Genetic landscape of 6089 inherited retinal dystrophies affected cases in Spain and their therapeutic and extended epidemiological implications

Inherited retinal diseases (IRDs), defined by dysfunction or progressive loss of photoreceptors, are disorders characterized by elevated heterogeneity, both at the clinical and genetic levels. Our main goal was to address the genetic landscape of IRD in the largest cohort of Spanish patients reported to date. A retrospective hospital-based cross-sectional study was carried out on 6089 IRD affected individuals (from 4403 unrelated families), referred for genetic testing from all the Spanish autonomous communities. Clinical, demographic and familiar data were collected from each patient, including family pedigree, age of appearance of visual symptoms, presence of any systemic findings and geographical origin. Genetic studies were performed to the 3951 families with available DNA using different molecular techniques. Overall, 53.2% (2100/3951) of the studied families were genetically characterized, and 1549 different likely causative variants in 142 genes were identified. The most common phenotype encountered is retinitis pigmentosa (RP) (55.6% of families, 2447/4403). The most recurrently mutated genes were PRPH2, ABCA4 and RS1 in autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL) NON-RP cases, respectively; RHO, USH2A and RPGR in AD, AR and XL for non-syndromic RP; and USH2A and MYO7A in syndromic IRD. Pathogenic variants c.3386G > T (p.Arg1129Leu) in ABCA4 and c.2276G > T (p.Cys759Phe) in USH2A were the most frequent variants identified. Our study provides the general landscape for IRD in Spain, reporting the largest cohort ever presented. Our results have important implications for genetic diagnosis, counselling and new therapeutic strategies to both the Spanish population and other related populations.This work was supported by the Instituto de Salud Carlos III (ISCIII) of the Spanish Ministry of Health (FIS; PI16/00425 and PI19/00321), Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER, 06/07/0036), IIS-FJD BioBank (PT13/0010/0012), Comunidad de Madrid (CAM, RAREGenomics Project, B2017/BMD-3721), European Regional Development Fund (FEDER), the Organización Nacional de Ciegos Españoles (ONCE), Fundación Ramón Areces, Fundación Conchita Rábago and the University Chair UAM-IIS-FJD of Genomic Medicine. Irene Perea-Romero is supported by a PhD fellowship from the predoctoral Program from ISCIII (FI17/00192). Ionut F. Iancu is supported by a grant from the Comunidad de Madrid (CAM, PEJ-2017-AI/BMD7256). Marta del Pozo-Valero is supported by a PhD grant from the Fundación Conchita Rábago. Berta Almoguera is supported by a Juan Rodes program from ISCIII (JR17/00020). Pablo Minguez is supported by a Miguel Servet program from ISCIII (CP16/00116). Marta Corton is supported by a Miguel Servet program from ISCIII (CPII17/00006). The funders played no role in study design, data collection, data analysis, manuscript preparation and/or publication decisions

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

Global overview of the management of acute cholecystitis during the COVID-19 pandemic (CHOLECOVID study)

Background: This study provides a global overview of the management of patients with acute cholecystitis during the initial phase of the COVID-19 pandemic. Methods: CHOLECOVID is an international, multicentre, observational comparative study of patients admitted to hospital with acute cholecystitis during the COVID-19 pandemic. Data on management were collected for a 2-month study interval coincident with the WHO declaration of the SARS-CoV-2 pandemic and compared with an equivalent pre-pandemic time interval. Mediation analysis examined the influence of SARS-COV-2 infection on 30-day mortality. Results: This study collected data on 9783 patients with acute cholecystitis admitted to 247 hospitals across the world. The pandemic was associated with reduced availability of surgical workforce and operating facilities globally, a significant shift to worse severity of disease, and increased use of conservative management. There was a reduction (both absolute and proportionate) in the number of patients undergoing cholecystectomy from 3095 patients (56.2 per cent) pre-pandemic to 1998 patients (46.2 per cent) during the pandemic but there was no difference in 30-day all-cause mortality after cholecystectomy comparing the pre-pandemic interval with the pandemic (13 patients (0.4 per cent) pre-pandemic to 13 patients (0.6 per cent) pandemic; P = 0.355). In mediation analysis, an admission with acute cholecystitis during the pandemic was associated with a non-significant increased risk of death (OR 1.29, 95 per cent c.i. 0.93 to 1.79, P = 0.121). Conclusion: CHOLECOVID provides a unique overview of the treatment of patients with cholecystitis across the globe during the first months of the SARS-CoV-2 pandemic. The study highlights the need for system resilience in retention of elective surgical activity. Cholecystectomy was associated with a low risk of mortality and deferral of treatment results in an increase in avoidable morbidity that represents the non-COVID cost of this pandemic

Plan de Acción en España para la erradicación de la poliomelitis: Vigilancia de la Parálisis Flácida Aguda y Vigilancia de Enterovirus en España. Informe 2020

Centro Nacional de Epidemiología y Centro Nacional de Microbiología. ISCIII. Plan de acción en España para la Erradicación de la Poliomielitis. Vigilancia de la Parálisis Flácida Aguda y Vigilancia de Enterovirus en España, Informe año 2020. Madrid, 5 de noviembre de 2021.[ES] En España la situación libre de polio se monitoriza con la vigilancia de Parálisis Flácida Aguda (PFA) en niños menores de 15 años, como recomienda la Organización Mundial de la Salud (OMS). La vigilancia la realizan los servicios de vigilancia autonómicos y la red de laboratorios de PFA y a nivel nacional se coordina en el Centro Nacional de Epidemiología (CNE, ISCIII) y en el Laboratorio de Poliovirus del Centro Nacional de Microbiología (CNM, ISCIII). En el año 2020 en España no hubo casos de poliomielitis. Se notificaron 0,17 casos de PFA por 100.000 niños menores de 15 años, por debajo del objetivo de sensibilidad establecido por la OMS de un caso de PFA al año por cada 100.000 menores de 15 años. Solamente se detectaron enterovirus no-polio (EVNP) en las muestras de dos casos (EV-D68 y EV-B, respectivamente). En España también se realiza la vigilancia de EVNP en otros síndromes neurológicos para complementar el sistema de vigilancia de PFA. En las muestras investigadas en 2020 no se identificó ningún poliovirus y los EVNP más frecuentemente identificados fueron E-18, CV-A6 y E-21. Mientras haya circulación de poliovirus en el mundo hay que mantener activos los sistemas de vigilancia para detectar a tiempo cualquier importación de poliovirus. [EN] Spain monitors its polio-free status by conducting surveillance for cases of acute flaccid paralysis (AFP) in children less than 15 years of age, as recommended by the World Health Organization (WHO). The AFP surveillance is performed by the 19 Regional Epidemiological Surveillance Units and the AFP Surveillance Laboratory Network, coordinated at national level by the National Centre for Epidemiology (CNE. ISCIII) and the National Poliovirus Laboratory at Nacional Center of Microbiology (CNM. ISCIII) respectively. In 2020, no cases of poliomyelitis were reported from clinical surveillance; Spain reported 0.17 non-polio AFP cases per 100,000 children, below the WHO's performance criterion for a sensitive surveillance system (1 non-polio AFP cases per 100,000 children). The non-polio enteroviruses EV-D68, EV-B were identified from clinical specimens collected from AFP cases. Spain also performs enterovirus surveillance to complement the clinical system In 2020, non poliovirus were identified; The non-polioviruses E-18, CV-A6 y E-21 were the most frequently identified serotypes. As long as poliovirus is circulating in the world, surveillance systems must remain active to detect any importation of poliovirus in a timely manner.1. Resumen. 2. Introducción. 3. Resultados de la vigilancia de Parálisis Flácida Aguda (PFA) en España, 2020. 4. Resultados de la vigilancia de enterovirus, España 2020. 5. Resultados de la vigilancia medioambiental de poliovirus. España, 2020. 6. Sistema de Información Microbiológica (SIM). Meningitis por enterovirus. Tendencia. 7. Conclusiones.N

Annual Epidemiological Report: Acute Flaccid Paralysis Surveillance and Enterovirus Surveillance, Spain, 2019

Centro Nacional de Epidemiología y Centro Nacional de Microbiología. ISCIII. Plan de acción en España para la Erradicación de la Poliomielitis. Vigilancia de la Parálisis Flácida Aguda y Vigilancia de Enterovirus en España, año 2019. Madrid, 1 julio 2020.[ES]Los resultados de la vigilancia de parálisis flácida aguda (PFA) y de la vigilancia de enterovirus (EV) muestran que en España en el año 2019 no hubo casos de poliomielitis ni circulación de poliovirus. La sensibilidad del sistema está por debajo del objetivo establecido por la OMS–Europa de 1 caso de PFA al año por cada 100.000 menores de 15 años, al situarse en 0,55/104 hab (0,58/104 <15años en 2018 ). Sin embargo, su estudio una vez detectados es adecuado. El índice de vigilancia, que sintetiza la sensibilidad del sistema de vigilancia y su estudio en laboratorio, fue de 0,28, similar a otros años. Gracias a la vigilancia de EV se detectó un PV derivado de vacuna (PVDV) en un paciente excretor inmunodeprimido; además se hallaron diferentes EV-no polio, los serotipos identificados fundamentalmente fueron E-7, E-30, E-11, CV-A6 y E-13. En 2019 la OMS declaró la eliminación del PV salvaje tipo 3(PVS3) a nivel mundial, aunque resulta preocupante el aumento en la detección de PVS1 y PVDVc 2 tanto en muestras humanas como medioambientales. La Evaluación de la Comisión Regional de Certificación clasifica a España en 2018 como de riesgo bajo de transmisión de poliovirus. En Europa hay tres países con riesgo alto, debido fundamentalmente a la baja inmunidad de su población. Hay que mantener los sistemas ya establecidos de vigilancia de la circulación de EV -polio y no polio- (vigilancia de PFA, meningitis víricas y EV), de manera que permitan detectar a tiempo la circulación inesperada de un poliovirus o de otro tipo de EV clínicamente relevante. [EN]The results of acute flaccid paralysis (AFP) and enterovirus (EV) surveillance show that there were no cases of polio or poliovirus circulation in Spain in 2019. The sensitivity of the system is below the target set by WHO-Europe of 1 case of AFP per year per 100,000 children under 15 years, at 0.55/104 inhab (0.58/104 <15 years in 2018 ). However, their study once detected is adequate. The surveillance index, which synthesizes the sensitivity of the surveillance system and its laboratory study, was 0.28, similar to other years. Thanks to the surveillance of EV, a vaccine derived PV (PVDV) was detected in an immunosuppressed excretory patient; in addition, different non-polio-EV were found. The serotypes identified were mainly E-7, E-30, E-11, CV-A6 and E-13. In 2019 the WHO declared the elimination of wild PV type 3 (PVS3) worldwide, although the increase in detection of PVS1 and cVP2 in both human and environmental samples is of concern. The evaluation of the Regional Certification Commission classifies Spain in 2019 as having a low risk of poliovirus transmission. In Europe there are three countries at high risk, mainly due to the low immunity of their population. The already established systems for surveillance of the circulation of EV-polio and non-polio- (surveillance of AFP, viral meningitis and EV) must be maintained, so that the unexpected circulation of a poliovirus or other clinically relevant EV can be detected in time.N

