Loop electrosurgical excision procedure versus cryotherapy in the treatment of cervical intraepithelialneoplasia: A systematic review and meta-analysis of randomized controlled trials

AIM: Invasive cervical cancer is proceeded by a phase of preinvasive disease that is slow to progress and can be detected, treated, and collectively referred to as cervical intraepithelial neoplasia (CIN). Several excisional and ablative treatments for CIN have been studied, with loop electrosurgical excision procedure (LEEP) and cryotherapy being the two most commonly utilized. The objective of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to compare the compare harms and benefits of LEEP versus cryotherapy in women with CIN. METHODS: Electronic databases were searched from their inception until May 2018. We included all RCTs comparing cryotherapy versus LEEP in women with CIN. We included trials evaluating both HIV-seropositive and HIV-seronegative women. The primary outcome was the persistence of the disease at 6-month follow-up. Meta-analysis was performed using the random-effects model to produce summary treatment effects in terms of relative risk (RR) with 95% confidence interval (CI). RESULTS: Four trials, including 1035 women with CIN, were identified as relevant and included in the meta-analysis. Women who received LEEP for CIN had a significantly lower persistence at 6-month follow-up biopsy (RR: 0.87, 95% CI: 0.76-0.99) and significantly lower recurrence at 12-month follow-up biopsy (RR: 0.91, 95% CI: 0.84-0.99) compared to those who received cryotherapy. No between-group differences were found in the complications rate, but the analyses were not powered for these outcomes. CONCLUSIONS: In women with CIN, treatment with LEEP was associated with a significantly lower risk of persistence disease at 6 months and recurrence disease at 12 months compared to treatment with cryotherapy

Agronomic performance of 21 new disease resistant winegrape varieties grown in northeast Italy

The goal of the field trial was to evaluate the agronomic performance of 21 (10 red and 11 white) winegrape varieties obtained from recent breeding programmes for disease resistance developed in Hungary, Germany, and Italy. The tested red varieties were as follows: ‘Cabernet Carbon’, ‘Cabernet Eidos’, ‘Cabernet Volos’, ‘Julius’, ‘Merlot Khorus’, ‘Merlot Kanthus’, ‘Monarch’, ‘Prior’, UD. 31.103, ‘Vinera’. The tested white varieties were as follows: ‘Aromera’, ‘Bronner’, ‘Fleurtai’, ‘Johanniter’, ‘Muscaris’, ‘Souvignier Gris’, ‘Sauvignon Kretos’, ‘Sauvignon Nepis’, ‘Sauvignon Rytos’, ‘Solaris’, ‘Soreli’. ‘Merlot’ (red) and ‘Glera’ (white) were included as control. The experimental vineyard was established in Castelfranco Veneto on the plain, in 2014. Spray treatments were applied against downy and powdery mildew, by using only copper and sulphur. Grape production, grape quality, and phenology were recorded over a six-year-period, while disease resistance (downy mildew, powdery mildew, black rot and anthracnose) was detected only during a few years. The most significant findings were: a) all varieties showed a good level of downy mildew resistance, especially ‘Cabernet Carbon’, ‘Monarch’, ‘Prior’, UD 31.103, ‘Muscaris’, ‘Solaris’, ‘Souvignier Gris’, ‘Bronner’, ‘Fleurtai’, ‘Aromera’; b) no powdery mildew attacks were detected in any variety; c) ‘Monarch’, ‘Muscaris’, ‘Solaris’ and ‘Souvignier Gris’ also showed a high level of resistance towards black rot and anthracnose; d) red grape varieties had an earlier bud burst as compared to ‘Merlot’, and, concerning ripening, some varieties were earlier than ‘Merlot’, other ones were later; e) white varieties had a later bud burst but an earlier ripening time as compared to ‘Glera’; f) grape production and quality changed significantly depending on the varieties, being titratable acidity higher than 6.4 g L-1 tartaric acid and pH lower than 3.5; also the year affected in a significant way those parameters as well as the interaction between the genotype and the year. In conclusion, the tested varieties behaved positively in terms of environmental sustainability

Higher risk of gastrointestinal parasite infection at lower elevation suggests possible constraints in the distributional niche of Alpine marmots

Alpine marmots Marmota marmota occupy a narrow altitudinal niche within high elevation alpine environments. For animals living at such high elevations where resources are limited, parasitism represents a potential major cost in life history. Using occupancy models, we tested if marmots living at higher elevation have a reduced risk of being infected with gastrointestinal helminths, possibly compensating the lower availability of resources (shorter feeding season, longer snow cover and lower temperature) than marmots inhabiting lower elevations. Detection probability of eggs and oncospheres of two gastro-intestinal helminthic parasites, Ascaris laevis and Ctenotaenia marmotae, sampled in marmot feces, was used as a proxy of parasite abundance. As predicted, the models showed a negative relationship between elevation and parasite detectability (i.e. abundance) for both species, while there appeared to be a negative effect of solar radiance only for C. marmotae. Site-occupancy models are used here for the first time to model the constrains of gastrointestinal parasitism on a wild species and the relationship existing between endoparasites and environmental factors in a population of free-living animals. The results of this study suggest the future use of site-occupancy models as a viable tool to account for parasite imperfect detection in ecoparasitological studies, and give useful insights to further investigate the hypothesis of the contribution of parasite infection in constraining the altitudinal niche of Alpine marmots

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

A genome-wide association study for survival from a multi-centre European study identified variants associated with COVID-19 risk of death

: The clinical manifestations of SARS-CoV-2 infection vary widely among patients, from asymptomatic to life-threatening. Host genetics is one of the factors that contributes to this variability as previously reported by the COVID-19 Host Genetics Initiative (HGI), which identified sixteen loci associated with COVID-19 severity. Herein, we investigated the genetic determinants of COVID-19 mortality, by performing a case-only genome-wide survival analysis, 60 days after infection, of 3904 COVID-19 patients from the GEN-COVID and other European series (EGAS00001005304 study of the COVID-19 HGI). Using imputed genotype data, we carried out a survival analysis using the Cox model adjusted for age, age2, sex, series, time of infection, and the first ten principal components. We observed a genome-wide significant (P-value < 5.0 × 10-8) association of the rs117011822 variant, on chromosome 11, of rs7208524 on chromosome 17, approaching the genome-wide threshold (P-value = 5.19 × 10-8). A total of 113 variants were associated with survival at P-value < 1.0 × 10-5 and most of them regulated the expression of genes involved in immune response (e.g., CD300 and KLR genes), or in lung repair and function (e.g., FGF19 and CDH13). Overall, our results suggest that germline variants may modulate COVID-19 risk of death, possibly through the regulation of gene expression in immune response and lung function pathways

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