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Cancer; Genetics; Risk factors Cáncer; Genética; Factores de riesgo Càncer; Genètica; Factors de risc Several studies have demonstrated the cost-effectiveness of genetic testing for surveillance and treatment of carriers of germline pathogenic variants associated with hereditary breast/ovarian cancer syndrome (HBOC). In Brazil, seventy percent of the population is assisted by the public Unified Health System (SUS), where genetic testing is still unavailable. And few studies were performed regarding the prevalence of HBOC pathogenic variants in this context. Here, we estimated the prevalence of germline pathogenic variants in BRCA1, BRCA2 and TP53 genes in Brazilian patients suspected of HBOC and referred to public healthcare service. Predictive power of risk prediction models for detecting mutation carriers was also evaluated. We found that 41 out of 257 tested patients (15.9%) were carriers of pathogenic variants in the analyzed genes. Most frequent pathogenic variant was the founder Brazilian mutation TP53 c.1010G > A (p.Arg337His), adding to the accumulated evidence that supports inclusion of TP53 in routine testing of Brazilian HBOC patients. Surprisingly, BRCA1 c.5266dupC (p.Gln1756fs), a frequently reported pathogenic variant in Brazilian HBOC patients, was not observed. Regarding the use of predictive models, we found that familial history of cancer might be used to improve selection or prioritization of patients for genetic testing, especially in a context of limited resources. We are very thankful to all patients and their families who participated in this study. We thank Eliana Abdelhay for providing the Ion AmpliSeq customized panel and funding the sequencing costs for this panel. And we also thank the Bioinformatics Core Facility (INCA-RJ), in special Dr. Nicole Scherer, for their support in this study. This work was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, Brazil: project 304339/2018-0), Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ, Brazil: projects 200.928/2021 and 211.309/2021), Fundação Ary Frauzino para Pesquisa e Controle do Câncer (Brazil), SWISS-BRIDGE Foundation, and Ministry of Health (Brazil).

Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Dementia; Dose-response; Thyroid dysfunction Demència; Dosi-resposta; Disfunció de la tiroide Demencia; Dosis-respuesta; Disfunción tiroidea Thyroid hormone, as a modifiable risk factor for dementia, promotes neurocognitive function and regulates metabolic processes. Various studies have defined different thyroid-stimulating hormone cutoffs, but the safest thyroid-stimulating hormone concentration was absent. A dose–response meta-analysis describing the overall functional relation and identifying exposure intervals associated with a higher or lower disease risk is thus desirable. Therefore, our current analysis was conducted to understand the influence of thyroid dysfunction on dementia risk. We searched PubMed, Embase, and Web of Science before May 1, 2020 for human studies published in English. Studies were considered for inclusion if they used a cohort study design to measure the risk of dementia in different thyroid function status groups, diagnosed thyroid functional status and all-cause dementia, included participants aged >18 years, and provided quantitative measures of data. The analysis contained 17 articles with 344,248 individuals with a 7.8-year mean follow-up. Ten studies with 329,287 participants indicated that only subclinical hyperthyroidism was associated with an increased risk of dementia. In contrast, subclinical hypothyroidism, clinical hyperthyroidism, and clinical hypothyroidism did not affect dementia. In the dose–response meta-analysis with 46,417 samples from 11 studies, the association of thyroid-stimulating hormone with the risk of dementia exhibited a U-shaped curve. Our study indicated that subclinical hyperthyroidism was associated with the risk of dementia and the thyroid-stimulating hormone concentration at around 1.55–1.60 mU/L as the optimum range for the risk of dementia. This work was supported by the National Natural Science Foundation of China (No. 82070851, 81870556, 81930019, 81670738), Beijing Municipal Administration of Hospital’s Youth Program (QML20170204), Excellent Talents in Dongcheng District of Beijing.

