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Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. Nonetheless, size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated.To assess whether and at which doses systemic corticosteroids are effective and safe in the treatment of people with COVID-19, to explore equity-related aspects in subgroup analyses, and to keep up to date with the evolving evidence base using a living systematic review approach.We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 6 January 2022.We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19. We included any type or dose of systemic corticosteroids and the following comparisons: systemic corticosteroids plus standard care versus standard care, different types, doses and timings (early versus late) of corticosteroids. We excluded corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment.We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of the evidence using the GRADE approach for the following outcomes: all-cause mortality up to 30 and 120 days, discharged alive (clinical improvement), new need for invasive mechanical ventilation or death (clinical worsening), serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections.We included 16 RCTs in 9549 participants, of whom 8271 (87%) originated from high-income countries. A total of 4532 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 3766). These studies included participants mostly older than 50 years and male. We also identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 11 RCTs (8019 participants), one of which did not report any of our pre-specified outcomes and thus our analyses included outcome data from 10 studies. Systemic corticosteroids plus standard care compared to standard care probably reduce all-cause mortality (up to 30 days) slightly (risk ratio (RR) 0.90, 95% confidence interval (CI) 0.84 to 0.97; 7898 participants; estimated absolute effect: 274 deaths per 1000 people not receiving systemic corticosteroids compared to 246 deaths per 1000 people receiving the intervention (95% CI 230 to 265 per 1000 people); moderate-certainty evidence). The evidence is very uncertain about the effect on all-cause mortality (up to 120 days) (RR 0.74, 95% CI 0.23 to 2.34; 485 participants). The chance of clinical improvement (discharged alive at day 28) may slightly increase (RR 1.07, 95% CI 1.03 to 1.11; 6786 participants; low-certainty evidence) while the risk of clinical worsening (new need for invasive mechanical ventilation or death) may slightly decrease (RR 0.92, 95% CI 0.84 to 1.01; 5586 participants; low-certainty evidence). For serious adverse events (two RCTs, 678 participants), adverse events (three RCTs, 447 participants), hospital-acquired infections (four RCTs, 598 participants), and invasive fungal infections (one study, 64 participants), we did not perform any analyses beyond the presentation of descriptive statistics due to very low-certainty evidence (high risk of bias, heterogeneous definitions, and underreporting). Different types, dosages or timing of systemic corticosteroids We identified one RCT (86 participants) comparing methylprednisolone to dexamethasone, thus the evidence is very uncertain about the effect of methylprednisolone on all-cause mortality (up to 30 days) (RR 0.51, 95% CI 0.24 to 1.07; 86 participants). None of the other outcomes of interest were reported in this study. We included four RCTs (1383 participants) comparing high-dose dexamethasone (12 mg or higher) to low-dose dexamethasone (6 mg to 8 mg). High-dose dexamethasone compared to low-dose dexamethasone may reduce all-cause mortality (up to 30 days) (RR 0.87, 95% CI 0.73 to 1.04; 1269 participants; low-certainty evidence), but the evidence is very uncertain about the effect of high-dose dexamethasone on all-cause mortality (up to 120 days) (RR 0.93, 95% CI 0.79 to 1.08; 1383 participants) and it may have little or no impact on clinical improvement (discharged alive at 28 days) (RR 0.98, 95% CI 0.89 to 1.09; 200 participants; low-certainty evidence). Studies did not report data on clinical worsening (new need for invasive mechanical ventilation or death). For serious adverse events, adverse events, hospital-acquired infections, and invasive fungal infections, we did not perform analyses beyond the presentation of descriptive statistics due to very low-certainty evidence. We could not identify studies for comparisons of different timing and systemic corticosteroids versus other active substances. Equity-related subgroup analyses We conducted the following subgroup analyses to explore equity-related factors: sex, age (lt; 70 years; ≥ 70 years), ethnicity (Black, Asian or other versus White versus unknown) and place of residence (high-income versus low- and middle-income countries). Except for age and ethnicity, no evidence for differences could be identified. For all-cause mortality up to 30 days, participants younger than 70 years seemed to benefit from systemic corticosteroids in comparison to those aged 70 years and older. The few participants from a Black, Asian, or other minority ethnic group showed a larger estimated effect than the many White participants. Outpatients with asymptomatic or mild disease There are no studies published in populations with asymptomatic infection or mild disease.Systemic corticosteroids probably slightly reduce all-cause mortality up to 30 days in people hospitalised because of symptomatic COVID-19, while the evidence is very uncertain about the effect on all-cause mortality up to 120 days. For younger people (under 70 years of age) there was a potential advantage, as well as for Black, Asian, or people of a minority ethnic group; further subgroup analyses showed no relevant effects. Evidence related to the most effective type, dose, or timing of systemic corticosteroids remains immature. Currently, there is no evidence on asymptomatic or mild disease (non-hospitalised participants). Due to the low to very low certainty of the current evidence, we cannot assess safety adequately to rule out harmful effects of the treatment, therefore there is an urgent need for good-quality safety data. Findings of equity-related subgroup analyses should be interpreted with caution because of their explorative nature, low precision, and missing data. We identified 42 ongoing and 23 completed studies lacking published results or relevant information on the study design, suggesting there may be possible changes of the effect estimates and certainty of the evidence in the future.

Thromboembolic events are common complications of COVID-19. Clinical study results on safety and efficacy of anticoagulation in COVID-19 are controversial.This report updates our systematic review and random-effects meta-analysis on randomized controlled trials (RCTs) comparing standard prophylactic anticoagulation and intermediate or therapeutic anticoagulation in COVID-19 patients. We searched eligible studies for the update up to 4 February 2022 by weekly monitoring of RCTs in the Cochrane COVID-19 Study Register. Certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation).For this update we included five new trials; a total of 13 RCTs with 7364 patients. Certainty of evidence was very low to low. We are uncertain whether low-dose prophylactic anticoagulation is favoured over placebo or no anticoagulation in the outpatient- or post-discharge-setting. In hospitalized patients with moderate and severe COVID-19, intermediate-dose anticoagulation may have little or no effect on thrombotic events or death (RR 1.03, 95 % CI 0.86-1.24), but may increase severe bleeding non-significantly (RR 1.48, 95 % CI 0.53-4.15). Therapeutic-dose anticoagulation may decrease thrombotic events or deaths in hospitalized patients with moderate COVID-19 (RR 0.64, 95 % CI 0.38-1.07; fixed-effect model RR 0.72, 95 % CI 0.57-0.91), but may have little or no effect in patients with severe disease (RR 0.98, 95 % CI 0.86-1.12). With therapeutic-dose anticoagulation, the risk of major bleeding may increase regardless of COVID-19 severity (RR 1.78, 95 % CI 1.15-2.74).Hospitalized, moderately ill COVID-19 patients may benefit from therapeutic-dose anticoagulation, while critically ill patients may not. Risk of major bleeding must be considered.

BACKGROUND: Inhaled corticosteroids are well established for the long‐term treatment of inflammatory respiratory diseases such as asthma or chronic obstructive pulmonary disease. They have been investigated for the treatment of coronavirus disease 2019 (COVID‐19). The anti‐inflammatory action of inhaled corticosteroids might have the potential to reduce the risk of severe illness resulting from hyperinflammation in COVID‐19. OBJECTIVES: To assess whether inhaled corticosteroids are effective and safe in the treatment of COVID‐19; and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID‐19 Study Register (which includes CENTRAL, PubMed, Embase, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID‐19 Global literature on coronavirus disease to identify completed and ongoing studies to 7 October 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating inhaled corticosteroids for COVID‐19, irrespective of disease severity, age, sex, or ethnicity. We included the following interventions: any type or dose of inhaled corticosteroids. We included the following comparison: inhaled corticosteroids plus standard care versus standard care (with or without placebo). We excluded studies examining nasal or topical steroids. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. For risk of bias assessment, we used the Cochrane RoB 2 tool. We rated the certainty of evidence using the GRADE approach for the outcomes of mortality, admission to hospital or death, symptom resolution, time to symptom resolution, serious adverse events, adverse events, and infections. MAIN RESULTS: Inhaled corticosteroids plus standard care versus standard care (with/without placebo) People with a confirmed diagnosis of moderate‐to‐severe COVID‐19 We found no studies that included people with a confirmed diagnosis of moderate‐to‐severe COVID‐19. People with a confirmed diagnosis of asymptomatic SARS‐CoV‐2 infection or mild COVID‐19 We included three RCTs allocating 3607 participants, of whom 2490 had confirmed mild COVID‐19. We analysed a subset of the total number of participants recruited to the studies (2171, 52% female) as some trials had a platform design where not all participants were allocated to treatment groups simultaneously. The included studies were community‐based, recruiting people who were able to use inhaler devices to deliver steroids and relied on remote assessment and self‐reporting of outcomes. Most people were older than 50 years and had co‐morbidities such as hypertension, lung disease, or diabetes. The studies were conducted in high‐income countries prior to wide‐scale vaccination programmes. A total of 1057 participants were analysed in the inhaled corticosteroid arm (budesonide: 860 participants; ciclesonide: 197 participants), and 1075 participants in the control arm. No studies included people with asymptomatic SARS‐CoV‐2 infection. With respect to the following outcomes, inhaled corticosteroids compared to standard care: – may result in little to no difference in all‐cause mortality (at up to day 30) (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.22 to 1.67; 2132 participants; low‐certainty evidence). In absolute terms, this means that for every nine deaths per 1000 people not receiving inhaled corticosteroids, there were six deaths per 1000 people who did receive the intervention (95% CI 2 to 16 per 1000 people); – probably reduces admission to hospital or death (at up to 30 days) (RR 0.72, 95% CI 0.51 to 0.99; 2025 participants; moderate‐certainty evidence); – probably increases resolution of all initial symptoms at day 14 (RR 1.19, 95% CI 1.09 to 1.30; 1986 participants; moderate‐certainty evidence); – may reduce the duration to symptom resolution (at up to day 30) (by −4.00 days, 95% CI −6.22 to −1.78 less than control group rate of 12 days; 139 participants; low‐certainty evidence); – the evidence is very uncertain about the effect on serious adverse events (during study period) (RR 0.51, 95% CI 0.09 to 2.76; 1586 participants; very low‐certainty evidence); – may result in little to no difference in adverse events (at up to day 30) (RR 0.78, 95% CI 0.47 to 1.31; 400 participants; low‐certainty evidence); – may result in little to no difference in infections (during study period) (RR 0.88, 95% CI 0.30 to 2.58; 400 participants; low‐certainty evidence). As studies did not report outcomes for subgroups (e.g. age, ethnicity, sex), we did not perform subgroup analyses. AUTHORS' CONCLUSIONS: In people with confirmed COVID‐19 and mild symptoms who are able to use inhaler devices, we found moderate‐certainty evidence that inhaled corticosteroids probably reduce the combined endpoint of admission to hospital or death and increase the resolution of all initial symptoms at day 14. Low‐certainty evidence suggests that corticosteroids make little to no difference in all‐cause mortality up to day 30 and may decrease the duration to symptom resolution. We do not know whether inhaled corticosteroids increase or decrease serious adverse events due to heterogeneity in the way they were reported across the studies. There is low‐certainty evidence that inhaled corticosteroids may decrease infections. The evidence we identified came from studies in high‐income settings using budesonide and ciclesonide prior to vaccination roll‐outs. We identified a lack of evidence concerning quality of life assessments, serious adverse events, and people with asymptomatic infection or with moderate‐to‐severe COVID‐19. The 10 ongoing and four completed, unpublished RCTs that we identified in trial registries address similar settings and research questions as in the current body of evidence. We expect to incorporate the findings of these studies in future versions of this review. We monitor newly published results of RCTs on inhaled corticosteroids on a weekly basis and will update the review when the evidence or our certainty in the evidence changes.

