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SummaryCommon variable immunodeficiency disorders (CVID) are multi-system disorders where target organ damage is mediated by infective, autoimmune and inflammatory processes. Bronchiectasis is probably the most common disabling complication of CVID. The risk factors for bronchiectasis in CVID patients are incompletely understood. The New Zealand CVID study (NZCS) is a nationwide longitudinal observational study of adults, which commenced in 2006. In this analysis, the prevalence and risk factors for bronchiectasis were examined in the NZCS. After informed consent, clinical and demographic data were obtained with an interviewer-assisted questionnaire. Linked electronic clinical records and laboratory results were also reviewed. Statistical methods were applied to determine if variables such as early-onset disease, delay in diagnosis and increased numbers of infections were associated with greater risk of bronchiectasis. One hundred and seven adult patients with a diagnosis of CVID are currently enrolled in the NZCS, comprising approximately 70% of patients known to have CVID in New Zealand. Fifty patients (46·7%) had radiologically proven bronchiectasis. This study has shown that patients with compared to those without bronchiectasis have an increased mortality at a younger age. CVID patients with bronchiectasis had a greater number of severe infections consequent to early-onset disease and delayed diagnosis. Indigenous Māori have a high prevalence of CVID and a much greater burden of bronchiectasis compared to New Zealand Europeans. Diagnostic latency has not improved during the study period. Exposure to large numbers of infections because of early-onset disease and delayed diagnosis was associated with an increased risk of bronchiectasis. Earlier diagnosis and treatment of CVID may reduce the risk of bronchiectasis and premature death in some patients.

Purpose To study the efficacy of lopinavir-ritonavir and hydroxychloroquine in critically ill patients with coronavirus disease 2019 (COVID-19). Methods Critically ill adults with COVID-19 were randomized to receive lopinavir-ritonavir, hydroxychloroquine, combination therapy of lopinavir-ritonavir and hydroxychloroquine or no antiviral therapy (control). The primary endpoint was an ordinal scale of organ support-free days. Analyses used a Bayesian cumulative logistic model and expressed treatment effects as an adjusted odds ratio (OR) where an OR > 1 is favorable. Results We randomized 694 patients to receive lopinavir-ritonavir (n = 255), hydroxychloroquine (n = 50), combination therapy (n = 27) or control (n = 362). The median organ support-free days among patients in lopinavir-ritonavir, hydroxychloroquine, and combination therapy groups was 4 (– 1 to 15), 0 (– 1 to 9) and—1 (– 1 to 7), respectively, compared to 6 (– 1 to 16) in the control group with in-hospital mortality of 88/249 (35%), 17/49 (35%), 13/26 (50%), respectively, compared to 106/353 (30%) in the control group. The three interventions decreased organ support-free days compared to control (OR [95% credible interval]: 0.73 [0.55, 0.99], 0.57 [0.35, 0.83] 0.41 [0.24, 0.72]), yielding posterior probabilities that reached the threshold futility (≥ 99.0%), and high probabilities of harm (98.0%, 99.9% and > 99.9%, respectively). The three interventions reduced hospital survival compared with control (OR [95% CrI]: 0.65 [0.45, 0.95], 0.56 [0.30, 0.89], and 0.36 [0.17, 0.73]), yielding high probabilities of harm (98.5% and 99.4% and 99.8%, respectively). Conclusion Among critically ill patients with COVID-19, lopinavir-ritonavir, hydroxychloroquine, or combination therapy worsened outcomes compared to no antiviral therapy. Supplementary Information The online version contains supplementary material available at 10.1007/s00134-021-06448-5.

