Beneficial Effect of Short-Term Supplementation of High Dose of Vitamin D3 in Hospitalized Patients With COVID-19: A Multicenter, Single-Blinded, Prospective Randomized Pilot Clinical Trial.

There is now sufficient evidence to support that vitamin D deficiency may predispose to SARS-CoV-2 infection and increase COVID-19 severity and mortality. It has been suggested that vitamin D3 supplementation may be used prophylactically as an affordable and safe strategy that could be added to the existing COVID-19 standard treatment. This multicenter, single-blinded, prospective randomized pilot clinical trial aimed to evaluate the safety, tolerability, and effectiveness of 10,000 IU/day in comparison with 2000 IU/day of cholecalciferol supplementation for 14 days to reduce the duration and severity of COVID-19 in 85 hospitalized individuals. The median age of the participants was 65 years (Interquartile range (IQR): 53-74), most of them (71%) were men and the mean baseline of 25-hydroxyvitamin D (25(OH)D) in serum was 15 ng/ml (standard deviation (SD):6). After 14 days of supplementation, serum 25(OH)D levels were significantly increased in the group who received 10,000IU/day (p < 0.0001) (n = 44) in comparison with the 2,000IU/day group (n = 41), especially in overweight and obese participants, and the higher dose was well tolerated. A fraction of the individuals in our cohort (10/85) developed acute respiratory distress syndrome (ARDS). The median length of hospital stay in these patients with ARDS was significantly different in the participants assigned to the 10,000IU/day group (n = 4; 7 days; IQR: 4-13) and the 2,000IU/day group (n = 6; 27 days; IQR: 12-45) (p = 0.04). Moreover, the inspired oxygen fraction was reduced 7.6-fold in the high dose group (p = 0.049). In terms of blood parameters, we did not identify overall significant improvements, although the platelet count showed a modest but significant difference in those patients who were supplemented with the higher dose (p = 0.0492). In conclusion, the administration of 10,000IU/day of vitamin D3 for 14 days in association with the standard clinical care during hospitalization for COVID-19 was safe, tolerable, and beneficial, thereby helping to improve the prognosis during the recovery process.This work was supported by Fundación Universidad Alfonso X el Sabio (FUAX, Madrid, Spain; ID Project: 1.012.010; ID Project EQA: 925.280); the Coordinated Research Activities at the National Center of Microbiology (Instituto de Salud Carlos III) (COV20_00679) to promote an integrated response against SARS-CoV-2 in Spain (Spanish Ministry of Science and Innovation) that is coordinated by Dr. Inmaculada Casas (WHO National Influenza Center of the CNM); a generous donation provided by Chiesi España, S.A.U. (Barcelona, Spain). The work of Montserrat Torres was financed by the Coordinated Research Activities at the CNM (Instituto de Salud Carlos III) (COV20_00679). The work of Lorena Vigón was supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Sara Rodríguez-Mora was financed by NIH grant R01AI143567.S

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p &lt; 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Tocilizumab efficacy in COVID-19 patients is associated with respiratory severity-based stages