Living systematic reviews (LSRs) are an increasingly common approach to keeping reviews up to date, in which new relevant studies are incorporated as they become available, so as to inform healthcare policy and practice in a timely manner. While journal publishers have been exploring the publication of LSRs using different updating and publishing approaches, readers cannot currently assess if the evidence underpinning a published LSR is up to date, as neither the search details, the selection process, nor the list of identified studies is made available between the publication of updates. We describe a new method to transparently report the living evidence surveillance process that occurs between published LSR versions. We use the example of the living Cochrane Review on nirmatrelvir combined with ritonavir (Paxlovid) for preventing and treating COVID-19 to illustrate how this can work in practice. We created a publicly accessible spreadsheet on the Open Science Framework platform, linking to the living Cochrane Review, that details the search and study selection process, enabling readers to track the progress of eligible ongoing or completed studies. Further automation of the evidence surveillance process should be explored.

Introduction The Cochrane COVID‐19 Study Register (CCSR) is a public, continually updated database of COVID‐19 study references. The aim of this study‐based register is to support rapid and living evidence synthesis, including an evidence ecosystem of COVID‐19 research (CEOsys). In November and December 2020 we conducted an evaluation of the CCSR for CEOsys, measured its performance and identified areas for improvement. Methods For the evaluation we generated a purposive sample of 286 studies from 20 reviews to calculate the CCSR's comprehensiveness (sensitivity), accuracy (correctly classified and linked studies) and currency (time to publish and process references). Results Our sample showed that the CCSR had an overall comprehensiveness of 77.2%, with the highest coverage for interventional studies (94.4%). The study register had 100% coverage for trial registry records, 86.5% for journal articles and 52.4% for preprints. 98.3% of references were correctly classified with regard to study type, and 93.4% with regard to study aim. 89% of studies were correctly linked. 81.4% of references were published to the register in under 30 days, with 0.5 day (median) for trial registry records, 2 days for journal articles and 56 days for preprints. Conclusion The CCSR had high comprehensiveness, accurate study classifications and short publishing times for journal articles and trial registry records in the sample. We identified that coverage and publishing time for preprints needed improvement. Finally, the evaluation illustrated the value of a study‐based register for identifying additional study references for analysis in evidence synthesis.

Post-COVID conditions in children and adolescents were mostly investigated as the incidence of individual or clusters of symptoms. We aimed to describe the findings of studies assessing key outcomes related to global wellbeing and recovery in children and adolescents from a public health perspective. We searched the Cochrane COVID-19 Study Register and WHO COVID-19 Global literature on coronavirus disease database on 5 November 2021 and tracked ongoing studies published after this date. We included observational studies on children and adolescents with a follow-up greater than 12 weeks and focused on the outcomes of quality of life, recovery/duration of symptoms, school attendance and resource use/rehabilitation. We assessed their methodological quality, and we prepared a narrative synthesis of the results. We included 21 longitudinal and 4 cross-sectional studies (6 with a control group) with over 68 thousand unvaccinated children and adolescents with mostly asymptomatic or mild disease. Study limitations included convenience sampling, a poor description of their study population and heterogeneous definitions of outcomes. Quality of life was not largely affected in adolescents following COVID-19, but there might be greater impairment in young children and in those with more severe forms of the disease (4 studies). There might also be an impairment in daily activities and increased school absenteeism following COVID-19, but the findings were heterogeneous (5 studies). A total of 22 studies provided highly variable estimates based on heterogeneous definitions of overall persistence of symptoms (recovery), ranging from 0 to 67% at 8–12 weeks and 8 to 51% at 6–12 months. We found limited data on resource use and the need for rehabilitation. One controlled study indicated that the quality of life of infected children and adolescents might not substantially differ from controls. All controlled studies found a higher burden of persistent symptoms in COVID-19 cases compared with test-negative controls or cases of influenza. There is limited evidence on the short and long-term well-being of children following SARS-CoV-2 infection. High-quality longitudinal studies with control groups are needed to describe the outcomes in this population, especially in vaccinated children and those affected by new variants of the virus.

Child and adolescent overweight and obesity have increased globally and are associated with significant short- and long-term health consequences.To assess the effects of surgery for treating obesity in childhood and adolescence.For this update, we searched Cochrane Central Register of Controlled Trials, MEDLINE, Latin American and Caribbean Health Science Information database (LILACS), World Health Organization International Clinical Trials Registry Platform (ICTRP)and ClinicalTrials.gov on 20 August 2021 (date of the last search for all databases). We did not apply language restrictions. We checked references of identified studies and systematic reviews.We selected randomised controlled trials (RCTs) of surgical interventions for treating obesity in children and adolescents (age18 years) with a minimum of six months of follow-up. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or which included participants with a secondary or syndromic cause of obesity, or who were pregnant.We used standard methodological procedures expected by Cochrane. Two review authors independently extracted data and assessed the risk of bias using the Cochrane Risk of Bias 2.0 tool. Where necessary, we contacted authors for additional information.With this update, we did not find any new RCTs. Therefore, this updated review still includes a single RCT (a total of 50 participants, 25 in both the intervention and comparator groups). The intervention focused on laparoscopic adjustable gastric banding surgery, which was compared to a control group receiving a multi-component lifestyle programme. The participating population consisted of Australian adolescents (a higher proportion of girls than boys) aged 14 to 18 years, with a mean age of 16.5 and 16.6 years in the gastric banding and lifestyle groups, respectively. The trial was conducted in a private hospital, receiving funding from the gastric banding manufacturer. For most of the outcomes, we identified a high risk of bias, mainly due to bias due to missing outcome data. Laparoscopic gastric banding surgery may reduce BMI by a mean difference (MD) of -11.40 kg/mLaparoscopic gastric banding led to greater body weight loss compared to a multi-component lifestyle program in one small study with 50 participants. These results have very limited application, primarily due to more recent recommendations derived from observation studies to avoid the use of banding in youth due to long-term reoperation rates. This systematic review update still highlights the lack of RCTs in this field. The authors are concerned that there may be ethical barriers to RTCs in this field, despite the lack of other effective therapies for severe obesity in children and adolescents and the significant morbidity and premature mortality caused by childhood obesity. Nevertheless, future studies, whether pre-registered and planned non-randomised or pragmatic randomised trials, should assess the impact of the surgical procedure and post-operative care to minimise adverse events, including the need for post-operative adjustments and revisional surgery. Long-term follow-up is also critical to comprehensively assess the impact of surgery as participants enter adulthood.

ObjectivesThe main objective was to systematically map evidence regarding the emergence of health inequalities in individuals aged 16–24 years during school-to-work and school-to-university transition (STWT). Second, we aimed to summarise the evidence on potential effects of contextual and compositional characteristics of specific institutional contexts entered during STWT on health and health behaviours.DesignScoping review.Study selectionRelevant literature was systematically searched following the methodological framework proposed by Arksey and O’Malley. Ovid MEDLINE and Web of Science, and websites of the International Labour Organization and National Institute for Occupational Safety and Health were searched, using a predetermined search strategy. Articles in English or German published between 1 January 2000 and 3 February 2020 were considered.Data extractionTo collect the main information from the selected studies, a data extraction spreadsheet was created. Data were summarised and grouped into five health outcomes and five institutional contexts (school, vocational training, university, work, unemployment).ResultsA total of 678 articles were screened for inclusion. To be able to draw a picture of the development of various health outcomes over time, we focused on longitudinal studies. Forty-six prospective studies mapping health-related outcomes during STWT were identified. Higher family socioeconomic position (SEP) was associated with higher levels of health behaviour and lower levels of health-damaging behaviour, but there was also some evidence pointing in the opposite direction. Disadvantaged family SEP negatively impacted on mental health and predicted an adverse weight development. There was limited evidence for the outcomes physical/somatic symptoms and self-rated health. Meso-level characteristics of the institutional contexts identified were not systematically assessed, only individual-level factors resulting from an exposure to these contexts, rendering an analysis of effects of contextual and compositional characteristics on health and health behaviours impossible.ConclusionsThis scoping review demonstrated a wide range of health inequalities during STWT for various health outcomes. However, knowledge on the role of the core institutional contexts regarding the development of health inequalities is limited.

