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AIDS-defining cancers declined after combined antiretroviral therapy (cART) introduction, but lymphomas are still elevated in HIV type 1 (HIV-1)-infected patients. In particular, non-Hodgkin's lymphomas (NHLs) represent the majority of all AIDS-defining cancers and are the most frequent cause of death in these patients. We have recently demonstrated that amino acid (aa) insertions at the HIV-1 matrix protein p17 COOH-terminal region cause protein destabilization, leading to conformational changes. Misfolded p17 variants (vp17s) strongly impact clonogenic B cell growth properties that may contribute to B cell lymphomagenesis as suggested by the significantly higher frequency of detection of vp17s with COOH-terminal aa insertions in plasma of HIV-1-infected patients with NHL. Here, we expand our previous observations by assessing the prevalence of vp17s in large retrospective cohorts of patients with and without lymphoma. We confirm the significantly higher prevalence of vp17s in lymphoma patients than in HIV-1-infected individuals without lymphoma. Analysis of 3,990 sequences deposited between 1985 and 2017 allowed us to highlight a worldwide increasing prevalence of HIV-1 mutants expressing vp17s over time. Since genomic surveillance uncovered a cluster of HIV-1 expressing a B cell clonogenic vp17 dated from 2011 to 2019, we conclude that aa insertions can be fixed in HIV-1 and that mutant viruses displaying B cell clonogenic vp17s are actively spreading.

An analysis of the structural effect of the mutations of the B.1.640.2 (IHU) Spike Receptor Binding Domain (RBD) and N-terminal Domain (NTD) is reported along with a comparison with the sister lineage B.1.640.1. and a selection of variants of concern. The effect of the mutations on the RBD–ACE2 interaction was also assessed. The structural analysis applied computational methods that are able to carry out in silico mutagenesis to calculate energy minimization and the folding energy variation consequent to residue mutations. Tools for electrostatic calculation were applied to quantify and display the protein surface electrostatic potential. Interactions at the RBD–ACE2 interface were scrutinized using computational tools that identify the interactions and predict the contribution of each interface residue to the stability of the complex. The comparison among the RBDs shows that the most evident differences between the variants is in the distribution of the surface electrostatic potential: that of B.1.640.1 is as that of the Alpha RBD, while B.1.640.2 appears to have an intermediate surface potential pattern with characteristics between those of the Alpha and Delta variants. Moreover, the B.1.640.2 Spike includes the mutation E484K that in other variants has been suggested to be involved in immune evasion. These properties may hint at the possibility that B.1.640.2 emerged with a potentially increased infectivity with respect to the sister B.1.640.1 variant, but significantly lower than that of the Delta and Omicron variants. However, the analysis of their NTD domains highlights deletions, destabilizing mutations and charge alterations that can limit the ability of the B.1.640.1 and B.1.640.2 variants to interact with cellular components, such as cell surface receptors.

The BQ.1 SARS-CoV-2 variant, also known as Cerberus, is one of the most recent Omicron descendant lineages. Compared to its direct progenitor BA.5, BQ.1 has some additional spike mutations in some key antigenic sites, which confer further immune escape ability over other circulating lineages. In such a context, here, we perform a genome-based survey aimed at obtaining a complete-as-possible nuance of this rapidly evolving Omicron subvariant. Genetic data suggest that BQ.1 represents an evolutionary blind background, lacking the rapid diversification that is typical of a dangerous lineage. Indeed, the evolutionary rate of BQ.1 is very similar to that of BA.5 (7.6 × 10−4 and 7 × 10−4 subs/site/year, respectively), which has been circulating for several months. The Bayesian Skyline Plot reconstruction indicates a low level of genetic variability, suggesting that the peak was reached around 3 September 2022. Concerning the affinity for ACE2, structure analyses (also performed by comparing the properties of BQ.1 and BA.5 RBD) indicate that the impact of the BQ.1 mutations may be modest. Likewise, immunoinformatic analyses showed moderate differences between the BQ.1 and BA5 potential B-cell epitopes. In conclusion, genetic and structural analyses on SARS-CoV-2 BQ.1 suggest no evidence of a particularly dangerous or high expansion capability. Genome-based monitoring must continue uninterrupted for a better understanding of its descendants and all other lineages.

