An explainable model of host genetic interactions linked to COVID-19 severity

We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as "Respiratory or thoracic disease", supporting their link with COVID-19 severity outcome.A multifaceted computational strategy identifies 16 genetic variants contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing dataset of a cohort of Italian patients

Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme ADAMTS13 (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage

Gain- and Loss-of-Function CFTR Alleles Are Associated with COVID-19 Clinical Outcomes

Carriers of single pathogenic variants of the CFTR (cystic fibrosis transmembrane conductance regulator) gene have a higher risk of severe COVID-19 and 14-day death. The machine learning post-Mendelian model pinpointed CFTR as a bidirectional modulator of COVID-19 outcomes. Here, we demonstrate that the rare complex allele [G576V;R668C] is associated with a milder disease via a gain-of-function mechanism. Conversely, CFTR ultra-rare alleles with reduced function are associated with disease severity either alone (dominant disorder) or with another hypomorphic allele in the second chromosome (recessive disorder) with a global residual CFTR activity between 50 to 91%. Furthermore, we characterized novel CFTR complex alleles, including [A238V;F508del], [R74W;D1270N;V201M], [I1027T;F508del], [I506V;D1168G], and simple alleles, including R347C, F1052V, Y625N, I328V, K68E, A309D, A252T, G542*, V562I, R1066H, I506V, I807M, which lead to a reduced CFTR function and thus, to more severe COVID-19. In conclusion, CFTR genetic analysis is an important tool in identifying patients at risk of severe COVID-19

La stampa 3D in ortopedia: indicazioni e limiti

Introduzione. Negli ultimi decenni, lo sviluppo delle tecniche e dei materiali ha permesso profondi passi avanti in diversi campi della tecnologia; la medicina, e in particolare l\u2019ortopedia, \ue8 tra i settori che ne han- no maggiormente giovato. Sebbene la tecnologia di stampa 3D sia disponibile da diversi decenni, le ele- vate spese di gestione e i risultati insufficienti ne avevano ridotto l\u2019applicazione solo in campo industriale e meccanico; negli ultimi anni, grazie anche alla riduzione dei prezzi, si \ue8 verificata una netta diffusione della stampa 3D anche in campo medico e in particolar modo ortopedico. La stampa tridimensionale permette il passaggio da un modello tridimensionale computerizzato a un manufatto reale, \u201cstampato\u201d da apposite stampanti 3D. Tale processo si basa sulla sovrapposizione progressiva di strati di spessore e materiali variabili, quali polimeri plastici o metalli, secondo uno schema preciso e computerizzato, che viene detto \u201cadditivo\u201d per contrapposizione alle tecniche di produzione tradizionali che prevedono la sottrazione di materiale in eccesso da un volume di partenza per la produzione del manufatto definitivo. Materiali e metodi. Sono stati valutati i principali campi di applicazione della stampa 3D in ortope- dia, analizzando il processo che porta all\u2019impianto di una protesi custom-made in titanio, stampata con tecnologia 3D. Risultati. Possiamo identificare sette principali usi in ortopedia: uso didattico, planning operatorio, informazione del paziente, produzione di protesi custom-made, produzione di strumenti chirurgici anche dedicati al singolo paziente, template per spaziatori in cemento antibiotato, produzione di ortesi esterne e tutori personalizzati. La corretta interazione tra ortopedico e ingegnere \ue8 alla base della riuscita del prodotto custom-made; una volta raggiunto un accordo, saranno necessari circa 30 giorni per avere il prodotto impiantabile. Conclusioni. La tecnologia di stampa 3D \ue8 da considerarsi oggi una valida arma nelle mani dell\u2019or - topedico per la risoluzione di casi difficili. I limiti pi\uf9 importanti sono oggi costituiti dal rischio di in- fezione e dall\u2019osteointegrazione. Altri sviluppi e indicazioni probabilmente si avranno parallelamente all\u2019ulteriore sviluppo tecnologico

Automatic management of atrial and ventricular stimulation in a contemporary unselected population of pacemaker recipients: The ESSENTIAL Registry

Aims We investigated the applicability of the Ventricular Capture Control (VCC) and Atrial Capture Control (ACC) algorithms for automatic management of cardiac stimulation featured by Biotronik pacemakers in a broad, unselected population of pacemaker recipients. Methods and results Ventricular Capture Control and Atrial Capture Control were programmed to work at a maximum adapted output voltage as 4.8 V in consecutive recipients of Biotronik pacemakers. Ambulatory threshold measurements were made 1 and 12 months after pacemaker implant/replacement in all possible pacing/sensing configurations, and were compared with manual measurements. Among 542 patients aged 80 (73-85) years, 382 had a pacemaker implant and 160 a pacemaker replacement. Ventricular Capture Control could work at long term in 97% of patients irrespectively of pacing indication, lead type, and lead service life, performance being superior with discordant pacing/sensing configurations. Atrial Capture Control could work in 93% of patients at 4.8 V maximum adapted voltage and at any pulse width, regardless of pacing indication, lead type, and service life. At 12-month follow-up, a ventricular threshold increase 651.5 V had occurred in 4.4% of patients uneventfully owing to VCC functioning. Projected pacemaker longevity at 1 month was strongly correlated with the 12-month estimate, and exceeded 13 years in >60% of patients. Conclusion These algorithms for automatic management of pacing output ensure patient safety in the event of a huge increase of pacing threshold, while enabling maximization of battery longevity. Their applicability is quite broad in an unselected pacemaker population irrespectively of lead choice and service of life

A enfermagem e a atenção à criança vítima de violência familiar La enfermería y la atención al niño victima de violencia familiar The nursing and the attention to the child who is victim of familiar violence

Estudo bibliográfico com o objetivo de refletir sobre a atenção de enfermagem à criança vítima de violência familiar a partir da análise da produção científica acerca desta temática. Foram analisadas 37 publicações (08 nacionais e 29 internacionais) indexadas (BDENF; LILACS e MEDLINE), localizadas no período de 1993-2003. A utilização da técnica de análise de conteúdo possibilitou a categorização do conhecimento em três núcleos temáticos: diagnóstico, capacitação do enfermeiro e atenção de enfermagem à criança vítima de violência familiar. Não se visualizou um crescimento significativo da produção científica da Enfermagem enfocando este tema nos últimos anos.<br>Estúdio bibliográfico con el objectivo de reflexionar sobre la atención de enfermería al nino víctima de violência familiar a partir del análisis de la produccion científica referente a esa temática. Fueron analisadas 37 publicaciones (08 nacionales y 29 internacionales) indexadas (BDENF, LILACS Y MEDLINE), sitas em nel período de 1993-2003. Los datos fueron analisados por médio de la técnica de análises de contenido, lo que propició la categorización del conocimiento in três núcleos temáticos: diagnóstico, capacitación del enfermero y atención de enfermería al nino víctima de violência familiar. Non se noto um crecimiento significativo de la producción científica de la enfermeria tratando de ese tema em los últimos años.<br>Bibliographic study that aimed to reflect about the nursing care to the child who is victim of familiar violence from the analysis of scientific production concerning this subject. Thirty-seven indexed publications were analyzed (08 national and 29 international) using the following bibliographic databases: BDENF; LILACS and MEDLINE. Estalishing the period of 1993-2003 as limit time. The results were analyzed applying the technique of content analysis becoming possible the distinction of knowledge in three topical cores: diagnostic, qualification of the nurse, and nursing care to the child victim of familiar violence. An increase of significant nursing scientific production focalizing this subject was not visualized in the last years