This collaborative meta-analysis was supported by the Swiss National Science Foundation and the Laura and John Arnold Foundation (grant supporting the post-doctoral fellowship at the Meta-Research Innovation Center at Stanford (METRICS), Stanford University). The funders had no role in the design of this collaborative meta-analysis; in the collection, analysis, and interpretation of data; or in the report writing., We would like to express our warm gratitude to all participating patients and convalescent plasma donors. We thank Katja Suter and Sina Ullrich, University of Basel, for their administrative assistance. For their helpful contribution to individual trials, we thank Erica Wood, Iain Gosbell, Richard Charlewood, Thomas Hills, Veronica Hoad, Kristina Kairaitis, Aikaj Jindal, John Gerrard, Hong Foo, Adam Stewart, and Nanette Trask (ASCOT trial); Amalia Bravo-Lindoro, Ral Carrillo-Esper, Karla Maldonado-Silva, Catalina Casillas-Suárez, Orlando Carrillo-Torres, Sandra Murrieta, Elizabeth Diaz-Padilla, Eli Omar Zavaleta, Yadira Bejar-Ramirez, and Evelyn Cortina-de la Rosa (CPC-SARS trial); Sheri Renaud, Roel Rolando-Almario, and Jacqueline Day (NCT04385199 trial); Sandra Tingsgrd, MD, Karen Brorup Heje Pedersen, MD, Michaela Tinggaard, MD, Louise Thorlacius-Ussing, MD, Clara Lundetoft Clausen, MD, Nichlas Hovmand, MD, Simone Bastrup Israelsen, MD, Cecilie Leding, MD, Katrine Iversen, MD, Maria Engel Miller, MD, Hkon Sandholdt, MSc biostatistician (CCAP-2 trial). On behalf of the IRCT20200310046736N1 trial, we thank the Khuzestan Blood Transfusion Organization for specialized assistance in the preparation and maintenance of plasma samples. On behalf of the NCT04332835 trial, we thank all the members of the "PC-COVID-19 Group" at the Clinica del Occidente and Hospital Universitario Mayor Mederi in Bogota, and Clinica CES in Medellin. On behalf of the NCT04403477 trial, we thank Miles Carroll for his support regarding the antibody testing in Bangladesh. The Co-CLARITY team would like to extend their gratitude to the Department of Science and Technology Philippine Council for Health Research and Development and the UP-Philippine General Hospital for all their support in the setting up and conduct of the trial. For helpfully communicating details of their trial, we thank members of the PlasmAr trial, NCT04359810 trial (Max O´Donnell), NCT04468009 trial, and CTRI/2020/05/025299 trial. Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute (https://www.cancer.gov/)., During the conduct of the study, the following is reported: Dr. Berry reports being employee with ownership role at Berry Consultants (receives payments for statistical modeling and design of REMAP-CAP). Dr. Castillo reports grants from DOST PCHRD. Dr. Daly reports grants from Medical Research Future Fund (Australian Govt) and RBWH. Dr. Denkinger reports grants from German Ministry for Education and Research. Dr. Dumagay reports grants from Philippine Council for Health Research and Development. Dr. Dunachie reports grants from UK Department of Health and Social Care, grants from UK National Institute of Health Research. Dr. Gauiran reports grants from Department of Science and Technology—Philippine Council for Health Research and Development. Dr. Gordon reports grants from NIHR, grants from NIHR Research Professorship (RP-2015-06-18), and non-financial support from NIHR Clinical Research Network. Dr. Higgins reports grants from NHMRC and from the Minderoo Foundation. Dr. Hills reports grants from Health Research Council of New Zealand. Dr. Holm reports grants from Swedish Government Funds for Clinical Research (ALF). Dr. Janssen and Dr. Müller-Tidow report grants from the Federal Ministry of Education and Research in Germany (BMBF) to the RECOVER clinical trial. Dr. Krapp reports grants from Department of Foreign Affairs, Trade, and Development of Canada, grants from Fundación Telefónica del Perú. Dr. J. Lim reports grants from the Department of Science and Technology, Philippine Council for Health Research and Development. Dr. Lucero reports grants from Philippine Council for Health Research and Development. Dr Manrique reports economic support from Grupo ISA Intercolombia for the project development of trial NCT04332835. Drs. McQuilten and Wood report grants from Medical Research Future Fund. Dr. McVerry reports grants from The Pittsburgh Foundation, Translational Breast Cancer Research Consortium, and from UPMC Learning While Doing Program. Mr. Mouncey reports grants from National Institute for Health Research and from the European Union FP7: PREPARE. Dr. Najdovski reports payment from KUL Leuven to Belgian Red Cross for supply of convalescent plasma. Dr. Nichol reports grants from Health Research Board of Ireland. Dr. D. Roberts reports grants from the National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call—Grant Reference Number COV19-RECPLAS) and the European Commission (SUPPORT-E #101015756). Dr. Rowan reports grants from the European Commission and from the UK National Institute for Health Research. Dr. Shankar-Hari reports grants from National Institute for Health Research UK, grants from UKRI-National Institute for Health Research UK. Dr. Turgeon reports grants from Canadian Institutes of Health Research. Dr. Venkatesh reports grants from Baxter. Dr. Webb reports grants from National Health and Medical Research Council, grants from Minderoo Foundation. Dr. Zacharowski reports grants from EU Horizon 2020. The ASCOT trial team (Drs Bowen, Daly, Davis, Denholm, Hammond, Jha, L. Lim, McQuilten, Molton, Morpeth, O’Sullivan, Paterson, Perry, Price, Rees, Roberts, Rogers, Sasadeusz, Snelling, Tong, Venkatesh, Wood) is funded by grants from from Royal Brisbane and Women’s Hospital Foundation, Pratt Foundation, Minderoo Foundation, BHP Foundation, Hospital Research Foundation, Macquarie Group Foundation, Health Research Council of New Zealand, Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE), and the collection and supply of convalescent plasma was conducted within Lifeblood’s funding arrangements. The CONFIDENT trial is funded by the Belgian KCE (blood establishments received payment for the convalescent plasma supplied in the clinical trial). REMAP-CAP was supported in part by funding from UKRIDHSC COVID-19 Rapid Response Rolling Call (Grant Reference Number COV19-RECPLAS). Collection of convalescent plasma for REMAP-CAP was funded by the Department of Health and Social Care, UK. The IRCT20200310046736N1 trial was supported by the Ahvaz Jundishapur University of Medical Sciences (Grant No. R.AJUMS.REC.1399.003, Dr. Pouladzadeh). The PC-COVID-19 Group is supported by the Universidad del Rosario, IDCBIS, ISA Group and Suramericana (Colombia). Outside the submitted work, the following is reported: Dr. Axfors reports postdoctoral grants from the Knut and Alice Wallenberg Foundation, Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. Dr. Aomar reports personal fees from SOBI, GEDEON RICHTER, and GSK. Dr. Benfield reports grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Hansen Foundation, Erik and Susanna Olesen’s Charitable Fund; grants and personal fees from GSK, Pfizer, Gilead; and personal fees from Boehringer Ingelheim, MSD, and Pentabase ApS. Dr. Estcourt reports being an investigator on the RECOVERY trial. Dr. Gordon reports personal fees from GlaxoSmithKline, Bristol Myers Squibb, and 30 Respiratory. Dr. Jha reports grants and personal fees from Baxter Healthcare, personal fees from Astra Zeneca, grants from NephroPlus. Dr. Laterre reports personal fees from Adrenomed. Dr. McVerry reports grants from NIH/NHLBI and Bayer Pharmaceuticals, Inc. Dr. Mondragon reports financial activities outside the submitted work (employment at Johnson & Johnson). Dr. Perry reports partner being employed at CSL and owning shares in CSL. Dr. Paterson reports involvement with ALLIANCE trial of COVID-19 treatments. Dr. J. Roberts reports other COVID-19 related trials (in different patient groups): tocilizumab in ICU patients; hydroxychloroquine dosing in ICU patients; planned study of remdesivir pharmacokinetics in patients during expanded access program; and in silico evaluation of ivermectin dosing. Dr Sasadeusz reports grants from various Pharma companies including Gilead Sciences, Abvvie, Merck, and Takeda. Dr. Zacharowski reports personal fees from Biotest AG, CSL Behring, GE Heathcare, and is President of the ESAIC., Background: Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX). Methods: In this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence. Results: A total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis. Conclusions: Convalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care., Amalia Bravo-Lindoro, BHP Foundation, Blanceflor Foundation, Department of Foreign Affairs, Trade, and Development of Canada, Eli Omar Zavaleta, Erik and Susanna Olesen’s Charitable Fund, Federal Ministry of Education and Research in Germany, Fundación Telefónica del Perú, IDCBIS, ISA Group and Suramericana, Kai Hansen Foundation, Katja Suter and Sina Ullrich, Khuzestan Blood Transfusion Organization, Macquarie Group Foundation, Medical Research Future Fund, NephroPlus, RBWH, Roel Rolando-Almario NCT04385199, Royal Brisbane, Sheri Renaud, Simonsen Foundation, UKRI-National Institute for Health Research UK, UKRIDHSC COV19-RECPLAS, UP-Philippine General Hospital CTRI/2020/05/025299, NCT04359810, NCT04468009, Women’s Hospital Foundation, National Institutes of Health, National Heart, Lung, and Blood Institute, Pittsburgh Foundation, Pfizer, Baxter International, Stanford University, Gilead Sciences, National Institute on Handicapped Research RP-2015-06-18, Meso Scale Diagnostics, Universität Basel, Laura and John Arnold Foundation, Health Research Board, Pratt Foundation, Canadian Institutes of Health Research, National Institute for Health Research, Department of Health and Social Care, European Commission 101015756, National Health and Medical Research Council, Department of Science and Technology, Ministry of Science and Technology, India, Health Research Council of New Zealand, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Sweden-America Foundation, Bundesministerium für Bildung und Forschung, Lundbeckfonden, Knut och Alice Wallenbergs Stiftelse, Seventh Framework Programme, Ahvaz Jundishapur University of Medical Sciences, Université Pierre et Marie Curie, Uppsala Universitet, Horizon 2020, Svenska Läkaresällskapet, Universidad del Rosario, Pharmaceuticals Bayer, Novo Nordisk Fonden, Department of Science and Technology, Philippines, Philippine Council for Health Research and Development, Minderoo Foundation

Background Asthma is the most common chronic disease in children, many of whom are managed solely with a short-acting β2-agonist (SABA). In adults, the evidence that budesonide-formoterol as sole reliever therapy markedly reduces the risk of severe exacerbations compared with SABA alone has contributed to the Global Initiative for Asthma recommending against SABA monotherapy in this population. The current lack of evidence in children means it is unknown whether these findings are also relevant to this demographic. High-quality randomised controlled trials (RCTs) are needed. Objective The aim of this study is to determine the efficacy and safety of as-needed budesonide-formoterol therapy compared with as-needed salbutamol in children aged 5 to 15 years with mild asthma, who only use a SABA. Methods A 52-week, open-label, parallel group, phase III RCT will recruit 380 children aged 5 to 15 years with mild asthma. Participants will be randomised 1:1 to either budesonide-formoterol (Symbicort Rapihaler®) 50/3 µg, two actuations as needed, or salbutamol (Ventolin®) 100 µg, two actuations as needed. The primary outcome is asthma attacks as rate per participant per year. Secondary outcomes assess asthma control, lung function, exhaled nitric oxide and treatment step change. A cost-effectiveness analysis is also planned. Conclusion This is the first RCT to assess the safety and efficacy of as-needed budesonide-formoterol in children with mild asthma. The results will provide a much-needed evidence base for the treatment of mild asthma in children., This protocol describes the first randomised controlled trial to investigate the efficacy and safety of budesonide/formoterol as sole reliever therapy for children with mild asthma, providing urgently needed evidence in this population https://bit.ly/35v0R3Z

Background The rate of community antibiotic use in New Zealand (NZ) is high and some may be unnecessary. Non-pharmaceutical public health interventions (Alert Levels) were implemented in 2020 to reduce the spread of COVID-19 in NZ and were likely to have affected antibiotic prescribing. Methods We aimed to identify the impact of these public health interventions on community antibiotic dispensing. We also examined rates of hospitalisation with infectious diseases that could be influenced by changing community antibiotic use. A retrospective review of two national databases was undertaken. Findings 1.17 million people received 1.19 million prescriptions for antibiotics between 23/02/2020 and 18/07/2020. Antibiotic dispensing rates fell from 14 prescriptions per 1000 population per week during pre-Alert Level weeks to 9 prescriptions per 1000 population per week (a reduction of 36%) during the weeks of COVID Alert Level 3–4. Large reductions were seen with antibiotics predominantly used for respiratory- or urinary-tract infections. Hospital discharges with sentinel infections did not increase over this period; pneumonia discharges during Alert Level weeks were lower than in 2017-2019 (3 vs 6 discharges per 100,000 population). Interpretation A large reduction in community antibiotic dispensing was observed in NZ during the implementation of non-pharmaceutical public health interventions to eliminate COVID-19. Despite this marked reduction in antibiotic use, there was no increase in rates of hospitalisation for sentinel infections that community antibiotic use could prevent. These findings suggest that countries with high rates of antibiotic use could significantly reduce their use without an increase in morbidity. Funding No financial support received.

BACKGROUNDThe evidence for benefit of convalescent plasma for critically ill patients with Covid-19 is inconsistent. We hypothesized that convalescent plasma would improve outcomes for critically ill adult patients with Covid-19.METHODSIn an ongoing adaptive platform trial, critically ill patients with confirmed Covid-19, defined as receiving intensive care-level organ support, were randomized to open-label convalescent plasma or not (i.e., control group). The primary end point was organ support-free days (i.e., days alive and free of ICU-based organ support) up to day 21. The primary analysis was a Bayesian cumulative logistic model with predefined criteria for superiority or futility. An odds ratio greater than 1 represented improved survival, more organ support–free days, or both.RESULTSThe convalescent plasma intervention was stopped after pre-specified criteria for futility were met. At that time, 1084 participants had been randomized to convalescent plasma and 916 to no convalescent plasma (control). The median organ support-free days were 0 (interquartile range, -1 to 16) for the convalescent plasma group and 3 (interquartile range, -1 to 16) days for the control group. The median adjusted odds ratio (OR) was 0.97 (95% credible interval 0.83 to 1.15) and posterior probability of futility (OR < 1.2) was 99.4% for convalescent plasma compared to control. In-hospital mortality was 37.3% (401/1075) in convalescent plasma group, and 38.4% (347/904) in controls. The observed treatment effects were consistent across primary and secondary outcomes.CONCLUSIONSIn critically ill adults with confirmed Covid-19, treatment with convalescent plasma, did not improve clinical outcomes.Clinicaltrials.gov:NCT02735707

Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

The rapid spread of coronavirus disease 2019 (COVID-19) brought into sharp focus the conundrum of how to balance evidence-based prescribing vs empiric treatment with repurposed drugs for a pandemic with a high mortality risk. Initial attention focused on hydroxychloroquine/chloroquine due to evidence of in vitro activity against the novel coronavirus SARS-CoV-2,1 yet the external validity of these data was limited by knowledge that in vitro antiviral activity did not equate to efficacy in randomised controlled trails (RCTs) of hydroxychloroquine/chloroquine treatment for influenza, dengue, chikungunya, and human immunodeficiency virus infection.1.

Unverified penicillin allergies are common but most patients with a penicillin allergy label can safely use penicillin antibiotics. Penicillin allergy labels are associated with poor clinical outcomes and overuse of second-line antibiotics. There is increasing focus on penicillin allergy “de-labeling” as a tool to improve antibiotic prescribing and antimicrobial stewardship. The effect of outpatient penicillin allergy de-labeling on long-term antibiotic use is uncertain. We performed a retrospective pre- and post- study of antibiotic dispensing patterns, from an electronic dispensing data repository, in patients undergoing penicillin allergy assessment at Auckland City Hospital, New Zealand. Over a mean follow-up of 4.55 years, 215/304 (70.7%) of de-labeled patients were dispensed a penicillin antibiotic. Rates of penicillin antibiotic dispensing were 0.24 (0.18–0.30) penicillin courses per year before de-labeling and 0.80 (0.67–0.93) following de-labeling with a reduction in total antibiotic use from 2.30 (2.06–2.54) to 1.79 (1.59–1.99) antibiotic courses per year. In de-labeled patients, the proportion of antibiotic courses that were penicillin antibiotics increased from 12.81 to 39.62%. Rates of macrolide, cephalosporin, trimethoprim/co-trimoxazole, fluoroquinolone, “other” non-penicillin antibiotic use, and broad-spectrum antibiotic use were all lower following de-labeling. Further, antibiotic costs were lower following de-labeling. In this study, penicillin allergy de-labeling was associated with significant changes in antibiotic dispensing patterns.

BackgroundSubstantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: Rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/). We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status.ResultsSixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I2=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects.ConclusionsWe found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Cement manufacture is responsible for around 7% of global anthropogenic CO2 emissions. The process is unique in that around two-thirds of the direct CO2 emissions are unavoidable as they come from the process chemistry rather than from fuel combustion. This makes reducing them particularly difficult, and carbon capture and storage is currently the only option that can reduce emissions by the extent required to allow cement manufacture to continue beyond the transition to low CO2-emission economies. Post-combustion capture options, which are similar to those described in Chapter 4, are available. Equally, oxy-fuel combustion is possible. Pre-combustion capture can only deal with one-third of emissions from combustion, and so is generally not considered. Other cement-specific options exist, such as direct separation, and the synergies between calcium looping and cement manufacture are noteworthy. High CO2 intensity coupled with the relatively low price of cement means that CCS is expensive per unit of cement manufactured. The lack of large-scale capture facilities means that the costs are rather uncertain, although several estimates are given in this chapter. A summary of existing pilot plants is provided, the challenges of rolling out carbon capture in the cement sector are discussed, and a way forward is suggested.

Background Clinical research methodology is evolving with the advent of pragmatic randomised controlled trials (PRCTs). Novel approaches for informed consent in PRCTs are needed. Objective To explore public opinion about different ways of giving informed consent for PRCTs. Design Web-based survey assessing acceptability of three PRCT consent scenarios for statin use. Setting Community-based study. Participants 678 (12%) adults responded to an open-access web-based survey. Measurements Participant-rated acceptability of three different options for giving informed consent for a PRCT testing two commonly prescribed, effective treatments: statins for hyperlipidaemia. Option A was written informed consent given a priori for a specific study, with verbal confirmation of consent at time of randomisation. Option B was written informed, general consent a priori for multiple comparative effectiveness studies, with verbal confirmation for a specific study at time of randomisation. Option C was written informed consent for a specific study at time of randomisation. Results Acceptability was higher for option A (475/529 (89.9%)) and B (441/487 (90.6%)) compared with C (339/481 (70.5%)). The estimates of differences in paired proportions were A versus C, 19.4% (95% CI 14.4 to 24.5), p Limitations The study design may have been subject to cognitive biases such as framing and anchoring effects. The anonymised web-based survey allowed no follow-up or verification for missing data. The sampling frame used an institutional database and social media and selection bias and halo effects may have been present. The 12.3% response rate may represent poor generalisability. Conclusion The concept of giving a priori consent, with subsequent confirmation at time of randomisation in a PRCT, was more favourable than the traditional model of consent in a general-practice-based study of statin use.

Nerve injuries usually present as pain, numbness, or weakness, and can have devastating consequences for patients. Procedures that are common in primary care can cause nerve injury. Iatrogenic nerve injuries are largely preventable by understanding nerve anatomical course and surface anatomy, and the risky interventions and regions. Most knowledge of nerve anatomical course is derived from early work on cadaver dissection, but modern imaging techniques more accurately map nerve anatomical course in living bodies. We provide an overview of nerve injuries in primary care, discuss updated nerve anatomical course and surface anatomy based on modern radiological evidence, and make recommendations to guide safer interventions in primary care. In New Zealand’s primary care treatment injury claims dataset there were 69 nerve injuries over 4 years (2% of primary care injuries).1 Venepuncture was the leading cause of nerve injury (27; 39%), followed by intramuscular injection (17; 25%), and steroid injection (15; 22%). Venepuncture injured the cutaneous nerve of the forearm (14), and the median (9) and radial (4) nerves; intramuscular injections injured the sciatic (11), lateral cutaneous (3), and axillary (3) nerves; steroid injections injured the median (12, carpal tunnel) and ulnar (3, medial epicondyle) nerves; intravenous cannulation in the forearm injured the superficial radial nerve (4); and minor surgical procedures injured the spinal accessory (3), common fibular (1), sural (1), and ilioinguinal nerves (1). Most nerve injuries were minor, but 17 (25%) were assessed as having major or serious potential consequences. …

Industrial processes account for one-third of global energy demand. The iron and steel, cement and refining sectors are particularly energy-intensive, together making up over 30% of total industrial energy consumption and producing millions of tonnes of CO2 per year. The aim of this paper is to provide a comprehensive overview of the technologies for reducing emissions from industrial processes by collating information from a wide range of sources. The paper begins with a summary of energy consumption and emissions in the industrial sector. This is followed by a detailed description of process improvements in the three sectors mentioned above, as well as cross-cutting technologies that are relevant to many industries. Lastly, a discussion of the effectiveness of government policies to facilitate the adoption of those technologies is presented. Whilst there has been significant improvement in energy efficiency in recent years, cost-effective energy efficient options still remain. Key energy efficiency measures include upgrading process units to Best Practice, installing new electrical equipment such as pumps and even replacing the process completely. However, these are insufficient to achieve the deep carbon reductions required if we are to avoid dangerous climate change. The paper concludes with recommendations for action to achieve further decarbonisation. © 2013 Elsevier Ltd.

The literature concerning the application of CCS to industry is reviewed. Costs are presented for different sectors including ‘‘high purity’’ (processes which inherently produce a high concentration of CO2), cement, iron and steel, refinery and biomass. The application of CCS to industry is a field which has had much less attention than its application to the electricity production sector. Costs range from less than $2011 10/tCO2 up to above $2011 100/tCO2. In the words of a synthesis report from the United Nations Industrial Development Organisation (UNIDO) ‘‘This area has so far not been the focus of discussions and therefore much attention needs to be paid to the application of CCS to industrial sources if the full potential of CCS is to be unlocked’’.

The LEILAC project will apply a revolutionary carbon capture technology to the cement and lime industries. It aims to enable the capture of unavoidable process CO 2 from limestone calcination for no energy cost and no extra capital cost (apart from compression). It is being developed by a consortium in a €21 M five-year Horizon 2020 project. A 240 t/d pilot will be built at HeidelbergCement's plant in Lixhe, Belgium, demonstrating that 95% of a plant's process CO 2 emissions could be captured (around 60% of a plant's total direct CO 2 emissions), and on-going R&D activities are reducing the uncertainties and risks involved.

Calcium-looping systems can be integrated in concentrated solar power (CSP) plants as an alternative for thermal energy storage. This storage concept is based in the high temperature reversible calcination-carbonation reactions, in which limestone and lime are alternatively converted. Energy from CSP can be stored by limestone calcination (endothermic reaction) at high temperatures producing pure streams of CaO and CO2. This energy can be later released when demand increases by means of carbonation reaction (exothermic) at relatively high temperatures. Calciner reactor is a complex system where heterogeneous chemical reactions take place while absorbing heat from solar concentrating equipment. It is a key element of the process. Depending on the design and the distribution of heat along the calciner, the amount of energy required to store the same amount of chemical energy in the form of lime varies, as well as the temperature of the solids. Optimal design and operating conditions will minimize average temperature in the calciner for a given flow of produced lime. In this work, the modelling of a multi-stage solar calciner is described in the frame of a new solar-based CSP plant.