Rapid and sustained reduction of serum growth hormone and insulin-like growth factor-1 in patients with acromegaly receiving lanreotide Autogel® therapy: a randomized, placebo-controlled, multicenter study with a 52 week open extension

The study was designed to evaluate the long-term efficacy and safety of the 28-day prolonged-release Autogel formulation of the somatostatin analogue lanreotide (Lan-Autogel) in unselected patients with acromegaly. The study comprised four phases: washout; a double-blind comparison with placebo, at a single randomized dose (60, 90 or 120 mg) of Lan-Autogel; a single-blind, fixed-dose phase for four injections (placebo group was re-allocated to active treatment); and eight injections with doses tailored according to biochemical response. Serum samples were assessed for growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels, at weeks 4, 13, 14, 15, 16, 32 and 52. 108 patients were enrolled and 99 completed 52 weeks’ treatment. Four weeks after the first injection, serum GH levels decreased by >50% from baseline in 63% of patients receiving Lan-Autogel compared with 0% receiving placebo (P < 0.001). After four injections, 72% of patients had a >50% reduction in GH levels; 49% patients achieved GH levels ≤ 2.5 ng/ml; 54% had normalized IGF-1; and 38% achieved the combined criterion of GH level ≤ 2.5 ng/ml and normalized IGF-1. The corresponding proportions by week 52 were 82, 54, 59 and 43%, respectively. In patients not requiring dose escalation to 120 mg, 85% achieved biochemical control (combined criterion). Treatment was well tolerated by all patients. In conclusion, Lan-Autogel was effective in controlling GH and IGF-1 hypersecretion in patients with acromegaly and showed a rapid onset of action

Factors associated with psychotropic drug use among community-dwelling older persons: A review of empirical studies

BACKGROUND: In the many descriptive studies on prescribed psychotropic drug use by community-dwelling older persons, several sociodemographic and other factors associated with drug use receive inconsistent support. METHOD: Empirical reports with data on at least benzodiazepine or antidepressant drug use in samples of older persons published between 1990 and 2001 (n = 32) were identified from major databases and analyzed to determine which factors are most frequently associated with psychotropic drug use in multivariate analyses. Methodological aspects were also examined. RESULTS: Most reports used probability samples of users and non-users and employed cross-sectional designs. Among variables considered in 5 or more reports, race, proximity to health centers, medical consultations, sleep complaints, and health perception were virtually always associated to drug use. Gender, mental health, and physical health status were associated in about two-thirds of reports. Associations with age, marital status, medication coverage, socioeconomic status, and social support were usually not observed. CONCLUSIONS: The large variety of methods to operationalize drug use, mental health status, and social support probably affected the magnitude of observed relationships. Employing longitudinal designs and distinguishing short-term from long-term use, focusing on samples of drug users exclusively, defining drug use and drug classes more uniformly, and utilizing measures of psychological well-being rather than only of distress, might clarify the nature of observed associations and the direction of causality. Few studies tested specific hypotheses. Most studies focused on individual characteristics of respondents, neglecting the potential contribution of health care professionals to the phenomenon of psychotropic drug use among seniors

Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in&nbsp;patients with chronic heart failure

Maria Rosa Ballester,1,2 Eul&agrave;lia Roig,3,4 Ignasi Gich,1,2 Montse Puntes,1 Joaqu&iacute;n Delgadillo,2,5 Benjam&iacute;n Santos,5 Rosa Maria Antonijoan1,21Drug Research Center (CIM), Biomedical Research Institute Sant Pau (IIB Sant Pau), Hospital de la Santa Creu i Sant Pau, Barcelona, 2Pharmacology and Therapeutics Department, Universitat Aut&ograve;noma de Barcelona (UAB), Bellaterra, 3Cardiology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, 4Universitat Aut&ograve;noma de Barcelona (UAB) Bellaterra, 5Scientific Area, Ferrer Internacional, SA, SpainPurpose: Diuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics.Methods: Randomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10&nbsp;mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24&nbsp;hours.Results: Ten patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096&plusmn;0.03&nbsp;mmol/&micro;g vs 0.015&plusmn;0.0007&nbsp;mmol/&micro;g; P&lt;0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR.Conclusion: In a study with a limited sample size, our results suggest that 10&nbsp;mg of torasemide-PR is more natriuretically efficient than 40&nbsp;mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics.Keywords: torasemide, furosemide, controlled-release preparation, efficiency, heart failure, pharmacodynamic