The COVID-19 pandemic continues to have a threatening impact on a global scale, largely due to the emergence of newly SARS-CoV-2 variants. The Mu (PANGO lineage B.1.621), was first identified in Colombia in January 2021 and was classified as a variant of interest (VOI) in August 2021, due to a constellation of mutations that likely-mediate an unexpectedly enhanced immune resistance to inactivated vaccine-elicited antibodies. Despite recent studies suggesting that the Mu variant appears to have less infectivity than the Delta variant, here we examined the structural effect of the Mu spike protein mutations and predicted the potential impact on infectivity of the Mu variant compared with the Delta and Delta plus spike protein.

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We investigated SARS-CoV-2 transmission dynamics in Italy, one of the countries hit hardest by the pandemic, using phylodynamic analysis of viral genetic and epidemiological data. We observed the co-circulation of multiple SARS-CoV-2 lineages over time, which were linked to multiple importations and characterized by large transmission clusters concomitant with a high number of infections. Subsequent implementation of a three-phase nationwide lockdown strategy greatly reduced infection numbers and hospitalizations. Yet we present evidence of sustained viral spread among sporadic clusters acting as “hidden reservoirs” during summer 2020. Mathematical modelling shows that increased mobility among residents eventually catalyzed the coalescence of such clusters, thus driving up the number of infections and initiating a new epidemic wave. Our results suggest that the efficacy of public health interventions is, ultimately, limited by the size and structure of epidemic reservoirs, which may warrant prioritization during vaccine deployment.

Among the more recently identified SARS-CoV-2 Variants of Interest (VOI) is the Lambda variant, which emerged in Peru and has rapidly spread to South American regions and the US. This variant remains poorly investigated, particularly regarding the effects of mutations on the thermodynamic parameters affecting the stability of the Spike protein and its Receptor Binding Domain. We report here an in silico study on the potential impact of the Spike protein mutations on the immuno-escape ability of the Lambda variant. Bioinformatics analysis suggests that a combination of shortening the immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy, potentially allowing this emerging viral variant to escape from host immunity.

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Purpose: To evaluate the predictive value of18F-FDG PET/CT semiquantitative parameters of the primary tumour and CA 19-9 levels assessed before treatment in patients with locally advanced pancreatic cancer (LAPC). Methods: Among one-hundred twenty patients with LAPC treated at our institution with initial chemotherapy followed by curative chemoradiotherapy (CRT) from July 2013 to January 2019, a secondary analysis with baseline18F-FDG PET/CT was conducted in fifty-eight patients. Pre-treatment CA 19-9 level and the maximum standardized uptake value (SUVmax), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) of primary tumour were measured. The receiving operating characteristics (ROC) analysis was performed to define the cut-off point of SUVmax, MTV, TLG and CA 19-9 values to use in prediction of early progression (EP), local progression (LP) and overall survival (OS). Areas under the curve (AUCs) were assessed for all variables. Post-test probability was calculated to evaluate the advantage for parameters combination. Results: For EP, CA 19-9 level > 698 U/mL resulted the best marker to identify patient at higher risk with OR of 5.96 (95% CI, 1.66–19.47; p = 0.005) and a Positive Predictive Value (PPV) of 61%. For LP, the most significant parameter was TLG (OR 9.75, 95% CI, 1.64–57.87, p = 0.012), with PPV of 83%. For OS, the most significant parameter was MTV (OR 3.12, 95% CI, 0.9–10.83, p = 0.07) with PPV of 88%. Adding consecutively each of the other parameters, PPV to identify patients at risk resulted further increased (>90%). Conclusions: Pre-treatment CA 19-9 level, as well as MTV and TLG values of primary tumour at baseline18F-FDG PET/CT and their combination, may represent significant predictors of EP, LP and OS in LAPC patients.

Italy is the first western country suffering heavy severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and disease impact after coronavirus disease-2019 pandemia started in China. Even though the presence of mutations on spike glycoprotein and nucleocapsid in Italian isolates has been reported, the potential impact of these mutations on viral transmission has not been evaluated. We have compared SARS-CoV-2 genome sequences from Italian patients with virus sequences from Chinese patients. We focussed upon three nonsynonymous mutations of genes coding for S(one) and N (two) viral proteins present in Italian isolates and absent in Chinese ones, using various bioinformatics tools. Amino acid analysis and changes in three-dimensional protein structure suggests the mutations reduce protein stability and, particularly for S1 mutation, the enhanced torsional ability of the molecule could favor virus binding to cell receptor(s). This theoretical interpretation awaits experimental and clinical confirmation.

