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

Distinct Mechanisms Underlying Interannual to Decadal Variability of Observed Salinity and Nutrient Concentration in the Northern North Sea

The influence of large-scale oceanic circulation on salinity in the northern North Sea has lead to the hypothesis that nutrient concentrations in this region are also driven by remote oceanic anomalies. Here, using a newly established biogeochemical data set of the North Sea, we show that interannual to decadal variability in winter nutrient concentrations exhibits distinct phase deviations from salinity. The variability in salinity is explained by zonal shifts in the position of the subpolar front (SPF) in the eastern North Atlantic and the associated advective delay. However, the high correlation and absence of advective delay between the position of the SPF and winter nutrient concentrations in the Shetland region (59–61°N, 1°W to 3°E) point to the role of atmospheric variability in driving concurrent changes in winter nutrient concentrations and the SPF position. Our analysis suggests that the prevailing wind direction and local distribution of winter nutrient concentrations together determine the interannual to decadal variability in winter nutrient concentrations in this region. In the analyzed observations, we find a strong spatial gradient in mean winter nutrient concentrations northwest of the Shetland region, which is absent in salinity. The horizontal shift of this spatial gradient, forced by changes in wind direction, has a larger influence on winter nutrient concentration in the Shetland region than the nutrient signal in oceanic anomalies originating from the eastern subpolar North Atlantic. Overall, we conclude that interannual to decadal variability in the observed nutrient concentrations is mainly driven by atmospheric variability here expressed as wind direction

Structural alterations in lateral prefrontal, parietal and posterior midline regions of men with chronic posttraumatic stress disorder

BackgroundSo far, the neural network associated with posttraumatic stress disorder (PTSD) has been suggested to mainly involve the amygdala, hippocampus and medial prefrontal cortex. However, increasing evidence indicates that cortical regions extending beyond this network might also be implicated in the pathophysiology of PTSD. We aimed to investigate PTSD-related structural alterations in some of these regions.MethodsWe enrolled highly traumatized refugees with and without (traumatized controls) PTSD and non-traumatized controls in the study. To increase the validity of our results, we combined an automatic cortical parcellation technique and voxel-based morphometry.ResultsIn all, 39 refugees (20 with and 19 without PTSD) and 13 controls participated in the study. Participants were middle-aged men who were free of psychoactive substances and consumed little to no alcohol. Patients with PTSD (and to a lesser extent traumatized controls) showed reduced volumes in the right inferior parietal cortex, the left rostral middle frontal cortex, the bilateral lateral orbitofrontal cortex and the bilateral isthmus of the cingulate. An influence of cumulative traumatic stress on the isthmus of the cingulate and the lateral orbitofrontal cortex indicated that, at least in these regions, structural alterations might be associated with repeated stress experiences. Voxel-based morphometry analyses produced largely consistent results, but because of a poorer signal-to-noise ratio, conventional statistics did not reach significance.LimitationsAlthough we controlled for several important confounding variables (e.g., sex, alcohol abuse) with our particular sample, this might limit the generalizibility of our data. Moreover, high comorbidity of PTSD and major depression hinders a definite separation of these conditions in our findings. Finally, the results concerning the lateral orbitofrontal cortex should be interpreted with caution, as magnetic resonance imaging acquisition in this region is affected by a general signal loss.ConclusionOur results indicate that lateral prefrontal, parietal and posterior midline structures are implicated in the pathophysiology of PTSD. As these regions are particularly involved in episodic memory, emotional processing and executive control, this might have important implications for the understanding of PTSD symptoms

Magnetic resonance volumetry and spectroscopy of hippocampus and insula in relation to severe exposure of traumatic stress

Severe and chronic stress affects the hippocampus, especially during development. However, studies concerning structural alterations of the hippocampus yielded a rather inconsistent picture. Moreover, further anxiety-relevant brain regions, such as the insula, might be implicated in the pathophysiology of posttraumatic stress disorder (PTSD). We combined magnetic resonance (MR) volumetric and spectroscopic analyses of hippocampus and insula in highly traumatized refugees without a history of alcohol/substance abuse or other comorbid diseases. No PTSD-related difference was apparent in the volumes or neurometabolite levels of bilateral hippocampus or insula. However, an association between left hippocampal N-acetyl-aspartate (NAA) and adverse childhood experiences indicated a potential detrimental effect of the early environment on hippocampal integrity. Our results add to increasing evidence that PTSD-related, morphological alterations in the hippocampus are a consequence of early adversity or may result from other factors, such as extensive use of alcohol

pangaea-data-publisher/pangaeapy: v1.0.18

<p>Fixed term.db error see #59</p&gt

Inulin solid dispersion technology to improve the absorption of the BCS Class IV drug TMC240

TMC240 is a very poorly soluble and poorly permeating HIV protease inhibitor. In order to enhance its oral bioavailability, a fast dissolving inulin-based solid dispersion tablet was developed. During the dissolution test in water (0.5% or 1.0% SLS), this tablet released at least 80% of TMC240 within 30min, while a tablet with the same composition, but manufactured as physical mixture, released only 6% after 2h. In a subsequent single-dose study in dogs (200mg of TMC240), plasma concentrations of TMC240 remained below the lower limit of quantification (<1.00ng/mL) in all animals (n=3 per tested formulation), except in one dog receiving the inulin solid dispersion tablet (C(max)=1.8ng/mL, AUC(0-7 h)=3.0ngh/mL). In the latter treatment group, ritonavir co-administration (10mg/kg b.i.d.) increased TMC240 exposure more than 30-fold (mean AUC(0-7 h)=108ngh/mL; F(rel)=3588%). Exposure was also 16-fold higher than after TMC240 administration as PEG400 suspension in the presence of ritonavir (AUC(0-7 h)=6.7ngh/mL). The current data demonstrate that a solid dispersion of TMC240 in an inulin matrix allows considerable improvement in the release of poorly water-soluble TMC240, both in vitro in the presence of a surfactant and in vivo upon oral administration

Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation

MS Raw Data. Each MS raw spectrum was named, based on the used protein and the corresponding reaction. The assignment will be added shorty. Currently, the assignment can be provided by Philipp Hartmann ([email protected])

Author Correction: Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation

Hartmann P, Bohdan K, Hommrich M, et al. Author Correction: Chemoselective umpolung of thiols to episulfoniums for cysteine bioconjugation. Nature chemistry. 2024