endovascular intervention for peripheral arterial disease is controversial, and no randomized trial to assess the value of peripheral endovascular intervention has ever been performed. The aim of this systematic review was to examine the practice of surveillance after peripheral endovascular intervention in randomized trials. METHODS: We used the Medline, Embase, Cochrane Library, and WHO trial registry databases in this systematic review of the literature to capture surveillance strategies used in randomized trials comparing endovascular interventions. Surveillance protocols were assessed for completeness, modalities used, duration, and intensity. RESULTS: Ninety-six different surveillance protocols were reported in 103 trials comparing endovascular interventions. Protocol specification was incomplete in 32% of trials. The majority of trials used multiple surveillance modalities (mean of 3.46 modalities), most commonly clinical examination (96%), ankle-brachial index (80%), duplex ultrasound examination (75%), and digital subtraction angiography (51%). Trials involving infrapopliteal lesions used more angiographic surveillance than trials with femoropopliteal lesions (P = .006). The median number of surveillance visits in the first 12 months after intervention was three and the mean surveillance duration was 21 months. Trials treating infrapopliteal vessels had a higher surveillance intensity compared with those treating femoropopliteal lesions in the first 12 months after endovascular intervention (mean 5 vs 3 surveillance visits; P = .017). Trials with drug-eluting devices had longer surveillance duration compared with those without (mean 26 vs 19 months; P = .020). CONCLUSIONS: There is a high level of variation in the modality, duration, and intensity of surveillance protocols used in randomized trials comparing different types of peripheral endovascular arterial intervention. Further research is required to determine the value and impact of postprocedural surveillance on patient outcomes.

Prognostic value of test(s) for O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation for predicting overall survival in people with glioblastoma treated with temozolomide.

BACKGROUND: Glioblastoma is an aggressive form of brain cancer. Approximately five in 100 people with glioblastoma survive for five years past diagnosis. Glioblastomas that have a particular modification to their DNA (called methylation) in a particular region (the O6-methylguanine-DNA methyltransferase (MGMT) promoter) respond better to treatment with chemotherapy using a drug called temozolomide. OBJECTIVES: To determine which method for assessing MGMT methylation status best predicts overall survival in people diagnosed with glioblastoma who are treated with temozolomide. SEARCH METHODS: We searched MEDLINE, Embase, BIOSIS, Web of Science Conference Proceedings Citation Index to December 2018, and examined reference lists. For economic evaluation studies, we additionally searched NHS Economic Evaluation Database (EED) up to December 2014. SELECTION CRITERIA: Eligible studies were longitudinal (cohort) studies of adults with diagnosed glioblastoma treated with temozolomide with/without radiotherapy/surgery. Studies had to have related MGMT status in tumour tissue (assessed by one or more method) with overall survival and presented results as hazard ratios or with sufficient information (e.g. Kaplan-Meier curves) for us to estimate hazard ratios. We focused mainly on studies comparing two or more methods, and listed brief details of articles that examined a single method of measuring MGMT promoter methylation. We also sought economic evaluations conducted alongside trials, modelling studies and cost analysis. DATA COLLECTION AND ANALYSIS: Two review authors independently undertook all steps of the identification and data extraction process for multiple-method studies. We assessed risk of bias and applicability using our own modified and extended version of the QUality In Prognosis Studies (QUIPS) tool. We compared different techniques, exact promoter regions (5'-cytosine-phosphate-guanine-3' (CpG) sites) and thresholds for interpretation within studies by examining hazard ratios. We performed meta-analyses for comparisons of the three most commonly examined methods (immunohistochemistry (IHC), methylation-specific polymerase chain reaction (MSP) and pyrosequencing (PSQ)), with ratios of hazard ratios (RHR), using an imputed value of the correlation between results based on the same individuals. MAIN RESULTS: We included 32 independent cohorts involving 3474 people that compared two or more methods. We found evidence that MSP (CpG sites 76 to 80 and 84 to 87) is more prognostic than IHC for MGMT protein at varying thresholds (RHR 1.31, 95% confidence interval (CI) 1.01 to 1.71). We also found evidence that PSQ is more prognostic than IHC for MGMT protein at various thresholds (RHR 1.36, 95% CI 1.01 to 1.84). The data suggest that PSQ (mainly at CpG sites 74 to 78, using various thresholds) is slightly more prognostic than MSP at sites 76 to 80 and 84 to 87 (RHR 1.14, 95% CI 0.87 to 1.48). Many variants of PSQ have been compared, although we did not see any strong and consistent messages from the results. Targeting multiple CpG sites is likely to be more prognostic than targeting just one. In addition, we identified and summarised 190 articles describing a single method for measuring MGMT promoter methylation status. AUTHORS' CONCLUSIONS: PSQ and MSP appear more prognostic for overall survival than IHC. Strong evidence is not available to draw conclusions with confidence about the best CpG sites or thresholds for quantitative methods. MSP has been studied mainly for CpG sites 76 to 80 and 84 to 87 and PSQ at CpG sites ranging from 72 to 95. A threshold of 9% for CpG sites 74 to 78 performed better than higher thresholds of 28% or 29% in two of three good-quality studies making such comparisons.