A través del estudio de las alternancias argumentales, este artículo analiza la flexibilidad sintáctica de los verbos y la flexibilidad semántica de las oraciones en las que participan. Aunque los verbos suelen clasificarse como transitivos e intransitivos, y estos últimos como inergativos e inacusativos, obedeciendo a su comportamiento más habitual, sus alternancias muestran que estas etiquetas son más adecuadas para caracterizar las oraciones, teniendo en cuenta que un mismo verbo puede participar en oraciones con características sintácticas contrapuestas. Dejando al margen las alternancias activa/pasiva y activa/media, en este artículo se analizan diversas alternancias de valencia y de diátesis que no presentan cambio morfológico en el verbo y que permiten mostrar en el aula de secundaria el comportamiento flexible de los verbos. Se analizan los efectos variados de las alternancias argumentales, como el cambio de caracterización sintáctica de las oraciones (transitiva/intransitiva, inergativa/inacusativa) o de sus argumentos, y la inversión de su orden oracional. También se estudian los cambios semánticos que se producen desde el punto de vista del aspecto léxico (proceso/estado) o de la afectación de un argumento (parcial/holística), así como la impersonalización de la oración. A través de l'estudi de les alternances argumentals, aquest article analitza la flexibilitat sintàctica dels verbs i la flexibilitat semàntica de les oracions en les quals hi participen. Encara que els verbs solen classificar-se com a transitius i intransitius, i aquests últims com a inergatius i inacusatius, obeint al seu comportament més habitual, les seves alternances mostren que aquestes etiquetes són més adequades per caracteritzar les oracions, tenint en compte que un mateix verb pot participar en oracions amb característiques sintàctiques contraposades. Deixant al marge les alternances activa/passiva i activa/mitjana, en aquest article s'analitzen diverses alternances de valència i de diàtesi que no presenten canvi morfològic en el verb i que permeten mostrar a l'aula de secundària el comportament flexible dels verbs. S'analitzen els efectes variats de les alternances argumentals, com el canvi de caracterització sintàctica de les oracions (transitiva/intransitiva, inergativa/*inacusativa) o dels seus arguments, i la inversió de la seva ordre oracional. També s'estudien els canvis semàntics que es produeixen des del punt de vista de l'aspecte lèxic (procés/estat) o de l'afectació d'un argument (parcial/holística), així com la impersonalizació de l'oració. Through the study of argument alternations, this article analyses the syntactic flexibility of verbs and the semantic flexibility of the sentences in which they participate. Although verbs tend to be classified as transitive and intransitive, and intransitive verbs are further subdivided into unergative and unaccusative, depending on how they usually behave, their alternations reveal that these labels are more appropriate for characterizing sentences, given that the same verb can participate in sentences with opposing syntactic characteristics. Leaving to one side the active/passive and the active/middle alternations, this article analyses several valence and diathesis alternations that do not present morphological change in the verb and that allow the flexible behaviour of verbs to be illustrated in the school classroom. The article examines the range of effects argument alternations can have such as the change in the syntactic characterization of sentences (transitive/in-transitive, unergative/unaccusative) or of their arguments, and the inversion of their sentence order. The article also studies the impersonalization of the sentence and the semantic changes that occur from the point of view of the lexical aspect (process/state) and the affectation of an argument (partial/holistic).

