11 research outputs found
Effectiveness and safety of integrase strand transfer inhibitors in Spain: a prospective real-world study
IntroductionSecond-generation integrase strand transfer inhibitors (INSTIs) are preferred treatment options worldwide, and dolutegravir (DTG) is the treatment of choice in resource-limited settings. Nevertheless, in some resource-limited settings, these drugs are not always available. An analysis of the experience with the use of INSTIs in unselected adults living with HIV may be of help to make therapeutic decisions when second-generation INSTIs are not available. This study aimed to evaluate the real-life effectiveness and safety of dolutegravir (DTG), elvitegravir/cobicistat (EVG/c), and raltegravir (RAL) in a large Spanish cohort of HIV-1-infected patients.MethodsReal-world study of adults living with HIV who initiated integrase INSTIs DTG, EVG/c, and RAL-based regimens in three settings (ART-naïve patients, ART-switching, and ART-salvage patients). The primary endpoint was the median time to treatment discontinuation after INSTI-based regimen initiation. Proportion of patients experiencing virological failure (VF) (defined as two consecutive viral loads (VL) ≥200 copies/mL at 24 weeks or as a single determination of VL ≥1,000 copies/mL while receiving DTG, EVG/c or RAL, and at least 3 months after INSTI initiation) and time to VF were also evaluated.ResultsVirological effectiveness of EVG/c- and RAL-based regimens was similar to that of DTG when given as first-line and salvage therapy. Treatment switching for reasons other than virological failure was more frequent in subjects receiving EVG/c and, in particular, RAL. Naïve patients with CD4+ nadir <100 cells/μL were more likely to develop VF, particularly if they initiated RAL or EVG/c. In the ART switching population, initiation of RAL and EVG/c was associated with both VF and INSTI discontinuation. There were no differences in the time to VF and INSTI discontinuation between DTG, EVG/c and RAL. Immunological parameters improved in the three groups and for the three drugs assessed. Safety and tolerability were consistent with expected safety profiles.DiscussionWhereas second-generation INSTIs are preferred treatment options worldwide, and DTG is one of the treatment of choices in resource-limited settings, first-generation INSTIs may still provide high virological and immunological effectiveness when DTG is not available
Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form
Global variations in diabetes mellitus based on fasting glucose and haemogloblin A1c
Fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) are both used to diagnose
diabetes, but may identify different people as having diabetes. We used data from 117
population-based studies and quantified, in different world regions, the prevalence of
diagnosed diabetes, and whether those who were previously undiagnosed and detected
as having diabetes in survey screening had elevated FPG, HbA1c, or both. We developed
prediction equations for estimating the probability that a person without previously
diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa.
The age-standardised proportion of diabetes that was previously undiagnosed, and
detected in survey screening, ranged from 30% in the high-income western region to 66%
in south Asia. Among those with screen-detected diabetes with either test, the agestandardised
proportion who had elevated levels of both FPG and HbA1c was 29-39%
across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and
middle-income regions, isolated elevated HbA1c more common than isolated elevated
FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and
underestimate diabetes prevalence. Our prediction equations help allocate finite
resources for measuring HbA1c to reduce the global gap in diabetes diagnosis and
surveillance.peer-reviewe
H, C and N Backbone chemical shift assignments of the n-terminal and central intrinsically disordered domains of SARS-CoV-2 nucleoprotein
International audienceThe nucleoprotein (N) from SARS-CoV-2 is an essential cofactor of the viral replication transcription complex and as such represents an important target for viral inhibition. It has also been shown to colocalize to the transcriptase-replicase complex, where many copies of N decorate the viral genome, thereby protecting it from the host immune system. N has also been shown to phase separate upon interaction with viral RNA. N is a 419 amino acid multidomain protein, comprising two folded, RNA-binding and dimerization domains spanning residues 45175 and 264365 respectively. The remaining 164 amino acids are predicted to be intrinsically disordered, but there is currently no atomic resolution information describing their behaviour. Here we assign the backbone resonances of the first two intrinsically disordered domains (N1, spanning residues 144 and N3, spanning residues 176263). Our assignment provides the basis for the identification of inhibitors and functional and interaction studies of this essential protein