Background Tocilizumab treatment is investigated, and effectiveness in ICU-admitted COVID-19 patients has been reported. Although controversy exists regarding the efficacy of tocilizumab treatment, it has been suggested that tocilizumab might show positive results depending on patient severity status. We examined an association between tocilizumab and distinct disease severity stages. Methods and Findings From March 3 to March 23 2020, 494 consecutively admitted COVID-19 patients received tocilizumab or standard treatment alone. Data were obtained retrospectively. Clinical respiratory severity (CRS) stages were defined by patient oxygenation status and were also associated to scores of WHO clinical progression scale. We categorized patients in three stages, mild/moderate CRS1 (FiSpO26). The primary outcome was the composite of death or ICU admission in patients of stages CRS1, CRS2, and CRS3, as well as in total patients. We also addressed mortality alone in total patients. Kaplan-Maier curves, Cox proportional regression and inverse probability weighting marginal structural models were used. We conducted the study from March 3 to April 7 2020 with broad-ranged severity patients; 167 tocilizumab-treated and 327 untreated. CRS1 patients showed no apparent benefit after treatment, while the risk of the primary outcome was greatly reduced in CRS2 treated participants ((HR=0.22; 95% CI (0.16-0.44)). Moreover, tocilizumab treatment was associated with significantly decreased CRS2 patient proportion that reached the outcome compared to non-treated controls (27.8.0% vs. 65.4%; p<0.001). Severe/critical CRS3 patients, also showed benefit after treatment (HR=0.38; 95% CI (0.16-90)), although not as robust as was that of CRS2 treated individuals. Tocilizumab was associated with reduced outcome risk in total patients (HR=0.42; 95% CI (0.26-0.66)) after CRS adjustment, but not if CRS classification was not accounted as confounding factor (HR=1.19; 95% CI (0.84-1.69)). The outcome of mortality alone upon tocilizumab treatment was significant (HR=0.58; 95% CI (0.35-0.96)) after accounting for CRS classification. Conclusions Tocilizumab treatment is associated with reduced COVID-19 escalation in CRS2 patients, suggesting efficacy in moderate/severe non-ICU-admitted patients. CRS classification could represent an essential confounding factor in evaluating tocilizumab in studies of broad-ranged severity patients.This work was partially supported by grants from the Fondo de Investigación de la Seguridad Social-Instituto de Salud Carlos III (PI18/01726), Spain. Programa de Actividades de I+D de la Comunidad de Madrid en Biomedicina (B2017/BMD-3804), Madrid, Spain. Instituto de Salud Carlos III CIBER Enfermedades hepaticas y Digestivas, Spain. Agencia Estatal de Investigacion. SAF2016-80803-R. Medicina individualizada traslacional, en inflamacion y cancer. Comunidad de Madrid. B2017/BMD-3804, Spain (to: MAM, CMA and DB). GR holds Juan de la Cierva grant (Ministerio de Ciencia e Innovacion).N

How do women living with HIV experience menopause? Menopausal symptoms, anxiety and depression according to reproductive age in a multicenter cohort

CatedresBackground: To estimate the prevalence and severity of menopausal symptoms and anxiety/depression and to assess the differences according to menopausal status among women living with HIV aged 45-60 years from the cohort of Spanish HIV/AIDS Research Network (CoRIS). Methods: Women were interviewed by phone between September 2017 and December 2018 to determine whether they had experienced menopausal symptoms and anxiety/depression. The Menopause Rating Scale was used to evaluate the prevalence and severity of symptoms related to menopause in three subscales: somatic, psychologic and urogenital; and the 4-item Patient Health Questionnaire was used for anxiety/depression. Logistic regression models were used to estimate odds ratios (ORs) of association between menopausal status, and other potential risk factors, the presence and severity of somatic, psychological and urogenital symptoms and of anxiety/depression. Results: Of 251 women included, 137 (54.6%) were post-, 70 (27.9%) peri- and 44 (17.5%) pre-menopausal, respectively. Median age of onset menopause was 48 years (IQR 45-50). The proportions of pre-, peri- and post-menopausal women who had experienced any menopausal symptoms were 45.5%, 60.0% and 66.4%, respectively. Both peri- and post-menopause were associated with a higher likelihood of having somatic symptoms (aOR 3.01; 95% CI 1.38-6.55 and 2.63; 1.44-4.81, respectively), while post-menopause increased the likelihood of having psychological (2.16; 1.13-4.14) and urogenital symptoms (2.54; 1.42-4.85). By other hand, post-menopausal women had a statistically significant five-fold increase in the likelihood of presenting severe urogenital symptoms than pre-menopausal women (4.90; 1.74-13.84). No significant differences by menopausal status were found for anxiety/depression. Joint/muscle problems, exhaustion and sleeping disorders were the most commonly reported symptoms among all women. Differences in the prevalences of vaginal dryness (p = 0.002), joint/muscle complaints (p = 0.032), and sweating/flush (p = 0.032) were found among the three groups. Conclusions: Women living with HIV experienced a wide variety of menopausal symptoms, some of them initiated before women had any menstrual irregularity. We found a higher likelihood of somatic symptoms in peri- and post-menopausal women, while a higher likelihood of psychological and urogenital symptoms was found in post-menopausal women. Most somatic symptoms were of low or moderate severity, probably due to the good clinical and immunological situation of these women

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization

Voce: Prelievi e analisi di campioni

Con la legge 30.6.2009 n. 85 l'Italia ha ratificato l'adesione al Trattato di Pr\ufcm, in vista del rafforzamento della cooperazione tra Stati nella lotta al terrorismo, alla criminalit\ue0 transfrontaliera e alla migrazione illegale, tramite lo scambio di informazioni genetiche. La novit\ue0 pi\uf9 saliente che l'adesione al Trattato ha importato nell'ordinamento interno concerne l'introduzione di un'inedita disciplina dei prelievi coattivi di materiale biologico, volta alla tutela dei diritti individuali nell'impiego processuale di strumenti tecnico-scientifici che consentano di non disperdere il materiale probatorio relativo ad un fatto criminoso. Il tema rievoca la tradizionale distinzione che attribuisce all'imputato la duplice funzione di \u201corgano\u201d ed \u201coggetto\u201d nella formazione della prova, a seconda del contributo attivo o passivo che lo stesso apporti alla vicenda processuale. Questi \ue8 considerato \u201corgano\u201d di prova nell'espletamento di attivit\ue0 che costituiscono esercizio del diritto di difesa, nelle due componenti, positiva e negativa, del diritto di difendersi provando e del diritto al silenzio. Viceversa, si parla di imputato come \u201coggetto\u201d di prova allorquando gli sia richiesto un mero pati rispetto all'attivit\ue0 di istruzione probatoria, come accade nelle ispezioni, nelle perquisizioni, nelle ricognizioni personali, nonch\ue9, pi\uf9 in generale, negli accertamenti che si espletano sul corpo del giudicabile, il quale viene in rilievo non come parte processuale, ma come mera entit\ue0 fisica. Il regime di nuovo conio \ue8 intervenuto a colmare la lacuna normativa lasciata dalla sentenza n. 238 del 1996 con cui la Corte costituzionale aveva dichiarato l'illegittimit\ue0 dell'art. 224, comma 2, c.p.p. nella parte in cui consentiva interventi peritali sul corpo della persona, in violazione del principio di riserva di legge che presidia, ex art. 13 Cost., la libert\ue0 personale. La pronuncia ha individuato un \u201cnocciolo duro\u201d rappresentato dalla libert\ue0 corporale, indissolubilmente legata ai principi di libert\ue0 morale, integrit\ue0 psico-fisica e salute della persona, non comprimibili a fini processuali. La Carta fondamentale prevede un'unica ipotesi di lesione del diritto alla salute nell'ambito dei trattamenti sanitari obbligatori, per finalit\ue0 estranee all'accertamento penale; la libert\ue0 morale, peraltro, rappresenta il quid pluris che sopravvive alla compressione del potere statale, persino durante la pi\uf9 intensa restrizione della libert\ue0 personale. Se questo \ue8 il quadro costituzionale di riferimento, \ue8 evidente come il previgente regime in materia di prelievi biologici coattivi abbia disatteso le indicazioni provenienti dalla Consulta. Difatti, a distanza di quasi un decennio dal monito del Giudice delle leggi, il legislatore intervenne (con la legge 31 luglio 2005, n. 155) \uabin un modo persino pi\uf9 imbarazzante dell'inerzia sino ad allora mantenuta\ubb, attribuendo un potere di intrusione corporale (attraverso il prelievo di capelli o saliva nel corso delle indagini) alla polizia giudiziaria, previa autorizzazione - anche orale, purch\ue9 confermata per iscritto - del pubblico ministero, a soli fini identificativi e purch\ue9 sussistesse il pericolo di alterazione o dispersione della res. Non era contemplato il potere giudiziale di disporre un prelievo biologico a fini peritali e l\u2019esclusivo orientamento teleologico dell\u2019atto d\u2019indagine ne limitava fortemente l\u2019utilit\ue0. Veniva, pertanto, inopinatamente elusa la doppia riserva, di legge e di giurisdizione, che presidia la materia. La riforma realizza una netta soluzione di continuit\ue0 rispetto alla normativa precedente, attraverso l'individuazione nell'organo giurisdizionale del baricentro del micro-sistema normativo dedicato ai prelievi biologici coattivi. Se la libert\ue0 personale pu\uf2 subire restrizioni per atto motivato dell'autorit\ue0 giudiziaria, pertanto anche del pubblico ministero, l'intrusione nella sfera corporale esige l'egida di un soggetto super partes, indifferente rispetto all'esito del processo. Il legislatore ha costruito una disciplina minuziosa, concernente sia l'an che il quomodo dei prelievi, in ossequio alla riserva di legge dettagliata (nei \u201cmodi\u201d e nei \u201ccasi\u201d) imposta dalla Consulta. Ne \ue8 derivato un apparato \uabmulti-livello\ubb, calibrato sulla sistematica del codice e diversificato in base all'orientamento teleologico dell'accertamento \u2013istituzionale, probatorio, investigativo o identificativo-, in cui ogni tipologia \ue8 rigidamente separata dalle altre