Breast and prostate cancer risks; Pathogenic variant Riscos de càncer de mama i pròstata; Variants patogèniques Riesgos de cáncer de mama y próstata; Variantes patogénicas Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management. The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861 and PPRPGM-Nov20\100002. The research leading to these results has received funding from the Italian Association for Cancer Research (AIRC) under IG 2018 - ID. 21389 and the Italian League for the Fight Against Cancer (LILT) under IG 2019 projects, P.I. Ottini Laura and Italian Ministry of Education, Universities and Research-Dipartimenti di Eccellenza-L. 232/2016. CIMBA: GCT is a National Health and Medical Research Council (NHMRC) Research Fellow. iCOGS and OncoArray data: the European Community’s Seventh Framework Programme under grant agreement No. 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (NIH) (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer (CRN-87521), and the Ministry of Economic Development, Innovation and Export Trade (PSR-SIIRI-701), Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund. The Personalized Risk Stratification for Prevention and Early Detection of Breast Cancer (PERSPECTIVE) and PERSPECTIVE I&I projects were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministry of Economy and Innovation through Genome Québec, and The Quebec Breast Cancer Foundation and the Ontario Research Fund. Breast Cancer Family Registry (BCFR): UM1 CA164920 from the National Cancer Institute (NCI). Baltic Familial Breast Ovarian Cancer Consortium (BFBOCC): Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015. Beth Israel Deaconess Medical Center (BIDMC): Breast Cancer Research Foundation. BRCA-gene mutations and breast cancer in South African women (BMBSA): Cancer Association of South Africa (PI Elizabeth J. van Rensburg). Spanish National Cancer Centre (CNIO): Spanish Ministry of Health PI16/00440 supported by Fondo Europeo de Desarrollo Regional (FEDER) funds, the Spanish Ministry of Economy and Competitiveness (MINECO) SAF2014-57680-R and the Spanish Research Network on Rare diseases (CIBERER). City of Hope - Clinical Cancer Genomics Community Research Network (COH-CCGCRN): Research reported in this publication was supported by the NCI of the NIH under grant No. R25CA112486, and RC4CA153828 (PI: J. Weitzel) from the NCI and the Office of the Director, NIH. CONsorzio Studi ITaliani sui Tumori Ereditari Alla Mammella (CONSIT TEAM): Associazione Italiana Ricerca sul Cancro (AIRC; IG2014 No.15547) to P. Radice. Funds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects ‘5x1000’) to S. Manoukian. Associazione CAOS Varese to M.G. Tibiletti. AIRC (IG2015 No.16732) to P. Peterlongo. National Centre for Scientific Research Demokritos (DEMOKRITOS): European Union (European Social Fund—ESF) and Greek national funds through the Operational Program “Education and Lifelong Learning” of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund. German Cancer Research Center (DFKZ): German Cancer Research Center. Epidemiological Study of Familial Breast Cancer (EMBRACE): Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an National Institute for Health Research (NIHR) grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden National Health Service (NHS) Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Fox Chase Cancer Center (FCCC): The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. AKG was in part funded by the NCI (R01 CA214545 and R01 CA140323), The Kansas Institute for Precision Medicine (P20 GM130423), and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. is the Chancellors Distinguished Chair in Biomedical Sciences Professor. Fundación Pública Galega de Medicina Xenómica (FPGMX): FISPI05/2275 and Mutua Madrileña Foundation (FMMA). German Familial Breast Group (GC-HBOC): German Cancer Aid (grant No. 110837, Rita K. Schmutzler) and the European Regional Development Fund and Free State of Saxony, Germany (LIFE—Leipzig Research Centre for Civilization Diseases, project No. 713-241202, No. 713-241202, No. 14505/2470, and No. 14575/2470). Genetic Modifiers of cancer risk in BRCA1/2 mutation carriers (GEMO): Ligue Nationale Contre le Cancer; the Association “Le cancer du sein, parlons-en!” Award, the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program and the French National Institute of Cancer (INCa grants 2013-1-BCB-01-ICH-1 and SHS-E-SP 18-015). Georgetown University (GEORGETOWN): the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Hereditary Cancer and Clinical Genomics Research, and Swing Fore the Cure. Ghent University Hospital (G-FAST): Bruce Poppe is a senior clinical investigator of FWO. Mattias Van Heetvelde obtained funding from IWT. Hospital Clinico San Carlos (HCSC): Spanish Ministry of Health PI15/00059, PI16/01292, and CB-161200301 CIBERONC from ISCIII (Spain), partially supported by European Regional Development FEDER funds. Helsinki Breast Cancer Study (HEBCS): Helsinki University Hospital Research Fund, the Finnish Cancer Society and the Sigrid Juselius Foundation. Hereditary Breast and Ovarian cancer study the Netherlands (HEBON): the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grants 110005 and 2014-187.WO76, the Biobanking and Biomolecular Resources Research Infrastructure (BBMRI) grant NWO 184.021.007/CP46 and the Transcan grant JTC 