DECLINE OF PREVALENCE OF RESISTANCE ASSOCIATED SUBSTITUTIONS TO NS3 AND NS5A INHIBITORS AT DAA- FAILURE IN HEPATITIS C VIRUS IN ITALY OVER THE YEARS 2015 TO 2018

Background: A minority of patients fails to eliminate HCV and resistance-associated substitutions (RASs) are commonly detected at failure of interferon-free DAA regimens . Methods: Within the Italian network VIRONET-C, the prevalence of NS3/NS5A/NS5B RASs was retrospectively evaluated in patients who failed an EASL recommended DAA-regimen in 2015-2018 . The geno2pheno system and Sorbo MC et al. Drug Resistance Updates 2018 were used to infer HCV- genotype/subtype and predict drug resistance . The changes in prevalence of RASs over time were evaluated by chi-square test for trend, predictors of RASs at failure were analysed by logistic regression . Results: We included 386 HCV infected patients: 75% males, median age was 56 years (IQR 52-61), metavir fibrosis stage F4 in 76%; 106 (28%) were treatment- experienced: 91 (86%) with IFN-based treatments, 26 (25%) with DAAs. Patients with HIV and HBV coinfection were 10% (33/317) and 8% (6/72), respectively. HCV genotype was 1b in 122 pts (32%), 3 in 109 (28%), 1a in 97 (25%), 4 in 37 (10%), 2 in 21 (5%). DAA regimens were: LDV/SOF in 115 (30%), DCV/SOF in 103 (27%), 3D in 83 (21%), EBR/GRZ in 32 (8%), VEL/SOF in 29 (7%), GLE/PIB in 18 (5%) and 2D in 6 (2%); ribavirin was administered in 123 (32%) . The NS5A fasta-sequence was available for all patients, NS5B for 361 (94%), NS3 for 365 (95%) . According to the DAA failed the prevalence of any RASs was 90%, namely 80/135 (59%) in NS3, 313/359 (87%) in NS5A, 114/286 (40%) in NS5B . The prevalence of any RASs significantly declined from 2015 to 2018 (93% vs 70%, p=0.004): NS5A RASs from 90% to 72% (p=0 .29), NS3 RASs from 74% to 18% (p<0 .001), while NS5B RASs remained stable . Independent predictors of any RASs included advanced fibrosis (AOR 6.1, CI 95% 1.8-20.3, p=0 .004) and genotype (G2 vs G1a AOR 0 .03, CI 95% 0 .002- 0 .31, p=0 .004; G3 vs G1a AOR 0 .08, CI 95% 0 .01-0 .62, p=0 .02; G4 vs G1a AOR 0 .05, CI 95% 0 .006-0 .46, p=0 .008), after adjusting for age, previous HCV treatment and year of genotype . Notably, full activity was predicted for GLE/PIB in 75% of cases and for at least two components of VEL/SOF/VOX in 53% of cases, no case with full-resistance to either regimen was found . Conclusion: Despite decreasing prevalence over the years, RASs remain common at virological failure of DAA treatment, particularly in patients with the highest grade of liver fibrosis. The identification of RASs after failure could play a crucial role in optimizing retreatment strategies

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

The influence of immunodeficiency, disease features, and patient characteristics on survival in plasmablastic lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavourable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across four countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and by whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age 55) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) were HIV-positive. The five-year OS for the entire cohort was 36% (95% CI 30-42%). In multivariate analysis, inferior OS was associated with EBV-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the IPI was associated with OS outcomes. Neither immunosuppression, nor HIV infection specifically, influenced OS. Among patients treated with curative intent (n=234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of PBL patients, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes

The Influence of Immunodeficiency, Disease Features and Patient Characteristics on Survival in Plasmablastic Lymphoma

Plasmablastic lymphoma (PBL) is a rare and aggressive non-Hodgkin lymphoma associated with immunodeficiency, characterized by uncertain treatment approaches and an unfavourable prognosis. We conducted a multicenter, international, retrospective cohort study, aiming to characterize the clinical features, risk factors, and outcomes of patients with PBL. Data were collected from 22 institutions across four countries regarding patients diagnosed with PBL between 1 January 1999 and 31 December 2020. Survival risk factors were analyzed using both univariate and multivariate regression models. Overall survival (OS) was calculated using Kaplan-Meier statistics. First-line treatment regimens were stratified into standard- and higher-intensity regimens, and by whether they incorporated a proteasome inhibitor (PI). A total of 281 patients (median age 55) were included. Immunodeficiency of any kind was identified in 144 patients (51%), and 99 patients (35%) were HIV-positive. The five-year OS for the entire cohort was 36% (95% CI 30-42%). In multivariate analysis, inferior OS was associated with EBV-negative lymphoma, poor performance status, advanced stage, and bone marrow involvement. In an independent univariate analysis, the IPI was associated with OS outcomes. Neither immunosuppression, nor HIV infection specifically, influenced OS. Among patients treated with curative intent (n=234), the overall response rate was 72%. Neither the intensity of the treatment regimen nor the inclusion of PIs in first-line therapy was associated with OS. In this large retrospective study of PBL patients, we identified novel risk factors for survival. PBL remains a challenging disease with poor long-term outcomes

Made in Carcere: Integral Human Development in Extreme Conditions

This paper analyzes the case of Made in Carcere, an innovative social enterprise providing jobs to one of the most margin- alized groups in society: convicted women. Relying on an extensive database that covers 8\ua0years of activity, we propose a micro-level analysis of the processes adopted by Made in Carcere to foster the integral human development of convicted women, its target stakeholders. We show that this complex effort has successfully unfolded through two macro-processes: creating a safe space for experimentation and allowing convicted women to bridge their experience to the outside reality. Our work provides evidence of an organization that successfully confronts the restrictive and dehumanizing setting of prisons by means of market mechanisms that can foster convicted women\u2019s integral human development

The DELPHI detector at LEP

DELPHI is a 4π detector with emphasis on particle identification, three-dimensional information, high granularity and precise vertex determination. The design criteria, the construction of the detector and the performance during the first year of operation at the large electron positron collider (LEP) at CERN are described. © 1991 - Elsevier Science Publishers B.V. (North-Holland)