Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (<0.01 s/n) in env gene than other EC. We postulate that these EEC represent cases of spontaneous functional HIV-1 cure. A non-functional and non-genetically evolving viral reservoir along with an HIV-1-specific immune response seems to be key for the spontaneous functional cure.Work in Centro Nacional de Microbiologia (ISCIII) was supported by grants SAF (2016–77894-R) from Ministerio de Economia y Competitividad (MINECO) (Spain) and Fondo de Investigación Sanitaria (FIS)-Instituto de Salud CarlosIII, grant FIS (PI 13/02269, ISCIII) and in part by the RIS-RETIC grants RD12/0017/0028 and RD16CIII/0002/0005 funded by the ISCIII-FEDER. MP has a contract of RIS-RETIC RD16CIII/0002/0005. This work was supported by grants from the MINECO, FIS-Instituto de Salud CarlosIII, Fondos Europeos para el Desarrollo Regional, FEDER, grant numbers PI16/00684, PI19/01127, CPII014/00025 to ER-M. and FI14/00431 to LT-D.; the Gilead Fellowship Program (grant numbers GLD17/00299); the Red de Investigación en Sida (grant number RD16/0025/0020). ER-M. is supported by Consejería de Salud y Bienestar Social of Junta de Andalucía through the Nicolás Monardes Program (C-0032/17). Research in VS-M group was supported by Fondo de Investigación Sanitaria (FIS)-Instituto de Salud CarlosIII, grant FIS (PI 17CIII/00049). Grifols partially supported work in the AIDS Research Institute IrsiCaixa. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.S

TERASENSE: THz device technology laboratory

The use of THz frequencies, particularly W and G band allows reaching higher resolution and deeper penetration in emerging applications like imaging, sensing, etc. The development of those new applications lays on reliable technologies, background of expertise and know-how. The CDS2008-00068 TERASENSE CONSOLIDER project has given the opportunity to extent upwards in frequency the previous background of the microwaves research group partners. This article summarizes the developments of the TERASENSE work package “THz Device Technology Laboratory”

TERASENSE: THz device technology laboratory: final summary

The use of THz frequencies, particularly W and G band allows reaching higher resolution and deeper penetration in emerging applications like imaging, sensing, etc. The development of those new applications lays on reliable technologies, background of expertise and know-how. The CDS2008-00068 TERASENSE CONSOLIDER project has given the opportunity to extent upwards in frequency the previous background of the microwaves research group partners. This article summarizes the developments of the TERASENSE work package “THz Device Technology Laboratory”.This work was supported by the Spanish Ministerio de Ciencia e Innovación through the CONSOLIDER-INGENIO 2010 program reference CSD2008-00068 TERASENSE

Importance of genotype for risk stratification in arrhythmogenic right ventricular cardiomyopathy using the 2019 ARVC risk calculator

none41siTo study the impact of genotype on the performance of the 2019 risk model for arrhythmogenic right ventricular cardiomyopathy (ARVC).Protonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry MProtonotarios, Alexandros; Bariani, Riccardo; Cappelletto, Chiara; Pavlou, Menelaos; García-García, Alba; Cipriani, Alberto; Protonotarios, Ioannis; Rivas, Adrian; Wittenberg, Regitze; Graziosi, Maddalena; Xylouri, Zafeirenia; Larrañaga-Moreira, José M; de Luca, Antonio; Celeghin, Rudy; Pilichou, Kalliopi; Bakalakos, Athanasios; Lopes, Luis Rocha; Savvatis, Konstantinos; Stolfo, Davide; Dal Ferro, Matteo; Merlo, Marco; Basso, Cristina; Freire, Javier Limeres; Rodriguez-Palomares, Jose F; Kubo, Toru; Ripoll-Vera, Tomas; Barriales-Villa, Roberto; Antoniades, Loizos; Mogensen, Jens; Garcia-Pavia, Pablo; Wahbi, Karim; Biagini, Elena; Anastasakis, Aris; Tsatsopoulou, Adalena; Zorio, Esther; Gimeno, Juan R; Garcia-Pinilla, Jose Manuel; Syrris, Petros; Sinagra, Gianfranco; Bauce, Barbara; Elliott, Perry

COVID19 Disease Map, a computational knowledge repository of virus-host interaction mechanisms.