2012 Cancer 12-054. HEBON thanks the registration teams of Dutch Cancer Registry (IKNL; S. Siesling, J. Verloop) and the Dutch Pathology database (PALGA; L. Overbeek) for part of the data collection. Study of Genetic Mutations in Breast and Ovarian Cancer patients in Hong Kong and Asia (HRBCP): Hong Kong Sanatorium and Hospital, Dr Ellen Li Charitable Foundation, The Kerry Group Kuok Foundation, National Institute of Health1R 03CA130065, and North California Cancer Center. Molecular Genetic Studies of Breast- and Ovarian Cancer in Hungary (HUNBOCS): Hungarian Research Grants KTIA-OTKA CK-80745 and NKFI_OTKA K-112228. Institut Català d’Oncologia (ICO): The authors would like to particularly acknowledge the support of the Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III (organismo adscrito al Ministerio de Economía y Competitividad) and “FEDER, una manera de hacer Europa” (PI10/01422, PI13/00285, PIE13/00022, PI15/00854, PI16/00563 and CIBERONC) and the Institut Català de la Salut and Autonomous Government of Catalonia (2009SGR290, 2014SGR338 and PERIS Project MedPerCan). International Hereditary Cancer Centre (IHCC): PBZ_KBN_122/P05/2004. Iceland Landspitali – University Hospital (ILUH): Icelandic Association “Walking for Breast Cancer Research” and by the Landspitali University Hospital Research Fund. INterdisciplinary HEalth Research Internal Team BReast CAncer susceptibility (INHERIT): Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program—grant No. CRN-87521 and the Ministry of Economic Development, Innovation and Export Trade—grant No. PSR-SIIRI-701. Istituto Oncologico Veneto (IOVHBOCS): Ministero della Salute and “5x1000” Istituto Oncologico Veneto grant. Portuguese Oncology Institute-Porto Breast Cancer Study (IPOBCS): Liga Portuguesa Contra o Cancro. Kathleen Cuningham Consortium for Research into Familial Breast Cancer (kConFab): The National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia. Korean Hereditary Breast Cancer Study (KOHBRA): the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), and the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (HI16C1127; 1020350; 1420190). Mayo Clinic (MAYO): NIH grants CA116167, CA192393 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), and a grant from the Breast Cancer Research Foundation. McGill University (MCGILL): Jewish General Hospital Weekend to End Breast Cancer, Quebec Ministry of Economic Development, Innovation and Export Trade. Marc Tischkowitz is supported by the funded by the European Union Seventh Framework Program (2007Y2013)/European Research Council (Grant No. 310018). Modifier Study of Quantitative Effects on Disease (MODSQUAD): MH CZ—DRO (MMCI, 00209805), MEYS—NPS I—LO1413 to LF, and by Charles University in Prague project UNCE204024 (MZ). Memorial Sloane Kettering Cancer Center (MSKCC): the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Andrew Sabin Research Fund and a Cancer Center Support Grant/Core Grant (P30 CA008748). Women’s College Research Institute Hereditary Breast and Ovarian Cancer Study (NAROD): 1R01 CA149429-01. National Cancer Institute (NCI): the Intramural Research Program of the US NCI, NIH, and by support services contracts NO2-CP-11019-50, N02-CP-21013-63 and N02-CP-65504 with Westat, Inc, Rockville, MD. National Israeli Cancer Control Center (NICCC): Clalit Health Services in Israel, the Israel Cancer Association and the Breast Cancer Research Foundation (BCRF), NY. N.N. Petrov Institute of Oncology (NNPIO): the Russian Foundation for Basic Research (grants 17-54-12007, 17-00-00171 and 18-515-12007). NRG Oncology: U10 CA180868, NRG SDMC grant U10 CA180822, NRG Administrative Office and the NRG Tissue Bank (CA 27469), the NRG Statistical and Data Center (CA 37517) and the Intramural Research Program, NCI. The Ohio State University Comprehensive Cancer Center (OSUCCG): Ohio State University Comprehensive Cancer Center. Università di Pisa (PBCS): AIRC [IG 2013 N.14477] and Tuscany Institute for Tumors (ITT) grant 2014-2015-2016. South East Asian Breast Cancer Association Study (SEABASS): Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives Foundation. Sheba Medical Centre (SMC): the Israeli Cancer Association. Swedish Breast Cancer Study (SWE-BRCA): the Swedish Cancer Society. University of Chicago (UCHICAGO): NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women’s Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an American Cancer Society (ACS) Clinical Research Professor. University of California Los Angeles (UCLA): Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research Foundation. University of California San Francisco (UCSF): UCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer Center. UK Familial Ovarian Cancer Registry (UKFOCR): Cancer Research UK. University of Pennsylvania (UPENN): NIH (R01-CA102776 and R01-CA083855); Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCA. Cancer Family Registry University of Pittsburg (UPITT/MWH): Hackers for Hope Pittsburgh. Victorian Familial Cancer Trials Group (VFCTG): Victorian Cancer Agency, Cancer Australia, National Breast Cancer Foundation. Women’s Cancer Program at Cedars-Sinai Medical Center (WCP): Dr Karlan is funded by the ACS Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124. TN-D is a recipient of a Career Development Fellow from the National Breast Cancer Foundation (Australia, ECF-17-001).

