Incidence of recently acquired hepatitis C virus infection among HIV-infected patients in southern Spain.

Objectives: Spain is close to HCV microelimination, so rates of recently acquired HCV infection (RAHC) should decrease. Nowadays, men who have sex with men (MSM) carry the highest risk of HCV acquisition. Our aim was to estimate the incidence of and the factors associated with RAHC, together with reinfection rates, among patients sexually infected by HIV.Methods: Primary RAHC infection was diagnosed when anti-HCV antibody seroconversion was documented. In anti-HCV positive patients, initially without HCV viraemia, a diagnosis of reinfection was established if plasma HCV RNA was detected.Results: All 350 patients tested negative for anti-HCV at baseline and had at least one follow-up visit. Among them, there were 16 RAHC cases from 2016 to 2019. RAHC incidence rates [IR (95% confidence interval, CI)] per 100 person-years were 3.77 (0.5-12.9) in 2016, 1.85 (0.6-4.3) in 2017, 1.49 (0.4-3.8) in 2018 and 1.98 (0.6-4.5) in 2019. Only previous sexually transmitted infections [incidence rate ratio (IRR) = 18.23, 95% CI: 1.93-172.1; P = 0.011], male sex (IRR = 8.33, 95% CI: 1.38-54.15; P = 0.026) and sharing chem-sex drugs (IRR: 4.93, 95% CI: 1.17-20.76; P = 0.030), were independently associated with RAHC. Four out of 42 (9.5%) patients became reinfected. Conclusions: The incidence of RAHC among HIV-infected patients showed a decrease after 2016, although a lower but steady incidence of residual cases still remains. HCV reinfections showed a similar pattern. New infections were associated with sharing chem-sex drugs among MSM.This study was partly supported by grants from the Ministerio de Economía, Industria y competitividad, Instituto de Salud Carlos III (grant no. PI15/01124) and from Grupo de Estudio de Hepatitis Vírica-SEIMC (grant no. GEHEP-001). AG-S and AR-J are recipients of Miguel Servet Research Contracts by the Ministerio de Ciencia, Promoción y Universidades of Spain (CP18/00146; CP18/00111). JM is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (grant no. B-0037). JAP is recipient of an intensification grant from the Instituto de Salud Carlos III (grant no. Programa-I3SNS)

Incidence of and factors associated with SARS-CoV-2 infection among people living with HIV in Southern Spain after one year of pandemic

Whether people living with HIV (PLWH) are at greater risk of acquiring SARS-CoV-2 infection is currently unknown. Prospective serologic studies may allow seroincidence analyses, where all infections are accurately identified. Because of this, we evaluated the incidence of associated factors with and the clinical outcome of SARS-CoV-2 infection in PLWH in Southern Spain. This prospective cohort study included PLWH from a Tertiary University Hospital in Southern Spain. Patients were enrolled in the study if (1) they had attended as outpatients our Unit from 1 August 2019 to 8 February 2020 and (2) had two subsequent evaluations from 9 February 2020 to 4 March 2021. SARS-CoV-2 infections were diagnosed by PCR, antigen detection or serology. Seven hundred and nine PLWH were included in the study. Of them, 55 [7.8%, 95% confidence interval (95% CI) 5.9%-9.9%] patients developed SARS-CoV-2 infection. Between 18 May and 29 November 2020, the rate of seroconversion was 5.3% (95% CI: 3.1%-9.0%) for the general population in the area of Seville and 2.3% (95% CI: 1.3%-2.6%) for PLWH in this study (p = .001). After multivariable analysis, adjusted by age, sex, and risk factors for HIV infection, active tobacco use and CDC stage, active tobacco smoking was the only factor independently associated with lower risk of SARS-Cov-2 infection [Incidence rate ratio: 0.29 (95% CI 0.16-0.55) p < .001]. In conclusion, the incidence of SARS-CoV-2 infection among PLWH in Southern Spain during the ongoing pandemic was lower than that reported for the general population in the same area.This work was supported in part by the Instituto de Salud CarlosIII (Project ‘PI16/01443’), integrated in the national I+D+i 2013–2016andco-fundedbytheEuropeanUnion(ERDF/ESF,‘Investinginyour future’), by the Spanish Network for AIDS investigation (RIS)(www.red.es/redes/inicio)(RD16/0025/0010,RD16/0025/0040),asapartoftheNacionalI+D+I,ISCIIISubdirecciónGeneraldeEvaluaciónand the European Fund for Development of Regions (FEDER). JuanA.PinedareceivedaresearchextensiongrantfromtheProgramadeIntensificacióndelaActividaddeInvestigacióndelServicioNacionaldeSaludCarlosIII(I3SNS).FedericoGarciareceivedaresearchextensiongrantfromtheProgramadeIntensificacióndelaActividaddeInves-tigacióndelServicioAndaluzdeSalud.AnaïsCorma-GomezreceivedaRíoHortegagrantfromtheInstitutodeSaludCarlosIII(grantnum-ber CM19/00251). Funding for open access charge: Universidad deMálaga/CBU

A Functional Pipeline of Genome-Wide Association Data Leads to Midostaurin as a Repurposed Drug for Alzheimer’s Disease

Genome-wide association studies (GWAS) constitute a powerful tool to identify the different biochemical pathways associated with disease. This knowledge can be used to prioritize drugs targeting these routes, paving the road to clinical application. Here, we describe DAGGER (Drug Repositioning by Analysis of GWAS and Gene Expression in R), a straightforward pipeline to find currently approved drugs with repurposing potential. As a proof of concept, we analyzed a meta-GWAS of 1.6 × 107 single-nucleotide polymorphisms performed on Alzheimer’s disease (AD). Our pipeline uses the Genotype-Tissue Expression (GTEx) and Drug Gene Interaction (DGI) databases for a rational prioritization of 22 druggable targets. Next, we performed a two-stage in vivo functional assay. We used a C. elegans humanized model over-expressing the Aβ1-42 peptide. We assayed the five top-scoring candidate drugs, finding midostaurin, a multitarget protein kinase inhibitor, to be a protective drug. Next, 3xTg AD transgenic mice were used for a final evaluation of midostaurin’s effect. Behavioral testing after three weeks of 20 mg/kg intraperitoneal treatment revealed a significant improvement in behavior, including locomotion, anxiety-like behavior, and new-place recognition. Altogether, we consider that our pipeline might be a useful tool for drug repurposing in complex diseases.Department of Surgery, Biochemistry and Immunology, School of Medicine, University of Malaga, Boulevard Louis Pasteur s/n, 29071 Malaga, Spain Departamento de Biología Molecular e Ingeniería Bioquímica, Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide (UPO), UPO/CSIC/JA, Ctra Utrera Km1, 41013 Sevilla, Spain Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), 28029 Madrid, Spain Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, 29590 Malaga, Spain Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Facultad de Psicología, Universidad de Málaga, 29071 Malaga, Spain Research Center and Memory Clinic, Ace Alzheimer Center Barcelona—Universitat Internacional de Catalunya, 08017 Barcelona, Spain Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), National Institute of Health Carlos III, 28029 Madrid, Spain Unidad de Gestion Clinica de Salud Mental, Hospital Universitario Regional de Malaga, 29010 Malaga, Spain Funding for open Access charge: Universidad de Málaga / CBU

Correction to: Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer's disease.