Funder: Bundesministerium für Bildung und ForschungFunder: Bundesministerium für Bildung und Forschung (BMBF)We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background: Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods: For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings: Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8-13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05-6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50-75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation: Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer, studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory, a versatile observatory designed to address the Hot and Energetic Universe science theme, selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), it aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over an hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR, browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters. Finally we briefly discuss on the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, and touch on communication and outreach activities, the consortium organisation, and finally on the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. (abridged).Comment: 48 pages, 29 figures, Accepted for publication in Experimental Astronomy with minor editin

The Athena X-ray Integral Field Unit: a consolidated design for the system requirement review of the preliminary definition phase

The Athena X-ray Integral Unit (X-IFU) is the high resolution X-ray spectrometer studied since 2015 for flying in the mid-30s on the Athena space X-ray Observatory. Athena is a versatile observatory designed to address the Hot and Energetic Universe science theme, as selected in November 2013 by the Survey Science Committee. Based on a large format array of Transition Edge Sensors (TES), X-IFU aims to provide spatially resolved X-ray spectroscopy, with a spectral resolution of 2.5 eV (up to 7 keV) over a hexagonal field of view of 5 arc minutes (equivalent diameter). The X-IFU entered its System Requirement Review (SRR) in June 2022, at about the same time when ESA called for an overall X-IFU redesign (including the X-IFU cryostat and the cooling chain), due to an unanticipated cost overrun of Athena. In this paper, after illustrating the breakthrough capabilities of the X-IFU, we describe the instrument as presented at its SRR (i.e. in the course of its preliminary definition phase, so-called B1), browsing through all the subsystems and associated requirements. We then show the instrument budgets, with a particular emphasis on the anticipated budgets of some of its key performance parameters, such as the instrument efficiency, spectral resolution, energy scale knowledge, count rate capability, non X-ray background and target of opportunity efficiency. Finally, we briefly discuss the ongoing key technology demonstration activities, the calibration and the activities foreseen in the X-IFU Instrument Science Center, touch on communication and outreach activities, the consortium organisation and the life cycle assessment of X-IFU aiming at minimising the environmental footprint, associated with the development of the instrument. Thanks to the studies conducted so far on X-IFU, it is expected that along the design-to-cost exercise requested by ESA, the X-IFU will maintain flagship capabilities in spatially resolved high resolution X-ray spectroscopy, enabling most of the original X-IFU related scientific objectives of the Athena mission to be retained. The X-IFU will be provided by an international consortium led by France, The Netherlands and Italy, with ESA member state contributions from Belgium, Czech Republic, Finland, Germany, Poland, Spain, Switzerland, with additional contributions from the United States and Japan.The French contribution to X-IFU is funded by CNES, CNRS and CEA. This work has been also supported by ASI (Italian Space Agency) through the Contract 2019-27-HH.0, and by the ESA (European Space Agency) Core Technology Program (CTP) Contract No. 4000114932/15/NL/BW and the AREMBES - ESA CTP No.4000116655/16/NL/BW. This publication is part of grant RTI2018-096686-B-C21 funded by MCIN/AEI/10.13039/501100011033 and by “ERDF A way of making Europe”. This publication is part of grant RTI2018-096686-B-C21 and PID2020-115325GB-C31 funded by MCIN/AEI/10.13039/501100011033

National trends in total cholesterol obscure heterogeneous changes in HDL and non-HDL cholesterol and total-to-HDL cholesterol ratio : a pooled analysis of 458 population-based studies in Asian and Western countries

Background: Although high-density lipoprotein (HDL) and non-HDL cholesterol have opposite associations with coronary heart disease, multi-country reports of lipid trends only use total cholesterol (TC). Our aim was to compare trends in total, HDL and nonHDL cholesterol and the total-to-HDL cholesterol ratio in Asian and Western countries. Methods: We pooled 458 population-based studies with 82.1 million participants in 23 Asian and Western countries. We estimated changes in mean total, HDL and non-HDL cholesterol and mean total-to-HDL cholesterol ratio by country, sex and age group. Results: Since similar to 1980, mean TC increased in Asian countries. In Japan and South Korea, the TC rise was due to rising HDL cholesterol, which increased by up to 0.17 mmol/L per decade in Japanese women; in China, it was due to rising non-HDL cholesterol. TC declined in Western countries, except in Polish men. The decline was largest in Finland and Norway, at similar to 0.4 mmol/L per decade. The decline in TC in most Western countries was the net effect of an increase in HDL cholesterol and a decline in non-HDL cholesterol, with the HDL cholesterol increase largest in New Zealand and Switzerland. Mean total-to-HDL cholesterol ratio declined in Japan, South Korea and most Western countries, by as much as similar to 0.7 per decade in Swiss men (equivalent to similar to 26% decline in coronary heart disease risk per decade). The ratio increased in China. Conclusions: HDL cholesterol has risen and the total-to-HDL cholesterol ratio has declined in many Western countries, Japan and South Korea, with only a weak correlation with changes in TC or non-HDL cholesterol.Peer reviewe