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

Global range dynamics of the Bearded Vulture (Gypaetus barbatus) from the Last Glacial Maximum to climate change scenarios

Species' ranges are dynamic, particularly at large temporal scales. The reconstruction of range dynamics has an obvious biogeographical interest and might also help to frame current knowledge on the ecology and conservation of a species within a wider biogeographical context. The Bearded Vulture Gypaetus barbatus is a charismatic high-altitude species occurring along mountain ranges of the Old World. The species has experienced a global range contraction in the last century mainly due to unintentional poisoning and direct persecution. Despite its declining status and high habitat specialization, little is known about how climate change is impacting the distribution of suitable habitat, or about global past range dynamics of the species. We modelled the current distribution of Bearded Vulture throughout its entire range and projected the Last Glacial Maxima (LGM), Mid-Holocene (MH) and future distribution under 2070s climate change scenarios. Overall, our models predicted that expansion of suitable areas at more northern latitudes for 2070, mostly in Russia and China, does not compensate for range contraction at more southern latitudes, resulting in a global loss of 15% of suitable habitat. Our fine-scale predictions of habitat contraction due to climate change will assist in identifying current portions of the range that might be particularly vulnerable in coming years. African populations (34% decrease) and more thermic areas in Asia are the most impacted areas, and should be at the forefront of future monitoring and conservation efforts. Our models suggest that the predicted contraction in habitat suitability during the 21st century largely continues the contraction experienced since the LGM (7% decline), albeit over a much shorter period of time. From a biogeographical perspective, our models suggest that there have not been relevant changes in the arrangement of the main suitable areas for the species since the LGM. This result challenges some of the main hypotheses proposed to explain the observed genetic structure of the global population

Estimation of Population Density of Bearded Vultures Using Line-Transect Distance Sampling and Identification of Perceived Threats in the Annapurna Himalaya Range of Nepal

Bearded Vulture (Gypaetus barbatus) populations are declining across most of the species' global range. We studied Bearded Vultures in the Annapurna Himalaya Range of Nepal using line-transect distance sampling, and quantified the perceptions of threats to the species by interviewing local people in two different elevational areas. We recorded 35 Bearded Vultures (26 adults, 5 non-adults, 4 birds of unknown age) along a 168-km transect, yielding an encounter rate of 0.21 individuals/km. Based on distance sampling, we estimated a vulture density of 0.184 individuals/km2 in the study area. Local people in the two areas perceived population status and threats to the Bearded Vulture differently. At the lower elevational range (1398-2108 m), people perceived that the vulture population is declining and that the major threats are food shortage and secondary poisoning via the use of poisons by livestock herders to kill mammalian carnivores. At higher elevations (2538-3813 m), people perceived that the vulture population is stable with no lack of food; there also was a larger prevalence of the use of vulture body parts for traditional medicine in this area. Our study suggests that unintentional poisoning, food shortage, and use of vulture body parts are the primary threats to the Bearded Vulture in the Annapurna Himalaya Range of Nepal.</p

A pipeline for identification and validation of tumor-specific antigens in a mouse model of metastatic breast cancer

Cancer immunotherapy continues to make headway as a treatment for advanced stage tumors, revealing an urgent need to understand the fundamentals of anti-tumor immune responses. Noteworthy is a scarcity of data pertaining to the breadth and specificity of tumor-specific T cell responses in metastatic breast cancer. Autochthonous transgenic models of breast cancer display spontaneous metastasis in the FVB/NJ mouse strain, yet a lack of knowledge regarding tumor-bound MHC/peptide immune epitopes in this mouse model limits the characterization of tumor-specific T cell responses, and the mechanisms that regulate T cell responses in the metastatic setting. We recently generated the NetH2pan prediction tool for murine class I MHC ligands by building an FVB/NJ H-2q ligand database and combining it with public information from six other murine MHC alleles. Here, we deployed NetH2pan in combination with an advanced proteomics workflow to identify immunogenic T cell epitopes in the MMTV-PyMT transgenic model for metastatic breast cancer. Five unique MHC I/PyMT epitopes were identified. These tumor-specific epitopes were confirmed to be presented by the class I MHC of primary MMTV-PyMT tumors and their T cell immunogenicity was validated. Vaccination using a DNA construct encoding a truncated PyMT protein generated CD8 + T cell responses to these MHC class I/peptide complexes and prevented tumor development. In sum, we have established an MHC-ligand discovery pipeline in FVB/NJ mice, identified and tracked H-2Dq/PyMT neoantigen-specific T cells, and developed a vaccine that prevents tumor development in this metastatic model of breast cancer