Copyright de los autores.Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2-DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.- Financiación del Consejo de Investigación Sueca, y el Parque de Investigación "Strong Research Environment MultiPark (Multidisciplinary Research in Parkinson’s and Alzheimer’s Disease" de la Universidad de Lund. - Bagadilico (consorciado esponsorizado por el Consejo de Investigación Sueca), la Fundación Sueca de Alzheimer, la fundación Sueca del Cerebro, Fundación A.E. Berger Foundation, la fundación Gyllenstiernska Krapperup, la Real Sociedad Fisiográfica, la Fundación Crafoord, Fundación Olle Engkvist Byggmästare, Fundación Wiberg, Fundación G&J Kock, Fundación Stohnes, Asociación Sueca de Demencia y la Facultad de Medicina de la Universidad de Lund. - Proyectos SAF2015-64171R (MINECO/FEDER, UE) - Instituto de Salud Carlos III (ISCiii) co-financiado por fondos FEDER de la Unión Europea por proyectos PI15/00796 y PI18/01557 (a AG), PI15/00957 y PI18/01556 (JV). - CIBERNED “Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid (AG y JV) - Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía Proyecto de Excelencia (CTS2035) (JV y AG). - Universidad de Málaga referencia PPIT.UMA.27(RSV) - AV y GCB recibieron fondos de la Iniciativa para Medicina Innovativa ref. 115976 (PHAGO). - Consejo de Investigación Sueca, Fundación Sueca del Cerebro, Fundación de Alzheimer y Fundación Ahlen (a HL y AF). - Proyecto de Fundación Knut and Alice Wallenberg (UJN) (KAW 2013.0022) y Consejo de Investigación Sueca (ref. 621-2012-2978)

Mendelian Randomisation Confirms the Role of Y-Chromosome Loss in Alzheimer’s Disease Aetiopathogenesis in Men

Mosaic loss of chromosome Y (mLOY) is a common ageing-related somatic event and has been previously associated with Alzheimer’s disease (AD). However, mLOY estimation from genotype microarray data only reflects the mLOY degree of subjects at the moment of DNA sampling. Therefore, mLOY phenotype associations with AD can be severely age-confounded in the context of genome-wide association studies. Here, we applied Mendelian randomisation to construct an age-independent mLOY polygenic risk score (mloy-PRS) using 114 autosomal variants. The mloy-PRS instrument was associated with an 80% increase in mLOY risk per standard deviation unit (p = 4.22 × 10−20) and was orthogonal with age. We found that a higher genetic risk for mLOY was associated with faster progression to AD in men with mild cognitive impairment (hazard ratio (HR) = 1.23, p = 0.01). Importantly, mloy-PRS had no effect on AD conversion or risk in the female group, suggesting that these associations are caused by the inherent loss of the Y chromosome. Additionally, the blood mLOY phenotype in men was associated with increased cerebrospinal fluid levels of total tau and phosphorylated tau181 in subjects with mild cognitive impairment and dementia. Our results strongly suggest that mLOY is involved in AD pathogenesis.P.G.-G. (Pablo García-González) is supported by CIBERNED employment plan CNV-304-PRF-866. CIBERNED is integrated into ISCIII (Instituto de Salud Carlos III). I.d.R is supported by a national grant from the Instituto de Salud Carlos III FI20/00215. A.C. (Amanda Cano) acknowledges the support of the Spanish Ministry of Science, Innovation, and Universities under the grant Juan de la Cierva (FJC2018-036012-I). M.B. (Mercé Boada) and A.R. (Agustín Ruiz) are also supported by national grants PI13/02434, PI16/01861, PI17/01474, PI19/01240, and PI19/01301. The Genome Research @ Fundació ACE project (GR@ACE) is supported by Grifols SA, Fundación bancaria “La Caixa”, Fundació ACE, and CIBERNED. Acción Estratégica en Salud is integrated into the Spanish National R + D + I Plan and funded by ISCIII (Instituto de Salud Carlos III)—Subdirección General de Evaluación—and the Fondo Europeo de Desarrollo Regional (FEDER—“Una manera de hacer Europa”). Genotyping of the ACE MCI-EADB samples was performed in the context of EADB (European Alzheimer DNA biobank) funded by the JPco-fuND FP-829-029 (ZonMW project number 733051061). This work was supported by a grant (European Alzheimer DNA BioBank, EADB) from the EU Joint Program—Neurodegenerative Disease Research (JPND). Partial funding for open access charge: Universidad de Málag

Response to glecaprevir/pibrentasvir in HIV/HCV-coinfected patients in clinical practice

HIV infection has been associated with lower rates of sustained viral response (SVR) with direct-acting antivirals (DAAs). There are few data on glecaprevir/pibrentasvir (G/P) in HIV/HCV coinfection outside clinical trials.Instituto de Salud Carlos III (España), Fondo Europeo de Desarrollo Regional PI018/00606Ministerio de Ciencia, Innovación y Universidades de España, Fondo Social Europeo CP18/00146Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación y Unión Europea, Fundación para la Investigación en Salud (FIS) del Instituto Carlos III (PI22/01098, PI21/00793 y PI18/01270

The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study)

Background & aims: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/ HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). Objective: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. Patients and methods: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-eronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. Results: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. Conclusions: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.Grupo de Estudio de Hepatitis Víricas from the Sociedad Espa˜nola de Enfermedades Infecciosas y Microbiología Clínica (GEHEP-012) and Consejería de Salud de la Junta de Andalucía (PI-0001/2017)CIBERINFEC -Consorcio Centro de Investigación Biomédica en Red de Enfermedades Infecciosas- CB21/13/00118Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea“Acciones para el refuerzo con recursos humanos de la actividad investigadora en las Unidades Clínicas del Servicio Andaluz de Salud 2021, acción B (Clínico-Investigadores)” B-0061- 202

Central nicotine induces browning through hypothalamic κ opioid receptor

[ENG]Increased body weight is a major factor that interferes with smoking cessation. Nicotine, the main bioactive compound in tobacco, has been demonstrated to have an impact on energy balance, since it affects both feeding and energy expenditure at the central level. Among the central actions of nicotine on body weight, much attention has been focused on its effect on brown adipose tissue (BAT) thermogenesis, though its effect on browning of white adipose tissue (WAT) is unclear. Here, we show that nicotine induces the browning of WAT through a central mechanism and that this effect is dependent on the κ opioid receptor (KOR), specifically in the lateral hypothalamic area (LHA). Consistent with these findings, smokers show higher levels of uncoupling protein 1 (UCP1) expression in WAT, which correlates with smoking status. These data demonstrate that central nicotine-induced modulation of WAT browning may be a target against human obesityThe research leading to these results has received funding from the Xunta de Galicia (J.L.L.-G.: ED431C 2018/10; R.N.: 2015-CP080 and 2016-PG057; M.L.: 2015-CP079 and 2016-PG068); Ministerio de Economía y Competitividad (MINECO) co-funded by the FEDER Program of EU (J.L.L.-G.: BFU2015–70523; R.N.: BFU2015–70664R; C.D.: BFU2017–87721-P; M.L.: RTI2018-101840-B100; BFU2015–70454-REDT/Adipoplast and RTI2018–101840-B-I00); Instituto de Salud Carlos III (J.L.L.-G.: RD16/0011/0016; J.M.F.-R.: PI15–01934); European Molecular Biology Organization (A.D.: EMBO-Installation Grant 3037); Human Frontier Science Program (A.D.: HFSP-RGY0070/2016); Howard Hughes Medical Institute (A.D.: HHMI-208576/Z/17/Z); US National Institutes of Health (K.R.: HL084207); American Heart Association (K.R.: EIA#14EIA18860041); the University of Iowa Fraternal Order of Eagles Diabetes Research Center (K.R.); Atresmedia Corporación (R.N. and M.L.: 2017-PO004); Fundación BBVA (R.N.), European Foundation for the Study of Diabetes (R.N.); and ERC Synergy Grant-2019-WATCH-810331 (R.N.). P.S.-C. is recipient of a fellowship from Xunta de Galicia (ED481B 2018/050). L.L.-P. is recipient of a fellowship from Xunta de Galicia (ED481A-2016/094); E.R.-P. is recipient of a fellowship from MINECO (BES-2015–072743). N.M.-S. is recipient of a fellowship from Xunta de Galicia (ED481B 2016/168–0) and from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie actions. The CiMUS is supported by the Xunta de Galicia (2016–2019, ED431G/05). CIBER de Fisiopatología de la Obesidad y Nutrición is an initiative of ISCIIIS