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Context: Beetroots have antioxidant and anti-inflammatory properties, which may help attenuate inflammation and oxidative stress, enhancing recovery from exercise-induced muscle damage (EIMD). Objective: To evaluate the effects of beetroot supplementation on oxidative stress, inflammation, and recovery after EIMD. Data Sources: SPORTDiscus, PubMed, Web of Science, and Scopus databases were searched, and hand-searching was performed by looking to relevant studies that were cited in other studies. Study Selection: For a study to be included in this review, the following inclusion criteria had to be met: (1) research conducted with human participants, (2) original articles in peer-reviewed publications, (3) original studies that had investigated beetroot supplementation intervention on muscle damage and recovery, (4) research conducted with 1 control/placebo group, and (5) articles published from inception to October 2020. Study Design: Systematic review using the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. Level of Evidence: Level 3. Data Extraction: Two of the 4 authors independently extracted data and assessed the methodological quality of the articles with the PEDro scale. All discrepancies were resolved through a consensus meeting. Results: A total of 9 studies were included in this review. The methodological quality of the included studies ranged from moderate to high. Most of the studies found a better recovery of functional variables and muscle soreness, but improvements in markers of muscle damage, inflammation, and oxidative stress were not reported. Conclusion: The existing evidence suggests that a short-term beetroot supplementation has the potential to accelerate recovery of functional measures and muscle soreness, but further research is needed to clarify if a longer supplementation period (with some days before exercise and some days after) could also promote recovery of markers of muscle damage, inflammation, and oxidative stress.

Fanconi anemia (FA) is a rare hereditary disorder caused by mutations in any one of the FANC genes. FA cells are mainly characterized by extreme hypersensitivity to interstrand crosslink (ICL) agents. Additionally, the FA proteins play a crucial role in concert with homologous recombination (HR) factors to protect stalled replication forks. Here, we report that the 5-methyl-2’-deoxycytidine (5mdC) demethylation (pathway) intermediate 5-hydroxymethyl-2’-deoxycytidine (5hmdC) and its deamination product 5-hydroxymethyl-2’-deoxyuridine (5hmdU) elicit a DNA damage response, chromosome aberrations, replication fork impairment and cell viability loss in the absence of FANCD2. Interestingly, replication fork instability by 5hmdC or 5hmdU was associated to the presence of Poly(ADP-ribose) polymerase 1 (PARP1) on chromatin, being both phenotypes exacerbated by olaparib treatment. Remarkably, Parp1 cells did not show any replication fork defects or sensitivity to 5hmdC or 5hmdU, suggesting that retained PARP1 at base excision repair (BER) intermediates accounts for the observed replication fork defects upon 5hmdC or 5hmdU incorporation in the absence of FANCD2. We therefore conclude that 5hmdC is deaminated in vivo to 5hmdU, whose fixation by PARP1 during BER, hinders replication fork progression and contributes to genomic instability in FA cells., The eHAP cell line were a generous gift from Dr. G. Crossan (MRC-LMB, Cambridge). DT40, NV012 and HSC72 cell lines were kindly provided by K.J. Patel (MRC WIMM, Oxford), and the MDA-MB-231, MDA-MB-436 and DLD1 BRCA2−/− were a gift from Dr. Pablo Huertas and Dr. Andrés Aguilera (CABIMER, Sevilla) respectively. We are in debt to Dr. J.A. Pérez-Simón (IBIS, Seville) for providing hosting and helpful advice. IVR´s lab is funded by MCIN/AEI/ 10.13039/501100011033, grant 18.06.03.3073 (RTI2018-100692-B-100), Consejerías de Salud, y de Economía y Conocimiento de la Junta de Andalucía, grants number PI-0005-2018, and 18.06.03.2404 (P18-RT-1271), Universidad de Sevilla “Programa Operativo FEDER Andalucía 2014–2020”, grant number 18.06.03.2319 (US-1381081), and by “ERDF A way of making Europe”. IVR is a recipient of Ramón y Cajal Contracts RYC2015-18670. SK lab was supported by ERC-2016-AdG/742654 grant.

Background: About 80% of breast cancer (BC) cases express estrogen receptor (ER), which has been correlated with good prognosis and response to estrogen deprivation Aim: To characterize ER positive advanced BC (ABC) patients treated at our institution assessing the impact of clinical pre-sentation (stage IV, de novo disease at diagnosis versus systemic recurrence) and BC subtype on survival rates. Material and Methods: We evaluated 211 ER+ advanced BC (ABC) patients, treated between 1997 and 2017. Results: The median overall survival (OS) was 37 months. Median OS for the period 1997/2006 and 2007/2017 were 33 and 42 months, respectively (p = 0.47). Luminal A, ABC stage IV disease at diagnosis displayed better OS rates than Luminal B stage IV tumors (100 and 32 months respectively, p < 0.01). Conclusions: Clinical presentation (stage IV vs. systemic recurrence) and tumor subtype are key determinants of OS in ABC.

Objective: Clinical guidelines recommend the use of endocrine therapy (ET) in advanced hormone receptor positive (HR+) human epidermal growth factor receptor type 2 negative (HER2-) breast cancer (...

Whilst avoidance of chemical modifications of DNA bases is essential to maintain genome stability, during evolution eukaryotic cells have evolved a chemically reversible modification of the cytosine base. These dynamic methylation and demethylation reactions on carbon-5 of cytosine regulate several cellular and developmental processes such as embryonic stem cell pluripotency, cell identity, differentiation or tumourgenesis. Whereas these physiological processes are well charac-terized, very little is known about the toxicity of these cytosine analogues when they incorporate during replication. Here, we report a role of the base excision repair factor XRCC1 in protecting replication fork upon incorporation of 5-hydroxymethyl-2-deoxycytosine (5hmC) and its deamination product 5-hydroxymethyl-2-deoxyuridine (5hmU) during DNA synthesis. In the absence of XRCC1, 5hmC exposure leads to increased genomic instability, replication fork impairment and cell lethality. Moreover, the 5hmC deamination product 5hmU recapitulated the genomic instability phenotypes observed by 5hmC exposure, suggesting that 5hmU accounts for the observed by 5hmC exposure. Remarkably, 5hmC-dependent genomic instability and replication fork impairment seen in Xrcc1 cells were exacerbated by the trapping of Parp1 on chromatin, indicating that XRCC1 maintains replication fork stability during processing of 5hmC and 5hmU by the base excision repair pathway. Our findings uncover natural epigenetic DNA bases 5hmC and 5hmU as genotoxic nucleosides that threaten replication dynamics and genome integrity in the absence of XRCC1., Grant 18.06.03.3073 RTI2018-100692-B-100 funded by MCIN/AEI/ 10.13039/501100011033 and, by “ERDF A way of making Europe”, Consejerías de Salud, y de Economía y Conocimiento, de la Junta de Andalucía, grants numbers PI-0005-2018, and P18-RT-1271, and Universidad de Sevilla “Programa Operativo FEDER Andalucía 2014-2020”, grant number US-1381081. I.V.R. is recipient of Ramón y Cajal Contract RYC2015-18670. M.S.-P. is a recipient of a JAEIntro fellowship JAEINT21_EX_0449. The APC was funded by RTI2018-100692-B-I00.