Background: SARS-CoV-2 is a new coronavirus that has spread globally, infecting more than 150000 people, and being declared pandemic by the WHO. We provide here bio-informatic, evolutionary analysis of 351 available sequences of its genome with the aim of mapping genome structural variations and the patterns of selection. Methods: A Maximum likelihood tree has been built and selective pressure has been investigated in order to find any mutation developed during the SARS-CoV-2 epidemic that could potentially affect clinical evolution of the infection. Finding: We have found in more recent isolates the presence of two mutations affecting the Non-Structural Protein 6 (NSP6) and the Open Reding Frame10 (ORF 10) adjacent regions. Amino acidic change stability analysis suggests both mutations could confer lower stability of the protein structures. Interpretation: One of the two mutations, likely developed within the genome during virus spread, could affect virus intracellular survival. Genome follow-up of SARS-CoV-2 spread is urgently needed in order to identify mutations that could significantly modify virus pathogenicity.

BACKGROUND: Postpartum haemorrhage (PPH) is a leading cause of maternal mortality and morbidity. Reducing deaths from PPH is a global challenge. The voices of women and healthcare providers have been missing from the debate around best practices for PPH prevention. The aim of this review was to identify, appraise and synthesize available evidence about the views and experiences of women and healthcare providers on interventions to prevent PPH. METHODS: We searched eight electronic databases and reference lists of eligible studies published between 1996 and 2018, reporting qualitative data on views and experiences of PPH in general, and of any specific preventative intervention(s). Authors' findings were extracted and synthesised using meta-ethnographic techniques. Confidence in the quality, coherence, relevance and adequacy of data underpinning the resulting themes was assessed using GRADE-CERQual. A line of argument synthesis was developed. RESULTS: Thirty-five studies from 29 countries met our inclusion criteria. Our results indicate that women and healthcare providers recognise the dangers of severe blood loss in the perinatal and postpartum period, but don't always share the same beliefs about the causes and consequences of PPH. Skilled birth attendants and traditional birth attendants (TBA's) want to prevent PPH but may lack the required resources and training. Women generally appreciate PPH prevention strategies, especially where their individual needs, beliefs and values are taken into account. Women and healthcare providers also recognize the value of using uterotonics (medications that contract the uterus) to prevent PPH but highlight safety concerns and potential misuse of the drugs as acceptability and implementation issues. CONCLUSIONS: Based on stakeholder views and experiences, PPH prevention strategies are more likely to be successful where all stakeholders agree on the causes and consequences of severe postpartum blood loss, especially in the context

Background: Risk of nodal involvement in T1 colorectal cancer is assessed by tumor histological features. In several tumors, the ratio between neutrophils and lymphocytes (NLR) or platelets and lymphocytes (PLR) have been applied to lymph-node metastases prediction. The aim of this study was to evaluate the role of NLR, derived NLR (dNLR) and PLR in predicting nodal involvement in T1 colorectal cancers. METHODS: NLR, dNLR and PLR in surgical resected T1 colorectal cancers were retrospectively calculated and analysed in nodal positive and negative cases. RESULTS: Data regarding 102 patients were considered. Nodal involvement rate was 10.8%. NLR values were higher in node positive patients (P=0.04). A trend toward significance (P=0.05) was found for higher dNLR values and positive nodal status. For NLR, ROC curve analysis allowed to choose a predictive cut-off value of 3.7 (AUC of 0.69; 95% CI: 0.48-0.89). Nodal positivity was reported in 71.5% of high NLR patients; only two N0 cases (28.5%) were registered in high NLR group (P<0.001). The logistic regression analysis aimed to evidence the predictive role of high NLR in node positivity resulted in a significant OR of 37.1 (P<0.0001; 95% CI: 0.48-0.89). NLR allowed to distinguish N0 from N1 patients in 99.4% of cases. CONCLUSIONS: NLR<3.7 was associated with lower risk of lymph-node metastases in T1 colorectal cancer patients. NLR could be used with histopathological data to identify patients at lower risk of nodal metastases.

Background Screening migrants from areas where hepatitis B virus (HBV) infection is endemic is important to implement preventive measures in Europe. The aim of our study was to assess (1) the feasibility of point-of-care screening in a primary care clinic and (2) hepatitis B surface antigen (HBsAg) prevalence, associated risk factors, and its clinical and epidemiological implications in undocumented migrants in Brescia, northern Italy. Methods A longitudinal prospective study was conducted from January 2006 to April 2010 to assess HBsAg reactivity and associated risk factors among consenting undocumented migrants who accessed the Service of International Medicine of Brescia's Local Health Authority. Genotyping assay was also performed in HBV DNA-positive patients. Results Screening was accepted by 3,728/4,078 (91.4%) subjects consecutively observed during the study period, 224 (6%) of whom were found to be HBsAg-positive. HBsAg reactivity was independently associated with the prevalence of HBsAg carriers in the geographical area of provenance (p < 0.001). On the contrary, current or past sexual risk behaviors (despite being common in our sample) were not associated with HBV infection. Half of the HBsAg patients (111/224) had either hepatitis B e-antigen (HBeAg)-positive or -negative chronic HBV infection with a possible indication for treatment. HBV genotypes were identified in 45 of 167 HBV-infected patients as follows: genotype D, 27 subjects; genotype A, 8; genotype B, 5; and genotype C, 5. The geographical distribution of genotypes reflected the geographic provenance. Conclusions Our results suggest that point-of-care screening is feasible in undocumented migrants and should be targeted according to provenance. Case detection of HBV infection among migrants could potentially reduce HBV incidence in migrants' contacts and in the general population by prompting vaccination of susceptible individuals and care of eligible infected patients.

BACKGROUND: Several social indicators have been used in epidemiological research to describe socioeconomic position (SEP) of people in societies. Among SEP indicators, those more frequently used are education, occupational class and income. Differences in the incidence of several health outcomes have been reported consistently, independently from the indicator employed. Main objectives of the study were to present the socioeconomic classifications of the social indicators which will be employed throughout the LIFEPATH project and to compare social gradients in all-cause mortality observed in the participating adult cohorts using the different SEP indicators. METHODS: Information on the available social indicators (education, own and father's occupational class, income) from eleven adult cohorts participating in LIFEPATH was collected and harmonized. Mortality by SEP for each indicator was estimated by Poisson regression on each cohort and then evaluated using a meta-analytical approach. RESULTS: In the meta-analysis, among men mortality was significantly inversely associated with both occupational class and education, but not with father's occupational class; among women, the increase in mortality in lower social strata was smaller than among men and, except for a slight increase in the lowest education category, no significant differences were found. CONCLUSIONS: Among men, the proposed three-level classifications of occupational class and education were found to predict differences in mortality which is consistent with previous research. Results on women suggest that classifying them through their sole SEP, without considering that of their partners, may imply a misclassification of their social position leading to attenuation of mortality differences.

INTRODUCTION: Inappropriate use of antimicrobials is one of the major modifiable contributors to antimicrobial resistance. There is currently no validated survey tool available to assess knowledge and confidence of medical students in infectious diseases (ID) compared to other diseases states, and little is known about this topic. MATERIALS AND METHODS: A cross-sectional survey of final year medical students attending universities around Australia was conducted between August and September, 2015. A survey unique from other published studies was developed to survey satisfaction in education, confidence and knowledge in ID, and how this compared to these factors in cardiovascular diseases. RESULTS: Reliability and validity was demonstrated in the survey tool used. Students were more likely to rate university education as sufficient for cardiovascular diseases (91.3%) compared to ID (72.5%), and were more confident in their knowledge of cardiovascular diseases compared to ID (74.38% vs. 53.76%). Students tended to answer more cardiovascular disease related clinical questions correctly (mean score 78%), compared to questions on antimicrobial use (mean score 45%). CONCLUSIONS: Poor knowledge and confidence amongst final year medical students in Australia were observed in ID. Antimicrobial stewardship agenda should include the provision of additional training in antimicrobial prescribing to the future medical workforce.