Post-COVID-19 conditions, also known as ‘Long-COVID-19’, describe a longer and more complex course of illness than acute COVID-19 with no widely accepted uniform case definition. We aimed to map the available evidence on persistent symptoms and sequelae following SARS-CoV-2 in children and adults. We searched the Cochrane COVID-19 Study Register and the WHO COVID-19 Global literature on coronavirus disease database on 5 November 2021. We included longitudinal and cross-sectional studies and we extracted their characteristics, including the type of core outcomes for post-COVID-19 conditions. We included 565 studies (657 records). Most studies were uncontrolled cohort studies. The median follow-up time was 13 weeks (IQR 9 to 24). Only 72% of studies were conducted in high-income countries, 93% included unvaccinated adults with mild-to-critical disease, only 10% included children and adolescents, and less than 5% included children under the age of five. While most studies focused on health symptoms, including respiratory symptoms (71%), neurological symptoms (57%), fatigue (54%), pain (50%), mental functioning (43%), cardiovascular functioning (40%), and post-exertion symptoms (28%), cognitive function (26%), fewer studies assessed other symptoms such as overall recovery (24%), the need for rehabilitation (18%), health-related quality of life (16%), changes in work/occupation and study (10%), or survival related to long-COVID-19 (4%). There is a need for controlled cohort studies with long-term follow-up and a focus on overall recovery, health-related quality of life, and the ability to perform daily tasks. Studies need to be extended to later phases of the pandemic and countries with low resources.

This search string covers the retrieval of information related to multiple trauma or polytrauma. The second part of the search string is optional, as it addresses specific traumata, which are sometimes also used in the polytrauma literature. The search string can be amended with the following more specific traumata, which are sometimes also used in the polytrauma literature: blunt trauma*[tiab] OR traumatic brain injur*[tw] OR craniocerebral trauma*[tw] OR cranio-cerebral trauma*[tw] OR cranial trauma* [tiab] OR chest trauma*[tw] OR chest wall trauma*[tw] OR thorax trauma*[tw] OR thoracic trauma*[tw] OR abdominal trauma*[tw] OR thoracoabdominal trauma*[tw] OR thoraco-abdominal trauma*[tw] OR pelvic trauma*[tw] OR pelvis trauma*"[tw] OR spinal trauma*[tw] OR spine trauma*[tw].

BACKGROUND: Acute respiratory distress syndrome (ARDS) represents the most severe course of COVID‐19 (caused by the SARS‐CoV‐2 virus), usually resulting in a prolonged stay in an intensive care unit (ICU) and high mortality rates. Despite the fact that most affected individuals need invasive mechanical ventilation (IMV), evidence on specific ventilation strategies for ARDS caused by COVID‐19 is scarce. Spontaneous breathing during IMV is part of a therapeutic concept comprising light levels of sedation and the avoidance of neuromuscular blocking agents (NMBA). This approach is potentially associated with both advantages (e.g. a preserved diaphragmatic motility and an optimised ventilation‐perfusion ratio of the ventilated lung), as well as risks (e.g. a higher rate of ventilator‐induced lung injury or a worsening of pulmonary oedema due to increases in transpulmonary pressure). As a consequence, spontaneous breathing in people with COVID‐19‐ARDS who are receiving IMV is subject to an ongoing debate amongst intensivists. OBJECTIVES: To assess the benefits and harms of early spontaneous breathing activity in invasively ventilated people with COVID‐19 with ARDS compared to ventilation strategies that avoid spontaneous breathing. SEARCH METHODS: We searched the Cochrane COVID‐19 Study Register (which includes CENTRAL, PubMed, Embase, Clinical Trials.gov WHO ICTRP, and medRxiv) and the WHO COVID‐19 Global literature on coronavirus disease to identify completed and ongoing studies from their inception to 2 March 2022. SELECTION CRITERIA: Eligible study designs comprised randomised controlled trials (RCTs) that evaluated spontaneous breathing in participants with COVID‐19‐related ARDS compared to ventilation strategies that avoided spontaneous breathing (e.g. using NMBA or deep sedation levels). Additionally, we considered controlled before‐after studies, interrupted time series with comparison group, prospective cohort studies and retrospective cohort studies. For these non‐RCT studies, we considered a minimum total number of 50 participants to be compared as necessary for inclusion. Prioritised outcomes were all‐cause mortality, clinical improvement or worsening, quality of life, rate of (serious) adverse events and rate of pneumothorax. Additional outcomes were need for tracheostomy, duration of ICU length of stay and duration of hospitalisation. DATA COLLECTION AND ANALYSIS: We followed the methods outlined in the Cochrane Handbook for Systematic Reviews of Interventions. Two review authors independently screened all studies at the title/abstract and full‐text screening stage. We also planned to conduct data extraction and risk of bias assessment in duplicate. We planned to conduct meta‐analysis for each prioritised outcome, as well as subgroup analyses of mortality regarding severity of oxygenation impairment and duration of ARDS. In addition, we planned to perform sensitivity analyses for studies at high risk of bias, studies using NMBA in addition to deep sedation level to avoid spontaneous breathing and a comparison of preprints versus peer‐reviewed articles. We planned to assess the certainty of evidence using the GRADE approach. MAIN RESULTS: We identified no eligible studies for this review. AUTHORS' CONCLUSIONS: We found no direct evidence on whether early spontaneous breathing in SARS‐CoV‐2‐induced ARDS is beneficial or detrimental to this particular group of patients. RCTs comparing early spontaneous breathing with ventilatory strategies not allowing for spontaneous breathing in SARS‐CoV‐2‐induced ARDS are necessary to determine its value within the treatment of severely ill people with COVID‐19. Additionally, studies should aim to clarify whether treatment effects differ between people with SARS‐CoV‐2‐induced ARDS and people with non‐SARS‐CoV‐2‐induced ARDS.

BACKGROUND: With potential antiviral and anti‐inflammatory properties, Janus kinase (JAK) inhibitors represent a potential treatment for symptomatic severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. They may modulate the exuberant immune response to SARS‐CoV‐2 infection. Furthermore, a direct antiviral effect has been described. An understanding of the current evidence regarding the efficacy and safety of JAK inhibitors as a treatment for coronavirus disease 2019 (COVID‐19) is required. OBJECTIVES: To assess the effects of systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo) on clinical outcomes in individuals (outpatient or in‐hospital) with any severity of COVID‐19, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID‐19 Study Register (comprising MEDLINE, Embase, ClinicalTrials.gov, World Health Organization (WHO) International Clinical Trials Registry Platform, medRxiv, and Cochrane Central Register of Controlled Trials), Web of Science, WHO COVID‐19 Global literature on coronavirus disease, and the US Department of Veterans Affairs Evidence Synthesis Program (VA ESP) Covid‐19 Evidence Reviews to identify studies up to February 2022. We monitor newly published randomised controlled trials (RCTs) weekly using the Cochrane COVID‐19 Study Register, and have incorporated all new trials from this source until the first week of April 2022. SELECTION CRITERIA: We included RCTs that compared systemic JAK inhibitors plus standard of care to standard of care alone (plus/minus placebo) for the treatment of individuals with COVID‐19. We used the WHO definitions of illness severity for COVID‐19. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using Cochrane's Risk of Bias 2 (RoB 2) tool. We used GRADE to rate the certainty of evidence for the following primary outcomes: all‐cause mortality (up to day 28), all‐cause mortality (up to day 60), improvement in clinical status: alive and without need for in‐hospital medical care (up to day 28), worsening of clinical status: new need for invasive mechanical ventilation or death (up to day 28), adverse events (any grade), serious adverse events, secondary infections. MAIN RESULTS: We included six RCTs with 11,145 participants investigating systemic JAK inhibitors plus standard of care compared to standard of care alone (plus/minus placebo). Standard of care followed local protocols and included the application of glucocorticoids (five studies reported their use in a range of 70% to 95% of their participants; one study restricted glucocorticoid use to non‐COVID‐19 specific indications), antibiotic agents, anticoagulants, and antiviral agents, as well as non‐pharmaceutical procedures. At study entry, about 65% of participants required low‐flow oxygen, about 23% required high‐flow oxygen or non‐invasive ventilation, about 8% did not need any respiratory support, and only about 4% were intubated. We also identified 13 ongoing studies, and 9 studies that are completed or terminated and where classification is pending. Individuals with moderate to severe disease Four studies investigated the single agent baricitinib (10,815 participants), one tofacitinib (289 participants), and one ruxolitinib (41 participants). Systemic JAK inhibitors probably decrease all‐cause mortality at up to day 28 (95 of 1000 participants in the intervention group versus 131 of 1000 participants in the control group; risk ratio (RR) 0.72, 95% confidence interval (CI) 0.57 to 0.91; 6 studies, 11,145 participants; moderate‐certainty evidence), and decrease all‐cause mortality at up to day 60 (125 of 1000 participants in the intervention group versus 181 of 1000 participants in the control group; RR 0.69, 95% CI 0.56 to 0.86; 2 studies, 1626 participants; high‐certainty evidence). Systemic JAK inhibitors probably make little or no difference in improvement in clinical status (discharged alive or hospitalised, but no longer requiring ongoing medical care) (801 of 1000 participants in the intervention group versus 778 of 1000 participants in the control group; RR 1.03, 95% CI 1.00 to 1.06; 4 studies, 10,802 participants; moderate‐certainty evidence). They probably decrease the risk of worsening of clinical status (new need for invasive mechanical ventilation or death at day 28) (154 of 1000 participants in the intervention group versus 172 of 1000 participants in the control group; RR 0.90, 95% CI 0.82 to 0.98; 2 studies, 9417 participants; moderate‐certainty evidence). Systemic JAK inhibitors probably make little or no difference in the rate of adverse events (any grade) (427 of 1000 participants in the intervention group versus 441 of 1000 participants in the control group; RR 0.97, 95% CI 0.88 to 1.08; 3 studies, 1885 participants; moderate‐certainty evidence), and probably decrease the occurrence of serious adverse events (160 of 1000 participants in the intervention group versus 202 of 1000 participants in the control group; RR 0.79, 95% CI 0.68 to 0.92; 4 studies, 2901 participants; moderate‐certainty evidence). JAK inhibitors may make little or no difference to the rate of secondary infection (111 of 1000 participants in the intervention group versus 113 of 1000 participants in the control group; RR 0.98, 95% CI 0.89 to 1.09; 4 studies, 10,041 participants; low‐certainty evidence). Subgroup analysis by severity of COVID‐19 disease or type of JAK inhibitor did not identify specific subgroups which benefit more or less from systemic JAK inhibitors. Individuals with asymptomatic or mild disease We did not identify any trial for this population. AUTHORS' CONCLUSIONS: In hospitalised individuals with moderate to severe COVID‐19, moderate‐certainty evidence shows that systemic JAK inhibitors probably decrease all‐cause mortality. Baricitinib was the most often evaluated JAK inhibitor. Moderate‐certainty evidence suggests that they probably make little or no difference in improvement in clinical status. Moderate‐certainty evidence indicates that systemic JAK inhibitors probably decrease the risk of worsening of clinical status and make little or no difference in the rate of adverse events of any grade, whilst they probably decrease the occurrence of serious adverse events. Based on low‐certainty evidence, JAK inhibitors may make little or no difference in the rate of secondary infection. Subgroup analysis by severity of COVID‐19 or type of agent failed to identify specific subgroups which benefit more or less from systemic JAK inhibitors. Currently, there is no evidence on the efficacy and safety of systemic JAK inhibitors for individuals with asymptomatic or mild disease (non‐hospitalised individuals).

Oral nirmatrelvir/ritonavir (Paxlovid®) aims to avoid severe COVID-19 in asymptomatic people or those with mild symptoms, thereby decreasing hospitalization and death. Due to its novelty, there are currently few published study results. It remains to be evaluated for which indications and patient populations the drug is suitable. OBJECTIVES: To assess the efficacy and safety of nirmatrelvir/ritonavir (Paxlovid®) plus standard of care compared to standard of care with or without placebo, or any other intervention for treating COVID-19 and for preventing SARS-CoV-2 infection. To explore equity aspects in subgroup analyses. To keep up to date with the evolving evidence base using a living systematic review (LSR) approach and make new relevant studies available to readers in-between publication of review updates.We searched the Cochrane COVID-19 Study Register, Scopus, and WHO COVID-19 Global literature on coronavirus disease database, identifying completed and ongoing studies without language restrictions and incorporating studies up to 11 July 2022. This is a LSR. We conduct monthly update searches that are being made publicly available on the open science framework (OSF) platform.Studies were eligible if they were randomized controlled trials (RCTs) comparing nirmatrelvir/ritonavir plus standard of care with standard of care with or without placebo, or any other intervention for treatment of people with confirmed COVID-19 diagnosis, irrespective of disease severity or treatment setting, and for prevention of SARS-CoV-2 infection. We screened all studies for research integrity. Studies were ineligible if they had been retracted, or if they were not prospectively registered including appropriate ethics approval.We followed standard Cochrane methodology and used the Cochrane risk of bias 2 tool. We rated the certainty of evidence using the GRADE approach for the following outcomes: 1. to treat outpatients with mild COVID-19; 2. to treat inpatients with moderate-to-severe COVID-19: mortality, clinical worsening or improvement, quality of life, (serious) adverse events, and viral clearance; 3. to prevent SARS-CoV-2 infection in post-exposure prophylaxis (PEP); and 4. pre-exposure prophylaxis (PrEP) scenarios: SARS-CoV-2 infection, development of COVID-19 symptoms, mortality, admission to hospital, quality of life, and (serious) adverse events. We explored inequity by subgroup analysis for elderly people, socially-disadvantaged people with comorbidities, populations from LICs and LMICs, and people from different ethnic and racial backgrounds.As of 11 July 2022, we included one RCT with 2246 participants in outpatient settings with mild symptomatic COVID-19 comparing nirmatrelvir/ritonavir plus standard of care with standard of care plus placebo. Trial participants were unvaccinated, without previous confirmed SARS-CoV-2 infection, had a symptom onset of no more than five days before randomization, and were at high risk for progression to severe disease. Prohibited prior or concomitant therapies included medications highly dependent on CYP3A4 for clearance and CYP3A4 inducers. We identified eight ongoing studies. Nirmatrelvir/ritonavir for treating COVID-19 in outpatient settings with asymptomatic or mild disease For the specific population of unvaccinated, high-risk patients nirmatrelvir/ritonavir plus standard of care compared to standard of care plus placebo may reduce all-cause mortality at 28 days (risk ratio (RR) 0.04, 95% confidence interval (CI) 0.00 to 0.68; 1 study, 2224 participants; estimated absolute effect: 11 deaths per 1000 people receiving placebo compared to 0 deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence, and admission to hospital or death within 28 days (RR 0.13, 95% CI 0.07 to 0.27; 1 study, 2224 participants; estimated absolute effect: 61 admissions or deaths per 1000 people receiving placebo compared to eight admissions or deaths per 1000 people receiving nirmatrelvir/ritonavir; low-certainty evidence). Nirmatrelvir/ritonavir plus standard of care may reduce serious adverse events during the study period compared to standard of care plus placebo (RR 0.24, 95% CI 0.15 to 0.41; 1 study, 2224 participants; low-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably has little or no effect on treatment-emergent adverse events (RR 0.95, 95% CI 0.82 to 1.10; 1 study, 2224 participants; moderate-certainty evidence), and probably increases treatment-related adverse events such as dysgeusia and diarrhoea during the study period compared to standard of care plus placebo (RR 2.06, 95% CI 1.44 to 2.95; 1 study, 2224 participants; moderate-certainty evidence). Nirmatrelvir/ritonavir plus standard of care probably decreases discontinuation of study drug due to adverse events compared to standard of care plus placebo (RR 0.49, 95% CI 0.30 to 0.80; 1 study, 2224 participants; moderate-certainty evidence). No study results were identified for improvement of clinical status, quality of life, and viral clearance. Subgroup analyses for equity Most study participants were younger than 65 years (87.1% of the : modified intention to treat (mITT1) population with 2085 participants), of white ethnicity (71.5%), and were from UMICs or HICs (92.1% of study centres). Data on comorbidities were insufficient. The outcome 'admission to hospital or death' was investigated for equity: age (65 years versus ≥ 65 years) and ethnicity (Asian versus Black versus White versus others). There was no difference between subgroups of age. The effects favoured treatment with nirmatrelvir/ritonavir for the White ethnic group. Estimated effects in the other ethnic groups included the line of no effect (RR = 1). No subgroups were reported for comorbidity status and World Bank country classification by income level. No subgroups were reported for other outcomes. Nirmatrelvir/ritonavir for treating COVID-19 in inpatient settings with moderate to severe disease No studies available. Nirmatrelvir/ritonavir for preventing SARS-CoV-2 infection (PrEP and PEP) No studies available.There is low-certainty evidence that nirmatrelvir/ritonavir reduces the risk of all-cause mortality and hospital admission or death based on one trial investigating unvaccinated COVID-19 participants without previous infection that were at high risk and with symptom onset of no more than five days. There is low- to moderate-certainty evidence that nirmatrelvir/ritonavir is safe in people without prior or concomitant therapies including medications highly dependent on CYP3A4. Regarding equity aspects, except for ethnicity, no differences in effect size and direction were identified. No evidence is available on nirmatrelvir/ritonavir to treat hospitalized people with COVID-19 and to prevent a SARS-CoV-2 infection. We will continually update our search and make search results available on OSF.

The cornerstone of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is reverse-transcription polymerase chain reaction (RT-PCR) of viral RNA. As a surrogate assay SARS-CoV-2 RNA detection does not necessarily imply infectivity. Only virus isolation in permissive cell culture systems can indicate infectivity. Here, we review the evidence on RT-PCR performance in detecting infectious SARS-CoV-2. We searched for any studies that used RT-PCR and cell culture to determine infectious SARS-CoV-2 in respiratory samples. We assessed (i) diagnostic accuracy of RT-PCR compared to cell culture as reference test, (ii) performed meta-analysis of positive predictive values (PPV) and (iii) determined the virus isolation probabilities depending on cycle threshold (Ct) or log

In view of disease-related threats, containment measures, and disrupted healthcare, individuals with pre-existing mental illness might be vulnerable to adverse effects of the COVID-19 pandemic. Previous reviews indicated increased mental distress, with limited information on peri-pandemic changes. In this systematic review, we aimed to identify longitudinal research investigating pre- to peri-pandemic and/or peri-pandemic changes of mental health in patients, focusing on the early phase and considering specific diagnoses. PsycINFO, Web of Science, the WHO Global literature on coronavirus disease database, and the Cochrane COVID-19 Study Register weresearched through 31 May 2021. Studies were synthesized using vote counting based on effect direction. We included 40 studies mostly from Western, high-income countries. Findings were heterogeneous, with improving and deteriorating mental health observed compared to pre-pandemic data, partly depending on underlying diagnoses. For peri-pandemic changes, evidence was limited, with some suggestion of recovery of mental distress. Study quality was heterogeneous; only few studies investigated potential moderators (e.g., chronicity of mental illness). Mental health effects on people with pre-existing conditions are heterogeneous within and across diagnoses for pre- to peri-pandemic and peri-pandemic comparisons. To improve mental health services amid future global crises, forthcoming research should understand medium- and long-term effects, controlling for containment measures.

Climate change and the COVID-19 pandemic challenge us to re-evaluate the way we live and work. In the academic sector, this includes organising and attending conferences and other scientific meetings. The pandemic has led EAHIL 2020 to be moved online, which is “greener” than physical meetings, but has interactional drawbacks. On the other hand, planning of physical conferences can make use of existing guidance to improve the environmental impact in areas such as venue and travel arrangements, catering, waste reduction as well as communication. In the future, conference organisers can draw upon insights into remote and virtual collaboration gained during the pandemic. Hybrid conferences that allow physical and remote attendance might become an option for increased sustainability of scientific meetings.