Background: Lung cancer (LC) is the second leading cause of cancer death in Chile, causing >3,000 deaths every year. Epidemiological LC data in Chile is scarce and scattered. Here, we aimed to quantify the prevalence of Epidermal Growth Factor Receptor (EGFR) gene mutations in a Chilean cancer center. These data may identify individuals that could benefit from targeted therapies such as Tyrosine Kinase Inhibitors (TKIs). Methods: A total of 1,405 Biopsies from 1,381 LC patients were retrospectively analyzed retrieving clinical data from EGFR mutants including age, gender, histological type, smoking habits and type of EGFR mutation. We also analyzed overall survival (OS) rates. Results: From all patients 21.7% had clinically relevant EGFR mutations, and a median age at diagnosis of 65 years. Most were female (64%), classified as adenocarcinomas (94.5%), and non-smokers/light smokers (93.1%). The most prevalent mutation was exon-19 deletions (50.6%) followed by Leucine-to Arginine 858; OS was 15 months. Clinical follow-up information was available for 83 patients. The use of TKIs in these patients significantly improved OS. Conclusion: The prevalence of EGFR mutations in the studied population was 21.7%, comparable to other countries in Latin America. The most frequent EGFR mutation was exon-19 deletion, OS in this group was 15 months, and TKIs significantly improved OS.

Objective: Tumor response to neoadjuvant chemotherapy (NAC) in breast cancer (BC) patients is a predictor for overall survival. The aim of our study was to determine a relationship between the neutrophil to lymphocyte ratio (NLR) prior to NAC, BC subtypes and the probability of a pathologic complete response (pCR). Materials and Methods: Medical records were collected retrospectively from Centro de Cancer at Red Salud UC-Christus. Clinical data collected included peripheral blood cell counts, BC subtype at diagnosis and the pathology report of surgery after chemotherapy. Results: A total of 88 patients were analyzed. Approximately, a 25% had a pCR, and displayed a significant correlation between BC subtype and pCR (p= 0.0138 Chi2); this was more frequent in epidermal growth factor receptor type 2 (HER2) enriched subtype patients (54%). Luminal B BC patients with a pCR had significantly lower NLR levels (t test, p= 0.0181). Conclusions: HER2-enriched tumors had a higher probability of pCR. In Luminal B tumors, NLR had a statistically significant relationship with the probability of pCR. In this subtype, NLR could be a useful biomarker to predict tumor response to NAC. Further studies including other clinical parameters for systemic inflammation such as platelet counts, intratumoral NLR or body mass index could help identify patients that would get the most benefit from NAC.

Introduction and objectives Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium . This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. Methods This was an observational, retrospective cohort study , which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing . Results Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 ± 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. Conclusions The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis.

Background Systematic reviews allow health decisions to be informed by the best available research evidence. However, their number is proliferating quickly, and many skills are required to identify all the relevant reviews for a specific question. Methods and findings We screen 10 bibliographic databases on a daily or weekly basis, to identify systematic reviews relevant for health decision-making. Using a machine-based approach developed for this project we select reviews, which are then validated by a network of more than 1000 collaborators. After screening over 1,400,000 records we have identified more than 300,000 systematic reviews, which are now stored in a single place and accessible through an easy-to-use search engine. This makes Epistemonikos the largest database of its kind. Conclusions Using a systematic approach, recruiting a broad network of collaborators and implementing automated methods, we developed a one-stop shop for systematic reviews relevant for health decision making.

PAHO/WHO proposes to implement the role of Advanced Practice Nurse (APN) in Latin America, to reduce gaps in coverage and access to health care. For this purpose, it is necessary to train nursing professionals with an expanded role, which allows them to collaborate in the diagnosis, treatment, and monitoring of people with specific diseases, under established protocols and clinical guidelines and within consolidated interdisciplinary health teams in a cost-effective way. One of the areas with the greatest coverage deficit in Latin America is adult oncology, with inequality in care opportunities for these patients. Part of the premature deaths attributable to this disease are due to the lack of access to timely diagnosis and treatment. As a contribution to the reduction of this gap, a training program of Advanced Nursing Practice was developed, addressing the most urgent needs in the field of oncology. The necessary competencies were defined to develop a professional-level master's degree program, considering prevention, early detection, diagnosis, treatment, and monitoring of people with oncological diseases at different levels of care. A program of this kind is an opportunity to reduce the access gap and coverage of health care for people with cancer, improving their quality of life and their survival.

Neuroendocrine Tumors (NETs) encompass a wide variety of tumors arising from neuroendocrine cells, which produce bioactive substances. The incidence of NETs increased significantly lately, becoming one of the most common tumors of the digestive tract. Their clinical presentation is as diverse as their capacity for hormone production. Carcinoid syndrome is the most common hormonal syndrome produced by NETs and is characterized by diarrhea, flushing and cardiac valvular lesions. New research brought multiple changes in the classification of these neoplasms and a new understanding about their diagnosis and treatment, promoting a multidisciplinary approach. Somatostatin analogues, radiation, biological, and cytotoxic drugs have improved the prognosis of these patients, which entails a great challenge for healthcare providers.

Countries should ensure equitable access to quality medicines. Regulatory systems for medicines and other health technologies are an essential part of well-functioning health systems and are a requisite for achieving Universal Health and the Sustainable Development Goals. The Pan American Health Organization, the World health Organization (WHO) regional office for the Americas, has assessed national regulatory capacities using a precursor of WHO Global Benchmarking Tool, and conducted an analysis of the data which suggests an association of regulatory capacity with population and the size of the economy. Regulatory capacity tends to decrease as population and gross domestic product decreases. This predominantly impacts the Caribbean sub-region in the Americas, which includes many states with small populations and economies. This paper will use the World Bank’s term ‘small states’ to refer to countries with 1.5 million people or less and other larger countries that face similar challenges. The regulatory challenges of small states include small markets and limited human and financial resources. However, small states can build regulatory systems with a narrower scope that are less resource intensive and still ensure appropriate regulation and oversight. The approach should be tailored to accomplish a subset of WHO recommended essential functions, including marketing authorisation, licensing of establishments and postmarket surveillance/pharmacovigilance, depending on the need to oversee local manufacturing, which requires a comprehensive system. The approach should also include adoption of efficiencies, such as regionalisation and reliance. This model is currently being put in practice in the small states of the Caribbean Community and Pacific Islands and can inform other small states around the world.

Leishmaniasis is a neglected tropical disease caused by Leishmania spp. The improvement of existing treatments and the discovery of new drugs remain ones of the major goals in control and eradication of this disease. From the parasite genome, we have identified the homologue of the human oncogene PES1 in Leishmania major (LmjPES). It has been demonstrated that PES1 is involved in several processes such as ribosome biogenesis, cell proliferation and genetic transcription. Our phylogenetic studies showed that LmjPES encodes a highly conserved protein containing three main domains: PES N-terminus (shared with proteins involved in ribosomal biogenesis), BRCT (found in proteins related to DNA repair processes) and MAEBL-type domain (C-terminus, related to erythrocyte invasion in apicomplexan). This gene showed its highest expression level in metacyclic promastigotes, the infective forms; by fluorescence microscopy assay, we demonstrated the nuclear localization of LmjPES protein. After generating mutant parasites overexpressing LmjPES, we observed that these clones displayed a dramatic increase in the ratio of cell infection within macrophages. Furthermore, BALB/c mice infected with these transgenic parasites exhibited higher footpad inflammation compared to those inoculated with non-overexpressing parasites.

The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major. Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania.

Gallbladder cancer is the most common malignancy of the biliary tract. Given the lack of therapeutic alternatives for advanced stage patients studies have suggested that palliative chemotherapy could benefit these patients.We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis, and generated a summary of findings table using the GRADE approach.We identified two systematic reviews including two studies overall, of which one was a randomized trial. We concluded that palliative chemotherapy may increase survival in advanced gallbladder cancer patients. However, palliative chemotherapy probably increases adverse effects. In addition, it is essential to carry out a new systematic review, since methodological errors were identified in the analysis and there is new evidence that has not been included in the previous reviews.El cáncer de vesícula es el cáncer más frecuente de la vía biliar. Debido a la escasez de alternativas terapéuticas para pacientes con etapas avanzadas de la enfermedad, se ha planteado que quimioterapia paliativa puede ser beneficiosa para estos pacientes.Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.Identificamos dos revisiones sistemáticas que en conjunto incluyeron dos estudios primarios, de los cuales, uno corresponde a un ensayo aleatorizado. Concluimos que la quimioterapia paliativa podría aumentar la sobrevida en cáncer de vesícula biliar avanzado. Sin embargo, probablemente aumenta los efectos adversos. Además, es imprescindible realizar una nueva revisión sistemática, ya que se identificaron errores metodológicos importantes en el análisis realizado y existe nueva evidencia que no ha sido incluida en revisiones previas.

Our aim was to analyze the influence of HLA-B haplotypes on liver fibrosis progression in HIV/hepatitis C virus (HCV) co-infected patients. Retrospective longitudinal study including HIV/HCV, non-cirrhotic and HCV treatment-naive patients. The main outcome variable was liver fibrosis progression of at least one stage. One hundred and four patients constituted the study population (F0-F1: 62 (59.6%); F2: 22 (21.2%); F3: 20 (19.2%)). During a median follow-up of 54.5 months (IQR: 26.2-77), 45 patients (43.3%) showed an increase in the stage of liver fibrosis (time to event: 29 (IQR: 14-49.5) months). HLA-B18pos patients more frequently had a higher and faster fibrosis progression rate (73.3%; 24 (IQR: 8-29) months) than HLA-B18neg patients (38.2%; 34.5 (IQR: 14.7-51.2) months). This association was also observed in the development of F3-F4 fibrosis among F0-F2 patients (HLA-B18pos: 69.2%; 18 (6.5-37) months vs HLA-B18neg: 28.2%; 37 (IQR: 19-52) months). These results could impact the timing of HCV therapy in F0-F2 patients.

PURPOSE: The purpose of this study was to analyse gender differences in neuromuscular behaviour of the gastrocnemius and vastus lateralis during the take-off phase of a countermovement jump (CMJ), using direct measures (ground reaction forces, muscle activity and dynamic ultrasound). METHODS: Sixty-four young adults (aged 18-25 years) participated voluntarily in this study, 35 men and 29 women. The firing of the trigger allowed obtainment of data collection vertical ground reaction forces (GRF), surface electromyography activity (sEMG) and dynamic ultrasound gastrocnemius of both legs. RESULTS: Statistically significant gender differences were observed in the jump performance, which appear to be based on differences in muscle architecture and the electrical activation of the gastrocnemius muscles and vastus lateralis. So while men developed greater peak power, velocity take-offs and jump heights, jump kinetics compared to women, women also required a higher electrical activity to develop lower power values. Additionally, the men had higher values pennation angles and muscle thickness than women. CONCLUSION: Men show higher performance of the jump test than women, due to significant statistical differences in the values of muscle architecture (pennation angle and thickness muscle), lower Neural Efficiency Index and a higher amount of sEMG activity per second during the take-off phase of a CMJ. Actividad Física y Deporte

Purpose Trastuzumab (TZM) improves survival and the risk of recurrence among patients with early-stage HER2+ breast cancer (BC). TZM treatment can be given intravenously (IV-TZM) or subcutaneously (SC-TZM). Although both methods have similar efficacy and safety, they differ in dosage and administration. Previous studies of cost minimization determined that SC-TZM is associated with lower costs than IV-TZM; however, those studies did not include the costs associated with body weight-based dosage and the treatment of adverse drug reactions (ADRs). Methods/Patients We performed a model-based cost-minimization analysis. The analysis included direct and indirect medical costs associated with TZM preparation (adjusted by body weight) and administration and also costs due to severe ADRs and non-medical costs that occurred during the total treatment course (18 cycles). We performed a sensitivity analysis to test the robustness of the results across various TZM costs and patient body weights. Results The overall cost (in USD) of IV-TZM treatment was $83,309.1 per patient compared with $77,067.7 per patient for SC-TZM. Thus, one year of SC-TZM treatment cost $6,241.4 less per patient than one year of IV-TZM treatment. The sensitivity analysis revealed that the results were mainly driven by the price of each TZM vial and body weight. Conclusion SC-TZM is a cost-saving therapy for Chilean patients with early-stage HER2+ BC. Given their similar efficacy and safety, we suggest the use of SC formulations rather than IV formulations. The use of SC-TZM instead of IV-TZM may have a significant economic impact on public/private healthcare systems.

Neuroendocrine tumors (NETs) are relatively rare and highly heterogeneous neoplasms. Despite this, recent studies from North America and Central Europe have suggested an increase in incidence. In Latin America, NET data are scarce and scattered with only a few studies reporting registries. Our goal was to establish a NET registry in Chile. Here, we report the establishment and our first 166 NET patients. We observed a slight preponderance of males, a median age at diagnosis of 53 years and a median overall survival of 110 months. As anticipated, most tumors were gastroenteropancreatic (GEP). Survival analyses demonstrated that non-GEP or stage IV tumors presented significantly lower overall survival (OS). Similarly, patients with surgery classified as R0 had better OS compared to R1, R2, or no surgery. Furthermore, patients with elevated chromogranin A (CgA) or high Ki67 showed a trend to poorer OS; however, these differences did not reach statistical significance (log-rank test p = 0.07). To the best of our knowledge, this is the first report of a NET registry in Chile. Median OS in our registry (110 months) is in line with other registries from Argentina and Spain. Other variables including age at diagnosis and gender were similar to previous studies; however, our data indicate a high proportion of small-bowel NETs compared to other cohorts, reflecting the need for NET regional registries. Indeed, these registries may explain regional discrepancies in incidence and distribution, adding to our knowledge on this seemingly rare, highly heterogeneous disease. Electronic supplementary material The online version of this article (10.1007/s12672-018-0354-5) contains supplementary material, which is available to authorized users.

The use of PET-CT could select a subgroup of advanced testicular seminoma patients that display post-chemotherapy residual masses measuring3 cm and could be managed with surveillance, avoiding unnecessary surgical resection of unviable tumor masses.We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.We identified three systematic reviews that included eleven primary studies; none of these were randomized trials. We concluded the assessment of postchemotherapy residual masses by PET-CT in testicular seminoma patients may prevent unnecessary surgeries, but the certainty of the evidence is low. Furthermore, PET-CT could also offer a favorable risk/benefit and cost/benefit ratio for the management of testicular seminoma patients. However, systematic reviews and primary studies assessing the direct diagnostic impact of PET-CT are required.En pacientes con cáncer testicular avanzado tipo seminoma que tienen lesiones residuales post quimioterapia de más de 3 cm, el PET-CT podría seleccionar un subgrupo susceptible de ser manejado con seguimiento, evitando una resección quirúrgica innecesaria de tumor no viable.Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE.Identificamos tres revisiones sistemáticas que en conjunto incluyeron 11 estudios primarios, de los cuales, ninguno es un ensayo aleatorizado. Concluimos que el uso de PET-CT en la evaluación de masas residuales post quimioterapia en pacientes con cáncer testicular tipo seminoma podría evitar un porcentaje importante de cirugías innecesarias (certeza de la evidencia baja). Además, el uso de PET-CT podría presentar balances riesgo/beneficio y costo/beneficio favorables en el manejo de pacientes con cáncer testicular tipo seminoma. Sin embargo, se requieren revisiones sistemáticas y estudios primarios que evalúen directamente el impacto diagnóstico del test.

Supplemental Digital Content is available in the text, Gastric cancer (GC) is the world's second-leading cause of neoplastic mortality. Genetic alterations, response to treatments, and mortality rates are highly heterogeneous across different regions. Within Latin America, GC is the leading cause of cancer death in Chile, affecting 17.6 per 100,000 people and causing >3000 deaths/y. Clinical outcomes and response to “one size fits all” therapies are highly heterogeneous and thus a better stratification of patients may aid cancer treatment and response. The Gastric Cancer Task Force is a Chilean collaborative, noninterventional study that seeks to stratify gastric adenocarcinomas using clinical outcomes and genomic, epigenomic, and protein alterations in a cohort of 200 patients. Tumor samples from the Pathology Department and the Cancer Center at UC-Christus healthcare network, Pontificia Universidad Católica de Chile will be analyzed using a panel of 143 known cancer genes (Oncomine Comprehensive Assay) at the Center of Excellence in Precision Medicine in Santiago, Chile. In addition, promoter methylation for selected genes will be performed along with tissue microarray for clinically relevant proteins (e.g., PD-L1, Erb-2, VEGFR2, among others) and Helicobacter pylori and Epstein–Barr virus status. Obtained data will be correlated to 120 clinical parameters retrieve from medical records, including general patient information, cancer history, laboratory studies, comorbidity index, chemotherapy, targeted therapies, efficacy, and follow-up. The development of a clinically meaningful classification that encompasses comprehensive clinical and molecular parameters may improve patient treatment, predict clinical outcomes, aid patient selection/stratification for clinical trials and may offer insights into future preventive and/or therapeutic strategies in patients from Latin America region. Trial registration: ClinicalTrials.gov Identifier: NCT03158571, Registered on May 18, 2017.

Nausea and vomiting are common side effects in cancer patients treated with chemotherapy. Proper control of these symptoms might improve quality of life in these patients. Addition of cannabinoids to standard antiemetic treatment has been proposed in order to improve control of these symptoms.To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.We identified 16 systematic reviews that include 61 primary studies. Out of these, four were randomized trials that answered our question. At present, given that the certainty of the evidence is very low, it is unclear whether the addition of cannabinoids to standard antiemetic regimes benefits patients with chemotherapy induced nausea and vomiting. Cannabinoids probably increase adverse effects substantively.El tratamiento de las náuseas y vómitos inducidos por quimioterapia podría mejorar la calidad de vida de los pacientes oncológicos; para lograrlo se ha propuesto la adición de cannabinoides a los esquemas de antieméticos habituales.Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos tablas de resumen de los resultados utilizando el método GRADE.Identificamos 16 revisiones sistemáticas que en conjunto incluyen 61 estudios primarios, de los cuales cuatro son ensayos aleatorizados que responden a la pregunta de interés. Concluimos que no hay claridad respecto a si los cannabinoides otorgan un beneficio al añadirlos a esquemas antieméticos habituales para el control de náuseas y vómitos inducidos por quimioterapia, porque la certeza de la evidencia es muy baja. Probablemente aumentan los efectos adversos de manera sustantiva.

Baseline serum HCV-RNA predicts sustained virological response in chronic hepatitis C patients treated with antiviral therapy. A threshold at 6 million IU/mL has been proposed to best discriminate treatment outcomes on sofosbuvir-based regimens. In comparison with the general population, immunosuppressed individuals exhibit greater viral load values.To estimate the rate and predictors of serum HCV-RNA above 6 millionIU/mL in chronic hepatitis C patients on care outside clinical trials.Serum HCV-RNA values recorded from all chronic hepatitis C patients consecutively attended at our clinic during the last decade were analyzed. Testing had been performed using the COBAS TaqMan HCV test v2.0.A total of 816 individuals with detectable serum HCV-RNA were identified. The main characteristics of this population were as follows: mean age 48.6 years-old; 73.4% males; mean ALT 82.6IU/L; mean HCV-RNA 6.02logIU/mL; 80.6% HCV genotypes 1 or 4; 34.9% advanced liver fibrosis; 35.4% IL28B-CC alleles. HIV coinfection in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 127 (15.6%) had serum HCV-RNA values6 millionIU/mL. This high viremia was found in 18.2% of HIV-positive versus 5.7% of HIV-negative subjects (p0.001). In multivariate analysis, serum HCV-RNA6 millionIU/mL was only significantly associated with HIV coinfection (OR: 4.03; 95% CI: 1.98-8.19, p0.01) and HCV genotypes 1 or 4 (OR: 1.88; 95% CI: 1.05-3.37, p=0.03).Serum HCV-RNA6 millionIU/mL is roughly seen in 6% of chronic hepatitis C monoinfected patients, and increases up to 18% in HIV coinfection.

Roughly 10 % of HIV-positive individuals worldwide have concomitant chronic hepatitis B virus (HBV) infection, with large differences between geographical regions and/or risk groups. Hepatitis B is a preventable infection with vaccines. However, it cannot be eradicated once acquired, resembling HIV and in contrast with HCV. In developed countries, hepatitis B exhibits particular features in the HIV population. First, HBV infection is less frequently misdiagnosed than in the general population. Second, nucleos(t)ide analogs active against HBV are widely used as part of antiretroviral combinations and are taken by most HIV patients. Lastly, as the HIV population ages given the success of antiretroviral therapy, non-AIDS co-morbidities are becoming a major cause of disease, for which specific drugs are required, increasing the risk of interactions and hepatotoxicity. Furthermore, concern on HBV reactivation is rising as immunosuppressive drug therapies are increasingly been used for cancers and other non-malignant conditions. In this scenario, new challenges are emerging in the management of hepatitis B in HIV-positive individuals. Among them, major interest is focused on failures to suppress HBV replication, HBV breakthroughs and reactivations, the meaning of isolated anti-HBc, screening for liver cancer, and the complexity arising when hepatitis viruses C and/or D are additionally present. This review will focus on these challenges and the major advances in HBV coinfection in HIV.

Aims Hypertrophic cardiomyopathy is one of the main causes of sudden death in young people. Recent clinical practice guidelines include a risk prediction model for sudden death (HCM Risk-SCD), which facilitates the decision of whether to implant a defibrillator. The aim of our study was to ascertain the percentage of events in our series of primary prevention implantable cardioverter-defibrillator recipients with hypertrophic cardiomyopathy and whether HCM Risk-SCD predicts the onset of arrhythmic events. Methods and results This was an observational, retrospective cohort study, which included 48 primary prevention defibrillator recipient patients with HCM. We compiled their demographic and clinical characteristics, estimated 5-year risk using HCM Risk-SCD, and collected the documentation on arrhythmias during follow-up. The majority was male (66.7%) and mean age at implantation was 44.44 ± 14.46 years. Non-sustained ventricular tachycardia was the most prevalent risk factor (66.67%), followed by a family history of sudden death (47.92%). Mean HCM Risk-SCD was 6.15 ± 5.01%. HCM Risk-SCD was the only factor independently associated with the onset of ventricular tachyarrhythmia, above any other classic risk factor or association [odds ratio = 1.46 (95% confidence interval 1.051–2.013); P = 0.02]. None of the 11 patients estimated as low risk using HCM Risk-SCD suffered any appropriate events ( P < 0.05). Conclusions During an average follow-up of 4 years, 16.67% presented appropriate events (4.16%/year). HCM Risk-SCD predicted the onset of events more suitably than classic risk factors.

The fixed-dose combination of three direct-acting antivirals (DAA), namely sofosbuvir, velpatasvir and voxilaprevir is the first pangenotypic, single tablet regimen developed for the treatment of HCV infection. Areas covered: The pharmacokinetics, pharmacodynamics, efficacy and safety of the co-formulation are reviewed. Information on drug absorption, distribution, metabolism and excretion of each of the three antivirals is evaluated. Finally, antiviral activity, safety and potential for drug interactions in phase II/III clinical trials in distinct patient populations are discussed. Expert opinion: The triple co-formulation of sofosbuvir-velpatasvir-voxilaprevir represents a major step towards HCV eradication. It depicts high efficacy even in patients infected with viruses harboring resistance-associated substitutions (RAS), including those selected after DAA failures. Likewise, very high success rates and good tolerance are seen in special patient populations, including decompensated cirrhotics, HIV coinfection, organ transplantation or renal insufficiency. A pill once daily for 8 weeks gives SVR rates above 95%. In prior DAA failures, extending treatment to 12 weeks maximizes SVR rates.

The introduction of direct-acting antivirals (DAA) has revolutionized the hepatitis C field. Most hepatitis C patients can now be cured, including those coinfected with HIV. However, drug-drug interactions (DDI) between DAA and antiretrovirals (ARV) should be known to prevent either toxicity due to drug overexposure or treatment failures due to low drug concentrations. Areas covered: Clinically significant DDI may be classified as major (when co-administration should be contraindicated) or minor (when they require close monitoring, changes in drug dosage or in timing). Strategies for preventing and managing DDI influence response rates in HIV/HCV-coinfected patients. Pharmacokinetic evidence of interactions from clinical trials and reports from real-world experience are discussed. Expert opinion: The most frequent DDI between DAA and ARV affect drug metabolism by CYP450 induction/inhibition, leading to abnormal drug exposures. Throughout this mechanism interact HCV and HIV boosted protease inhibitors, and most non-nucleoside HCV and HIV polymerase inhibitors. In contrast, HIV and HCV nucleos(t)ide analogue polymerase inhibitors, most HCV NS5A inhibitors and HIV integrase inhibitors (e.g., dolutegravir), do not or only marginally affect CYP450, and therefore are relatively free of DDI. Exposure to some HIV and HCV nucleos(t)ide analogues (e.g., tenofovir and sofosbuvir, respectively) is subject to induction/inhibition of drug transporters (e.g., P-glycoprotein) and requires special attention in patients with renal insufficiency.

The advent of oral direct-acting antivirals (DAA) has revolutionized the hepatitis C virus (HCV) therapeutic landscape providing cure rates over 90%. However, a subset of patients remains at higher risk for treatment failure, including those infected with: i) genotype 3 and cirrhosis; ii) resistance-associated substitutions (RAS) occurring either as natural polymorphisms or selected after prior DAA failure; and iii) poor drug adherence associated with social disabilities (homeless, psychiatric illnesses, injection drug use, alcoholism, etc.). Whereas discovery of new DAA with increased antiviral activity across all genotypes and over RAS may enhance efficacy, development of fixed dose combinations (FDC) may be the best way to improve drug adherence in difficult-to-treat HCV populations. Areas covered: Three FDC regimens are in the last steps of clinical development for treating hepatitis C. Two distinct nucleotide analogues that inhibit the HCV polymerase, sofosbuvir and uprifosbuvir, are part of the FDC from Gilead and Merck, respectively. The AbbVie dual FDC does not include a polymerase inhibitor. All three new FDC include second-generation NS3 protease inhibitors and NS5A inhibitors active across all HCV genotypes and over common RAS. Expert opinion: Hepatitis C cure rates over 95% are expected with all three next-coming DAA, even in the most difficult-to-treat and/or cure patient populations. These regimens would be particularly needed for the growing number of prior DAA failures. Co-formulations and 8-week shorter treatment lengths will help to overcome drug adherence challenges in certain populations.

For two decades, triple combinations of antiretrovirals have been the standard treatment for HIV infection. The challenges of such lifelong therapy include long-term side effects, high costs and reduced drug adherence. The recent advent of more potent and safer antiretrovirals has renewed the interest for simpler HIV regimens. Areas covered: We discuss the pros and cons of dual antiretroviral therapies in both drug-naïve and in treatment-experienced patients with viral suppression (switch strategy). Expert opinion: Some dual antiretroviral regimens are safe and efficacious, particularly as maintenance therapy. At this time, combinations of dolutegravir plus rilpivirine represent the best dual regimen. Longer follow-up and larger study populations are needed before supporting dolutegravir plus lamivudine. In contrast, dual therapy based on maraviroc is less effective. Although dual regimens with boosted protease inhibitors plus either lamivudine or raltegravir may be effective, they are penalized by metabolic side effects and risk for drug interactions. The newest dual regimens could save money, reduce toxicity and spare drug options for the future. For the first time in HIV therapeutics, less can be more. Dual therapy switching has set up a new paradigm in HIV treatment that uses induction-maintenance.

Current treatment with oral nucleos(t)ides entecavir or tenofovir provide sustained suppression of HBV replication and clinical benefit in most chronic hepatitis B virus (HBV) infected persons. However, HBV rebound generally occurs upon drug discontinuation due to persistence of genomic HBV reservoirs as episomic cccDNA and chromosomic integrated HBV-DNA. There is renewed enthusiasm on HBV drug discovery following recent successes with antivirals for hepatitis C and immunotherapies for some cancers. Areas covered: New drugs that target distinct steps of the HBV life cycle are been developed, including inhibitors of viral entry, new polymerase inhibitors, capsid and assembly inhibitors, virus release blockers, and disruptors of cccDNA formation and transcription. Alongside these antivirals, agents that enhance anti-HBV specific immune responses are being tested, including TLR agonists, checkpoint inhibitors and therapeutic vaccines. Expert opinion: The achievement of a 'functional cure' for chronic HBV infection, with sustained HBsAg clearance and undetectable viremia once medications are stopped, represents the next step in the pace towards HBV elimination. Hopefully, the combination of new drugs that eliminate or functionally inactivate the genomic HBV reservoirs (cccDNA and integrated HBV-DNA) along with agents that enhance or activate immune responses against HBV will lead to a 'definitive cure' for chronic HBV infection.

Background Roughly 15 million people worldwide have hepatitis delta, the most severe form of chronic viral hepatitis that often leads to cirrhosis and liver cancer. Injection drug users (IDUs) are the largest HDV reservoir. Their resurgence in North America and Europe may represent a new opportunity for HDV to spread more widely. Methods We examined all consecutive active IDUs seen for the first time and enrolled in detoxification programmes at two clinics in Spain during two periods (1993–1996 and 2011–2014, respectively). Serum markers of HIV, HBV and HDV infection were tested. Results A total of 209 IDUs were examined in the first period. Mean age was 27-years-old. All had markers of past or current HBV infection. The rate of HIV-antibody (Ab), hepatitis B surface antigen (HBsAg) and HDV-Ab was as follows: 122 (58.4%), 73 (34.9%) and 62 (29.7%), respectively. Serum HDV-Ab was recognized in 53.4% of HBsAg+ and 16.9% of HBsAg- patients ( PConclusions Acute HBV–HDV coinfections and self-limited HDV infections were frequent in the 1990s among IDUs in Spain, especially in HIV+ individuals. In contrast, circulation of HDV has dramatically declined among active IDUs in Spain and is currently very rare, being concentrated in foreign immigrants. It may refect the benefit of universal HBV vaccination as well as the success of needle exchange programmes in Spain.

Junín arenavirus infections are associated with high levels of interferons in both severe and fatal cases. Upon Junín virus (JUNV) infection a cell signaling cascade initiates, that ultimately attempts to limit viral replication and prevent infection progression through the expression of host antiviral proteins. The interferon stimulated gene (ISG) viperin has drawn our attention as it has been highlighted as an important antiviral protein against several viral infections. The studies of the mechanistic actions of viperin have described important functional domains relating its antiviral and immune-modulating actions through cellular lipid structures. In line with this, through silencing and overexpression approaches, we have identified viperin as an antiviral ISG against JUNV. In addition, we found that lipid droplet structures are modulated during JUNV infection, suggesting its relevance for proper virus multiplication. Furthermore, our confocal microscopy images, bioinformatics and functional results also revealed viperin-JUNV protein interactions that might be participating in this antiviral pathway at lipid droplet level. Altogether, these results will help to better understand the factors mediating innate immunity in arenavirus infection and may lead to the development of pharmacological agents that can boost their effectiveness thereby leading to new treatments for this viral disease. Fil: Peña Cárcamo, José Rafael. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Morell, María Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Vázquez, Cecilia Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Vatansever, Sezen. Koc University; Turquía Fil: Upadhyay, Arunkumar S.. Universidad de Umea; Suecia Fil: Överby, Anna K.. Universidad de Umea; Suecia Fil: Cordo, Sandra Myriam. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Garcia, Cybele. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina

Mechanisms leading to the observed immune dysregulation in chronic HIV infection are not well understood. The MHC-II class ligand, lymphocyte activation gene-3 (LAG-3, CD223), has been implicated in the complex regulation mechanism of immune functions. In this study, we describe a new population of HIV-specific CD8(+) T cells expressing LAG-3. These LAG-3(+)CD8(+) T cells do not display immunophenotypic patterns traditionally attributed to regulatory T cells. The LAG3(+)CD8(+) T cells are CCR7(+),CD127(-), and display heterogeneous surface expressions of CD45RA and CD25. Interestingly, HIV-specific LAG-3(+)CD8(+) T cells do not substantially express CTLA-4 and LAG-3 expression does not correlate with interleukin (IL)-10 or tumor growth factor (TGF)-β production. In addition, HIV-specific LAG3(+)CD8(+) T cells do not produce interferon (IFN-γ) or express CD107a. The frequency of HIV-specific LAG3(+)CD8(+) T cells negative correlated with plasma viral load. Our study introduces a new population of HIV-specific CD8(+) T cells and proposes additional mechanisms of immune regulation in chronic HIV infection.

Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.

HLA-B18 as risk factor of liver fibrosis progression in HIV/HCV treatment-experienced patients

Co-infections of influenza virus and bacteria are known to cause severe disease, but little information exists on co-infections with other acute viruses. Seasonal influenza and dengue viruses (DENV) regularly co-circulate in tropical regions. The pandemic spread of influenza virus H1N1 (hereafter H1N1) in 2009 led to additional severe disease cases that were co-infected with DENV. Here, we investigated the impact of co-infection on immune responses and pathogenesis in a new mouse model. Co-infection of otherwise sublethal doses of a Nicaraguan clinical H1N1 isolate and two days later with a virulent DENV2 strain increased systemic DENV titers and caused 90% lethality. Lungs of co-infected mice carried both viruses, developed severe pneumonia, and expressed a unique pattern of host mRNAs, resembling only partial responses against infection with either virus alone. A large number of monocytes were recruited to DENV-infected but not to co-infected lungs, and depletion and adoptive transfer experiments revealed a beneficial role of monocytes. Our study shows that co-infection with influenza and DENV impairs host responses, which fail to control DENV titers and instead, induce severe lung damage. Further, our findings identify key inflammatory pathways and monocyte function as targets for future therapies that may limit immunopathology in co-infected patients.

Background Cure rates above 90% have been reported in most Phase III clinical trials using distinct all-oral direct-acting antivirals (DAAs) in chronic hepatitis C patients. Preliminary results in real-world patients have confirmed this, although efficacy tends to be lower. Methods All consecutive chronic hepatitis C patients treated with all-oral DAA regimens at three hepatitis clinics in Spain were retrospectively examined. Host and viral factors were tested as predictors of treatment failure. Results A total of 363 chronic hepatitis C patients had completed a course of all-oral DAA therapy outside clinical trials up to the end of 2015. All but 14 (4%) patients achieved sustained virological response. There were 10 failures that occurred after 12 weeks of sofosbuvir-ledipasvir, despite 5 of them being on ribavirin. All failures but one were relapses. The only patient with viral breakthrough selected NS5B L159F and NS5A Y93H. In multivariate analyses, only advanced liver fibrosis (Metavir F3–F4) and HIV coinfection were significantly associated with treatment failure. A trend towards lower response was seen for HCV genotype 4. Conclusions Treatment failures outside clinical trials are roughly seen in 4% of chronic hepatitis C patients who complete a course of all-oral DAA therapy, resembling what is seen in registration trials. In our series, outcomes were not significantly influenced by ribavirin addition, IL28B polymorphisms, HCV genotype, high baseline HCV RNA or prior interferon failure. However, advanced liver fibrosis and HIV coinfection were significantly associated with treatment failure. Our findings support that there is still room for individualization of current DAA therapy.

Background Baseline serum HCV RNA predicts treatment success in chronic hepatitis C patients. Thresholds at 0.8, 2, 4 and 6 million IU/ml discriminate treatment outcomes using distinct antiviral regimens. Compared to the general population, immunosuppressed individuals exhibit greater viral load values. This has been confirmed in HIV– HCV-coinfected patients, although little is known about the influence of antiretroviral therapy. Methods Serum HCV RNA results recorded from all chronic hepatitis C patients who consecutively attended at our clinic were analysed. Results A total of 813 patients with detectable HCV RNA were identified. HIV coinfection was present in 78.7%, of whom 91% were on antiretroviral therapy. Overall, 467 (57%), 273 (34%), 170 (21%) and 127 (16%) had HCV RNA >0.8, >2, >4 and >6 million IU/ml, respectively. These high viral load values were found in 60%/36%/23%/18% of HIV-positive versus 47%/25%/11%/6% of HIV-negative individuals ( P≤0.01), respectively. In multivariate analysis, the greatest HCV RNA values were only significantly associated with HIV coinfection and HCV genotypes-1 or -4. Greater HCV RNA values were paradoxically found in HIV patients on than off antiretroviral therapy. Conclusions Serum HCV RNA values above 0.8, 2, 4 and 6 million IU/ml are roughly seen in 47%, 25%, 11% and 6% of chronic hepatitis C monoinfected patients, respectively. Despite being on antiretroviral therapy, the corresponding figures are 1.3- to 3.0-fold greater in HIV–HCV-coinfected patients, who may benefit less frequently from shorter oral HCV treatment lengths.

Changes in natural killer (NK) cells according to their phenotype and expression of certain regulatory receptors were analyzed in a double-blind, controlled study of antiretroviral therapy (ART)-untreated HIV-seropositive patients, who had been vaccinated with monocyte-derived dendritic cells pulsed with inactivated HIV-1 autologous virus. This work extends other recently published studies of the same group of HIV-1(+) vaccinated patients, which demonstrated that the viral load significantly decreases and correlates inversely with an increase in HIV-specific T-cell responses in vaccinated patients, but not in controls who received placebo. Our results indicate that this vaccine raises the level of the NK CD56(neg) cell subpopulation, while levels of the NK CD56(dim) and NK CD56(bright) cells expressing the inhibitory receptor CD85j/ILT-2 fell in vaccinated patients. Taken together, these results suggest that this vaccine might enhance innate immunity by amplifying the inflammatory and cytolytic capacity.

OBJECTIVE To determine prevalence and risk factors for hypertension and isolated office hypertension diagnosed by ambulatory blood pressure monitoring in HIV-infected patients. METHODS Cross-sectional study of 310 patients. A 24-hour ambulatory blood pressure monitoring procedure was performed on the nondominant arm in those patients showing office systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg. RESULTS Twenty patients (6.5%) had a prior diagnosis of hypertension. Hypertension was confirmed by ambulatory blood pressure monitoring in 26 patients and isolated office hypertension in 17 patients. Isolated office hypertension and hypertension prevalence were 5.5% (95% confidence interval: 3 to 8) and 14.8% (95% confidence interval; 10.8 to 18.8), respectively. Isolated office hypertension was present in 39% of patients with office hypertension. In the univariate analysis, variables significantly associated with hypertension were age, waist circumference, established cardiovascular disease, family history of hypertension, lipoatrophy, metabolic syndrome, duration of infection, CD4 nadir, HIV RNA

The immunomodulatory receptor CD300a is expressed on human B cells. Naive B cells express very low levels of this receptor, whereas memory B cells and plasmablasts/cells express variable levels of CD300a. Germinal center B cells are negative for CD300a expression. Stimulation of naive B cells via B-cell receptor (BCR) and Toll-like receptor 9, along with T-cell help, failed to up-regulate CD300a cell surface expression despite the increased expression of the memory marker CD27 and the down-regulation of CD305. However, Toll-like receptor 9 stimulation alone significantly increased CD300a expression on memory B cells, whereas interleukin-4 and transforming growth factor-β1 act as negative regulators of CD300a expression on memory B cells. Coligation of BCR and CD300a inhibits Ca2+ mobilization and nuclear factor of activated T cell transcriptional activity evoked by BCR ligation alone. Suppression of CD300a expression in primary B cells with siRNA resulted in increased BCR-mediated proliferation, thereby confirming the inhibitory capacity of CD300a. Finally, we show that CD300a expression levels are significantly down-regulated in the circulating B cells of HIV-infected patients. Altogether, these data demonstrate a novel mechanism for suppressing the activity of B cells and suggest a potential role for CD300a in the B-cell dysfunction observed in HIV-induced immunodeficiency.

Flaviviruses, such as dengue virus (DENV), depend on the host endoplasmic reticulum for translation, replication, and packaging of their genomes. Here we report that DENV-2 infection modulates the unfolded protein response in a time-dependent manner. We show that early DENV-2 infection triggers and then suppresses PERK-mediated eIF2α phosphorylation and that in mid and late DENV-2 infection, the IRE1-XBP1 and ATF6 pathways are activated, respectively. Activation of IRE1-XBP1 correlated with induction of downstream targets GRP78, CHOP, and GADD34. Furthermore, induction of CHOP did not induce apoptotic markers, such as suppression of anti-apoptotic protein Bcl-2, activation of caspase-9 or caspase-3, and cleavage of poly(ADP-ribose) polymerase. Finally, we show that DENV-2 replication is affected in PERK(-/-) and IRE1(-/-) mouse embryo fibroblasts when compared with wild-type mouse embryo fibroblasts. These results demonstrate that time-dependent activation of the unfolded protein response by DENV-2 can override inhibition of translation, prevent apoptosis, and prolong the viral life cycle.

Although changes in atrioventricular conduction frequently occur after percutaneous implantation of an aortic valve prosthesis, little is known about the mechanisms involved or how these changes progress. We investigated ECG abnormalities and predictors of pacemaker need after percutaneous implantation of the CoreValve® aortic valve prosthesis.Between April 2008 and October 2009, 65 patients with symptomatic severe aortic stenosis received a CoreValve® prosthesis. Clinical and ECG parameters were recorded and predictors of pacemaker need due to advanced atrioventricular block were investigated. The analysis excluded three patients because they had pacemakers and a fourth who died during the procedure.The patients' mean age was 79 ± 7.8 years and their logistic EuroSCORE was 20 ± 14%. Implantation was successful in 98.4%. After implantation, 47.5% had left bundle branch block and 21 patients (34.4%) required a permanent pacemaker. The need for a pacemaker was associated with a greater depth of prosthesis implantation in the left ventricular outflow tract (LVOT): 13 ± 2.5 mm vs. 8.8 ± 2.8 mm (P.001). Moreover, depth was the only predictor: odds ratio 1.9, 95% confidence interval 1.19-3.05 (P.007). A cutpoint of 11.1 mm for the prosthesis depth in the LVOT had a sensitivity of 81% and a specificity of 84.6% for predicting the need for a pacemaker.After CoreValve® aortic valve prosthesis implantation, a high percentage of patients needed a permanent pacemaker for advanced atrioventricular block. The only independent predictor was the depth of the prosthesis in the LVOT, which could serve as an early indicator of pacemaker need.

