Cardiovascular therapy use, modification, and in-hospital death in patients with COVID-19: A cohort study

AIMS: To assess the associations of exposure and modifications in exposure (i.e., discontinuation on admission, initiation during hospitalization) to eight common cardiovascular therapies with the risk of in-hospital death among inpatients with coronavirus disease 2019 (COVID-19). METHODS: In this observational study including 838 hospitalized unvaccinated adult patients with confirmed COVID-19, the use of cardiovascular therapies was assessed using logistic regression models adjusted for potential confounders. RESULTS: No cardiovascular therapy used before hospitalization was associated with an increased risk of in-hospital death. During hospitalization, the use of diuretics (aOR 2.59 [1.68–3.98]) was associated with an increase, and the use of agents acting on the renin-angiotensin system (aOR 0.39 [0.23–0.64]) and lipid-lowering agents (aOR 0.41 [0.24–0.68]) was associated with a reduction in the odds of in-hospital death. Exposure modifications associated with decreased survival were the discontinuation of an agent acting on the renin-angiotensin system (aOR 4.42 [2.08–9.37]), a β-blocker (aOR 5.44 [1.16–25.46]), a lipid-modifying agent (aOR 3.26 [1.42–7.50]) or an anticoagulant (aOR 5.85 [1.25–27.27]), as well as the initiation of a diuretic (aOR 5.19 [2.98–9.03]) or an antiarrhythmic (aOR 6.62 [2.07–21.15]). Exposure modification associated with improved survival was the initiation of an agent acting on the renin-angiotensin system (aOR 0.17 [0.03–0.82]). CONCLUSION: In hospitalized and unvaccinated patients with COVID-19, there was no detrimental association of the prehospital use of any regular cardiovascular medication with in-hospital death, and these therapies should be continued as recommended

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Immunosuppressant; Quality of life; TransplantationImmunosupressor; Qualitat de vida; TrasplantamentInmunosupresor; Calidad de vida; TrasplanteIntroduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings. Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12). Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p < 0.05) and VAS (by 4 percentage points, p < 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]). Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation.The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 754995. Open access funding by University of Lausanne

North America’s oldest boreal trees are more efficient water users due to increased [CO2], but do not grow faster

Due to anthropogenic emissions and changes in land use, trees are now exposed to atmospheric levels of [CO2] that are unprecedented for 650,000 y [Lüthi et al. (2008) Nature 453:379–382] (thousands of tree generations). Trees are expected to acclimate by modulating leaf–gas exchanges and alter water use efficiency which may result in forest productivity changes. Here, we present evidence of one of the strongest, nonlinear, and unequivocal postindustrial increases in intrinsic water use efficiency (iWUE) ever documented (+59%). A dual-isotope tree-ring analysis (δ13C and δ18O) covering 715 y of growth of North America’s oldest boreal trees (Thuja occidentalis L.) revealed an unprecedented increase in iWUE that was directly linked to elevated assimilation rates of CO2 (A). However, limited nutrient availability, changes in carbon allocation strategies, and changes in stomatal density may have offset stem growth benefits awarded by the increased iWUE. Our results demonstrate that even in scenarios where a positive CO2 fertilization effect is observed, other mechanisms may prevent trees from assimilating and storing supplementary anthropogenic emissions as above-ground biomass. In such cases, the sink capacity of forests in response to changing atmospheric conditions might be overestimated

Immunosuppressant drugs and quality-of-life outcomes in kidney transplant recipients: An international cohort study (EU-TRAIN)

Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings.Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12).Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p &lt; 0.05) and VAS (by 4 percentage points, p &lt; 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]).Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation

Population Pharmacokinetics of Cabotegravir Following Oral Administration and Long‐Acting Intramuscular Injection in Real‐World People with HIV

Long‐acting cabotegravir has been studied mainly in the stringent framework of clinical trials, which does not necessarily reflect the situation of people with HIV (PWH) in routine clinical settings. The present population pharmacokinetic analysis aims to build real‐world reference percentile curves of cabotegravir concentrations, accounting for patient‐related factors that may affect cabotegravir exposure. The second objective is to simulate whether dosing interval adjustments of cabotegravir could be considered in specific subpopulations. Overall, 238 PWH contributed to 1,038 cabotegravir levels (186 during the initial oral administration phase and 852 after intramuscular injection). Cabotegravir pharmacokinetics was best described using a one‐compartment model with distinct first order‐absorption for oral and intramuscular administrations, and identical volume and clearance. Our model showed almost 40% faster absorption and 30% higher clearance than previously reported, resulting in a time to steady‐state of 8 months and an elimination half‐life of 4.6 weeks for long‐acting cabotegravir. Sex and body mass index significantly influenced absorption, and bodyweight affected clearance. Model‐based simulations showed that cabotegravir trough concentrations in females were 25% lower 4 weeks after the intramuscular loading dose, but 42% higher during the late maintenance phase. Finally, simulations indicated that in females, despite significantly higher cabotegravir concentrations, longer intervals between injections may not consistently ensure levels above the 4‐fold protein‐adjusted 90% inhibitory target concentration

Use of GLP1 receptor agonists in early pregnancy and reproductive safety: a multicentre, observational, prospective cohort study based on the databases of six Teratology Information Services.

OBJECTIVES Glucagon-like peptide 1 receptor agonists (GLP1-RA) are indicated for the treatment of type 2 diabetes and more recently for weight loss. The aim of this study was to assess the risks associated with GLP1-RA exposure during early pregnancy. DESIGN This multicentre, observational prospective cohort study compared pregnancy outcomes in women exposed to GLP1-RA in early pregnancy either for diabetes or obesity treatment with those in two reference groups: (1) women with diabetes exposed to at least one non-GLP1-RA antidiabetic drug during the first trimester and (2) a reference group of overweight/obese women without diabetes, between 2009 and 2022. SETTING Data were collected from the databases of six Teratology Information Services. PARTICIPANTS This study included 168 pregnancies of women exposed to GLP1-RA during the first trimester, alongside a reference group of 156 pregnancies of women with diabetes and 163 pregnancies of overweight/obese women. RESULTS Exposure to GLP1-RA in the first trimester was not associated with a risk of major birth defects when compared with diabetes (2.6% vs 2.3%; adjusted OR, 0.98 (95% CI, 0.16 to 5.82)) or to overweight/obese (2.6% vs 3.9%; adjusted OR 0.54 (0.11 to 2.75)). For the GLP1-RA group, cumulative incidence for live births, pregnancy losses and pregnancy terminations was 59%, 23% and 18%, respectively. In the diabetes reference group, corresponding estimates were 69%, 26% and 6%, while in the overweight/obese reference group, they were 63%, 29% and 8%, respectively. Cox proportional cause-specific hazard models indicated no increased risk of pregnancy losses in the GLP1-RA versus the diabetes and the overweight/obese reference groups, in both crude and adjusted analyses. CONCLUSIONS This study offers reassurance in cases of inadvertent exposure to GLP1-RA during the first trimester of pregnancy. Due to the limited sample size, larger studies are required to validate these findings

Improving Data Collection in Pregnancy Safety Studies: Towards Standardisation of Data Elements in Pregnancy Reports from Public and Private Partners, A Contribution from the ConcePTION Project.

INTRODUCTION AND OBJECTIVE The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework. METHODS Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available. RESULTS The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs). CONCLUSIONS Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible

Identification of the top TESS objects of interest for atmospheric characterization of transiting exoplanets with JWST

Funding: Funding for the TESS mission is provided by NASA's Science Mission Directorate. This work makes use of observations from the LCOGT network. Part of the LCOGT telescope time was granted by NOIRLab through the Mid-Scale Innovations Program (MSIP). MSIP is funded by NSF. This paper is based on observations made with the MuSCAT3 instrument, developed by the Astrobiology Center and under financial support by JSPS KAKENHI (grant No. JP18H05439) and JST PRESTO (grant No. JPMJPR1775), at Faulkes Telescope North on Maui, HI, operated by the Las Cumbres Observatory. This paper makes use of data from the MEarth Project, which is a collaboration between Harvard University and the Smithsonian Astrophysical Observatory. The MEarth Project acknowledges funding from the David and Lucile Packard Fellowship for Science and Engineering, the National Science Foundation under grant Nos. AST-0807690, AST-1109468, AST-1616624 and AST-1004488 (Alan T. Waterman Award), the National Aeronautics and Space Administration under grant No. 80NSSC18K0476 issued through the XRP Program, and the John Templeton Foundation. C.M. would like to gratefully acknowledge the entire Dragonfly Telephoto Array team, and Bob Abraham in particular, for allowing their telescope bright time to be put to use observing exoplanets. B.J.H. acknowledges support from the Future Investigators in NASA Earth and Space Science and Technology (FINESST) program (grant No. 80NSSC20K1551) and support by NASA under grant No. 80GSFC21M0002. K.A.C. and C.N.W. acknowledge support from the TESS mission via subaward s3449 from MIT. D.R.C. and C.A.C. acknowledge support from NASA through the XRP grant No. 18-2XRP18_2-0007. C.A.C. acknowledges that this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). S.Z. and A.B. acknowledge support from the Israel Ministry of Science and Technology (grant No. 3-18143). The research leading to these results has received funding from the ARC grant for Concerted Research Actions, financed by the Wallonia-Brussels Federation. TRAPPIST is funded by the Belgian Fund for Scientific Research (Fond National de la Recherche Scientifique, FNRS) under the grant No. PDR T.0120.21. The postdoctoral fellowship of K.B. is funded by F.R.S.-FNRS grant No. T.0109.20 and by the Francqui Foundation. H.P.O.'s contribution has been carried out within the framework of the NCCR PlanetS supported by the Swiss National Science Foundation under grant Nos. 51NF40_182901 and 51NF40_205606. F.J.P. acknowledges financial support from the grant No. CEX2021-001131-S funded by MCIN/AEI/ 10.13039/501100011033. A.J. acknowledges support from ANID—Millennium Science Initiative—ICN12_009 and from FONDECYT project 1210718. Z.L.D. acknowledges the MIT Presidential Fellowship and that this material is based upon work supported by the National Science Foundation Graduate Research Fellowship under grant No. 1745302. P.R. acknowledges support from the National Science Foundation grant No. 1952545. This work is partly supported by JSPS KAKENHI grant Nos. JP17H04574, JP18H05439, JP21K20376; JST CREST grant No. JPMJCR1761; and Astrobiology Center SATELLITE Research project AB022006. This publication benefits from the support of the French Community of Belgium in the context of the FRIA Doctoral Grant awarded to M.T. D.D. acknowledges support from TESS Guest Investigator Program grant Nos. 80NSSC22K1353, 80NSSC22K0185, and 80NSSC23K0769. A.B. acknowledges the support of M.V. Lomonosov Moscow State University Program of Development. T.D. was supported in part by the McDonnell Center for the Space Sciences. V.K. acknowledges support from the youth scientific laboratory project, topic FEUZ-2020-0038.JWST has ushered in an era of unprecedented ability to characterize exoplanetary atmospheres. While there are over 5000 confirmed planets, more than 4000 Transiting Exoplanet Survey Satellite (TESS) planet candidates are still unconfirmed and many of the best planets for atmospheric characterization may remain to be identified. We present a sample of TESS planets and planet candidates that we identify as “best-in-class” for transmission and emission spectroscopy with JWST. These targets are sorted into bins across equilibrium temperature Teq and planetary radius Rp and are ranked by a transmission and an emission spectroscopy metric (TSM and ESM, respectively) within each bin. We perform cuts for expected signal size and stellar brightness to remove suboptimal targets for JWST. Of the 194 targets in the resulting sample, 103 are unconfirmed TESS planet candidates, also known as TESS Objects of Interest (TOIs). We perform vetting and statistical validation analyses on these 103 targets to determine which are likely planets and which are likely false positives, incorporating ground-based follow-up from the TESS Follow-up Observation Program to aid the vetting and validation process. We statistically validate 18 TOIs, marginally validate 31 TOIs to varying levels of confidence, deem 29 TOIs likely false positives, and leave the dispositions for four TOIs as inconclusive. Twenty-one of the 103 TOIs were confirmed independently over the course of our analysis. We intend for this work to serve as a community resource and motivate formal confirmation and mass measurements of each validated planet. We encourage more detailed analysis of individual targets by the community.Peer reviewe

Guidance for the Interpretation of Long-Acting Cabotegravir and Rilpivirine Concentrations Based on Real-World Therapeutic Drug Monitoring Data and Documented Failures.

The interpretation of long-acting cabotegravir and rilpivirine concentrations is complicated by the lack of consensus on the threshold to consider. Building on real-world therapeutic drug monitoring data and documented virologic failures, this article provides a reappraisal of the existing thresholds and guidance for the interpretation of cabotegravir and rilpivirine concentrations

Vital signs and laboratory values at hospital admission in patients with modified lipid modifying agents exposure status with (discontinuation vs continuation) and without (absence vs initiation) prior exposure to this therapy.

(PDF)</p