SMARCE1-related meningiomas: A clear example of cancer predisposing syndrome

We report the case of a 16-year-old girl presenting with spinal clear-cell multiple meningiomas (CCMs). In view of this presentation, we sequenced a bioinformatic panel of genes associated with susceptibility to meningioma, identifying a germline heterozygous variant in SMARCE1. Somatic DNA investigations in the CCM demonstrated the deletion of the wild-type allele (loss of heterozygosity, LOH), supporting the causative role of this variant. Family segregation study detected the SMARCE1 variant in the asymptomatic father and in the asymptomatic sister who, nevertheless, presents 2 spinal lesions. Germline heterozygous loss-of-function (LoF) variants in SMARCE1, encoding a protein of the chromatin-remodeling complex SWI/SNF, have been described in few fa-milial cases of susceptibility to meningioma, in particular the CCM subtype. Our case confirms the role of NGS in investigating predisposing genes for meningiomas (multiple or recurrent), with specific regard to SMARCE1 in case of pediatric CCM. In addition to the age of onset, the presence of familial clustering or the coexistence of multiple synchronous meningiomas also supports the role of a genetic predisposition that deserves a molecular assessment. Additionally, given the incomplete penetrance, it is of great importance to follow a specific screening or follow-up program for symptomatic and asymptomatic carriers of pathogenic variants in SMARCE1

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

The polymorphism L412F in TLR3 inhibits autophagy and is a marker of severe COVID-19 in males

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19. This association increases in the sub-cohort of males. Impaired macroautophagy/autophagy and reduced TNF/TNFα production was demonstrated in HEK293 cells transfected with TLR3L412F-encoding plasmid and stimulated with specific agonist poly(I:C). A statistically significant reduced survival at 28 days was shown in L412F COVID-19 patients treated with the autophagy-inhibitor hydroxychloroquine (p = 0.038). An increased frequency of autoimmune disorders such as co-morbidity was found in L412F COVID-19 males with specific class II HLA haplotypes prone to autoantigen presentation. Our analyses indicate that L412F polymorphism makes males at risk of severe COVID-19 and provides a rationale for reinterpreting clinical trials considering autophagy pathways. Abbreviations: AP: autophagosome; AUC: area under the curve; BafA1: bafilomycin A1; COVID-19: coronavirus disease-2019; HCQ: hydroxychloroquine; RAP: rapamycin; ROC: receiver operating characteristic; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; TLR: toll like receptor; TNF/TNF-α: tumor necrosis factor

Il neonato asfittico: ruolo dell'ipotermia sulla funzionalita' cardiaca e renale

L’asfissia perinatale è la più grave, e spesso imprevista, delle complicanze legate al parto. Non solo rappresenta, a livello mondiale, una delle maggiori cause di morte, ma è anche responsabile di sequele neurologiche permanenti in molti dei bambini sopravvissuti, nonché di insufficienza multiorgano in epoca neonatale. L’American Academy of Pediatrics definisce l’ipotermia moderata come lo standard di trattamento per i neonati asfittici, unico intervento di provata efficacia nel migliorare l’outcome neurologico a 18 mesi. Tuttavia, mentre è vivace la ricerca relativa alla neuroprotezione, sono ancora pochi i dati in letteratura relativi alla gestione acuta della disfunzione multiorgano. La compromissione internistica può essere però causa diretta del decesso entro i primi giorni di vita e influenzare ampiamente il decorso clinico del paziente. Scopo di questa tesi è pertanto quello di contribuire all’analisi della condizione internistica del neonato asfittico, valutando in proposito gli eventuali effetti dell’ipotermia. In particolare, abbiamo posto attenzione allo studio della funzionalità cardiaca e renale, critiche per la sopravvivenza del neonato. Nell’U.O. Neonatologia di Pisa, dall’Aprile del 2009, sono stati trattati con ipotermia 31 neonati. Abbiamo confrontato una serie di parametri relativi alla funzione cardiaca e renale di questo gruppo di pazienti con quelli di una coorte storica di controllo. I risultati ottenuti suggeriscono l’efficacia del trattamento per un maggiore e più rapido recupero del danno miocardico e renale post-asfittico. I nostri dati, che pure necessitano di ulteriore approfondimento per la completa comprensione dei meccanismi, sono incoraggianti e forniscono spunti per progettare nuove strategie di ricerca volte a corroborare l’ipotesi che l’ipotermia nel neonato possa essere, oltre che trattamento neuroprotettivo, anche cardio e nefroprotettivo