Antiplatelet and Anticoagulant Use in Randomised Trials of Patients Undergoing Endovascular Intervention for Peripheral Arterial Disease: Systematic Review and Narrative Synthesis.

OBJECTIVE: Randomised trials of new devices for peripheral arterial endovascular intervention are published regularly. The evidence for which antiplatelet and/or anticoagulant (antithrombotic) therapy to use after an intervention is lacking. The aim of this systematic review was to examine the antithrombotic regimens in randomised trials for peripheral arterial endovascular intervention to understand choices made and trends with time or type of device. METHODS: Data sources were the Medline, Embase, and Cochrane Library databases. Randomised trials including participants with peripheral arterial disease undergoing any endovascular arterial intervention were included. Trial methods were assessed to determine whether an antithrombotic protocol had been specified, its completeness, and the agent(s) prescribed. Antithrombotic therapy protocols were classed as peri-procedural (preceding and during intervention), immediate post-procedural (up to 30 days following intervention), and maintenance post-procedural (therapy continuing beyond 30 days). RESULTS: Ninety-four trials were included in narrative synthesis. Study quality was low. None of the trials justified their antithrombotic therapy protocol. Only 29% of trials had complete peri-procedural antithrombotic protocols, and 34% had complete post-procedural protocols. In total, 64 different peri-procedural protocols, and 51 separate post-procedural protocols were specified. Antiplatelet monotherapy and unfractionated heparin were the most common regimen choices in the peri-procedural setting, and dual antiplatelet therapy (55%) was most commonly utilised post procedure. Over time there has been an increasing tendency to use dual therapy (p < .001). This corresponds with the introduction of newer technologies and trials focussed on below knee intervention. CONCLUSION: Randomised trials comparing different types of peripheral endovascular arterial intervention have a high level of heterogeneity in their antithrombotic regimens. Antiplatelet therapy needs to be standardised in trials comparing endovascular technologies to reduce potential confounding. To do this, an independent randomised trial specifically examining antiplatelet therapy following peripheral arterial endovascular intervention is needed.

Intraoperative interventions for preventing surgical site infection: an overview of Cochrane Reviews.

BACKGROUND: Surgical site infection (SSI) rates vary from 1% to 5% in the month following surgery. Due to the large number of surgical procedures conducted annually, the costs of these SSIs can be considerable in financial and social terms. Many interventions are used with the aim of reducing the risk of SSI in people undergoing surgery. These interventions can be broadly delivered at three stages: preoperatively, intraoperatively and postoperatively. The intraoperative interventions are largely focused on decontamination of skin using soap and antiseptics; the use of barriers to prevent movement of micro-organisms into incisions; and optimising the patient's own bodily functions to promote best recovery. Both decontamination and barrier methods can be aimed at people undergoing surgery and operating staff. Other interventions focused on SSI prevention may be aimed at the surgical environment and include methods of theatre cleansing and approaches to managing theatre traffic. OBJECTIVES: To present an overview of Cochrane Reviews of the effectiveness and safety of interventions, delivered during the intraoperative period, aimed at preventing SSIs in all populations undergoing surgery in an operating theatre. METHODS: Published Cochrane systematic reviews reporting the effectiveness of interventions delivered during the intraoperative period in terms of SSI prevention were eligible for inclusion in this overview. We also identified Cochrane protocols and title registrations for future inclusion into the overview. We searched the Cochrane Library on 01 July 2017. Two review authors independently screened search results and undertook data extraction and 'Risk of bias' and certainty assessment. We used the ROBIS (risk of bias in systematic reviews) tool to assess the quality of included reviews, and we used GRADE methods to assess the certainty of the evidence for each outcome. We summarised the characteristics of included reviews in the text and in additional tables. MAIN RESULTS: We included 32 Cochrane Reviews in this overview: we judged 30 reviews as being at low risk of bias and two at unclear risk of bias. Thirteen reviews had not been updated in the past three years. Two reviews had no relevant data to extract. We extracted data from 30 reviews with 349 included trials, totaling 73,053 participants. Interventions assessed included gloving, use of disposable face masks, patient oxygenation protocols, use of skin antiseptics for hand washing and patient skin preparation, vaginal preparation, microbial sealants, methods of surgical incision, antibiotic prophylaxis and methods of skin closure. Overall, the GRADE certainty of evidence for outcomes was low or very low. Of the 77 comparisons providing evidence for the outcome of SSI, seven provided high- or moderate-certainty evidence, 39 provided low-certainty evidence and 31 very low-certainty evidence. Of the nine comparisons that provided evidence for the outcome of mortality, five provided low-certainty evidence and four very low-certainty evidence.There is high- or moderate-certainty evidence for the following outcomes for these intraoperative interventions. (1) Prophylactic intravenous antibiotics administered before caesarean incision reduce SSI risk compared with administration after cord clamping (10 trials, 5041 participants; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.44 to 0.81; high-certainty evidence - assessed by review authors). (2) Preoperative antibiotics reduce SSI risk compared with placebo after breast cancer surgery (6 trials, 1708 participants; RR 0.74, 95% CI 0.56 to 0.98; high-certainty evidence - assessed by overview authors). (3) Antibiotic prophylaxis probably reduce SSI risk in caesarean sections compared with no antibiotics (82 relevant trials, 14,407 participants; RR 0.40, 95% CI 0.35 to 0.46; moderate-certainty evidence; downgraded once for risk of bias - assessed by review authors). (4) Antibiotic prophylaxis probably reduces SSI risk for hernia repair compared with placebo or no treatment (17 trials, 7843 participants; RR 0.67, 95% CI 0.54 to 0.84; moderate-certainty evidence; downgraded once for risk of bias - assessed by overview authors); (5) There is currently no clear difference in the risk of SSI between iodine-impregnated adhesive drapes compared with no adhesive drapes (2 trials, 1113 participants; RR 1.03, 95% CI 0.66 to 1.60; moderate-certainty evidence; downgraded once for imprecision - assessed by review authors); (6) There is currently no clear difference in SSI risk between short-term compared with long-term duration antibiotics in colorectal surgery (7 trials; 1484 participants; RR 1.05 95% CI 0.78 to 1.40; moderate-certainty evidence; downgraded once for imprecision - assessed by overview authors). There was only one comparison showing negative effects associated with the intervention: adhesive drapes increase the risk of SSI compared with no drapes (5 trials; 3082 participants; RR 1.23, 95% CI 1.02 to 1.48; high-certainty evidence - rated by review authors). AUTHORS' CONCLUSIONS: This overview provides the most up-to-date evidence on use of intraoperative treatments for the prevention of SSIs from all currently published Cochrane Reviews. There is evidence that some interventions are useful in reducing SSI risk for people undergoing surgery, such as antibiotic prophylaxis for caesarean section and hernia repair, and also the timing of prophylactic intravenous antibiotics administered before caesarean incision. Also, there is evidence that adhesive drapes increase SSI risk. Evidence for the many other treatment choices is largely of low or very low certainty and no quality-of-life or cost-effectiveness data were reported. Future trials should elucidate the relative effects of some treatments. These studies should focus on increasing participant numbers, using robust methodology and being of sufficient duration to adequately assess SSI. Assessment of other outcomes such as mortality might also be investigated as part of non-experimental prospective follow-up of people with SSI of different severity, so the risk of death for different subgroups can be better understood.

Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.

Maximal exercise capacity is reduced at altitude or during hypoxia at sea level. It has been suggested that this might reflect increased right ventricular afterload due to hypoxic pulmonary vasoconstriction. We have shown previously that the pulmonary vascular sensitivity to hypoxia is enhanced by sustained isocapnic hypoxia, and inhibited by intravenous iron. In this study, we tested the hypothesis that elevated pulmonary artery pressure contributes to exercise limitation during acute hypoxia. Twelve healthy volunteers performed incremental exercise tests to exhaustion breathing 12% oxygen, before and after sustained (8-h) isocapnic hypoxia at sea level. Intravenous iron sucrose (n = 6) or saline placebo (n = 6) was administered immediately before the sustained hypoxia. In the placebo group, there was a substantial (12.6 ± 1.5 mmHg) rise in systolic pulmonary artery pressure (SPAP) during sustained hypoxia, but no associated fall in maximal exercise capacity breathing 12% oxygen. In the iron group, the rise in SPAP during sustained hypoxia was markedly reduced (3.4 ± 1.0 mmHg). There was a small rise in maximal exercise capacity following sustained hypoxia within the iron group, but no overall effect of iron, compared with saline. These results do not support the hypothesis that elevated SPAP inhibits maximal exercise capacity during acute hypoxia in healthy volunteers.

Prevalence of BRAFV600 in glioma and use of BRAF Inhibitors in patients with BRAFV600 mutation-positive glioma: systematic review.

BACKGROUND: Detailed prevalence estimates of BRAFV600 mutations and BRAF inhibitor (BRAFi) treatment responses in V600-mutant glioma will inform trial development. METHODS: Our systematic review analyzed overall prevalence of BRAFV600 mutations in glioma and BRAFi treatment response. RESULTS: Based on 13 682 patients in 182 publications, the prevalence of BRAFV600 in epithelioid glioblastoma (eGBM) was 69% [95% CI: 45-89%]; pleomorphic xanthoastrocytoma (PXA): 56% [48-64%] anaplastic pleomorphic xanthoastrocytoma (aPXA): 38% [23-54%], ganglioglioma (GG): 40% [33-46%], and anaplastic ganglioglioma (aGG): 46% [18-76%]. Prevalence in astroblastoma was 24% [8-43%], desmoplastic infantile astrocytoma (DIA): 16% [0-57%], subependymal giant cell astrocytoma (SEGA): 8% [0-37%], dysembryoplastic neuroepithelial tumor (DNET): 3% [0-11%], diffuse astrocytoma (DA): 3% [0-9%], and pilocytic astrocytoma (PA): 3% [2-5%]. We reviewed 394 V600-mutant gliomas treated with BRAFi from 130 publications. One hundred and twenty-nine pediatric low-grade gliomas showed 4 (3.1%) complete response (CR); 53 (41.1%) partial response (PR); 64 (49.6%) stable disease (SD) and 8 (6.2%) progressive disease (PD). 25 pediatric high-grade gliomas showed CR; PR; SD; PD in 4 (16.0%); 10 (40.0%), 4 (16.0%); and 7 (28.0%) respectively. Thirty-nine adult low-grade gliomas showed CR; PR; SD; PD of 4 (10.3%); 17 (43.6%); 16 (41.0%) and 2 (5.1%) respectively. Ninety-seven adult high-grade gliomas showed CR; PR; SD; PD of 6 (6.2%); 31 (32.0%); 27 (27.8%); and 33 (34.0%) respectively. CONCLUSIONS: BRAFV600 prevalence is highest in eGBM, PXA, aPXA, GG, aGG, and lower in astroblastoma, DIA, SEGA, DNET, DA, and PA. Our data provide the rationale for adjuvant clinical trials of BRAFi in V600-mutant glioma.

MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review.

BACKGROUND: The DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) causes resistance of tumor cells to alkylating agents. It is a predictive biomarker in high-grade gliomas treated with temozolomide, however, there is no consensus on which test method, methylation sites, and cutoff values to use. METHODS: We performed a Cochrane Review to examine studies using different techniques to measure MGMT and predict survival in glioblastoma patients treated with temozolomide. Eligible longitudinal studies included (i) adults with glioblastoma treated with temozolomide with or without radiotherapy, or surgery; (ii) where MGMT status was determined in tumor tissue, and assessed by 1 or more technique; and (iii) where overall survival was an outcome parameter, with sufficient information to estimate hazard ratios (HRs). Two or more methods were compared in 32 independent cohorts with 3474 patients. RESULTS: Methylation-specific PCR (MSP) and pyrosequencing (PSQ) techniques were more prognostic than immunohistochemistry for MGMT protein, and PSQ is a slightly better predictor than MSP. CONCLUSIONS: We cannot draw strong conclusions about use of frozen tissue vs formalin-fixed paraffin-embedded in MSP and PSQ. Also, our meta-analysis does not provide strong evidence about the best CpG sites or threshold. MSP has been studied mainly for CpG sites 76-80 and 84-87 and PSQ at CpG sites ranging from 72 to 95. A cutoff threshold of 9% for CpG sites 74-78 performed better than higher thresholds of 28% or 29% in 2 of the 3 good-quality studies. About 190 studies were identified presenting HRs from survival analysis in patients in which MGMT methylation was measured by 1 technique only.

Systematic review of the impact of the COVID-19 pandemic on suicidal behaviour amongst health and social care workers across the world.

BACKGROUND: The COVID-19 pandemic has had an impact on the mental health of healthcare and social care workers, and its potential effect on suicidal thoughts and behaviour is of particular concern. METHODS: This systematic review identified and appraised the published literature that has reported on the impact of COVID-19 on suicidal thoughts and behaviour and self-harm amongst healthcare and social care workers worldwide up to May 31, 2021. RESULTS: Out of 37 potentially relevant papers identified, ten met our eligibility criteria. Our review has highlighted that the impact of COVID-19 has varied as a function of setting, working relationships, occupational roles, and psychiatric comorbidities. LIMITATIONS: There have been no completed cohort studies comparing pre- and post-pandemic suicidal thoughts and behaviours. It is possible some papers may have been missed in the search. CONCLUSIONS: The current quality of evidence pertaining to suicidal behaviour in healthcare workers is poor, and evidence is entirely absent for those working in social care. The clinical relevance of this work is to bring attention to what evidence exists, and to encourage, in practice, proactive approaches to interventions for improving healthcare and social care worker mental health.

Crizanlizumab and comparators for adults with sickle cell disease: a systematic review and network meta-analysis.

OBJECTIVES: Treatment options for preventing vaso-occlusive crises (VOC) among patients with sickle cell disease (SCD) are limited, especially if hydroxyurea treatment has failed or is contraindicated. A systematic literature review (SLR) and network meta-analysis (NMA) were conducted to evaluate the efficacy and safety of crizanlizumab for older adolescent and adult (≥16 years old) SCD patients. METHODS: The SLR included randomised controlled trials (RCTs) and uncontrolled studies. Bayesian NMA of VOC, all-cause hospitalisation days and adverse events were conducted. RESULTS: The SLR identified 51 studies and 9 RCTs on 14 treatments that met the NMA inclusion criteria. The NMA found that crizanlizumab 5.0 mg/kg was associated with a reduction in VOC (HR 0.55, 95% credible interval (0.43, 0.69); Bayesian probability of superiority >0.99), all-cause hospitalisation days (0.58 (0.50, 0.68); >0.99) and no evidence of difference on adverse events (0.91 (0.59, 1.43) 0.66) or serious adverse events (0.93 (0.47, 1.87); 0.59) compared with placebo. The HR for reduction in VOC for crizanlizumab relative to L-glutamine was (0.67 (0.50, 0.88); >0.99). These results were sensitive to assumptions regarding whether patient age is an effect modifier. CONCLUSIONS: This NMA provides preliminary evidence comparing the efficacy of crizanlizumab with other treatments for VOC prevention.

Treatment interventions to maintain abstinence from alcohol in primary care: systematic review and network meta-analysis.

OBJECTIVE: To determine the most effective interventions in recently detoxified, alcohol dependent patients for implementation in primary care. DESIGN: Systematic review and network meta-analysis. DATA SOURCES: Medline, Embase, PsycINFO, Cochrane CENTRAL, ClinicalTrials.gov, and the World Health Organization's International Clinical Trials Registry Platform. STUDY SELECTION: Randomised controlled trials comparing two or more interventions that could be used in primary care. The population was patients with alcohol dependency diagnosed by standardised clinical tools and who became detoxified within four weeks. DATA EXTRACTION: Outcomes of interest were continuous abstinence from alcohol (effectiveness) and all cause dropouts (as a proxy for acceptability) at least 12 weeks after start of intervention. RESULTS: 64 trials (43 interventions) were included. The median probability of abstinence across placebo arms was 25%. Compared with placebo, the only intervention associated with increased probability of abstinence and moderate certainty evidence was acamprosate (odds ratio 1.86, 95% confidence interval 1.49 to 2.33, corresponding to an absolute probability of 38%). Of the 62 included trials that reported all cause dropouts, interventions associated with a reduced number of dropouts compared with placebo (probability 50%) and moderate certainty of evidence were acamprosate (0.73, 0.62 to 0.86; 42%), naltrexone (0.70, 0.50 to 0.98; 41%), and acamprosate-naltrexone (0.30, 0.13 to 0.67; 17%). Acamprosate was the only intervention associated with moderate confidence in the evidence of effectiveness and acceptability up to 12 months. It is uncertain whether other interventions can help maintain abstinence and reduce dropouts because of low confidence in the evidence. CONCLUSIONS: Evidence is lacking for benefit from interventions that could be implemented in primary care settings for alcohol abstinence, other than for acamprosate. More evidence from high quality randomised controlled trials is needed, as are strategies using combined interventions (combinations of drug interventions or drug and psychosocial interventions) to improve treatment of alcohol dependency in primary care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049779.

The impact of the COVID-19 pandemic on self-harm and suicidal behaviour: update of living systematic review.

Background: The COVID-19 pandemic has caused considerable morbidity, mortality and disruption to people's lives around the world. There are concerns that rates of suicide and suicidal behaviour may rise during and in its aftermath. Our living systematic review synthesises findings from emerging literature on incidence and prevalence of suicidal behaviour as well as suicide prevention efforts in relation to COVID-19, with this iteration synthesising relevant evidence up to 19 th October 2020. Method:  Automated daily searches feed into a web-based database with screening and data extraction functionalities. Eligibility criteria include incidence/prevalence of suicidal behaviour, exposure-outcome relationships and effects of interventions in relation to the COVID-19 pandemic. Outcomes of interest are suicide, self-harm or attempted suicide and suicidal thoughts. No restrictions are placed on language or study type, except for single-person case reports. We exclude one-off cross-sectional studies without either pre-pandemic measures or comparisons of COVID-19 positive vs. unaffected individuals. Results: Searches identified 6,226 articles. Seventy-eight articles met our inclusion criteria. We identified a further 64 relevant cross-sectional studies that did not meet our revised inclusion criteria. Thirty-four articles were not peer-reviewed (e.g. research letters, pre-prints). All articles were based on observational studies. There was no consistent evidence of a rise in suicide but many studies noted adverse economic effects were evolving. There was evidence of a rise in community distress, fall in hospital presentation for suicidal behaviour and early evidence of an increased frequency of suicidal thoughts in those who had become infected with COVID-19. Conclusions:  Research evidence of the impact of COVID-19 on suicidal behaviour is accumulating rapidly. This living review provides a regular synthesis of the most up-to-date research evidence to guide public health and clinical policy to mitigate the impact of COVID-19 on suicide risk as the longer term impacts of the pandemic on suicide risk are researched.

Risk of bias and reporting completeness of randomised controlled trials in burn care: protocol for a systematic review.

INTRODUCTION: Burn care represents a healthcare and economic burden to patients internationally. Choice of the most clinically effective treatment strategies requires evidence which is best obtained through high-quality randomised controlled trials (RCT). The number of published RCTs of burn care is increasing. However, trial quality and reporting standards are unclear. This study will assess the risk of bias and adequacy of reporting in recent burn care RCTs using tools endorsed by the Cochrane Collaboration. METHODS AND ANALYSIS: A systematic literature review will be undertaken, assessing parallel group RCTs evaluating therapeutic interventions for patients with cutaneous burns. Literature searches will use Ovid Medline, Ovid Embase, Web of Science and the Cochrane Library. Separate searches for each database will include medical subject heading and free text terms including 'burn', 'scald', 'thermal injury' and 'RCT'. Two reviewers will independently assess each study for inclusion. Risk of bias (RoB) will be assessed with the revised tool (RoB 2) and reporting completeness with the CONsolidated Standards of Reporting Trials (CONSORT) 2010 guidelines. We will report a narrative synthesis of all studies, including domain specific, and overall risk of bias for the primary outcome of each trial. Inter-rater agreement for RoB 2 will be reported using Fleiss's Kappa. For adherence to the CONSORT guidelines, we will generate a completeness of reporting index for the five domains. ETHICS AND DISSEMINATION: No ethics approval is required because published documents will be used. Findings of the study will be disseminated in a peer-reviewed journal and presented at conferences. PROSPERO REGISTRATION NUMBER: CRD42018111020.

Intravenous iron delivers a sustained (8-week) lowering of pulmonary artery pressure during exercise in healthy older humans.

In older individuals, pulmonary artery pressure rises markedly during exercise, probably due in part to increased pulmonary vascular resistance and in part to an increase in left-heart filling pressure. Older individuals also show more marked pulmonary vascular response to hypoxia at rest. Treatment with intravenous iron reduces the rise in pulmonary artery pressure observed during hypoxia. Here, we test the hypothesis that intravenous iron administration may also attenuate the rise in pulmonary artery pressure with exercise in older individuals. In a randomized double-blind placebo-controlled physiology study in 32 healthy participants aged 50-80 years, we explored the hypothesis that iron administration would deliver a fall in systolic pulmonary artery pressure (SPAP) during moderate cycling exercise (20 min duration; increase in heart rate of 30 min-1 ) and a change in maximal cycling exercise capacity ( V˙O2max ). Participants were studied before, and at 3 h to 8 weeks after, infusion. SPAP was measured using Doppler echocardiography. Iron administration resulted in marked changes in indices of iron homeostasis over 8 weeks, but no significant change in hemoglobin concentration or inflammatory markers. Resting SPAP was also unchanged, but SPAP during exercise was lower by ~3 mmHg in those receiving iron (P < 0.0001). This effect persisted for 8 weeks. Although V˙O2max remained unaffected in the iron-replete healthy participants studied here, this study demonstrates for the first time the ability of intravenous iron supplementation to reduce systolic pulmonary artery pressure during exercise.

Effects of modest iron loading on iron indices in healthy individuals.

Intravenous iron administration is typically indicated in individuals who have iron deficiency refractory to oral iron. However, in certain chronic disease states such as heart failure, it may be beneficial to administer intravenous iron to individuals who are not strictly iron deficient. The purpose of this study was to define a dose-response relationship between clinical indices of iron status and modest loading with intravenous iron in healthy, iron-replete participants. This was a double-blind, controlled study involving 18 male participants. Participants were block-randomized 2:1 to the iron and saline (control) groups. Participants in the iron group received 3.75 mg/kg body wt up to a maximum of 250 mg of intravenous iron, once a month for 6 mo, provided that their ferritin remained measured <300 µg/l within the week before a dose was due and their transferrin saturation remained <45%. Otherwise they received a saline infusion, as did the control participants. Iron indices were measured monthly during the study. The pulmonary vascular response to sustained hypoxia and total hemoglobin mass were measured before, at 3 mo (hemoglobin mass only), and at 6 mo as variables that may be affected by iron loading. Serum ferritin was robustly elevated by intravenous iron by 0.21 µg·l-1·mg-1 of iron delivered (95% confidence interval: 0.15-0.26 µg·l-1·mg-1), but the effects on all other iron indices did not reach statistical significance. The pulmonary vascular response to sustained hypoxia was significantly suppressed by iron loading at 6 mo, but the hemoglobin mass was unaffected. We conclude that the robust effect on ferritin provides a quantitative measure for the degree of iron loading in iron-replete individuals.NEW & NOTEWORTHY There has been an increasing interest in administering intravenous iron to patients to alter their iron status. Here, we explore various indices of iron loading and show that in healthy volunteers serum ferritin provides a robust indicator of the amount of iron loaded, with a value of 21 µg/l increase in ferritin per 100 mg of iron loaded.

Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia.

Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least 3 days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured, using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia.

Therapeutic interventions for alcohol dependence in non-inpatient settings: a systematic review and network meta-analysis (protocol).

BACKGROUND: Alcohol dependence is common and serious cause of social and physical harm. However, the optimal management of those with moderate and severe alcohol dependence in primary and community care after detoxification remains unclear. The aim of this review is to evaluate the effectiveness of interventions for maintaining abstinence in people with alcohol dependence following detoxification. METHODS: We will systematically search electronic databases and clinical trial registries for randomized controlled trials (RCTs) examining the effectiveness of pharmacological and/or psychosocial interventions for maintaining abstinence in recently detoxified, alcohol-dependent adults. The searches will be complemented by checking references and citations from included studies and other relevant systematic reviews. No limitation on language, year, or publication status will be applied. RCTs will be selected using prespecified criteria. Descriptive information, study characteristics, and results of eligible RCTs will be extracted. A revised version of the Cochrane Risk of Bias tool (RoB 2.0) will be used to assess the risk of bias in eligible RCTs. Results will be synthesized and analyzed using network meta-analysis (NMA). Overall strength of the evidence and publication bias will be evaluated. Subgroup and sensitivity analysis will also be performed. DISCUSSION: This network meta-analysis aims to appraise and summarize the total evidence of therapeutic interventions for alcohol-dependent patients that require support for detoxification and can be treated in the community. The evidence will determine which combination of interventions are most promising for current practice and further investigation. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016049779.

Perturbing effects of carvedilol on a model membrane system: role of lipophilicity and chemical structure.

Carvedilol, a beta-adrenergic blocker used to treat cardiovascular diseases, protects cell membranes from lipid peroxidative damage. Previous studies suggested the drug resides in a non-polar environment and partitions into cell membranes, perturbing their fluidity. Here differential scanning calorimetry (DSC) and fluorescence spectroscopy were applied to further investigate interactions of carvedilol with a liposome model. Results indicate the association is relatively unaffected by pH or temperature, but could be sensitive to liposome composition. The drug's carbazole group plays the dominant role in bilayer perturbation. Compared with other beta-blockers examined, carvedilol produced the strongest liposome DSC perturbation. Locations of carbazole and carvedilol in the liposome were determined using depth-dependent fluorescent probes. Both compounds are situated in the middle of the bilayer, consistent with strong hydrophobic interactions. This combination of high lipophilicity and specific chemical structure appear required for carvedilol's novel antioxidant activity, and may enhance cardioprotection.

Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia.

Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 h. Thus any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6 h) hypoxia on 4 separate days (days 0, 1, 8, and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ∼50%, and this response remained suppressed on both days 8 and 43 (P < 0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation, and hepcidin concentration rose significantly (P < 0.001, P < 0.005, and P < 0.001, respectively), and values for transferrin concentration fell significantly (P < 0.001). These changes remained significant at day 43 We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension.