36 research outputs found
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Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.
Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (nâ=â143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (nâ=â152), or no hydrocortisone (nâ=â108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (nâ=â137), shock-dependent (nâ=â146), and no (nâ=â101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; pâ=â0.40). There was no significant effect of DMF on any secondary outcome
Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial
Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; pâ=â0.40). There was no significant effect of DMF on any secondary outcome
Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19
IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19.
Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19.
DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 nonâcritically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022).
INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (nâ=â257), ARB (nâ=â248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; nâ=â10), or no RAS inhibitor (control; nâ=â264) for up to 10 days.
MAIN OUTCOMES AND MEASURES The primary outcome was organ supportâfree days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes.
RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ supportâfree days among critically ill patients was 10 (â1 to 16) in the ACE inhibitor group (nâ=â231), 8 (â1 to 17) in the ARB group (nâ=â217), and 12 (0 to 17) in the control group (nâ=â231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ supportâfree days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively).
CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes.
TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570
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The Case of a Disappearing Left Atrial Appendage Thrombus Direct Visualization of Left Atrial Thrombus Migration, Captured by Echocardiography, in a Patient With Atrial Fibrillation, Resulting in a Stroke
Dabigatran and Warfarin in Vitamin K Antagonist-Naive and -Experienced Cohorts With Atrial Fibrillation
Backgroundâ
The comparison of anticoagulants dabigatran and warfarin might be most equitable in vitamin K antagonist (VKA)ânaive patients.
Methods and Resultsâ
Warfarin and 2 doses of dabigatranâ110 mg BID (D110) and 150 mg BID (D150)âwere compared in a balanced population of VKA-naive (â€62 days of lifetime VKA exposure, with 33% never prescribed a VKA) and VKA-experienced patients with atrial fibrillation (n=18 113). For VKA-naive and -experienced patients assigned warfarin, the time in therapeutic range (international normalized ratio 2.0 to 3.0) was 62% and 67%, respectively, and 61% and 66% for those never and ever prescribed a VKA. In VKA-naive patients, stroke and systemic embolism rates were 1.57%, 1.07%, and 1.69% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (
P
=0.65); D150 was superior (
P
=0.005). Major bleeding rates were 3.11%, 3.34%, and 3.57% per year, respectively. D110 and D150 were similar to warfarin (
P
=0.19 and
P
=0.55). Intracranial bleeding rates were 0.19%, 0.33%, and 0.73% per year, respectively. D110 and D150 were lower than warfarin (
P
<0.001 and
P
=0.005). In VKA-experienced patients, stroke and systemic embolism rates were 1.51%, 1.15%, and 1.74% per year for D110, D150, and warfarin, respectively. D110 was similar to warfarin (
P
=0.32); D150 was superior (
P
=0.007). Major bleeding rates were 2.66%, 3.30%, and 3.57% per year, respectively. D110 was lower than warfarin (
P
=0.003); D150 was similar (
P
=0.41). Intracranial bleeding rates were 0.26%, 0.32%, and 0.79% per year, respectively. D110 and D150 were lower than warfarin (
P
<0.001 for both). Results were similar for patients never on a VKA.
Conclusionsâ
Previous VKA exposure does not influence the benefits of dabigatran at either dose compared with warfarin.
Clinical Trial Registrationâ
http://www.clinicaltrials.gov
. Unique identifier: NCT00262600.
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Living multiculture: understanding the new spatial and social relations of ethnicity and multiculture in England
Since 2001, as the social and spatial compositions of multiculture and migration have become more complicated and diverse, geography has moved back to the centre of policy, political and academic arguments about cultural difference and ethnic diversity in England. This spatial turn is most obvious in preoccupations with notions of increasing ethnic segregation but it is also apparent in discussions of the possibility of everyday multicultural exchanges in relationally understood places. Responding to the work of others on these questions and in these places, and informed by data from research exploring Ghanaian and Somali migrant settlement in Milton Keynes this paper reviews some of the quantitative and qualitative evidence being drawn on in academic, policy and political debates about contemporary multiculture. The paper problematises the dominance of the concept of segregation in these debates and examines the value of the concept of conviviality for understanding the âin-developmentâ ways in which multiculture is lived
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Prostatic Ductal Adenocarcinoma Controlled for Tumor Grade, Stage, and Margin Status Does Not Independently Influence the Likelihood of Biochemical Recurrence in Localized Prostate Cancer After Radical Prostatectomy
Context.â
Prostatic ductal adenocarcinoma (PDA) has historically been considered to be an aggressive subtype of prostate cancer.
Objective.â
To investigate if PDA is independently associated with worse biochemical recurrence (BCR)âfree survival after radical prostatectomy.
Design.â
A review of 1584 radical prostatectomies was performed to grade, stage, and assess margin status in each tumor nodule. Radical prostatectomies with localized PDA (ie, those lacking metastasis) in the tumor nodule with the highest grade and stage and worst margin status were matched with prostatic acinar adenocarcinoma according to grade, stage, and margin status. The effect of PDA on BCR was assessed by multivariable Cox regression and Kaplan-Meier analyses.
Results.â
Prostatic ductal adenocarcinoma was present in 171 cases. We excluded 24 cases because of lymph node metastasis (n = 13), PDA not in the highest-grade tumor nodule (n = 9), and positive surgical margin in a lower-grade tumor nodule (n = 2). The remaining 147 cases included 26 Grade Group (GG) 2, 44 GG3, 6 GG4, and 71 GG5 cancers. Seventy-six cases had extraprostatic extension, 33 had seminal vesicle invasion, and 65 had positive margins. Follow-up was available for 113 PDA and 109 prostatic acinar adenocarcinoma cases. Prostate-specific antigen density (odds ratio, 3.7; P = .001), cancer grade (odds ratio, 3.3â4.3; P = .02), positive surgical margin (odds ratio, 1.7; P = .02), and tumor volume (odds ratio, 1.3; P = .02) were associated with BCR in multivariable analysis. Prostatic ductal adenocarcinoma, its percentage, intraductal carcinoma, and cribriform Gleason pattern 4 were not significant independent predictors of BCR.
Conclusions.â
Advanced locoregional stage, higher tumor grade, and positive surgical margin status rather than the mere presence of PDA are more predictive of worse BCR-free survival outcomes following radical prostatectomy in men with a component of PDA