The intrinsically disordered SARS-CoV-2 nucleoprotein in dynamic complex with its viral partner nsp3a
International audienceThe processes of genome replication and transcription of SARS-CoV-2 represent important targets for viral inhibition. Betacoronaviral nucleoprotein (N) is a highly dynamic cofactor of the replication-transcription complex (RTC), whose function depends on an essential interaction with the amino-terminal ubiquitin-like domain of nsp3 (Ubl1). Here, we describe this complex (dissociation constant - 30 to 200 nM) at atomic resolution. The interaction implicates two linear motifs in the intrinsically disordered linker domain (N3), a hydrophobic helix ((219)LALLLLDRLNQL(230)) and a disordered polar strand ((243)GQTVTKKSAAEAS(255)), that mutually engage to form a bipartite interaction, folding N3 around Ubl1. This results in substantial collapse in the dimensions of dimeric N, forming a highly compact molecular chaperone, that regulates binding to RNA, suggesting a key role of nsp3 in the association of N to the RTC. The identification of distinct linear motifs that mediate an important interaction between essential viral factors provides future targets for development of innovative strategies against COVID-19
Large-Scale Recombinant Production of the SARS-CoV-2 Proteome for High-Throughput and Structural Biology Applications
The highly infectious disease COVID-19 caused by the Betacoronavirus SARS-CoV-2 poses a severe threat to humanity and demands the redirection of scientific efforts and criteria to organized research projects. The international COVID19-NMR consortium seeks to provide such new approaches by gathering scientific expertise worldwide. In particular, making available viral proteins and RNAs will pave the way to understanding the SARS-CoV-2 molecular components in detail. The research in COVID19-NMR and the resources provided through the consortium are fully disclosed to accelerate access and exploitation. NMR investigations of the viral molecular components are designated to provide the essential basis for further work, including macromolecular interaction studies and high-throughput drug screening. Here, we present the extensive catalog of a holistic SARS-CoV-2 protein preparation approach based on the consortium’s collective efforts. We provide protocols for the large-scale production of more than 80% of all SARS-CoV-2 proteins or essential parts of them. Several of the proteins were produced in more than one laboratory, demonstrating the high interoperability between NMR groups worldwide. For the majority of proteins, we can produce isotope-labeled samples of HSQC-grade. Together with several NMR chemical shift assignments made publicly available on covid19-nmr.com, we here provide highly valuable resources for the production of SARS-CoV-2 proteins in isotope-labeled form.This work was supported by Goethe University (Corona funds),
the DFG-funded CRC: “Molecular Principles of RNA-Based
Regulation,” DFG infrastructure funds (project numbers:
277478796, 277479031, 392682309, 452632086, 70653611), the
state of Hesse (BMRZ), the Fondazione CR Firenze (CERM),
and the IWB-EFRE-program 20007375. This project has
received funding from the European Union’s Horizon 2020
research and innovation program under Grant Agreement No.
871037. AS is supported by DFG Grant SCHL 2062/2-1 and by the
JQYA at Goethe through project number 2019/AS01. Work in the
lab of KV was supported by a CoRE grant from the University of
New Hampshire. The FLI is a member of the Leibniz Association
(WGL) and financially supported by the Federal Government of
Germany and the State of Thuringia. Work in the lab of RM was
supported by NIH (2R01EY021514) and NSF (DMR-2002837).
BN-B was supported by theNSF GRFP.MCwas supported byNIH
(R25 GM055246 MBRS IMSD), and MS-P was supported by the
HHMI Gilliam Fellowship. Work in the labs of KJ and KT was
supported by Latvian Council of Science Grant No. VPP-COVID
2020/1-0014. Work in the UPAT’s lab was supported by the
INSPIRED (MIS 5002550) project, which is implemented under
the Action “Reinforcement of the Research and Innovation
Infrastructure,” funded by the Operational Program
“Competitiveness, Entrepreneurship and Innovation” (NSRF
2014–2020) and cofinanced by Greece and the EU (European
Regional Development Fund) and the FP7 REGPOT CT-2011-
285950–“SEE-DRUG” project (purchase of UPAT’s 700MHz
NMR equipment). Work in the CM-G lab was supported by
the Helmholtz society. Work in the lab of ABö was supported
by the CNRS, the French National Research Agency (ANR, NMRSCoV2-
ORF8), the Fondation de la Recherche Médicale (FRM,
NMR-SCoV2-ORF8), and the IR-RMN-THC Fr3050 CNRS.