Here, we describe the results of a genome-wide study conducted in 11939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P= 60 years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided., Instituto de Salud Carlos III European Commission COV20_00622 COV20/00792 COV20_00181 COV20_1144 PI20/00876, European Union (ERDF) 'A way of making Europe', Fundacion Amancio Ortega, Banco de Santander, Estrella de Levante S.A., Colabora Mujer Association, La Caixa Foundation, Agencia Estatal de Investigacion RTC-2017-6471-1, Cabildo Insular de Tenerife (Apuestas cientificas del ITER para colaborar en la lucha contra la COVID-19) CGIEU0000219140, Fundacion Canaria Instituto de Investigacion Sanitaria de Canarias PIFIISC20/57

Viral hepatitis; Liver cirrhosis Hepatitis viral; Cirrosis del hígado Hepatitis viral; Cirrosi del fetge

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.

Publisher Copyright: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. Objective: Identifying common genetic variants that confer genetic risk for cluster headache. Methods: We conducted a case–control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trøndelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results: An association was found with cluster headache for 4 independent loci (r2 < 0.1) with genomewide significance (p < 5 × 10−8), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33–1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37–1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26–1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54–0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r2 = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation: This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headache with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021;90:203–216.

Malalties metabòliques hereditàries; Malaltia rara; Procés de transició Enfermedades metabólicas hereditarias; Enfermedad rara; Proceso de transición:es Inherited metabolic disease(s); Rare disease; Transition process Inherited Metabolic Diseases (IMDs) are rare diseases caused by genetic defects in biochemical pathways. Earlier diagnosis and advances in treatment have improved the life expectancy of IMD patients over the last decades, with the majority of patients now surviving beyond the age of 20. This has created a new challenge: as they grow up, the care of IMD patients' needs to be transferred from metabolic pediatricians to metabolic physicians specialized in treating adults, through a process called “transition.” The purpose of this study was to assess how this transition is managed in Europe: a survey was sent to all 77 centers of the European Reference Network for Hereditary Metabolic Disorders (MetabERN) to collect information and to identify unmet needs regarding the transition process. Data was collected from 63/77 (81%) healthcare providers (HCPs) from 20 EU countries. Responders were mostly metabolic pediatricians; of these, only ~40% have received appropriate training in health issues of adolescent metabolic patients. In most centers (~67%) there is no designated transition coordinator. About 50% of centers provide a written individualized transition protocol, which is standardized in just ~20% of cases. In 77% of centers, pediatricians share a medical summary, transition letter and emergency plan with the adult team and the patient. According to our responders, 11% of patients remain under pediatric care throughout their life. The main challenges identified by HCPs in managing transition are lack of time and shortage of adult metabolic physician positions, while the implementations that are most required for a successful transition include: medical staff dedicated to transition, a transition coordinator, and specific metabolic training for adult physicians. Our study shows that the transition process of IMD patients in Europe is far from standardized and in most cases is inadequate or non-existent. A transition coordinator to facilitate collaboration between the pediatric and adult healthcare teams should be central to any transition program. Standardized operating procedures, together with adequate financial resources and specific training for adult physicians focused on IMDs are the key aspects that must be improved in the rare metabolic field to establish successful transition processes in Europe. This work was generated within the European Reference Network for Rare Hereditary Metabolic Disorders (MetabERN), co-funded by the European Union within the framework of the Third Health Programme ERN-2016 - Framework Partnership Agreement 2017–2021, Project ID No. 739543.

Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

The use of artificial intelligence techniques to find out which Single Nucleotide Polymorphisms (SNPs) promote the development of a disease is one of the features of medical research, as such techniques may potentially aid early diagnosis and help in the prescription of preventive measures. In particular, the aim is to help physicians to identify the relevant SNPs related to Type 2 diabetes, and to build a decision-support tool for risk prediction. Methods: We use the Random Forest (RF) technique in order to search for the most important attributes (SNPs) related to diabetes, giving a weight (degree of importance), ranging between 0 and 1, to each attribute. Support Vector Machines and Logistic Regression have also been used since they are two other machine learning techniques that are well-established in the health community. Their performance has been compared to that achieved by RF. Furthermore, the relevance of the attributes obtained through the use of RF has then been used to perform predictions with k-Nearest Neighbour method weighting attributes in the similarity measure according to the relevance of the attributes with RF. Results: Testing is performed on a set of 677 subjects. RF is able to handle the complexity of features' interactions, overfitting, and unknown attribute values, providing the SNPs' relevance with an up to 0.89 area under the ROC curve in terms of risk prediction. RF outperforms all the other tested machine learning techniques in terms of prediction accuracy, and in terms of the stability of the estimated relevance of the attributes. Conclusions: The Random Forest is a useful method for learning predictive models and the relevance of SNPs without any underlying assumption This work was supported by the European Unions Horizon 2020 research and innovation programme [grant number 689810, PEPPER]; the University of Girona [grant number MPCUdG2016]; and the Spanish MINECO [grant number DPI2013-47450-C21-R].

The use of artificial intelligence techniques to find out which Single Nucleotide Polymorphisms (SNPs) promote the development of a disease is one of the features of medical research, as such techniques may potentially aid early diagnosis and help in the prescription of preventive measures. In particular, the aim is to help physicians to identify the relevant SNPs related to Type 2 diabetes, and to build a decision-support tool for risk prediction. Methods: We use the Random Forest (RF) technique in order to search for the most important attributes (SNPs) related to diabetes, giving a weight (degree of importance), ranging between 0 and 1, to each attribute. Support Vector Machines and Logistic Regression have also been used since they are two other machine learning techniques that are well-established in the health community. Their performance has been compared to that achieved by RF. Furthermore, the relevance of the attributes obtained through the use of RF has then been used to perform predictions with k-Nearest Neighbour method weighting attributes in the similarity measure according to the relevance of the attributes with RF. Results: Testing is performed on a set of 677 subjects. RF is able to handle the complexity of features' interactions, overfitting, and unknown attribute values, providing the SNPs' relevance with an up to 0.89 area under the ROC curve in terms of risk prediction. RF outperforms all the other tested machine learning techniques in terms of prediction accuracy, and in terms of the stability of the estimated relevance of the attributes. Conclusions: The Random Forest is a useful method for learning predictive models and the relevance of SNPs without any underlying assumption This work was supported by the European Unions Horizon 2020 research and innovation programme [grant number 689810, PEPPER]; the University of Girona [grant number MPCUdG2016]; and the Spanish MINECO [grant number DPI2013-47450-C21-R].

Starting from the analysis of constructions employed to express the category of reflexive in Hittite, encoded both by the verbal ending set of the middle and by the pronominal marker -za with both active and middle verbal forms, we present a typological parallelism with the Baltic languages that has consistently developed, from a pronominal, a verbal strategy to mark reflexivity. It is also shown that a development regarding the ways of encoding reflexivity involve other Indo-European languages as well. The Anatolian languages attest the reflexes of the original set of endings referring to the semantic categories of Reflexive, Middle and “Resultative”, while the other Indo-European languages attest an innovated “mixed morphology” for the category of Middle and Reflexive as opposed to the proper endings of the historical perfect. Within such a theoretical framework, the development of alternative strategies, using pronominal devices or particles, aims to disambiguate a wide polysemous ending set. A ‘Wackernagel’ (2P) particle in Hittite, namely -z, is particularly active in disambiguating reflexivity. Lithuanian -si, an original pronoun that developed at first into a 2P particle and subsequently into a verbal suffix, extends its functional field and takes over the place of the original middle, as in other Baltic and Slavonic languages.

