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) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). 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 (n = 137), shock-dependent (n = 146), and no (n = 101) 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

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Funder: Galderma; doi: http://dx.doi.org/10.13039/501100009754Funder: NIHR-BRC Cambridge core grantFunder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272Funder: NHS EnglandAbstract: T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma

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 non–critically 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 (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free 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 support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (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 support–free 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

Are single-session smoking cessation groups a feasible option for rural Australia?: outcomes from a pilot study

Introduction: Single-session group smoking cessation interventions have received little attention in the literature.\ud \ud Aims: This study aimed to test the feasibility and outcomes of a single-session large group smoking cessation intervention in a rural area of New South Wales.\ud \ud Methods: Participants from a smoking cessation course (N = 42) were asked about cigarette consumption, quit attempts, and readiness and confidence to quit at registration and six months. The two-hour intervention occurred in a group setting and comprised of cognitive behaviour therapy and pharmacotherapy advice.\ud \ud Results: The analysis revealed a 26.2% (N = 11) quit rate based on self-report and/or carbon monoxide validation at 6 months (intention to treat). Those who quit all used pharmacotherapy: eight (73%) Nicotine Replacement Therapy (NRT); two (18%) varenicline and one (9%) bupropion with NRT. Seven people (17%) used medicines to reduce consumption of cigarettes. A paired samples t test of those still smoking showed a statistically significant decrease in the numbers of cigarettes smoked per day (p<.001).\ud \ud Conclusion: The quit rate of 26.2% from this large single-session smoking cessation course is comparable to that expected from groups having multiple sessions. As a pilot study, these data suggest that a multi-faceted single-session two-hour smoking cessation intervention can successfully support quit attempts in a rural location

Knowledge and views about maternal tobacco smoking and barriers for cessation in Aboriginal and Torres Strait islanders: a systematic review and meta-ethnography

Maternal smoking rates in Australian Aboriginal women are triple that of the general population, with little evidence for successful interventions. We reviewed the literature to understand smoking and cessation in Aboriginal and Torres Strait Islander women and provide recommendations for targeted interventions. METHODS Six databases were searched using terms related to smoking, pregnancy, and Aboriginal Australians. Two reviewers independently assessed papers for inclusion and quality. Meta-ethnography synthesized first- and second-order constructs from included studies and constructed a line of argument. RESULTS Seven relevant studies were analyzed. The synthesis illustrates 11 third-order constructs operating on the levels of self, family, and social networks, the wider Aboriginal community, and broader external influences. Highlighted are social norms and stressors within the Aboriginal community perpetuating tobacco use; insufficient knowledge of smoking harms; inadequate saliency of antismoking messages; and lack of awareness and use of pharmacotherapy. Indigenous Health Workers have a challenging role, not yet fulfilling its potential. Pregnancy is an opportunity to encourage positive change where a sense of a protector role is expressed. CONCLUSIONS This review gives strength to evidence from individual studies across diverse Indigenous cultures. Pregnant Aboriginal and Torres Strait Islander smokers require comprehensive approaches, which consider the environmental context, increase knowledge of smoking harms and cessation methods, and provide culturally targeted support. Long term, broad strategies should de-normalize smoking in Aboriginal and Torres Strait Islander communities. Further research needs to examine causes of resistance to antitobacco messages, clarify contributing roles of stress and depression, and attitudes to pharmacotherapy

Postpartum Opioid Use Among Military Health System Beneficiaries: Lessons for the Nation

INTRODUCTION: The opioid epidemic in the US has been given much attention in recent years. The most common source of prescription opioids, among people who misuse them, is through family or friends, implicating that healthcare providers are likely overprescribing. METHODS: We evaluated postpartum opioid prescriptions at discharge among patients insured by TRICARE using the Military Health System Data Repository. The primary outcome compared the prevalence of opioid prescription at discharge for postpartum patients within civilian purchased care and direct military treatment facilities. Secondary outcomes investigated mode of delivery and demographics for those receiving opioid prescriptions. We included women age 15-49 years old insured by TRICARE between 2010-2015 with a pregnancy-related postpartum discharge diagnosis. We excluded abortive pregnancy outcomes and incomplete data sets. We extracted data using ICD-9 and CPT codes, and performed logistic regression using SAS 9.4. RESULTS: Postpartum patients receiving civilian purchased care were more likely to be discharged with an opioid prescription compared to direct care (OR 3.9, 95% CI 3.8-3.99). Asian race was least likely to receive an opioid prescription postpartum (OR 0.79, 95% CI 0.75-0.83). Age 15-19 had a lower odds of opioid prescription at discharge. CONCLUSION: Our data indicates that women who are cared for in civilian facilities were more likely to be prescribed an opioid at time of discharge when compared to military facilities. Factors such as race and age were also associated with opioid prescribing practices. OB/GYNs may be overprescribing opioids postpartum, and this study highlights areas for improvement

Postpartum Opioid Use Among Military Health System Beneficiaries: Lessons for the Nation

INTRODUCTION: The opioid epidemic in the US has been given much attention in recent years. The most common source of prescription opioids, among people who misuse them, is through family or friends, implicating that healthcare providers are likely overprescribing. METHODS: We evaluated postpartum opioid prescriptions at discharge among patients insured by TRICARE using the Military Health System Data Repository. The primary outcome compared the prevalence of opioid prescription at discharge for postpartum patients within civilian purchased care and direct military treatment facilities. Secondary outcomes investigated mode of delivery and demographics for those receiving opioid prescriptions. We included women age 15-49 years old insured by TRICARE between 2010-2015 with a pregnancy-related postpartum discharge diagnosis. We excluded abortive pregnancy outcomes and incomplete data sets. We extracted data using ICD-9 and CPT codes, and performed logistic regression using SAS 9.4. RESULTS: Postpartum patients receiving civilian purchased care were more likely to be discharged with an opioid prescription compared to direct care (OR 3.9, 95% CI 3.8-3.99). Asian race was least likely to receive an opioid prescription postpartum (OR 0.79, 95% CI 0.75-0.83). Age 15-19 had a lower odds of opioid prescription at discharge. CONCLUSION: Our data indicates that women who are cared for in civilian facilities were more likely to be prescribed an opioid at time of discharge when compared to military facilities. Factors such as race and age were also associated with opioid prescribing practices. OB/GYNs may be overprescribing opioids postpartum, and this study highlights areas for improvement