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

Temporal Changes in Hypertensive Disorders of Pregnancy and Impact on Cardiovascular and Obstetric Outcomes

Hypertensive disorders of pregnancy (HDP) are a major cause of maternal morbidity. However, short-term outcomes of HDP subgroups remain unknown. Using National Inpatient Sample database, all delivery hospitalizations between 2004 and 2014 with or without HDP (preeclampsia/eclampsia, chronic hypertension, superimposed preeclampsia on chronic hypertension, and gestational hypertension) were analyzed to examine the association between HDP and adverse in-hospital outcomes. We identified >44 million delivery hospitalizations, within which the prevalence of HDP increased from 8% to 11% over a decade with increasing comorbidity burden. Women with chronic hypertension have higher risks of myocardial infarction, peripartum cardiomyopathy, arrhythmia, and stillbirth compared to women with preeclampsia. Out of all HDP subgroups, the superimposed preeclampsia population had the highest risk of stroke (odds ratio [OR] 7.83, 95% confidence interval [CI] 6.25 to 9.80), myocardial infarction (OR 5.20, 95% CI 3.11 to 8.69), peripartum cardiomyopathy (OR 4.37, 95% CI 3.64 to 5.26), preterm birth (OR 4.65, 95% CI 4.48 to 4.83), placental abruption (OR 2.22, 95% CI 2.09 to 2.36), and stillbirth (OR 1.78, 95% CI 1.66 to 1.92) compared to women without HDP. In conclusion, we are the first to evaluate chronic systemic hypertension without superimposed preeclampsia as a distinct subgroup in HDP and show that women with chronic systemic hypertension are at even higher risk of some adverse outcomes compared to women with preeclampsia. In conclusion, the chronic hypertension population, with and without superimposed preeclampsia, is a particularly high-risk group and may benefit from increased antenatal surveillance and the use of a prognostic risk assessment model incorporating HDP to stratify intrapartum care

Some hydrogeological problems peculiar to various types of small islands

There are many problems associated with the investigation of small island hydrogeology, including (i) the availability of data and the distribution of both spatial and temporal data sets, (ii) the dynamics of the groundwater to sea-water interface and the shape of the so-called groundwater lens, and (iii) the difficulties of evaluating recharge to groundwater and of calculating the volume of groundwater discharge to the sea. These issues are compounded by (a) the ratio of coast to area in small islands, (b) the problems of extreme topography, and (c) the identification of baseflow to rivers and streams. A simple classification of island types assists in evaluating hydro-geological regimes, and the importance of groundwater in an island context cannot be over-emphasised

Time-Resolved Detection of Conformational Changes in Oat Phytochrome A: Time-Dependent Diffusion

Conformational changes in oat phytochrome A (phy) in solution after photoexcitation of the red-absorbing form (Pr) were studied in time-domain by the pulsed laser-induced transient grating technique. It was found that the diffusion coefficient (D) of far-red-absorbing form (Pfr) of large phy (1.3 × 10(−11) m(2) s(−1)) is markedly reduced compared with that of Pr (5.8 × 10(−11) m(2) s(−1)). This large reduction indicates that the conformation of Pfr is significantly changed from that of Pr, so that the intermolecular interaction with water molecules increases. This change completes within 1 ms after the photoexcitation. On the other hand, D of Pr of intact phy (4.1 × 10(−11) m(2) s(−1)) first decreases upon photoexcitation to 0.89 × 10(−11) m(2) s(−1) within 1 ms and then gradually increases with a time constant of 100 ms to the value of Pfr, 1.7 × 10(−11) m(2) s(−1). This slower phase suggests that the conformation of the N-terminal region changes with 100 ms to decrease the intermolecular interaction with water after a global change in the large phy region. The increase of D was interpreted in terms of α-helix formation in the Pfr form from the random coil structure in the Pr form