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19

Data availability: Downloadable summary data are available through the GenOMICC data site (https://genomicc.org/data). Summary statistics are available, but without the 23andMe summary statistics, except for the 10,000 most significant hits, for which full summary statistics are available. The full GWAS summary statistics for the 23andMe discovery dataset will be made available through 23andMe to qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For further information and to apply for access to the data, see the 23andMe website (https://research.23andMe.com/dataset-access/). All individual-level genotype and whole-genome sequencing data (for both academic and commercial uses) can be accessed through the UKRI/HDR UK Outbreak Data Analysis Platform (https://odap.ac.uk). A restricted dataset for a subset of GenOMICC participants is also available through the Genomics England data service. Monocyte RNA-seq data are available under the title ‘Monocyte gene expression data’ within the Oxford University Research Archives (https://doi.org/10.5287/ora-ko7q2nq66). Sequencing data will be made freely available to organizations and researchers to conduct research in accordance with the UK Policy Framework for Health and Social Care Research through a data access agreement. Sequencing data have been deposited at the European Genome–Phenome Archive (EGA), which is hosted by the EBI and the CRG, under accession number EGAS00001007111.Extended data figures and tables are available online at https://www.nature.com/articles/s41586-023-06034-3#Sec21 .Supplementary information is available online at https://www.nature.com/articles/s41586-023-06034-3#Sec22 .Code availability: Code to calculate the imputation of P values on the basis of SNPs in linkage disequilibrium is available at GitHub (https://github.com/baillielab/GenOMICC_GWAS).Acknowledgements: We thank the members of the Banco Nacional de ADN and the GRA@CE cohort group; and the research participants and employees of 23andMe for making this work possible. A full list of contributors who have provided data that were collated in the HGI project, including previous iterations, is available online (https://www.covid19hg.org/acknowledgements).Change history: 11 July 2023: A Correction to this paper has been published at: https://doi.org/10.1038/s41586-023-06383-z. -- In the version of this article initially published, the name of Ana Margarita Baldión-Elorza, of the SCOURGE Consortium, appeared incorrectly (as Ana María Baldion) and has now been amended in the HTML and PDF versions of the article.Copyright © The Author(s) 2023, Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).GenOMICC was funded by Sepsis Research (the Fiona Elizabeth Agnew Trust), the Intensive Care Society, a Wellcome Trust Senior Research Fellowship (to J.K.B., 223164/Z/21/Z), the Department of Health and Social Care (DHSC), Illumina, LifeArc, the Medical Research Council, UKRI, a BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070 and BBS/E/D/30002275) and UKRI grants MC_PC_20004, MC_PC_19025, MC_PC_1905 and MRNO2995X/1. A.D.B. acknowledges funding from the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z), the Edinburgh Clinical Academic Track (ECAT) programme. This research is supported in part by the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (grant MC_PC_20029). Laboratory work was funded by a Wellcome Intermediate Clinical Fellowship to B.F. (201488/Z/16/Z). We acknowledge the staff at NHS Digital, Public Health England and the Intensive Care National Audit and Research Centre who provided clinical data on the participants; and the National Institute for Healthcare Research Clinical Research Network (NIHR CRN) and the Chief Scientist’s Office (Scotland), who facilitate recruitment into research studies in NHS hospitals, and to the global ISARIC and InFACT consortia. GenOMICC genotype controls were obtained using UK Biobank Resource under project 788 funded by Roslin Institute Strategic Programme Grants from the BBSRC (BBS/E/D/10002070 and BBS/E/D/30002275) and Health Data Research UK (HDR-9004 and HDR-9003). UK Biobank data were used in the GSMR analyses presented here under project 66982. The UK Biobank was established by the Wellcome Trust medical charity, Medical Research Council, Department of Health, Scottish Government and the Northwest Regional Development Agency. It has also had funding from the Welsh Assembly Government, British Heart Foundation and Diabetes UK. The work of L.K. was supported by an RCUK Innovation Fellowship from the National Productivity Investment Fund (MR/R026408/1). J.Y. is supported by the Westlake Education Foundation. SCOURGE is funded by the Instituto de Salud Carlos III (COV20_00622 to A.C., PI20/00876 to C.F.), European Union (ERDF) ‘A way of making Europe’, Fundación Amancio Ortega, Banco de Santander (to A.C.), Cabildo Insular de Tenerife (CGIEU0000219140 ‘Apuestas científicas del ITER para colaborar en la lucha contra la COVID-19’ to C.F.) and Fundación Canaria Instituto de Investigación Sanitaria de Canarias (PIFIISC20/57 to C.F.). We also acknowledge the contribution of the Centro National de Genotipado (CEGEN) and Centro de Supercomputación de Galicia (CESGA) for funding this project by providing supercomputing infrastructures. A.D.L. is a recipient of fellowships from the National Council for Scientific and Technological Development (CNPq)-Brazil (309173/2019-1 and 201527/2020-0)