[ger] Zusammenfassung Der Forschungsgegenstand der Dissertation ist die multidimensionale Variation bei den unakkusativischen Bewegungsverben gehen und kommen im Gebrauch. Diese Variation erfolgt nämlich auf struktureller Ebene durch das Phänomen der Diathesenbildung und auf interaktionellfunktionaler Ebene durch die verbal und/oder gestisch realisierte Person- und/oder Lokaldeixis. Ziel der Studie ist die Untersuchung des Zusammenhangs zwischen der strukturellen und interaktionellen Variation bei gehen und kommen und dem jeweiligen Produktionskontext, der seinerseits einen entscheidenden Einfluss auf die kognitiven Prozesse des Sprechers ausübt. In diesem Sinne wird die jeweilige Wahl eines kommunikativen Mittels gegenüber einem anderen zu einer subjektiven Perspektive. Der Produktionskontext betrifft hier zwei Aspekte: die jeweils verwendete thematische Entfaltung (ergebnis- und erlebnisbezogenen Narrationen, objekt- und ereignisbezogenen Deskriptionen sowie Argumentationen) einerseits und den stilistisch-individuellen Faktor. Die Daten stammen aus einem Korpus gesprochener Sprache mit Produktionen auf Deutsch als Muttersprache und im audiovisuellen Format, was seinerseits die Behandlung der Multimodalität in dieser Studie zur Variation je nach Kontext ermöglicht. Die Sprachproduktionen wurden transliteriert und anschließend lemmatisiert, um die Repräsentativität der analysierten gehen- und kommen-Prädikate zu gewährleisten. Bei der Ermittlung von diathetischer (i. S. v. struktureller) und deiktischer (i. S. v. interaktioneller) Alternanz betrifft die methodologische Strategie jeweils zwei Analysen. Der Ermittlung von diathetischer Alternanz liegt eine syntaktisch-semantische Analyse einerseits zugrunde. Dabei warden der Satzbauplan jedes Prädikats, die semantische Rolle jeder Ergänzung und die entsprechende Prädikatsklasse (Handlungen, Aktivitäten, Zustände und Vorgänge) bestimmt. Anhand von dieser Information ist es möglich, die Diathesen von gehen und kommen durch die semantisch dynamischen Prädikate ohne eine Agens-Rolle an der Subjekt-Stelle zu lokalisieren (Ein- und Ausschaltung der Agens-Rolle im Satzbauplan von gehen und kommen als Indikator für strukturelle Variation). Die Ermittlung von deiktischer Alternanz setzt andererseits eine Origo-Analyse zur Bestimmung von Person- und/oder Lokaldeixis bei denselben realisierten Prädikaten voraus. Das audiovisuelle Format der analysierten Daten ermöglicht darüber hinaus das Lokalisieren von nicht nur verbal, sondern auch von gestisch realisierter Person- und/oder Lokaldeixis. Durch eine solche Origo-Analyse lokalisiert man die deiktisch realisierten Prädikate, bei denen die Sprecher- oder die Hörer-Figur vom Produktionskontext referentiell als räumlicher Referenzpunkt (Origo als ‚ich-hier’) am Prädikat teilnehmen. Das referentielle (Nicht-)Vorkommen des Sprechers oder des Hörers bei einem realisierten Bewegungsprädikat stellt den Indikator zur interaktionellen Variation dar. Durch die Kombination der ermittelten strukturellen und interaktionellen Variation mit dem Produktionskontext, d. h. mit dem textthematischen und dem stilistisch-individuellen Faktor kann man beobachten, dass der stilistisch-individuelle Faktor diathetische und deiktische Variation bei allen Probanden begünstigt. Die Betrachtung derselben Daten nach dem textthematischen Faktor zeigt dagegen eine Tendenz zur Perspektivenkonsistenz bzgl. der diathetischen und der deiktischen Alternanz bei jeder thematischen Entfaltung. Darüber hinaus begünstigt der Faktor der thematischen Entfaltung sehr exklusive Distributionen in Bezug auf die beobachteten Analyseeinheiten, d. h. Satzbauplan, semantische Rollen, Prädikatsklasse, Deixisdimension sowie die mediale Kodierung der Deixis. Dementsprechend kommen bspw. die diathetischen Varianten von gehen und kommen ausschließlich bei den deskriptiven Texten vor, während diese unter Betrachtung des stilistischindividuellen Faktors bei allen Probanden dokumentiert werden. Der Faktor der thematischen Entfaltung ist somit restriktiver bzgl. des Vorkommens von Variation als der individuelle Faktor, der direkt an die kognitiven Prozesse des jeweiligen Sprechers, d. h. an die Sprechersubjektivität gebunden ist, was mit dem Vorkommen von variierenden Strukturen in mehreren Fällen in Verbindung zu stehen scheint. Diese Beobachtungen lassen darauf schließen, dass nicht alle Faktoren des Produktionskontextes in gleichem Maße zur Variation beitragen. Die hohe Anzahl an deiktisch realisierten Prädikaten deutet nicht nur darauf hin, dass die interaktionelle Variation sehr beschränkt ist. Vielmehr spricht dies dafür, dass die analysierten Bewegungsprädikate aus einer vorwiegend intrinsischen Perspektive realisiert wurden. Der hohe Deixisgebrauch ist auch in allen thematischen Entfaltun en zu dokumentieren, sogar auch in den ergebnisbezogenen Narrationen (i. S. v. Erörterungen) und den objektbezogenen Deskriptionen, die theoretisch eine eher extrinsische Perspektive begünstigen sollten., [eng] The present investigation focuses on structural and multimodal-interactional variation in use of the German dynamic verbs “gehen” and “kommen”. In this regard, production context plays an important role, since it interacts with the speaker’s cognitive processes. Thus, the choice of a concrete communicative variant leads in each case to a subjective perspective. The main goal of this study is to look for interrelations between respectively diathetical (structural) and deictic (multimodal-interactional) variation and the production context, represented in this study by thematic development and the stilistic-individual factor. The study data were extracted from an oral language corpus of audiovisual records. It consists of 35 productions and 7 speakers (5 productions per speaker). Each of these 5 productions corresponds to a thematic development (objective and subjective narrations, procedural and object oriented descriptions and argumentations). All records were transcribed and lemmatised to ensure sufficient representativeness of each dynamic predicate in all thematic developments (157 realizations for “gehen” and 121 realizations for “kommen”). In order to pursue the research goal, a methodological strategy based on a two-level analysis was developed. On the one hand, the structural analysis involves recognizing and classifying units of analysis, such as sentence structure (“Satzbauplan”) of each predicate, semantic role of each complement subcategorized by the verb (“Ergänzung”), and predicate class (actions, activities, processes, and states), which leads to exploration of the syntactic-semantic predicate relations. This allows distinction between prototypical use of “gehen” and “kommen” (dynamic actions/activities with explicit agent as grammatical subject) and their non prototypical diathetical variants (dynamic actions with non agentive subject, and blocked yet implicit agent). On the other hand, the multimodalinteractional analysis focuses on the referential capacity of the same gehen and kommen predicates. It involves the verbal and/or gestural identification of the origin or reference point (‘me-here’) in such a predicate with the speaker or hearer as entities of the production context of each used predicate. This eventual identification forms the basis for the distinction between deictic or not deictic dynamic predicates. The combination of studied diathetical and deictic variation with the aspect of thematic development and the stilictic-individual factor shows that the textual context aspect tends to perspective consistancy. This consistancy regarding structural and multimodal-interactional variation is observed in all thematic developments, which neutralizes the distinction between objective and subjective narrations on the one hand, and procedural and object oriented descriptions on the other hand. The textual aspect also favours a very restrictive distribution of the observed units of analysis. Thus, diathetical predicates are only observed in descriptions. In contrast to this, the stilictic individual factor, which is tightly bound to the cognitive processes of the same speaker, is not so restrictive and favours therefore the occurrence of variation in more cases. This finding allows to conclude that not all production context aspects contribute to variation occurrence to the same extent.