Appropriate feeding of infants and young children is essential for healthy growth and the prevention of stunting, wasting, and overweight. We aimed to assess the beneficial versus harmful effects of providing fortified complementary foods to children in the complementary feeding period.In this systematic review and meta-analysis, we searched the databases Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, Global Index Medicus, Web of Science, ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform from inception to March 9, 2021. We included randomised controlled trials and controlled clinical trials done in infants and children aged 6-23 months with no identified health problems. Consumption of foods fortified centrally (ie, during industrial processing) with one micronutrient or a combination of vitamins, minerals, or both was compared with the same complementary foods, but without micronutrient fortification. Two review authors independently screened studies for eligibility, extracted data, assessed risk of bias, and rated the certainty of the evidence. The main outcomes were growth (measured by Z scores for weight for age, weight for height or length, and height or length for age, or other growth measures), stunting, wasting, nutrient adequacy or excess, anaemia, haemoglobin concentration, iron status, serum zinc concentration, and serum retinol concentration. We used a random-effects meta-analysis for combining data. This study is registered with PROSPERO, CRD42021245876.We included 16 studies with 6423 participants, 13 of which were done in malaria-endemic areas. Overall, 12 studies were included in the quantitative syntheses. We identified five further ongoing studies. There was no difference between participants who received fortified complementary foods and those who received non-fortified complementary foods in weight-for-age Z scores (mean difference -0·01, 95% CI -0·07 to 0·06; five trials; 1206 participants; moderate-certainty evidence), weight-for-height or length Z scores (-0·05, -0·19 to 0·10; four trials; 1109 participants; moderate-certainty evidence), and height or length-for-age Z scores (-0·01, -0·21 to 0·20; four trials; 811 participants; low-certainty evidence); stunting and wasting were not assessed in any study as outcomes. Moderate-certainty evidence from six trials with 1209 patients showed that providing fortified complementary foods to children aged 6-23 months reduced the risk of anaemia (risk ratio 0·57, 95% CI 0·39 to 0·82). Those who received fortified complementary foods compared with those who did not had higher haemoglobin concentrations (mean difference 3·44 g/L, 95% CI 1·33 to 5·55; 11 trials; 2175 participants; moderate-certainty evidence) and ferritin concentration (0·43 μg/L on log scale, 0·14 to 0·72; six trials; 903 participants; low-certainty evidence). The intervention led to no effects on serum zinc concentration (-0·13 g/dL, -0·82 to 0·56; two trials; 333 participants; low-certainty evidence) and serum retinol concentration (0·03 μmol/L, -0·02 to 0·08; five trials; 475 participants; moderate-certainty evidence).Fortified complementary foods are effective strategies to prevent anaemia in infants and young children aged 6-23 months in malaria-endemic regions. Effects of complementary food fortification should be further investigated in low-income and middle-income countries, but should also be assessed in high-income countries, and in regions where malaria is not endemic.WHO.

This feature is part of a series about medical library services in various countries. It gives an overview of the state of and selected current developments of medical library services to support research, education and clinical practice in Germany. Findings from an online survey and issues of access to health information are discussed in relation to the German health care system.J.M.

Background Despite numerous studies and meta-analyses the prognostic effect of cardiac rehabilitation is still under debate. This update of the Cardiac Rehabilitation Outcome Study (CROS II) provides a contemporary and practice focused approach including only cardiac rehabilitation interventions based on published standards and core components to evaluate cardiac rehabilitation delivery and effectiveness in improving patient prognosis. Design A systematic review and meta-analysis. Methods Randomised controlled trials and retrospective and prospective controlled cohort studies evaluating patients after acute coronary syndrome, coronary artery bypass grafting or mixed populations with coronary artery disease published until September 2018 were included. Results Based on CROS inclusion criteria out of 7096 abstracts six additional studies including 8671 patients were identified (two randomised controlled trials, two retrospective controlled cohort studies, two prospective controlled cohort studies). In total, 31 studies including 228,337 patients were available for this meta-analysis (three randomised controlled trials, nine prospective controlled cohort studies, 19 retrospective controlled cohort studies; 50,653 patients after acute coronary syndrome 14,583, after coronary artery bypass grafting 163,101, mixed coronary artery disease populations; follow-up periods ranging from 9 months to 14 years). Heterogeneity in design, cardiac rehabilitation delivery, biometrical assessment and potential confounders was considerable. Controlled cohort studies showed a significantly reduced total mortality (primary endpoint) after cardiac rehabilitation participation in patients after acute coronary syndrome (prospective controlled cohort studies: hazard ratio (HR) 0.37, 95% confidence interval (CI) 0.20–0.69; retrospective controlled cohort studies HR 0.64, 95% CI 0.53–0.76; prospective controlled cohort studies odds ratio 0.20, 95% CI 0.08–0.48), but the single randomised controlled trial fulfilling the CROS inclusion criteria showed neutral results. Cardiac rehabilitation participation was also associated with reduced total mortality in patients after coronary artery bypass grafting (retrospective controlled cohort studies HR 0.62, 95% CI 0.54–0.70, one single randomised controlled trial without fatal events), and in mixed coronary artery disease populations (retrospective controlled cohort studies HR 0.52, 95% CI 0.36–0.77; two out of 10 controlled cohort studies with neutral results). Conclusion CROS II confirms the effectiveness of cardiac rehabilitation participation after acute coronary syndrome and after coronary artery bypass grafting in actual clinical practice by reducing total mortality under the conditions of current evidence-based coronary artery disease treatment. The data of CROS II, however, underscore the urgent need to define internationally accepted minimal standards for cardiac rehabilitation delivery as well as for scientific evaluation.

BACKGROUND: The effect of antibiotics with potential antiviral and anti‐inflammatory properties are being investigated in clinical trials as treatment for COVID‐19. The use of antibiotics follows the intention‐to‐treat the viral disease and not primarily to treat bacterial co‐infections of individuals with COVID‐19. A thorough understanding of the current evidence regarding effectiveness and safety of antibiotics as anti‐viral treatments for COVID‐19 based on randomised controlled trials (RCTs) is required. OBJECTIVES: To assess the efficacy and safety of antibiotics compared to each other, no treatment, standard of care alone, placebo, or any other active intervention with proven efficacy for treatment of COVID‐19 outpatients and inpatients. SEARCH METHODS: We searched the Cochrane COVID‐19 Study Register (including MEDLINE, Embase, ClinicalTrials.gov, WHO ICTRP, medRxiv, CENTRAL), Web of Science and WHO COVID‐19 Global literature on coronavirus disease to identify completed and ongoing studies to 14 June 2021. SELECTION CRITERIA: RCTs were included that compared antibiotics with each other, no treatment, standard of care alone, placebo, or another proven intervention, for treatment of people with confirmed COVID‐19, irrespective of disease severity, treated in the in‐ or outpatient settings. Co‐interventions had to be the same in both study arms. We excluded studies comparing antibiotics to other pharmacological interventions with unproven efficacy. DATA COLLECTION AND ANALYSIS: We assessed risk of bias of primary outcomes using the Cochrane risk of bias tool (ROB 2) for RCTs. We used GRADE to rate the certainty of evidence for the following primary outcomes: 1. to treat inpatients with moderate to severe COVID‐19: mortality, clinical worsening defined as new need for intubation or death, clinical improvement defined as being discharged alive, quality of life, adverse and serious adverse events, and cardiac arrhythmias; 2. to treat outpatients with asymptomatic or mild COVID‐19: mortality, clinical worsening defined as hospital admission or death, clinical improvement defined as symptom resolution, quality of life, adverse and serious adverse events, and cardiac arrhythmias. MAIN RESULTS: We included 11 studies with 11,281 participants with an average age of 54 years investigating antibiotics compared to placebo, standard of care alone or another antibiotic. No study was found comparing antibiotics to an intervention with proven efficacy. All studies investigated azithromycin, two studies investigated other antibiotics compared to azithromycin. Seven studies investigated inpatients with moderate to severe COVID‐19 and four investigated mild COVID‐19 cases in outpatient settings. Eight studies had an open‐label design, two were blinded with a placebo control, and one did not report on blinding. We identified 19 ongoing and 15 studies awaiting classification pending publication of results or clarification of inconsistencies. Of the 30 study results contributing to primary outcomes by included studies, 17 were assessed as overall low risk and 13 as some concerns of bias. Only studies investigating azithromycin reported data eligible for the prioritised primary outcomes. Azithromycin doses and treatment duration varied among included studies. Azithromycin for the treatment of COVID‐19 compared to placebo or standard of care alone in inpatients We are very certain that azithromycin has little or no effect on all‐cause mortality at day 28 compared to standard of care alone (risk ratio (RR) 0.98; 95% confidence interval (CI) 0.90 to 1.06; 8600 participants; 4 studies; high‐certainty evidence). Azithromycin probably has little or no effect on clinical worsening or death at day 28 (RR 0.95; 95% CI 0.87 to 1.03; 7311 participants; 1 study; moderate‐certainty evidence), on clinical improvement at day 28 (RR 0.96; 95% CI 0.84 to 1.11; 8172 participants; 3 studies; moderate‐certainty evidence), on serious adverse events during the study period (RR 1.11; 95% CI 0.89 to 1.40; 794 participants; 4 studies; moderate‐certainty evidence), and cardiac arrhythmias during the study period (RR 0.92; 95% CI 0.73 to 1.15; 7865 participants; 4 studies; moderate‐certainty evidence) compared to placebo or standard of care alone. Azithromycin may increase any adverse events slightly during the study period (RR 1.20; 95% CI 0.92 to 1.57; 355 participants; 3 studies; low‐certainty evidence) compared to standard of care alone. No study reported quality of life up to 28 days. Azithromycin for the treatment of COVID‐19 compared to placebo or standard of care alone in outpatients Azithromycin may have little or no effect compared to placebo or standard of care alone on all‐cause mortality at day 28 (RR 1.00 ; 95% CI 0.06 to 15.69; 876 participants; 3 studies; low‐certainty evidence), on admission to hospital or death within 28 days (RR 0.94 ; 95% CI 0.57 to 1.56; 876 participants; 3 studies; low‐certainty evidence), and on symptom resolution at day 14 (RR 1.03; 95% CI 0.95 to 1.12; 138 participants; 1 study; low‐certainty evidence). We are uncertain whether azithromycin increases or reduces serious adverse events compared to placebo or standard of care alone (0 participants experienced serious adverse events; 454 participants; 2 studies; very low‐certainty evidence). No study reported on adverse events, cardiac arrhythmias during the study period or quality of life up to 28 days. Azithromycin for the treatment of COVID‐19 compared to any other antibiotics in inpatients and outpatients One study compared azithromycin to lincomycin in inpatients, but did not report any primary outcome. Another study compared azithromycin to clarithromycin in outpatients, but did not report any relevant outcome for this review. AUTHORS' CONCLUSIONS: We are certain that risk of death in hospitalised COVID‐19 patients is not reduced by treatment with azithromycin after 28 days. Further, based on moderate‐certainty evidence, patients in the inpatient setting with moderate and severe disease probably do not benefit from azithromycin used as potential antiviral and anti‐inflammatory treatment for COVID‐19 regarding clinical worsening or improvement. For the outpatient setting, there is currently low‐certainty evidence that azithromycin may have no beneficial effect for COVID‐19 individuals. There is no evidence from RCTs available for other antibiotics as antiviral and anti‐inflammatory treatment of COVID‐19. With accordance to the living approach of this review, we will continually update our search and include eligible trials to fill this evidence gap. However, in relation to the evidence for azithromycin and in the context of antimicrobial resistance, antibiotics should not be used for treatment of COVID‐19 outside well‐designed RCTs.

