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

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

Assessment of pollution levels, potential ecological risk and human health risk of heavy metals/metalloids in dust around fuel filling stations from the Kumasi Metropolis, Ghana

The aim of this study was to evaluate the levels of selected heavy metals/metalloids in filling station dust from the Kumasi Metropolis, Ghana. A total of forty (40) dust samples were analysed for Fe, Ti, Zn, Zr, Mn, Sr, Ba, Cr, Pd, Ni, Cu, As and Mo using X-ray Fluorescence technique. Mean concentrations of Ba, As, Cr, Cu, Fe, Mn, Mo, Ni, Pb, Sr, Ti, Zn and Zr were 92.26, 6.20, 70.41, 50.18, 466.22, 163.68, 4.63, 44.05, 46.93, 106.69, 327.51, 280.32 and 182.05 mg/kg, respectively. The pollution index (PI) and geo-accumulation (Igeo) index values were in the order of Ba  Pb > Ni > Cu > Cr > Zn > Mn > Ba. The contribution of hazard quotient via ingestion for most of the heavy metals/metalloids were high with 11.83% for adults and 88.17% for children. For health risk assessment, non-carcinogenic values were below the threshold values, except hazard index via ingestion. The main exposure pathway for both children and adults was ingestion, followed by dermal contact and inhalation

Risk of heavy metal ingestion from the consumption of two commercially valuable species of fish from the fresh and coastal waters of Ghana.

The need to evaluate the human health safety of fishery resources remain urgent in the mist of the ever-increasing fear of heavy metal toxicity from the consumption of Ghana's fisheries resource, as a consequence of pollution from several anthropogenic activities including artisanal gold mining. Nevertheless, the bigeye grunt (Brachydeuterus auritus) and Bagrid catfish (Chrysichthys nigrodigitatus) remain commercially valuable fish species in West Africa and continue to attract high patronage.Forty-five specimens each of C. nigrodigitatus and B. auritus collected from the Weija Dam and the Tema Fishing Habour in Ghana, between June and September 2016, were analysed for seven heavy metals using Atomic Absorption Spectrometry.Lead and Cadmium were below detection in all samples while Cu was not detected in B. auritus. Levels of the remaining metals (mg kg-1) were below FAO/WHO maximum permissible limits in fish and occurred in the rank order Se (3.5) > Zn (2.34) > Cu (0.59) > As (0.37) > Hg (0.19) in C. nigrodigitatus and Se (2.97) > Zn (2.28) > Hg (0.31) > As (0.21) in B. auritus. Only As in C. nigrodigitatus recorded Estimated Weekly Intake (EWI) greater than FAO/WHO Provisional Tolerable Weekly Intake (PTWI). Also, As in C. nigrodigitatus and Hg in B. auritus had Targeted Hazard Quotient (THQ) greater than 1 for individuals consuming the fishes on daily basis and therefore, raising concerns. However, for both species of fish, cancer risk of As was 1 in 10,000,000,000 and modified Health Benefits values of Se (HBVSe) were positive indicating the health risks that might accompany Hg exposure would be negated. Since toxicity depends on the concentration and quantity of a pollutant consumed, safe maximum consumption rate of C. nigrodigitatus based on As concentrations was 0.21 mg per day and that of B. auritus was 0.058 mg per day for Hg. With an average of 0.227 kg fish per meal of an adult human, these translated into not more than 24 C. nigrodigitatus and nine (9) B. auritus meals in a month but because fish is consumed at 0.0685 kg per person per day in Ghana, these values respectively translates to 93 and 30 safe days of consumption per month.At the rate of 0.0685 kg fish per person per day that fish is consumed in Ghana, the consumption of the two species of fish in Ghana would essentially be of little or no consequence to consumers

Frequency distribution of metal concentrations in the muscle tissues of <i>Chrysichthys nigrodigitatus</i> and <i>Brachydeuterus auritus</i> from the waters of Ghana.

<p>Note: Pb, Cd and Cu were excluded from <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0194682#pone.0194682.g001" target="_blank">Fig 1</a> because Pb and Cd were below detection in all samples while 96% of the C. nigrodigitatus and 100% of the B. auritus samples had Cu levels below detections.</p

Comparison of heavy metals concentrations between the muscle tissues of <i>Chrysichthys nigrodigitatus</i> and <i>Brachydeuterus auritus</i> from the waters of Ghana.

<p>Note: <i>Mean ± SD with different letters in columns are significantly different (Mann–Whitney U test</i>, <i>p > 0</i>.<i>05)</i>.</p

Trends in the concentration of heavy metals in the muscle tissues of <i>Chrysichthys nigrodigitatus</i> from the Weija Dam of the Densu River in Ghana.

<p>Note: Pb and Cd were below detection limits in C. nigrodigitatus. Note: Concentrations of As and Se, As and Zn, Hg and Se, as well as Hg and Zn were significantly different (Kruskal-Wallis Test with Fisher’s LSD post hoc, H_3,0.05 = 118.779, p < 0.05).</p

Standard length of <i>Chrysichthys nigrodigitatus</i> and <i>Brachydeuterus auritus</i> respectively from the fresh and coastal waters in Ghana.

<p>Standard length of <i>Chrysichthys nigrodigitatus</i> and <i>Brachydeuterus auritus</i> respectively from the fresh and coastal waters in Ghana.</p

Map of Ghana showing the Weija Dam and the Tema fishing harbour where fish specimens were collected.

<p>Map of Ghana showing the Weija Dam and the Tema fishing harbour where fish specimens were collected.</p