Coronary in-stent restenosis: Assessment with CT coronary angiography

Purpose: To compare accuracy and radiation exposure of a new computed tomographic (CT) scanner with improved spatial resolution (scanner A) with those of a CT scanner with standard spatial resolution (scanner B) for evaluation of coronary in-stent restenosis (ISR) by using invasive coronary angiography (ICA) and intravascular ultrasonography (US) as reference methods. Materials and Methods: Written informed consent was obtained and study protocol was approved by institutional ethics committee. A total of 180 consecutive patients (154 men [mean age \ub1 standard deviation, 66 years \ub1 12; range, 51-79 years] and 36 women [mean age, 70 years \ub1 12; range, 55-83 years]) scheduled to undergo ICA for suspected ISR were enrolled. Ninety patients were studied with scanner A (group 1: 72 men [mean age, 65 years \ub1 11; range, 52-79], 18 women [mean age, 68 years \ub1 12; range, 55-83 years]) and 90 with scanner B (group 2: 74 men [mean age, 64 years \ub1 10; range, 51-77 years], 16 women [mean age, 68 years \ub1 11; range, 55-82 years). Examination with the two scanners was compared with ICA and intravascular US. Radiation dose exposure was estimated. To compare stent evaluability between the two groups, \u3c72 test was used. Results: Stent evaluability was higher in group 1 than in group 2 (99% vs 92%, P = .0021). A significantly lower rate of beam-hardening artifact was observed in group 1 (two cases) than group 2 (12 cases, P < .05). For stent-based analysis, sensitivity, specificity, and accuracy of multidetector CT for ISR identification were 96%, 95%, and 96% in group 1 and 90%, 91%, and 91% in group 2, respectively, without statistically significant differences. The correlation between percent ISR evaluated at multidetector CT versus intravascular US was higher in group 1 than in group 2 (r = 0.89 vs r = 0.58; P = .019). The correlations of diameter and area measurements at reference site and stent maximal lumen narrowing site between multidetector CT and intravascular US were higher in group 1 than in group 2. Radiation dose was low in both multidetector CT groups (1.9 mSv \ub1 0.2). Conclusion: Scanner A, with improved spatial resolution, allowed reliable detection and quantification of coronary ISR with low radiation exposure. \ua9 RSNA, 2012

Radiation dose and diagnostic accuracy of multidetector computed tomography for the detection of significant coronary artery stenoses: A meta-analysis

We conducted a meta-analysis evaluating the critical ratio between effective radiation dose (ED), feasibility (Fe) and diagnostic accuracy (Ac) of multidetector computed tomography (MDCT) for the detection of significant coronary artery disease. By using our predetermined criteria, we selected human studies published in English in which the ED and raw data of Ac vs. invasive coronary angiography in a segment based model were specified. Data from 31 studies including 3661 patients (mean age 61.9 \ub1 4.5 years, heart rate 62.5 \ub1 6.7 bpm) and 50,236 coronary artery segments were analysed and are reported. Overall, Fe, sensitivity, specificity, negative predictive value, positive predictive value, Ac and ED were 95%, 90%, 96%, 99%, 69%, 95% and 10.4 \ub1 5.4 mSv, respectively. Multivariate analysis showed that prospective ECG-gating (- 8.8 mSv CI95% - 13.4 to - 4.3 mSv, p = 0.001), dual-source (- 3.7 mSv CI95% - 7.9 to 0 mSv, p = 0.05) and BMI-adapted scanning protocols (- 4.5 mSv CI95% - 8.7 to - 2.7 mSv, p = 0.03) were independent predictors of ED reduction. In patients with low heart rate, the best compromise between ED, Fe and Ac (2.5 mSv, 97% and 98%, respectively) was obtained combining prospective ECG-gating and BMI-adapted scanning protocols, while in patients with high heart rate the strategy associated with the best results (10 mSv, 98% and 97%, respectively) was the use of dual-source MDCT with retrospective ECG gating and modulation dose. In conclusion, careful selection of CT scanning protocols according to the patient's characteristics is critical for keeping the radiation exposure "as low as reasonably achievable" (ALARA) without impairing Fe and Ac