BACKGROUND: The development of severe coronavirus disease 2019 (COVID-19) and poor clinical outcomes are associated with hyperinflammation and a complex dysregulation of the immune response. Colchicine is an anti-inflammatory medicine and is thought to improve disease outcomes in COVID-19 through a wide range of anti-inflammatory mechanisms. Patients and healthcare systems need more and better treatment options for COVID-19 and a thorough understanding of the current body of evidence. OBJECTIVES: To assess the effectiveness and safety of Colchicine as a treatment option for COVID-19 in comparison to an active comparator, placebo, or standard care alone in any setting, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (comprising CENTRAL, MEDLINE (PubMed), Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv), Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index), and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 21 May 2021. SELECTION CRITERIA: We included randomised controlled trials evaluating colchicine for the treatment of people with COVID-19, irrespective of disease severity, age, sex, or ethnicity. We excluded studies investigating the prophylactic effects of colchicine for people without severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection but at high risk of SARS-CoV-2 exposure. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. We used the Cochrane risk of bias tool (ROB 2) to assess bias in included studies and GRADE to rate the certainty of evidence for the following prioritised outcome categories considering people with moderate or severe COVID-19: all-cause mortality, worsening and improvement of clinical status, quality of life, adverse events, and serious adverse events and for people with asymptomatic infection or mild disease: all-cause mortality, admission to hospital or death, symptom resolution, duration to symptom resolution, quality of life, adverse events, serious adverse events. MAIN RESULTS: We included three RCTs with 11,525 hospitalised participants (8002 male) and one RCT with 4488 (2067 male) non-hospitalised participants. Mean age of people treated in hospital was about 64 years, and was 55 years in the study with non-hospitalised participants. Further, we identified 17 ongoing studies and 11 studies completed or terminated, but without published results. Colchicine plus standard care versus standard care (plus/minus placebo) Treatment of hospitalised people with moderate to severe COVID-19 All-cause mortality: colchicine plus standard care probably results in little to no difference in all-cause mortality up to 28 days compared to standard care alone (risk ratio (RR) 1.00, 95% confidence interval (CI) 0.93 to 1.08; 2 RCTs, 11,445 participants; moderate-certainty evidence). Worsening of clinical status: colchicine plus standard care probably results in little to no difference in worsening of clinical status assessed as new need for invasive mechanical ventilation or death compared to standard care alone (RR 1.02, 95% CI 0.96 to 1.09; 2 RCTs, 10,916 participants; moderate-certainty evidence). Improvement of clinical status: colchicine plus standard care probably results in little to no difference in improvement of clinical status, assessed as number of participants discharged alive up to day 28 without clinical deterioration or death compared to standard care alone (RR 0.99, 95% CI 0.96 to 1.01; 1 RCT, 11,340 participants; moderate-certainty evidence). Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is very uncertain about the effect of colchicine on adverse events compared to placebo (RR 1.00, 95% CI 0.56 to 1.78; 1 RCT, 72 participants; very low-certainty evidence). Serious adverse events: the evidence is very uncertain about the effect of colchicine plus standard care on serious adverse events compared to standard care alone (0 events observed in 1 RCT of 105 participants; very low-certainty evidence). Treatment of non-hospitalised people with asymptomatic SARS-CoV-2 infection or mild COVID-19 All-cause mortality: the evidence is uncertain about the effect of colchicine on all-cause mortality at 28 days (Peto odds ratio (OR) 0.57, 95% CI 0.20 to 1.62; 1 RCT, 4488 participants; low-certainty evidence). Admission to hospital or death within 28 days: colchicine probably slightly reduces the need for hospitalisation or death within 28 days compared to placebo (RR 0.80, 95% CI 0.62 to 1.03; 1 RCT, 4488 participants; moderate-certainty evidence). Symptom resolution: we identified no studies reporting this outcome. Quality of life, including fatigue and neurological status: we identified no studies reporting this outcome. Adverse events: the evidence is uncertain about the effect of colchicine on adverse events compared to placebo . Results are from one RCT reporting treatment-related events only in 4412 participants (low-certainty evidence). Serious adverse events: colchicine probably slightly reduces serious adverse events (RR 0.78, 95% CI 0.61 to 1.00; 1 RCT, 4412 participants; moderate-certainty evidence). Colchicine versus another active treatment (e.g. corticosteroids, anti-viral drugs, monoclonal antibodies) No studies evaluated this comparison. Different formulations, doses, or schedules of colchicine No studies assessed this. AUTHORS' CONCLUSIONS: Based on the current evidence, in people hospitalised with moderate to severe COVID-19 the use of colchicine probably has little to no influence on mortality or clinical progression in comparison to placebo or standard care alone. We do not know whether colchicine increases the risk of (serious) adverse events. We are uncertain about the evidence of the effect of colchicine on all-cause mortality for people with asymptomatic infection or mild disease. However, colchicine probably results in a slight reduction of hospital admissions or deaths within 28 days, and the rate of serious adverse events compared with placebo. None of the studies reported data on quality of life or compared the benefits and harms of colchicine versus other drugs, or different dosages of colchicine. We identified 17 ongoing and 11 completed but not published RCTs, which we expect to incorporate in future versions of this review as their results become available. Editorial note: due to the living approach of this work, we monitor newly published results of RCTs on colchicine on a weekly basis and will update the review when the evidence or our certainty in the evidence changes.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the effects (benefits and harms) of surgical versus non‐surgical interventions for the treatment of ankle fractures in adults.

BACKGROUND: Systemic corticosteroids are used to treat people with COVID-19 because they counter hyper-inflammation. Existing evidence syntheses suggest a slight benefit on mortality. So far, systemic corticosteroids are one of the few treatment options for COVID-19. Nonetheless, size of effect, certainty of the evidence, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated. OBJECTIVES: To assess whether systemic corticosteroids are effective and safe in the treatment of people with COVID-19, and to keep up to date with the evolving evidence base using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which includes PubMed, Embase, CENTRAL, ClinicalTrials.gov, WHO ICTRP, and medRxiv), Web of Science (Science Citation Index, Emerging Citation Index), and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies to 16 April 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that evaluated systemic corticosteroids for people with COVID-19, irrespective of disease severity, participant age, gender or ethnicity. We included any type or dose of systemic corticosteroids. We included the following comparisons: systemic corticosteroids plus standard care versus standard care (plus/minus placebo), dose comparisons, timing comparisons (early versus late), different types of corticosteroids and systemic corticosteroids versus other active substances. We excluded studies that included populations with other coronavirus diseases (severe acute respiratory syndrome or Middle East respiratory syndrome), corticosteroids in combination with other active substances versus standard care, topical or inhaled corticosteroids, and corticosteroids for long-COVID treatment. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess the risk of bias in included studies, we used the Cochrane 'Risk of bias' 2 tool for RCTs. We rated the certainty of evidence using the GRADE approach for the following outcomes: all-cause mortality, ventilator-free days, new need for invasive mechanical ventilation, quality of life, serious adverse events, adverse events, and hospital-acquired infections. MAIN RESULTS: We included 11 RCTs in 8075 participants, of whom 7041 (87%) originated from high-income countries. A total of 3072 participants were randomised to corticosteroid arms and the majority received dexamethasone (n = 2322). We also identified 42 ongoing studies and 16 studies reported as being completed or terminated in a study registry, but without results yet. Hospitalised individuals with a confirmed or suspected diagnosis of symptomatic COVID-19 Systemic corticosteroids plus standard care versus standard care plus/minus placebo We included 10 RCTs (7989 participants), one of which did not report any of our pre-specified outcomes and thus our analysis included outcome data from nine studies. All-cause mortality (at longest follow-up available): systemic corticosteroids plus standard care probably reduce all-cause mortality slightly in people with COVID-19 compared to standard care alone (median 28 days: risk difference of 30 in 1000 participants fewer than the control group rate of 275 in 1000 participants; risk ratio (RR) 0.89, 95% confidence interval (CI) 0.80 to 1.00; 9 RCTs, 7930 participants; moderate-certainty evidence). Ventilator-free days: corticosteroids may increase ventilator-free days (MD 2.6 days more than control group rate of 4 days, 95% CI 0.67 to 4.53; 1 RCT, 299 participants; low-certainty evidence). Ventilator-free days have inherent limitations as a composite endpoint and should be interpreted with caution. New need for invasive ventilation: the evidence is of very low certainty. Because of high risk of bias arising from deaths that occurred before ventilation we are uncertain about the size and direction of the effects. Consequently, we did not perform analysis beyond the presentation of descriptive statistics. Quality of life/neurological outcome: no data were available. Serious adverse events: we included data on two RCTs (678 participants) that evaluated systemic corticosteroids compared to standard care (plus/minus placebo); for adverse events and hospital-acquired infections, we included data on five RCTs (660 participants). Because of high risk of bias, heterogeneous definitions, and underreporting we are uncertain about the size and direction of the effects. Consequently, we did not perform analysis beyond the presentation of descriptive statistics (very low-certainty evidence). Different types, dosages or timing of systemic corticosteroids We identified one study that compared methylprednisolone with dexamethasone. The evidence for mortality and new need for invasive mechanical ventilation is very low certainty due to the small number of participants (n = 86). No data were available for the other outcomes. We did not identify comparisons of different dosages or timing. Outpatients with asymptomatic or mild disease Currently, there are no studies published in populations with asymptomatic infection or mild disease. AUTHORS' CONCLUSIONS: Moderate-certainty evidence shows that systemic corticosteroids probably slightly reduce all-cause mortality in people hospitalised because of symptomatic COVID-19. Low-certainty evidence suggests that there may also be a reduction in ventilator-free days. Since we are unable to adjust for the impact of early death on subsequent endpoints, the findings for ventilation outcomes and harms have limited applicability to inform treatment decisions. Currently, there is no evidence for asymptomatic or mild disease (non-hospitalised participants). There is an urgent need for good-quality evidence for specific subgroups of disease severity, for which we propose level of respiratory support at randomisation. This applies to the comparison or subgroups of different types and doses of corticosteroids, too. Outcomes apart from mortality should be measured and analysed appropriately taking into account confounding through death if applicable. We identified 42 ongoing and 16 completed but not published RCTs in trials registries suggesting possible changes of effect estimates and certainty of the evidence in the future. Most ongoing studies target people who need respiratory support at baseline. With the living approach of this review, we will continue to update our search and include eligible trials and published data.

BACKGROUND: Remdesivir is an antiviral medicine with properties to inhibit viral replication of SARS-CoV-2. Positive results from early studies attracted media attention and led to emergency use authorisation of remdesivir in COVID-19. A thorough understanding of the current evidence regarding the effects of remdesivir as a treatment for SARS-CoV-2 infection based on randomised controlled trials (RCTs) is required. OBJECTIVES: To assess the effects of remdesivir compared to placebo or standard care alone on clinical outcomes in hospitalised patients with SARS-CoV-2 infection, and to maintain the currency of the evidence using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register (which comprises the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and medRxiv) as well as Web of Science (Science Citation Index Expanded and Emerging Sources Citation Index) and WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions. We conducted the searches on 16 April 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included RCTs evaluating remdesivir for the treatment of SARS-CoV-2 infection in hospitalised adults compared to placebo or standard care alone irrespective of disease severity, gender, ethnicity, or setting. We excluded studies that evaluated remdesivir for the treatment of other coronavirus diseases. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess risk of bias in included studies, we used the Cochrane RoB 2 tool for RCTs. We rated the certainty of evidence using the GRADE approach for outcomes that were reported according to our prioritised categories: all-cause mortality at up to day 28, duration to liberation from invasive mechanical ventilation, duration to liberation from supplemental oxygen, new need for mechanical ventilation (high-flow oxygen or non-invasive or invasive mechanical ventilation), new need for invasive mechanical ventilation, new need for non-invasive mechanical ventilation or high-flow oxygen, new need for oxygen by mask or nasal prongs, quality of life, adverse events (any grade), and serious adverse events. MAIN RESULTS: We included five RCTs with 7452 participants diagnosed with SARS-CoV-2 infection and a mean age of 59 years, of whom 3886 participants were randomised to receive remdesivir. Most participants required low-flow oxygen (n=4409) or mechanical ventilation (n=1025) at baseline. We identified two ongoing studies, one was suspended due to a lack of COVID-19 patients to recruit. Risk of bias was considered to be of some concerns or high risk for clinical status and safety outcomes because participants who had died did not contribute information to these outcomes. Without adjustment, this leads to an uncertain amount of missing values and the potential for bias due to missing data. Effects of remdesivir in hospitalised individuals Remdesivir probably makes little or no difference to all-cause mortality at up to day 28 (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.81 to 1.06; risk difference (RD) 8 fewer per 1000, 95% CI 21 fewer to 7 more; 4 studies, 7142 participants; moderate-certainty evidence). Considering the initial severity of condition, only one study showed a beneficial effect of remdesivir in patients who received low-flow oxygen at baseline (RR 0.32, 95% CI 0.15 to 0.66, 435 participants), but conflicting results exists from another study, and we were unable to validly assess this observations due to limited availability of comparable data. Remdesivir may have little or no effect on the duration to liberation from invasive mechanical ventilation (2 studies, 1298 participants, data not pooled, low-certainty evidence). We are uncertain whether remdesivir increases or decreases the chance of clinical improvement in terms of duration to liberation from supplemental oxygen at up to day 28 (3 studies, 1691 participants, data not pooled, very low-certainty evidence). We are very uncertain whether remdesivir decreases or increases the risk of clinical worsening in terms of new need for mechanical ventilation at up to day 28 (high-flow oxygen or non-invasive ventilation or invasive mechanical ventilation) (RR 0.78, 95% CI 0.48 to 1.24; RD 29 fewer per 1000, 95% CI 68 fewer to 32 more; 3 studies, 6696 participants; very low-certainty evidence); new need for non-invasive mechanical ventilation or high-flow oxygen (RR 0.70, 95% CI 0.51 to 0.98; RD 72 fewer per 1000, 95% CI 118 fewer to 5 fewer; 1 study, 573 participants; very low-certainty evidence); and new need for oxygen by mask or nasal prongs (RR 0.81, 95% CI 0.54 to 1.22; RD 84 fewer per 1000, 95% CI 204 fewer to 98 more; 1 study, 138 participants; very low-certainty evidence). The evidence suggests that remdesivir may decrease the risk of clinical worsening in terms of new need for invasive mechanical ventilation (67 fewer participants amongst 1000 participants; RR 0.56, 95% CI 0.41 to 0.77; 2 studies, 1159 participants; low-certainty evidence). None of the included studies reported quality of life. Remdesivir probably decreases the serious adverse events rate at up to 28 days (RR 0.75, 95% CI 0.63 to 0.90; RD 63 fewer per 1000, 95% CI 94 fewer to 25 fewer; 3 studies, 1674 participants; moderate-certainty evidence). We are very uncertain whether remdesivir increases or decreases adverse events rate (any grade) (RR 1.05, 95% CI 0.86 to 1.27; RD 29 more per 1000, 95% CI 82 fewer to 158 more; 3 studies, 1674 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: Based on the currently available evidence, we are moderately certain that remdesivir probably has little or no effect on all-cause mortality at up to day 28 in hospitalised adults with SARS-CoV-2 infection. We are uncertain about the effects of remdesivir on clinical improvement and worsening. There were insufficient data available to validly examine the effect of remdesivir on mortality in subgroups depending on the extent of respiratory support at baseline. Future studies should provide additional data on efficacy and safety of remdesivir for defined core outcomes in COVID-19 research, especially for different population subgroups. This could allow us to draw more reliable conclusions on the potential benefits and harms of remdesivir in future updates of this review. Due to the living approach of this work, we will update the review periodically.

Background\ud Ivermectin, an antiparasitic agent used to treat parasitic infestations, inhibits the replication of viruses in vitro. The molecular hypothesis of ivermectin's antiviral mode of action suggests an inhibitory effect on severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replication in the early stages of infection. Currently, evidence on efficacy and safety of ivermectin for prevention of SARS‐CoV‐2 infection and COVID‐19 treatment is conflicting.\ud \ud Objectives\ud To assess the efficacy and safety of ivermectin compared to no treatment, standard of care, placebo, or any other proven intervention for people with COVID‐19 receiving treatment as inpatients or outpatients, and for prevention of an infection with SARS‐CoV‐2 (postexposure prophylaxis).\ud \ud Search methods\ud We searched the Cochrane COVID‐19 Study Register, Web of Science (Emerging Citation Index and Science Citation Index), medRxiv, and Research Square, identifying completed and ongoing studies without language restrictions to 26 May 2021.\ud \ud Selection criteria\ud We included randomized controlled trials (RCTs) comparing ivermectin to no treatment, standard of care, placebo, or another proven intervention for treatment of people with confirmed COVID‐19 diagnosis, irrespective of disease severity, treated in inpatient or outpatient settings, and for prevention of SARS‐CoV‐2 infection.\ud \ud Co‐interventions had to be the same in both study arms. \ud \ud We excluded studies comparing ivermectin to other pharmacological interventions with unproven efficacy.\ud \ud Data collection and analysis\ud We assessed RCTs for bias, using the Cochrane risk of bias 2 tool. The primary analysis excluded studies with high risk of bias. We used GRADE to rate the certainty of evidence for the following outcomes 1. to treat inpatients with moderate‐to‐severe COVID‐19: mortality, clinical worsening or improvement, adverse events, quality of life, duration of hospitalization, and viral clearance; 2. to treat outpatients with mild COVID‐19: mortality, clinical worsening or improvement, admission to hospital, adverse events, quality of life, and viral clearance; (3) to prevent SARS‐CoV‐2 infection: SARS‐CoV‐2 infection, development of COVID‐19 symptoms, adverse events, mortality, admission to hospital, and quality of life.\ud \ud Main results\ud We found 14 studies with 1678 participants investigating ivermectin compared to no treatment, placebo, or standard of care. No study compared ivermectin to an intervention with proven efficacy. There were nine studies treating participants with moderate COVID‐19 in inpatient settings and four treating mild COVID‐19 cases in outpatient settings. One study investigated ivermectin for prevention of SARS‐CoV‐2 infection. Eight studies had an open‐label design, six were double‐blind and placebo‐controlled. Of the 41 study results contributed by included studies, about one third were at overall high risk of bias. \ud \ud Ivermectin doses and treatment duration varied among included studies. \ud \ud We identified 31 ongoing and 18 studies awaiting classification until publication of results or clarification of inconsistencies.\ud \ud Ivermectin compared to placebo or standard of care for inpatient COVID‐19 treatment\ud \ud We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.14 to 2.51; 2 studies, 185 participants; very low‐certainty evidence) and clinical worsening up to day 28 assessed as need for invasive mechanical ventilation (IMV) (RR 0.55, 95% CI 0.11 to 2.59; 2 studies, 185 participants; very low‐certainty evidence) or need for supplemental oxygen (0 participants required supplemental oxygen; 1 study, 45 participants; very low‐certainty evidence), adverse events within 28 days (RR 1.21, 95% CI 0.50 to 2.97; 1 study, 152 participants; very low‐certainty evidence), and viral clearance at day seven (RR 1.82, 95% CI 0.51 to 6.48; 2 studies, 159 participants; very low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on clinical improvement up to 28 days (RR 1.03, 95% CI 0.78 to 1.35; 1 study; 73 participants; low‐certainty evidence) and duration of hospitalization (mean difference (MD) −0.10 days, 95% CI −2.43 to 2.23; 1 study; 45 participants; low‐certainty evidence). No study reported quality of life up to 28 days.\ud \ud Ivermectin compared to placebo or standard of care for outpatient COVID‐19 treatment\ud \ud We are uncertain whether ivermectin compared to placebo or standard of care reduces or increases mortality up to 28 days (RR 0.33, 95% CI 0.01 to 8.05; 2 studies, 422 participants; very low‐certainty evidence) and clinical worsening up to 14 days assessed as need for IMV (RR 2.97, 95% CI 0.12 to 72.47; 1 study, 398 participants; very low‐certainty evidence) or non‐IMV or high flow oxygen requirement (0 participants required non‐IMV or high flow; 1 study, 398 participants; very low‐certainty evidence). We are uncertain whether ivermectin compared to placebo reduces or increases viral clearance at seven days (RR 3.00, 95% CI 0.13 to 67.06; 1 study, 24 participants; low‐certainty evidence). Ivermectin may have little or no effect compared to placebo or standard of care on the number of participants with symptoms resolved up to 14 days (RR 1.04, 95% CI 0.89 to 1.21; 1 study, 398 participants; low‐certainty evidence) and adverse events within 28 days (RR 0.95, 95% CI 0.86 to 1.05; 2 studies, 422 participants; low‐certainty evidence). None of the studies reporting duration of symptoms were eligible for primary analysis. No study reported hospital admission or quality of life up to 14 days.\ud \ud Ivermectin compared to no treatment for prevention of SARS‐CoV‐2 infection\ud \ud We found one study. Mortality up to 28 days was the only outcome eligible for primary analysis. We are uncertain whether ivermectin reduces or increases mortality compared to no treatment (0 participants died; 1 study, 304 participants; very low‐certainty evidence). The study reported results for development of COVID‐19 symptoms and adverse events up to 14 days that were included in a secondary analysis due to high risk of bias. No study reported SARS‐CoV‐2 infection, hospital admission, and quality of life up to 14 days.\ud \ud Authors' conclusions\ud Based on the current very low‐ to low‐certainty evidence, we are uncertain about the efficacy and safety of ivermectin used to treat or prevent COVID‐19. The completed studies are small and few are considered high quality. Several studies are underway that may produce clearer answers in review updates. Overall, the reliable evidence available does not support the use ivermectin for treatment or prevention of COVID‐19 outside of well‐designed randomized trials.