L'Enciclopedia dell'italiano, ideata e diretta da Raffaele Simone con la collaborazione di Paolo D'Achille e Gaetano Berruto, e pubblicata dall'Istituto dell'Enciclopedia Italiana fondato da G. Treccani, costituisce strumento di consultazione, di studio e di lettura relativo alla lingua italiana ricco, esteso e dettagliato e con pochi eguali al mondo. La voce in questione tratta delle costruzioni passive, cioè del gruppo di costrutti sintattici che servono a esprimere una delle diatesi possibili in italiano. Le costruzioni passive vengono analizzate nella loro formazione, quindi relativamente all'uso degli ausiliari, e nella loro distribuzione, oltre che in diacronia, cioè nel passaggio dal latino all'italiano e, nello specifico, da un passivo sintetico ad uno analitico.

La gramática bizantina ha llegado a nosotros como un corpus amplio de material anónimo atravesado por algunos nombres famosos y otros difícilmente identificables. Si la acusación de repetitivo y desordenado es muchas veces justificada, la gramática bizantina ofrece también análisis de calidad. Además de algunas ideas originales, en este marco se desarrolla una actividad argumentativa novedosa ligada al análisis exhaustivo de posibilidades lógicas y procedimientos refutativos que estaba ausente en los modelos canónicos del período helenístico. Nuestro trabajo se concentrará en el estudio de pasajes en que Querobosco y los escoliastas de la Τέχνη γραμματικη de Dionisio Tracio tratan problemáticas puntuales ligadas a los μέρη του y la λόγου διάθεσις. Ambas problemáticas, que se remontan incluso más allá de los orígenes de la gramática como disciplina autónoma, muestran cómo, en la perspectiva bizantina, los temas clásicos están sujetos a una relectura teórica que profundiza y depura el andamiaje discursivo y argumentativo de la gramática, de un modo tal que se convierte en un logro sustantivo atribuible a esta época de la disciplina., Byzantine grammar has come to us as a large corpus of anonymous material traversed by some famous names and others difficult to identify. If the allegation of being repetitive and messy is often justified, Byzantine grammar also offers analysis of high quality. In addition to some original ideas, in this framework there is innotative argumentation linked to the comprehensive analysis of logical possibilities and procedures of refutation which was absent in the canonical models of the Hellenistic period. Our work will focus on the study of passages in which Choeroboscus and the scholiasts of the Τέχνη γραμματικη by Dionysius Thrax treat specific problems about the μέρη του y la λόγου διάθεσις. Both problems, going back even beyond the origins of grammar as an autonomous discipline, show how in the Byzantine perspective classical themes are subject to a re-reading that deepens and refi nes argumentative patterns in grammar, in a way that becomes a substantive achievement of this period.

Ci sono molteplici vie attraverso cui il sacro riesce a emergere in età tardoantica. Tra di esse, spicca il percorso testuale delle Enneadi di Plotino. Questo articolo considera il testo plotiniano come un viaggio cognitivo ed etico insieme e ne sviluppa un’analisi che è insieme semiotico-narrativa e filosofica. Questi due approcci sono tenuti insieme, ovvero interconnessi nella prospettiva qui proposta di una filosofia della narratività, attraverso alcuni concetti chiave, tra cui viene approfondito in particolare quello di diatesi/disposizione.