Deep Underground Neutrino Experiment (DUNE) Near Detector Conceptual Design Report

International audienceThe Deep Underground Neutrino Experiment (DUNE) is an international, world-class experiment aimed at exploring fundamental questions about the universe that are at the forefront of astrophysics and particle physics research. DUNE will study questions pertaining to the preponderance of matter over antimatter in the early universe, the dynamics of supernovae, the subtleties of neutrino interaction physics, and a number of beyond the Standard Model topics accessible in a powerful neutrino beam. A critical component of the DUNE physics program involves the study of changes in a powerful beam of neutrinos, i.e., neutrino oscillations, as the neutrinos propagate a long distance. The experiment consists of a near detector, sited close to the source of the beam, and a far detector, sited along the beam at a large distance. This document, the DUNE Near Detector Conceptual Design Report (CDR), describes the design of the DUNE near detector and the science program that drives the design and technology choices. The goals and requirements underlying the design, along with projected performance are given. It serves as a starting point for a more detailed design that will be described in future documents

Deep Underground Neutrino Experiment (DUNE), Far Detector Technical Design Report, Volume I Introduction to DUNE

International audienceThe preponderance of matter over antimatter in the early universe, the dynamics of the supernovae that produced the heavy elements necessary for life, and whether protons eventually decay—these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our universe, its current state, and its eventual fate. The Deep Underground Neutrino Experiment (DUNE) is an international world-class experiment dedicated to addressing these questions as it searches for leptonic charge-parity symmetry violation, stands ready to capture supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector technical design report (TDR) describes the DUNE physics program and the technical designs of the single- and dual-phase DUNE liquid argon TPC far detector modules. This TDR is intended to justify the technical choices for the far detector that flow down from the high-level physics goals through requirements at all levels of the Project. Volume I contains an executive summary that introduces the DUNE science program, the far detector and the strategy for its modular designs, and the organization and management of the Project. The remainder of Volume I provides more detail on the science program that drives the choice of detector technologies and on the technologies themselves. It also introduces the designs for the DUNE near detector and the DUNE computing model, for which DUNE is planning design reports. Volume II of this TDR describes DUNE's physics program in detail. Volume III describes the technical coordination required for the far detector design, construction, installation, and integration, and its organizational structure. Volume IV describes the single-phase far detector technology. A planned Volume V will describe the dual-phase technology

Reconstruction of interactions in the ProtoDUNE-SP detector with Pandora

International audienceThe Pandora Software Development Kit and algorithm libraries provide pattern-recognition logic essential to the reconstruction of particle interactions in liquid argon time projection chamber detectors. Pandora is the primary event reconstruction software used at ProtoDUNE-SP, a prototype for the Deep Underground Neutrino Experiment far detector. ProtoDUNE-SP, located at CERN, is exposed to a charged-particle test beam. This paper gives an overview of the Pandora reconstruction algorithms and how they have been tailored for use at ProtoDUNE-SP. In complex events with numerous cosmic-ray and beam background particles, the simulated reconstruction and identification efficiency for triggered test-beam particles is above 80% for the majority of particle type and beam momentum combinations. Specifically, simulated 1 GeV/$c$ charged pions and protons are correctly reconstructed and identified with efficiencies of 86.1$\pm0.6$% and 84.1$\pm0.6$%, respectively. The efficiencies measured for test-beam data are shown to be within 5% of those predicted by the simulation

The DUNE Far Detector Vertical Drift Technology, Technical Design Report

International audienceDUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals