State of the Art, Unresolved Issues, and Future Research Directions in the Fight against Hepatitis C Virus: Perspectives for Screening, Diagnostics of Resistances, and Immunization

Hepatitis C virus (HCV) still represents a major public health threat, with a dramatic burden from both epidemiological and clinical points of view. New generation of direct-acting antiviral agents (DAAs) has been recently introduced in clinical practice promising to cure HCV and to overcome the issues related to the interferon-based therapies. However, the emergence of drug resistance and the suboptimal activity of DAAs therapies against diverse HCV genotypes have been observed, determining treatment failure and hampering an effective control of HCV spread worldwide. Moreover, these treatments remain poorly accessible, particularly in low-income countries. Finally, effective screening strategy is crucial to early identifying and treating all HCV chronically infected patients. For all these reasons, even though new drugs may contribute to impacting HCV spread worldwide a preventive HCV vaccine remains a cornerstone in the road to significantly reduce the HCV spread globally, with the ultimate goal of its eradication. Advances in molecular vaccinology, together with a strong financial, political, and societal support, will enable reaching this fundamental success in the coming years. In this comprehensive review, the state of the art about these major topics in the fight against HCV and the future of research in these fields are discussed

Interruzione del trattamento nei pazienti con schizofrenia che ricevono olanzapina o aripiprazolo: metanalisi degli studi clinici controllati

BACKGROUND: In schizophrenia the drop-out rate can be used as proxy of effectiveness. The drop-out evaluation is also important considering the relevant economic impact for NHS of an antipsychotic therapy discontinuation in terms of patient hospitalization and other related healthcare resources consumption. OBJECTIVE: To analyze the differences in the rates of drop-out from clinical trials between olanzapine and aripiprazole. METHODS: Literature search was based on MEDLINE, on Iowa-IDIS and Drugdex databases (1966-Dec 2004). Analysis included 12 randomized controlled trials (3.778 patients), 8 for olanzapine (2.559 patients) and 4 for aripiprazole (1.219 patients). RCT inclusion criteria were: a) Patients affected by schizophrenia; b) Randomized assignment to olanzapine or aripiprazole treatment group; c) Number of patients included in the treatment group higher than 100; d) Drop-out frequency evaluation between 4th and 26th weeks of follow-up. RESULTS: The rate of treatment discontinuation was greater for aripiprazole than for olanzapine (42,2% vs. 31,6% respectively). The comparison between drop-out percentages is statistically significant (

The impact of 10-valent and 13-valent pneumococcal conjugate vaccines on hospitalization for pneumonia in children: A systematic review and meta-analysis

Abstract Background This systematic review and meta-analysis aimed at summarizing available data on the impact of PCV10 and PCV13 in reducing the incidence of CAP hospitalizations in children aged Methods A systematic search of the literature was conducted. We included time-series analyses and before-after studies, reporting the incidence of hospitalization for pneumonia in the periods before and after the introduction of PCV10 or PCV13 into the immunization program. Pooled estimates of Incidence Rate Ratio (IRR) were calculated by using a random-effects meta-analytic model. Results were stratified according to age-groups ( Results A total of 1533 potentially relevant articles were identified. Of these, 12 articles were included in the analysis. In children aged In children aged 24–59 months, the meta-analysis showed a reduction of 9% (95%CI: 5–14%, p-value High heterogeneity was detected among studies evaluating the hospitalization rate for clinically and radiologically confirmed pneumonia. Conclusions The results of this study revealed a significant impact of PCV10 and PCV13 in reducing the hospitalizations for pneumonia, particularly in children age

Impatto della pertosse nella popolazione e strategie di prevenzione vaccinale

L'impatto epidemiologico della pertosse ha subito variazioni rilevanti soprattutto in et\ue0 pedia-trica, in seguito alla disponibilit\ue0 di vaccini cellulari altamente efficaci e alla successiva dif-fusione di preparati acellulari, caratterizzati da un migliore profilo di tollerabilit\ue0 e formulati in combinazione con altre componenti antigeniche. Cionondimeno, la pertosse rappresenta tutt\u2019oggi un\u2019importante causa di morbosit\ue0 e mortalit\ue0 nei neonati non ancora vaccinati o che non hanno completato il ciclo primario, e che possono essere infettati dai contatti suscettibili. Le coperture vaccinali sub-ottimali, la progressiva riduzione della protezione immunitaria conferita sia dall\u2019infezione naturale sia dalla vaccinazione e la mancata effettuazione dei richiami vaccinali contribuiscono, infatti, a rendere gli adolescenti e gli adulti le fonti princi-pali di trasmissione dell'infezione ai neonati. Strategie di prevenzione integrate e indirizzate a tutti i target coinvolti nella trasmissione dell'infezione (i.e. soggetti in et\ue0 pediatrica, ado-lescente e adulta, le donne in gravidanza, e gli operatori sanitari) rappresentano, pertanto, uno strumento chiave per il controllo della pertosse

Structure of the lectin mannose 6-phosphate receptor homology (MRH) domain of glucosidase II an enzyme that regulates glycoprotein folding quality control in the endoplasmic reticulum

Here we report for the first time the three-dimensional structure of a mannose 6-phosphate receptor homology (MRH) domain present in a protein with enzymatic activity, glucosidase II (GII). GII is involved in glycoprotein folding in the endoplasmic reticulum. GII removes the two innermost glucose residues from the Glc3Man9GlcNAc2 transferred to nascent proteins and the glucose added by UDP-Glc:glycoprotein glucosyltransferase. GII is composed of a catalytic GIIα subunit and a regulatory GIIβ subunit. GIIβ participates in the endoplasmic reticulum localization of GIIα and mediates in vivo enhancement of N-glycan trimming by GII through its C-terminal MRH domain. We determined the structure of a functional GIIβ MRH domain by NMR spectroscopy. It adopts a β-barrel fold similar to that of other MRH domains, but its binding pocket is the most shallow known to date as it accommodates a single mannose residue. In addition, we identified a conserved residue outside the binding pocket (Trp-409) present in GIIβ but not in other MRHs that influences GII glucose trimming activity.Fil: Olson, Linda J.. Medical College Of Wisconsin; Estados UnidosFil: Orsi, Ramiro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Alculumbre, Solana G.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Peterson, Francis C.. Medical College Of Wisconsin; Estados UnidosFil: Stigliano, Ivan Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Parodi, Armando Jose A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: D'alessio, Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina. Universidad de Buenos Aires; ArgentinaFil: Dahms, Nancy M.. Medical College Of Wisconsin; Estados Unido

MIS-C Treatment: Is IVIG Always Necessary?

Background: MIS-C is a potentially severe inflammatory syndrome associated with SARS-CoV-2 exposure. Intravenous immunoglobulin (IVIG) is considered the first-tier therapy, but it implies infusion of large fluid volumes that may worsen cardiac function. Patients and Methods: Since April 2020, we have developed a treatment protocol that avoids the infusion of IVIG as first-line therapy in the early phase of MIS-C. In this study, we retrospectively analyzed a cohort of consecutive patients treated according to this protocol between 01/04/2020 and 01/04/2021. Results: In the last year, 31 patients have been treated according to the protocol: 25 with high-dose pulse MP (10 mg/kg) and 6 with 2 mg/kg. 67.7% of the patients responded to the initial treatment, while the others needed a step-up, either with Anakinra (25.8%) or with MP dose increase (6.5%). IVIG was administered in four patients. Overall, only one patient (3.2%) needed ICU admission and inotropic support; one patient developed a small coronary artery aneurysm. Conclusions: Timely start of MP therapy and careful fluid management might improve the outcomes of MIS-C patients

Insulin resistance, diabetic kidney disease, and all-cause mortality in individuals with type 2 diabetes. a prospective cohort study

BACKGROUND: It is unclear whether insulin resistance (IR) contributes to excess mortality in patients with type 2 diabetes independent of diabetic kidney disease (DKD), which is strongly associated with IR and is a major risk factor for cardiovascular disease (CVD), the main cause of death in these individuals. We tested this hypothesis in patients with type 2 diabetes from the Renal Insufficiency And Cardiovascular Events Italian Multicentre Study.METHODS: This observational, prospective, cohort study enrolled 15,773 patients with type 2 diabetes attending 19 Italian Diabetes Clinics in 2006-2008. Insulin sensitivity was assessed as estimated glucose disposal rate (eGDR), which was validated against the euglycaemic-hyperinsulinemic clamp technique. Vital status on October 31, 2015, was retrieved for 15,656 patients (99.3%). Participants were stratified by eGDR tertiles from T1 (≥ 5.35mg/kg/min) to T3 (≤ 4.14mg/kg/min, highest IR).RESULTS: CVD risk profile was worse in T2 and T3 vs T1. eGDR tertiles were independently associated with micro- and macroalbuminuria and the albuminuric DKD phenotypes (albuminuria with preserved or reduced estimated glomerular filtration rate [eGFR]) as well as with eGFR categories or the nonalbuminuric DKD phenotype. Over a 7.4-year follow-up, unadjusted death rates and mortality risks increased progressively across eGDR tertiles, but remained significantly elevated after adjustment only in T3 vs T1 (age- and gender- adjusted death rate, 22.35 vs 16.74 per 1000 person-years, p<0.0001, and hazard ratio [HR] adjusted for multiple confounders including DKD, 1.140 [95% confidence interval [CI], 1.049-1.238], p=0.002). However, eGDR was independently associated with mortality in participants with no DKD (adjusted HR, 1.214 [95% CI, 1.072-1.375], p=0.002) and in those with nonalbuminuric DKD (1.276 [1.034-1.575], p=0.023), but not in those with the albuminuric DKD phenotypes. Moreover, the association was stronger in males and in younger individuals and was observed in those without but not with prior CVD, though interaction was significant only for age.CONCLUSIONS: The proxy of insulin sensitivity eGDR predicts all-cause mortality in type 2 diabetes, independent of confounders including DKD. However, the impact of IR in individuals with albuminuric DKD may be mediated by its relationship with albuminuria.TRIAL REGISTRATION: ClinicalTrials.gov , NCT00715481, retrospectively registered 15 July 2008

Independent association of atherogenic dyslipidaemia with all-cause mortality in individuals with type 2 diabetes and modifying effect of gender. a prospective cohort study

Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes

Distribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study

BACKGROUND: The National Kidney Foundation's Kidney Disease Outcomes Quality Initiative (NKF's KDOQI) staging system for chronic kidney disease (CKD) is based primarily on estimated GFR (eGFR). This study aimed at assessing whether reclassification of subjects with type 2 diabetes using two recent classifications based on both eGFR and albuminuria, the Alberta Kidney Disease Network (AKDN) and the Kidney Disease: Improving Global Outcomes (KDIGO), provides a better definition of burden from cardiovascular disease (CVD) and diabetic retinopathy (DR) than the NKF's KDOQI classification. METHODS: This is a cross-sectional analysis of patients with type 2 diabetes (n = 15,773) from the Renal Insufficiency And Cardiovascular Events Italian Multicenter Study, consecutively visiting 19 Diabetes Clinics throughout Italy in years 2007-2008. Exclusion criteria were dialysis or renal transplantation. CKD was defined based on eGFR, as calculated from serum creatinine by the simplified Modification of Diet in Renal Disease Study equation, and albuminuria, as measured by immunonephelometry or immunoturbidimetry. DR was assessed by dilated fundoscopy. Prevalent CVD, total and by vascular bed, was assessed from medical history by recording previous documented major acute events. RESULTS: Though prevalence of complications increased with increasing CKD severity with all three classifications, it differed significantly between NKF's KDOQI stages and AKDN or KDIGO risk categories. The AKDN and KDIGO systems resulted in appropriate reclassification of uncomplicated patients in the lowest risk categories and a more graded independent association with CVD and DR than the NKF's KDOQI classification. However, CVD, but not DR prevalence was higher in the lowest risk categories of the new classifications than in the lowest stages of the NKF's KDOQI, due to the inclusion of subjects with reduced eGFR without albuminuria. CVD prevalence differed also among eGFR and albuminuria categories grouped into AKDN and KDIGO risk category 1 and moderate, respectively, and to a lesser extent into higher risk categories. CONCLUSIONS: Though the new systems perform better than the NKF's KDOQI in grading complications and identifying diabetic subjects without complications, they might underestimate CVD burden in patients assigned to lower risk categories and should be tested in large prospective studies

Arqueo-escuela: reflexiones tras cinco años de divulgación en Arqueología

Arqueo-escuela es un equipo independiente y autogestivo constituido por arqueólogos y arqueólogas (la mayoría becarios y becarias del CONICET) con formación docente, enfocado en la divulgación de los métodos empleados por la arqueología para la interpretación de nuestro pasado. En 2021 cumplimos cinco años de actividad. En este tiempo hemos desarrollado distintas propuestas didácticas, y participado en múltiples y diversos espacios del ámbito público y privado relativos a la educación y la comunicación de la ciencia, en Jujuy y Buenos Aires. En este trabajo, a modo de primera objetivación colectiva, presentamos nuestros lineamientos pedagógicos y las diferentes propuestas de taller que diseñamos. A su vez, a partir de cuatro experiencias transformadoras, planteamos una serie de reflexiones y balances respecto de la divulgación de nuestra disciplina.Arqueo-escuela is an independent and self-managed team made up of archaeologists (mostly CONICET scholarship holders) with teaching training and focused on the dissemination of the methods used by archaeology for the interpretation of our past. In 2021 we celebrated our 5th anniversary. During this time we have developed different didactic proposals, and participated in multiple and diverse public and private spaces related to education and science communication, in Jujuy and Buenos Aires. In this work, as a first collective objectification, we present our pedagogical guidelines and the different workshop proposals we designed. At the same time, based on four transforming experiences, we propose a series of reflections and balances regarding the dissemination of our discipline.Fil: Pey, Maria Laura. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Arqueología; ArgentinaFil: Carreras, Jesica Tamara. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto Interdisciplinario Tilcara; ArgentinaFil: Eguia, Luciana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Arqueología; ArgentinaFil: Petit de Murat, Facundo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto Interdisciplinario Tilcara; ArgentinaFil: Bocelli, Sebastián. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro de Investigaciones y Transferencia de Catamarca. Universidad Nacional de Catamarca. Centro de Investigaciones y Transferencia de Catamarca; ArgentinaFil: Carranza, Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Saavedra 15. Instituto Multidisciplinario de Historia y Ciencias Humanas; ArgentinaFil: Gentile, María Cecilia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Secretaría de Cultura de la Nación. Dirección Nacional de Cultura y Museos. Instituto Nacional de Antropología y Pensamiento Latinoamericano; ArgentinaFil: Orsi, Juan Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Instituto de Arqueología; ArgentinaFil: Tulissi, Leticia. Universidad de Belgrano. Facultad de Derecho y Ciencias Sociales.; Argentin