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.
Background
The pharmacokinetics of vancomycin, a drug used for the treatment of methicillin-resistant
Staphylococcus aureus
(MRSA), varies between paediatric and adult patients.
Objective
The ...objective of this study was to assess the pharmacokinetics of vancomycin in preterm neonates and determine the optimum dose regimen.
Methods
This was a randomised double-blind study of preterm neonates admitted to neonatal intensive care units. They all received vancomycin 15 mg/kg every 12 h. Blood was sampled just before administration of the third, sixth and ninth vancomycin dose. Pharmacokinetic parameters were estimated using a Bayesian approach implemented in Monolix 2018R2 software. Covariates assessed included postmenstrual age, current weight, creatinine clearance, albumin, gestational age, body surface area and current age. We used Monte Carlo simulations for dose regimen optimisation targeting area under the concentration–time curve up to 24 h (AUC
0–24h
) of ≥ 400 mg × h/L.
Results
In total, 19 preterm neonates were enrolled in the study with a median age of 14 (3–58) days. A one-compartment model with linear elimination best described the pharmacokinetics of vancomycin. Volume of distribution and clearance was 0.88 L and 0.1 L/h, respectively, for a typical neonate weighing 1.48 kg. Simulation of the current dose regimen showed that 27.5% of the neonates would achieve the target AUC
0–24h
of ≥ 400 mg × h/L, and 70.7% of the neonates would achieve it with 12 mg/kg every 8 h.
Conclusion
The majority of the neonates were under dosed. Vancomycin 12 mg/kg should be administered every 8 h over 1 h infusion to improve the likelihood of achieving the AUC
0–24h
target of ≥ 400 mg × h/L. This target is considered optimal for MRSA infections, where the vancomycin minimum inhibitory concentration is ≤ 1 µg/mL.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Tuberculosis, bacterial community-acquired pneumonia (CAP), and Pneumocystis jirovecii pneumonia (PJP) are the three commonest causes of hospitalisation in HIV-infected adults. Prompt diagnosis and ...treatment initiation are important to reduce morbidity and mortality, but are hampered by limited diagnostic resources in resource poor settings. C-reactive protein (CRP) and procalcitonin have shown diagnostic utility for respiratory tract infections, however few studies have focussed on their ability to distinguish between tuberculosis, CAP, and PJP in HIV-infected inpatients.
We evaluated the diagnostic accuracy of CRP and procalcitonin, compared with composite reference standards, to discriminate between the three target infections in adult HIV-infected inpatients in two district level hospitals in Cape Town, South Africa. Participants were admitted with current cough and danger signs in accordance with the WHO algorithm for tuberculosis in seriously ill HIV-infected patients. Study clinicians were blinded to CRP and procalcitonin results.
Two hundred forty-eight participants met study case definitions: 133 with tuberculosis, 61 with CAP, 16 with PJP, and 38 with mixed infection. In the 210 particpants with single infections the differences in median CRP and procalcitonin concentrations between the three infections were statistically significant, but distributions overlapped considerably. CRP and procalcitonin concentrations were highest in the CAP group and lowest in the PJP group. CRP and procalcitonin cut-offs with sensitivities of ≥90% were found for all three target infection pairs, but corresponding specificities were low. Highest receiver operating characteristic areas under the curve for CRP and procalcitonin were for PJP versus tuberculosis and PJP versus CAP (0.68 and 0.71, and 0.74 and 0.69 respectively).
CRP and procalcitonin showed limited value in discriminating between the three target infections due to widely overlapping distributions, but diagnostic accuracy was higher for discriminating PJP from CAP or tuberculosis. Our findings show limitations for CRP and procalcitonin, particularly for discriminiation of tuberculosis form CAP, however they may have greater diagnostic utility as part of a panel of biomarkers or in clinical prediction rules.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
The relationship between Antarctic Circumpolar Current jets and eddy fluxes in the Indo–western Pacific Southern Ocean (90°–145°E) is investigated using an eddy-resolving model. In this ...region, transient eddy momentum flux convergence occurs at the latitude of the primary jet core, whereas eddy buoyancy flux is located over a broader region that encompasses the jet and the interjet minimum. In a small sector (120°–144°E) where jets are especially zonal, a spatial and temporal decomposition of the eddy fluxes further reveals that fast eddies act to accelerate the jet with the maximum eddy momentum flux convergence at the jet center, while slow eddies tend to decelerate the zonal current at the interjet minimum. Transformed Eulerian mean (TEM) diagnostics reveals that the eddy momentum contribution accelerates the jets at all model depths, whereas the buoyancy flux contribution decelerates the jets at depths below ~600 m. In ocean sectors where the jets are relatively well defined, there exist jet-scale overturning circulations with sinking motion on the equatorward flank and a rising motion on the poleward flank of the jets. These jet-scale TEM overturning circulations, which are also discernible in potential density coordinates, cannot be attributed to Ekman downwelling because the Ekman vertical velocities are much weaker and their meridional structure shares little resemblance to the rapidly varying jet-scale overturning pattern. Instead, the location and structure of these thermally indirect circulations suggest that they are driven by the eddy momentum flux convergence, much like the Ferrel cell in the atmosphere.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Cancer in Sub-Saharan Africa is becoming an important challenge for health services due to rising numbers of patients. In Addis Ababa with around 3.5 million inhabitants, more than 2000 cases are ...diagnosed annually. In this retrospective population-based cohort study we assessed completeness of and waiting time for cancer-therapy among patients registered in the Addis Ababa City Cancer Registry (AACCR), Ethiopia. Patient hospital files were retrieved to complete the data from AACCR. A total of 588 files were found (51% of those diagnosed from January to March 2012 and 2014). We analyzed completeness and waiting time of chemotherapy and radiotherapy; with completeness defined as ≥85% therapy received according to local guidelines. Analysis was done for the five most common cancer-types commonly treated with chemotherapy (breast, colorectal, non-Hodgkin`s lymphoma, lung and ovarian) and the four most common cancer-types commonly treated with radiotherapy (breast, cervical, head and neck and rectal). In our study, half of the patients (54.1%) received adequately dosed chemotherapy and 24.5% of patients received adequately dosed radiotherapy. The median waiting time was 2.1 months (Range: 0 to 20.72) for chemotherapy and 7 months (Range: 0.17 to 21.8) for radiotherapy. This study underscores the need for health system measures to improve cancer-directed therapy in Ethiopia, especially concerning radiotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Lesser Flamingos Phoeniconaias minor regularly collide with power lines in South Africa. Attaching light-emitting markers to overhead wires seems to be an effective mitigation measure; however, the ...cost of these devices is prohibitive of large-scale installation. Spatial predictions about flamingo collision risk are thus important for achieving efficient and effective proactive mitigation. In this study, collision risk was defined as a combination of factors related to threat exposure. A habitat suitability index was developed according to changes in surface water occurrence and Chlorophyll-a concentrations, which proved accurate in predicting Lesser Flamingo occurrence. Habitat suitability, and three other species and threat exposure variables, were then used in logistic regression models predicting the occurrence of historic collisions. The most parsimonious model included habitat suitability and flight height. Flamingos were only at risk of collision with power lines when flying lower than 50 m and within 3 km from the water’s edge. High-risk power line sections were thus identified from 3 km buffers around waterbodies ranked according to habitat suitability, which significantly reduced the number of power line spans predicted for proactive marking. While our models indicated that aspects related to exposure were important for predicting flamingo power line collisions, aspects related to sensitivity (e.g., nocturnal behavior) must also guide the choice of mitigation.
Using the coupled climate model CLIMBER-3α, we investigate changes in sea surface elevation due to a weakening of the thermohaline circulation (THC). In addition to a global sea level rise due to a ...warming of the deep sea, this leads to a regional dynamic sea level change which follows quasi-instantaneously any change in the ocean circulation. We show that the magnitude of this dynamic effect can locally reach up to ~1 m, depending on the initial THC strength. In some regions the rate of change can be up to 20-25 mm/yr. The emerging patterns are discussed with respect to the oceanic circulation changes. Most prominent is a south-north gradient reflecting the changes in geostrophic surface currents. Our results suggest that an analysis of observed sea level change patterns could be useful for monitoring the THC strength.PUBLICATION ABSTRACT
Abstract
Background
Dolutegravir concentrations are reduced by efavirenz induction effect necessitating twice-daily dolutegravir dosing when coadministered. Efavirenz induction persists for several ...weeks after stopping, which could potentially select for dolutegravir resistance if switching occurred with unsuppressed human immunodeficiency virus type 1 (HIV-1) RNA levels and standard dolutegravir dosing. We evaluated the need for a lead-in supplementary dolutegravir dose in adults failing first-line tenofovir-emtricitabine-efavirenz (TEE).
Methods
We conducted a randomized, double-blind, placebo-controlled, phase 2 trial in Khayelitsha, South Africa. Eligible patients had virologic failure (2 consecutive HIV-1 RNA ≥1000 copies/mL) on first-line TEE. Participants were randomly assigned (1:1) to switch to tenofovir-lamivudine-dolutegravir (TLD) with a supplementary 50 mg dolutegravir dose or placebo taken 12 hours later for 14 days. Primary outcome was proportion with HIV-1 RNA <50 copies/mL at week 24. This study was not powered to compare arms.
Results
One hundred thirty participants were randomized (65 to each arm). Median baseline HIV-1 RNA was 4.0 log10 copies/mL and 76% had baseline resistance to both tenofovir and lamivudine. One participant died and 2 were lost to follow-up. At week 24, 55 of 64 (86% 95% confidence interval {CI}: 75%–93%) in the supplementary dolutegravir arm and 53 of 65 (82% 95% CI: 70%–90%) in the placebo arm had HIV-1 RNA <50 copies/mL. Grade 3 or 4 adverse events were similar in frequency between arms. None of 6 participants (3 in each arm) eligible for resistance testing by 24 weeks developed dolutegravir resistance.
Conclusions
Our findings do not support the need for initial dolutegravir dose adjustment in patients switching to TLD who failed first-line TEE.
Clinical Trials Registration
NCT03991013.
Among adults switching to second-line tenofovir-lamivudine-dolutegravir with unsuppressed HIV-1 RNA levels and substantial baseline nucleoside reverse transcriptase inhibitor resistance, a high proportion achieved virologic suppression.
Clinical Trials Registration. NCT03991013
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.
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