Observation of Cabibbo-suppressed two-body hadronic decays and precision mass measurement of the Ωc0\Omega_{c}^{0} baryon

The first observation of the singly Cabibbo-suppressed $\Omega_{c}^{0}\to\Omega^{-}K^{+}$ and $\Omega_{c}^{0}\to\Xi^{-}\pi^{+}$ decays is reported, using proton-proton collision data at a centre-of-mass energy of $13\,{\rm TeV}$, corresponding to an integrated luminosity of $5.4\,{\rm fb}^{-1}$, collected with the LHCb detector between 2016 and 2018. The branching fraction ratios are measured to be $\frac{\mathcal{B}(\Omega_{c}^{0}\to\Omega^{-}K^{+})}{\mathcal{B}(\Omega_{c}^{0}\to\Omega^{-}\pi^{+})}=0.0608\pm0.0051({\rm stat})\pm 0.0040({\rm syst})$, $\frac{\mathcal{B}(\Omega_{c}^{0}\to\Xi^{-}\pi^{+})}{\mathcal{B}(\Omega_{c}^{0}\to\Omega^{-}\pi^{+})}=0.1581\pm0.0087({\rm stat})\pm0.0043({\rm syst})\pm0.0016({\rm ext})$. In addition, using the $\Omega_{c}^{0}\to\Omega^{-}\pi^{+}$ decay channel, the $\Omega_{c}^{0}$ baryon mass is measured to be $M(\Omega_{c}^{0})=2695.28\pm0.07({\rm stat})\pm0.27({\rm syst})\pm0.30({\rm ext})\,{\rm MeV}/c^{2}$, improving the precision of the previous world average by a factor of four.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-011.html (LHCb public pages

Measurement of ZZ boson production cross-section in pppp collisions at s=5.02\sqrt{s} = 5.02 TeV

The first measurement of the $Z$ boson production cross-section at centre-of-mass energy $\sqrt{s} = 5.02\,$TeV in the forward region is reported, using $pp$ collision data collected by the LHCb experiment in year 2017, corresponding to an integrated luminosity of $100 \pm 2\,\rm{pb^{-1}}$. The production cross-section is measured for final-state muons in the pseudorapidity range $2.0 20\,\rm{GeV/}\it{c}$. The integrated cross-section is determined to be $$\sigma_{Z \rightarrow \mu^{+}\mu^{-}} = 39.6 \pm 0.7\,(\rm{stat}) \pm 0.6\,(\rm{syst}) \pm 0.8\,(\rm{lumi}) \ \rm{pb}$$ for the di-muon invariant mass in the range $60<M_{\mu\mu}<120\,\rm{GeV/}\it{c^{2}}$. This result and the differential cross-section results are in good agreement with theoretical predictions at next-to-next-to-leading order in the strong coupling. Based on a previous LHCb measurement of the $Z$ boson production cross-section in $p$Pb collisions at $\sqrt{s_{NN}}=5.02$ TeV, the nuclear modification factor $R_{p\rm{Pb}}$ is measured for the first time at this energy. The measured values are $1.2^{+0.5}_{-0.3}\,(\rm{stat}) \pm 0.1\,(\rm{syst})$ in the forward region ($1.53<y^*_{\mu}<4.03$) and $3.6^{+1.6}_{-0.9}\,(\rm{stat}) \pm 0.2\,(\rm{syst})$ in the backward region ($-4.97<y^*_{\mu}<-2.47$), where $y^*_{\mu}$ represents the muon rapidity in the centre-of-mass frame.Comment: All figures and tables, along with any supplementary material and additional information, are available at https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-010.html (LHCb public pages