BACKGROUND: The role of vitamin D supplementation as a treatment for COVID-19 has been a subject of considerable discussion. A thorough understanding of the current evidence regarding the effectiveness and safety of vitamin D supplementation for COVID-19 based on randomised controlled trials is required. OBJECTIVES: To assess whether vitamin D supplementation is effective and safe for the treatment of COVID-19 in comparison to an active comparator, placebo, or standard of care alone, and to maintain the currency of the evidence, using a living systematic review approach. SEARCH METHODS: We searched the Cochrane COVID-19 Study Register, Web of Science and the WHO COVID-19 Global literature on coronavirus disease to identify completed and ongoing studies without language restrictions to 11 March 2021. SELECTION CRITERIA: We followed standard Cochrane methodology. We included randomised controlled trials (RCTs) evaluating vitamin D supplementation for people with COVID-19, irrespective of disease severity, age, gender or ethnicity. We excluded studies investigating preventive effects, or studies including populations with other coronavirus diseases (severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS)). DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. To assess bias in included studies, we used the Cochrane risk of bias tool (ROB 2) for RCTs. We rated the certainty of evidence using the GRADE approach for the following prioritised outcome categories: individuals with moderate or severe COVID-19: all-cause mortality, clinical status, quality of life, adverse events, serious adverse events, and for individuals with asymptomatic or mild disease: all-cause mortality, development of severe clinical COVID-19 symptoms, quality of life, adverse events, serious adverse events. MAIN RESULTS: We identified three RCTs with 356 participants, of whom 183 received vitamin D. In accordance with the World Health Organization (WHO) clinical progression scale, two studies investigated participants with moderate or severe disease, and one study individuals with mild or asymptomatic disease. The control groups consisted of placebo treatment or standard of care alone. Effectiveness of vitamin D supplementation for people with COVID-19 and moderate to severe disease We included two studies with 313 participants. Due to substantial clinical and methodological diversity of both studies, we were not able to pool data. Vitamin D status was unknown in one study, whereas the other study reported data for vitamin D deficient participants. One study administered multiple doses of oral calcifediol at days 1, 3 and 7, whereas the other study gave a single high dose of oral cholecalciferol at baseline. We assessed one study with low risk of bias for effectiveness outcomes, and the other with some concerns about randomisation and selective reporting. All-cause mortality at hospital discharge (313 participants) We found two studies reporting data for this outcome. One study reported no deaths when treated with vitamin D out of 50 participants, compared to two deaths out of 26 participants in the control group (Risk ratio (RR) 0.11, 95% confidence interval (CI) 0.01 to 2.13). The other study reported nine deaths out of 119 individuals in the vitamin D group, whereas six participants out of 118 died in the placebo group (RR 1.49, 95% CI 0.55 to 4.04]. We are very uncertain whether vitamin D has an effect on all-cause mortality at hospital discharge (very low-certainty evidence). Clinical status assessed by the need for invasive mechanical ventilation (237 participants) We found one study reporting data for this outcome. Nine out of 119 participants needed invasive mechanical ventilation when treated with vitamin D, compared to 17 out of 118 participants in the placebo group (RR 0.52, 95% CI 0.24 to 1.13). Vitamin D supplementation may decrease need for invasive mechanical ventilation, but the evidence is uncertain (low-certainty evidence). Quality of life We did not find data for quality of life. Safety of vitamin D supplementation for people with COVID-19 and moderate to severe disease We did not include data from one study, because assessment of serious adverse events was not described and we are concerned that data might have been inconsistently measured. This study reported vomiting in one out of 119 participants immediately after vitamin D intake (RR 2.98, 95% CI 0.12 to 72.30). We are very uncertain whether vitamin D supplementation is associated with higher risk for adverse events (very low-certainty). Effectiveness and safety of vitamin D supplementation for people with COVID-19 and asymptomatic or mild disease We found one study including 40 individuals, which did not report our prioritised outcomes, but instead data for viral clearance, inflammatory markers, and vitamin D serum levels. The authors reported no events of hypercalcaemia, but recording and assessment of further adverse events remains unclear. Authors administered oral cholecalciferol in daily doses for at least 14 days, and continued with weekly doses if vitamin D blood levels were > 50 ng/mL. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation as a treatment of COVID-19. The evidence for the effectiveness of vitamin D supplementation for the treatment of COVID-19 is very uncertain. Moreover, we found only limited safety information, and were concerned about consistency in measurement and recording of these outcomes. There was substantial clinical and methodological heterogeneity of included studies, mainly because of different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. There is an urgent need for well-designed and adequately powered randomised controlled trials (RCTs) with an appropriate randomisation procedure, comparability of study arms and preferably double-blinding. We identified 21 ongoing and three completed studies without published results, which indicates that these needs will be addressed and that our findings are subject to change in the future. Due to the living approach of this work, we will update the review periodically.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the efficacy and safety of ivermectin compared to standard of care, placebo, or any other proven intervention (1) for prevention of an infection with SARS‐CoV‐2 (post‐exposure prophylaxis), and (2) for people with COVID‐19 receiving treatment as outpatients or inpatients.

Background: Scientific guidelines have been developed to update and harmonize exercise based cardiac rehabilitation (ebCR) in German speaking countries. Key recommendations for ebCR indications have recently been published in part 1 of this journal. The present part 2 updates the evidence with respect to contents and delivery of ebCR in clinical practice, focusing on exercise training (ET), psychological interventions (PI), patient education (PE). In addition, special patients’ groups and new developments, such as telemedical (Tele) or home-based ebCR, are discussed as well. Methods: Generation of evidence and search of literature have been described in part 1. Results: Well documented evidence confirms the prognostic significance of ET in patients with coronary artery disease. Positive clinical effects of ET are described in patients with congestive heart failure, heart valve surgery or intervention, adults with congenital heart disease, and peripheral arterial disease. Specific recommendations for risk stratification and adequate exercise prescription for continuous-, interval-, and strength training are given in detail. PI when added to ebCR did not show significant positive effects in general. There was a positive trend towards reduction in depressive symptoms for “distress management” and “lifestyle changes”. PE is able to increase patients’ knowledge and motivation, as well as behavior changes, regarding physical activity, dietary habits, and smoking cessation. The evidence for distinct ebCR programs in special patients’ groups is less clear. Studies on Tele-CR predominantly included low-risk patients. Hence, it is questionable, whether clinical results derived from studies in conventional ebCR may be transferred to Tele-CR. Conclusions: ET is the cornerstone of ebCR. Additional PI should be included, adjusted to the needs of the individual patient. PE is able to promote patients self-management, empowerment, and motivation. Diversity-sensitive structures should be established to interact with the needs of special patient groups and gender issues. Tele-CR should be further investigated as a valuable tool to implement ebCR more widely and effectively.

The antiparasitic ivermectin has received particular attention as a potential treatment option for COVID-19. Understandably, there is high interest in repurposing an approved inexpensive drug, readily available as an oral formulation. However, Garegnani et al 1 recently pointed out the proportion of misleading information on ivermectin for COVID-19 published in journals, on preprint servers and websites. A relevant number of systematic reviews report the use of methodological tools such as assessing bias at study level with the Cochrane Risk of Bias tool or grading the certainty of the evidence following the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, thus suggesting a putative high credibility. Indeed, some published findings seem impressive. A …