Work in the lab of BM was supported by the Swiss National
Science Foundation (Grant number 200020_188711), the
Günthard Stiftung für Physikalische Chemie, and the ETH
Zurich. Work in the labs of ABö and BM was supported by a
common grant from SNF (grant 31CA30_196256). This work was
supported by the ETHZurich, the grant ETH40 18 1, and the grant
Krebsliga KFS 4903 08 2019. Work in the lab of the IBS Grenoble
was supported by the Agence Nationale de Recherche (France)
RA-COVID SARS2NUCLEOPROTEIN and European Research
Council Advanced Grant DynamicAssemblies. Work in the
CA lab was supported by Patto per il Sud della Regione
Siciliana–CheMISt grant (CUP G77B17000110001). Part of
this work used the platforms of the Grenoble Instruct-ERIC
center (ISBG; UMS 3518 CNRS-CEA-UGA-EMBL) within the
Grenoble Partnership for Structural Biology (PSB), supported
by FRISBI (ANR-10-INBS-05-02) and GRAL, financed within
the University Grenoble Alpes graduate school (Ecoles
Universitaires de Recherche) CBH-EUR-GS (ANR-17-EURE-
0003). Work at the UW-Madison was supported by grant
numbers NSF MCB2031269 and NIH/NIAID AI123498. MM
is a Ramón y Cajal Fellow of the Spanish AEI-Ministry of
Science and Innovation (RYC2019-026574-I), and a “La
Caixa” Foundation (ID 100010434) Junior Leader Fellow
(LCR/BQ/PR19/11700003). Funded by project COV20/00764
fromthe Carlos III Institute of Health and the SpanishMinistry
of Science and Innovation to MMand DVL. VDJ was supported
by the Boehringer Ingelheim Fonds. Part of this work used the
resources of the Italian Center of Instruct-ERIC at the CERM/
CIRMMP infrastructure, supported by the Italian Ministry for
University and Research (FOE funding). CF was supported by
the Stiftung Polytechnische Gesellschaft. Work in the lab of
JH was supported by NSF (RAPID 2030601) and NIH
(R01GM123249).Peer reviewe
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Effects of pre-operative isolation on postoperative pulmonary complications after elective surgery: an international prospective cohort study an international prospective cohort study
We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care. We aimed to determine the impact of pre-operative isolation on postoperative pulmonary complications after elective surgery during the global SARS-CoV-2 pandemic. We performed an international prospective cohort study including patients undergoing elective surgery in October 2020. Isolation was defined as the period before surgery during which patients did not leave their house or receive visitors from outside their household. The primary outcome was postoperative pulmonary complications, adjusted in multivariable models for measured confounders. Pre-defined sub-group analyses were performed for the primary outcome. A total of 96,454 patients from 114 countries were included and overall, 26,948 (27.9%) patients isolated before surgery. Postoperative pulmonary complications were recorded in 1947 (2.0%) patients of which 227 (11.7%) were associated with SARS-CoV-2 infection. Patients who isolated pre-operatively were older, had more respiratory comorbidities and were more commonly from areas of high SARS-CoV-2 incidence and high-income countries. Although the overall rates of postoperative pulmonary complications were similar in those that isolated and those that did not (2.1% vs 2.0%, respectively), isolation was associated with higher rates of postoperative pulmonary complications after adjustment (adjusted OR 1.20, 95%CI 1.05–1.36, p = 0.005). Sensitivity analyses revealed no further differences when patients were categorised by: pre-operative testing; use of COVID-19-free pathways; or community SARS-CoV-2 prevalence. The rate of postoperative pulmonary complications increased with periods of isolation longer than 3 days, with an OR (95%CI) at 4–7 days or ≥ 8 days of 1.25 (1.04–1.48), p = 0.015 and 1.31 (1.11–1.55), p = 0.001, respectively. Isolation before elective surgery might be associated with a small but clinically important increased risk of postoperative pulmonary complications. Longer periods of isolation showed no reduction in the risk of postoperative pulmonary complications. These findings have significant implications for global provision of elective surgical care
Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c
International audienceAbstract Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29–39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance
Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c
: Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance
General and abdominal adiposity and hypertension in eight world regions: a pooled analysis of 837 population-based studies with 7·5 million participants
International audienceSummaryBackground Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension.MethodsWe used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20–64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson’s correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI).FindingsThe correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m² (95% CI 2·31–3·28) lower for women and 1·28 kg/m² (1·02–1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone.InterpretationBMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions