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. Nonetheless, ...size of effect, optimal therapy regimen, and selection of patients who are likely to benefit most are factors that remain to be evaluated.
Objectives
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.
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 6 January 2022.
Selection criteria
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.
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 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.
Main results
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 (< 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.
Authors' conclusions
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.
Eukaryotic ribosome biogenesis involves RNA folding and processing that depend on assembly factors and small nucleolar RNAs (snoRNAs). The 90S (SSU-processome) is the earliest pre-ribosome ...structurally analyzed, which was suggested to assemble stepwise along the growing pre-rRNA from 5′ > 3′, but this directionality may not be accurate. Here, by analyzing the structure of a series of 90S assembly intermediates from Chaetomium thermophilum, we discover a reverse order of 18S rRNA subdomain incorporation. Large parts of the 18S rRNA 3′ and central domains assemble first into the 90S before the 5′ domain is integrated. This final incorporation depends on a contact between a heterotrimer Enp2-Bfr2-Lcp5 recruited to the flexible 5′ domain and Kre33, which reconstitutes the Kre33-Enp-Brf2-Lcp5 module on the compacted 90S. Keeping the 5′ domain temporarily segregated from the 90S scaffold could provide extra time to complete the multifaceted 5′ domain folding, which depends on a distinct set of snoRNAs and processing factors.
Display omitted
•Series of cryo-EM structures of the 90S pre-ribosome depicting its assembly order•5′ domain of the 18S rRNA is integrated into the 90S pre-ribosome at later stages•Kre33-Enp2-Brf2-Lcp5 module mediates the final compaction of 90S pre-ribosome•Temporal rRNA segregation from the 90S scaffold provides time for 5′ domain folding
Cheng et al. report a series of 90S pre-ribosome structures that reveal a reverse order of 18S rRNA subdomain incorporation. Accordingly, the 5′ domain is stably assembled only after the 3′ and central domains have been integrated into the 90S. This final compaction depends on the conserved Kre33-Enp2-Bfr2-Lcp5 module.
Optimization of Free Online/Electronic Resources for Dictionary Compilation — A Trilingual Dictionary Experiment. The availability of multilingual dictionaries is crucial, not only for direct target ...users, but also for indirect target users, especially in the case of languages with scarce resources such as Venda. This article explores the optimal use of free electronic/online resources for compiling a trilingual e-dictionary for Venda, English and Afrikaans. Our approach is based on an experiment in which the compilation process was automated as far as possible to achieve savings in terms of time and manpower. English is used as a bridge for the translation between the source language, Venda, and the target language, Afrikaans. The general finding is that certain limitations can be expected in such a semi-automated process that requires a certain amount of human intervention. Although the composite e-dictionary cannot be considered a final product, the dictionary compilation program Lexonomy, which has been used successfully in this study due to its adaptability and easy layout, provides the opportunity for human input to make the necessary adaptations in a user-friendly manner. The proposed concept is useful for creating multilingual online dictionaries, compiled using available online or electronic resources. The resulting trilingual dictionary is available online as proof of concept on which further work can build. The fact that the database underlying the dictionary is available in a machine-readable format, namely XML, is important for indirect target users for reuse to develop electronic resources, especially for resource-scarce languages.
The availability of multilingual dictionaries is crucial, not only for direct target users, but also for indirect target users, especially in the case of languages with scarce resources such as ...Venda. This article explores the optimal use of free electronic / online resources for compiling a trilingual e-dictionary for Venda, English and Afrikaans. Our approach is based on an experiment in which the compilation process was automated as far as possible to achieve savings in terms of time and manpower. English is used as a bridge for the translation between the source language, Venda, and the target language, Afrikaans. The general finding is that certain limitations can be expected in such a semi-automated process that requires a certain amount of human intervention. Although the composite e-dictionary cannot be considered a final product, the dictionary compilation program Lexonomy, which has been used successfully in this study due to its adaptability and easy layout, provides the opportunity for human input to make the necessary adaptations in a user-friendly manner. The proposed concept is useful for creating multilingual online dictionaries, compiled using available online or electronic resources. The resulting trilingual dictionary is available online as proof of concept on which further work can build. The fact that the database underlying the dictionary is available in a machine-readable format, namely XML, is important for indirect target users for reuse to develop electronic resources, especially for resource-scarce languages. Keywords: DICTIONARY COMPILATION, VENDA-ENGLISH-AFRIKAANS, TRILINGUAL DICTIONARY, ELECTRONIC /ONLINE RESOURCES, MACHINE TRANSLATION SYSTEMS, LEXONOMY, CORPUS SEARCH, TARGET USERS Die beskikbaarheid van meertalige woordeboeke is deurslaggewend, nie slegs vir direkte teikengebruikers nie, maar ook vir indirekte teikengebruikers soos menslike taaltegno-loe, veral in die geval van tale met skaars hulpbronne, soos byvoorbeeld Venda. In hierdie artikel word die optimale benutting van gratis elektroniese/aanlyn hulpbronne vir die samestelling van 'n drietalige e-woordeboek vir Venda, Engels en Afrikaans ondersoek. Ons benadering is gebaseer op 'n eksperiment waarin die samestellingsproses so ver moontlik geoutomatiseer is om besparing in terme van tyd en mensekrag teweeg te bring. Engels word as 'n brug vir die vertaling tussen die brontaal, Venda, en die doeltaal, Afrikaans, gebruik. Die algemene bevindinge is dat daar sekere beperkings te wagte kan wees in so 'n semi-outomatiese proses wat wel 'n sekere mate van mens-like intervensie verg. Hoewel die saamgestelde e-woordeboek nie as 'n finale produk beskou kan word nie, bied die woordeboeksamestellingsprogram Lexonomy, wat vanwee sy aanpasbaarheid en maklike uitleg suksesvol in hierdie studie gebruik is, die geleentheid vir menslike insette om die nodige aanpassings op 'n gebruikersvriendelike wyse te doen. Die geformuleerde konsepvoorstel is nuttig vir die skep van meertalige aanlyn woordeboeke, saamgestel met behulp van beskikbare aanlyn of elektroniese hulpbronne. Die resulterende drietalige woordeboek is aanlyn beskikbaar as bewys van die konsep waarop verdere werk kan bou. Die feit dat die databasis onderliggend aan die woordeboek beskikbaar is in 'n masjienleesbare formaat, naamlik XML, is belangrik vir indirekte teikengebruikers vir hergebruik om elektroniese hulpbronne te ontwikkel, veral vir hulpbronarm tale. Sleutelwoorde: WOORDEBOEKSAMESTELLING, VENDA-ENGELS-AFRIKAANS, DRIE-TALIGE WOORDEBOEK, ELEKTRONIESE/AANLYN HULPBRONNE, MASJIENVERTAAL-SISTEME, LEXONOMY, KORPUSSOEKTOG, TEIKENGEBRUIKERS
Elderly patients are vulnerable to adverse drug reactions (ADRs). Drug-related readmissions (DRRs) can be a major consequence of ADR. Therefore, this study aimed to investigate the effects of a ...ward-based, comprehensive pharmaceutical care service on the occurrence of DRRs as the endpoint in dependent-living elderly patients.
A randomized, controlled trial was performed at a German University Hospital. Patients fulfilling the following criteria were eligible: admission to a cooperating ward, existing drug therapy at admission, 65 years of age and older, home-care or nursing home residents in ambulatory care, and a minimum hospital stay of three days. Patients received either standard care (control group) or pharmaceutical care (intervention group). Follow-up consultations were conducted for each patient at 1, 8, 26, and 52 weeks after discharge. The time to DRR was defined as the primary outcome measure and was analysed using the log-rank test. The Cox-proportional hazard model was used for risk factor analysis.
Sixty patients (n = 31 intervention group, n = 29 control group) participated in the study. For patients in the intervention group, the median time to DRR was prolonged; however, the level of statistical significance was not reached (log-rank test P = 0.068; HR = 3.28, P = 0.086). When the risk factors 'age' or 'length of stay on the ward' were added to the Cox proportional hazard model, patients in the control group exhibited a significantly higher risk of experiencing a DRR than patients of the intervention group (HR = 4.62; P = 0.028 including age and HR = 5.76; P = 0.033 including length of stay on the ward).
Our findings demonstrate the successful implementation of ward-based, comprehensive pharmaceutical care for dependent-living elderly. Despite a low participation rate, which led to an underpowered study, the results provide a preliminary efficacy signal and effect size estimates to power a definitive trial.
Clinicaltrials.gov identifier: NCT01578525 , prospectively registered April 13, 2012.
It is with great sadness that we heard of the passing away of Hendrik Jacobus Erasmus on 15 June 2016, an esteemed member of the Editorial Board of Fundamina and a frequent contributor of legal ...historical contributions to this legal journal. Hennie Erasmus was a man of many talents. He had a formidable reputation as academic, as author, as judge, and as historian. He was born on 10 January 1935 in Ladysmith, Natal. After matriculation at the Kroonstad High School in 1952, he obtained the degrees BA and MA (both cum laude) from the University of the Free State, followed by an LLB from the University of South Africa and a DLitt et Phil (cum laude) from Leiden.
It is with great sadness that we heard of the passing away of Hendrik Jacobus Erasmus on 15 June 2016, an esteemed member of the Editorial Board of Fundamina and a frequent contributor of legal ...historical contributions to this legal journal. Hennie Erasmus was a man of many talents. He had a formidable reputation as academic, as author, as judge, and as historian. He was born on 10 January 1935 in Ladysmith, Natal. After matriculation at the Kroonstad High School in 1952, he obtained the degrees BA and MA (both cum laude) from the University of the Free State, followed by an LLB from the University of South Africa and a DLitt et Phil (cum laude) from Leiden.
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