Aims Cardiac resynchronization therapy (CRT) improves survival and quality of life in advanced heart failure (HF). Although mitral regurgitation (MR) reduction has been reported, its presence has been associated with non-response to CRT. This study was undertaken to assess the potential role of significant mitral regurgitation (SMR) persistence after CRT on clinical outcome, major arrhythmic events, and echocardiographic response in the mid-long term. Methods and results Seventy-six patients (28.9% women, 63 ± 11 years) with dilated cardiomyopathy in advanced HF were included. SMR, defined as regurgitant orifice area ≥0.20 cm2, was assessed at baseline and its evolution 6 months after CRT. Clinical outcome (cardiovascular death/HF readmission), major arrhythmic events, and echocardiographic response (reverse remodelling) were recorded on follow-up. Thirty-two patients (42.1%) presented baseline SMR, becoming non-significant in 11 of the 32 patients (34.3%) 6 months after CRT. Its persistence was associated with higher rates of clinical events (46.4 vs. 18.7%, P = 0.011), arrhythmic events (35.7 vs. 14.5%, P = 0.034), and less reverse remodelling (28.5 vs. 83.3%, P < 0.001). Conclusion CRT can reduce moderate or severe baseline MR to non-significant in one-third of patients. However, its persistence was associated with worse clinical evolution, greater incidence of arrhythmic events, and less reverse remodelling.

Pseudomonas aeruginosa -induced activation of NF-κB and secretion of proinflammatory cytokines by airway epithelial cells require that the bacteria express flagellin. We tested whether P. aeruginosa and human airway epithelial cells secrete factors that modulated this response. Experiments were performed with both the Calu-3 cell line and primary cultures of tracheal epithelial cells. P. aeruginosa strain PAK Δ fliC (flagellin knockout) did not activate NF-κB or interleukin-8 (IL-8) but inhibited flagellin-activated NF-κB by 40 to 50% and IL-8 secretion by 20 to 25%. PAK Δ fliC also inhibited NF-κB induced by IL-1β and Toll-like receptor 2 agonist Pam3CSK4. Similar inhibitions were observed with strains PAK, PAO1, and PA14. The inhibitory factor was present in conditioned medium isolated from PAK Δ fliC or Calu-3 plus PAK Δ fliC , but it was not present in conditioned medium isolated from Calu-3 cells alone or from PAK Δ fliC that had been heat treated. Inhibition by PAK Δ fliC -conditioned medium was exerted from either the apical or the basolateral side of the epithelium, was enhanced in simple Ringer's solution over that in tissue culture medium, and did not result from altered pH or depletion of glucose. The inhibitory effect of conditioned medium was abolished by boiling and appeared from filtration studies to result from effects of a factor with a molecular mass of P. aeruginosa results from a balance of proinflammatory effects of flagellin and antiinflammatory effects of a small (

We report a new case of the unusual myeloproliferative syndrome chronic neutrophilic leukemia (CNL) that met all the criteria generally required for the diagnosis of this entity. The patient presented abnormalities in platelet function not previously reported that may explain the bleeding tendency observed in these patients. The study of neutrophil function suggested also defective mobility and intracellular bactericidal activity. The chromosomal study revealed original abnormalities consisting of multiple chromosomal ruptures and figures. The disease was controlled with busulfan. After 20 months, the patient died of sepsis. An autopsy was performed confirming the diagnosis and ruling out the existence of a cause of a leukemoid reaction, such as cancer or granulomatous disease.

The aim of this study was to compare the effects of cardiac resynchronization therapy on left ventricular function and reverse remodeling in patients in sinus rhythm with the effects in patients with atrial fibrillation who have not undergone atrioventricular node ablation. Echocardiographic and clinical parameters were evaluated at baseline and after 6 months of cardiac resynchronization therapy in 55 patients: 15 had atrial fibrillation and 40 were in sinus rhythm. Device programming was similar in the 2 groups, as were the reductions in QRS interval and echocardiographic measures of asynchrony observed after implantation. However, although significant improvements in end-systolic volume and ejection fraction were seen in both groups, reverse remodeling was greater in patients in sinus rhythm (reduction in end-systolic volume 30.9%+/-24.6% vs 12.5%+/-18.6%; P=.024), as was the relative increase in ejection fraction (15.4%+/-12.6% vs 5.0%+/-7.2%; P=.010). Cardiac resynchronization therapy in patients with atrial fibrillation who had not undergone atrioventricular node ablation resulted in significant improvements in ejection fraction and reverse remodeling, but these were less than those observed in patients in sinus rhythm.

Background The use of HAART combining 2 nucleoside analogues reverse transcriptase inhibitors (NRTIs) plus one protease inhibitor (PI) or 2 NRTIs + 1 non-nucleoside reverse transcriptase inhibitor (NNRTI) has shown comparable efficacy. The study was designed to compare long term (2 years) effectiveness of two antiretroviral (ARV) treatment strategies in patients not previously treated: starting with a nelfinavir based HAART switching to nevirapine in case of failure or side effects or the reverse sequence. Methods This multicenter, randomized, open label clinical trial enrolled ARV-naive HIV patients with CD4 counts below 500 cells/mm3. They were randomly assigned to start ddI + d4T + nelfinavir (switching to ZDV + 3TC + NEV in case of failure or toxicity) (PI-NEV arm) or ddI + d4T + nevirapine, switching to ZDV + 3TC + NFV in case of failure or toxicity (NEV-PI arm). The primary study endpoint was the Kaplan-Meier estimates of the time to failure after switching to second regimen if necessary (considering failure as two consecutive plasma HIV-1 RNA determinations above 200 copies/mL, death, a new category C event or toxicity leading to treatment discontinuation of the second regimen) after a minimum follow-up of two years. Results A total of 137 patients were evaluable (67 and 70 in the PI-NEV and NEV-PI arms respectively). Baseline characteristics did not differ among groups. Kaplan-Meier estimates of time to failure did not show differences between the two arms neither in the on-treatment (OT) analysis (log rank test, p = 0.81) nor in the intent-to-treat (ITT) analysis (p = 0.58). At 24 months, the estimated proportion of patients free of failure were 72% and 66% respectively in the PI-NEV and NEV-PI arms OT analysis (p = 0.54) and 73% and 64% in the PI-NEV and NEV-PI arms in the ITT analysis (p = 0.49). The difference in the median in CD4+ lymphocyte count at 24 months was not significantly different in the two groups: 393 and307 CD4 cells/mm3 in the PI-NEV and NEV-PI arms respectively (p = 0.167). The incidence of adverse events (AEs) in the two arms was very similar: 50 (75%) in the PI-NEV and 54 (70%) in the NEV-PI group, as it was for grade 3-4 AEs leading to drug switching. Conclusion At two years both treatments strategies (PI-NEV vs NEV-PI) had a high and comparable efficacy and were generally well tolerated.

Aims Cardiac resynchronization therapy (CRT) reduces the degree of functional mitral regurgitation (FMR). However, FMR has also been associated with a lack of clinical response to CRT. We undertook this study to determine whether the presence of FMR influences the reverse remodelling induced by CRT. Methods and results We used Doppler echocardiography to assess 20 patients with dilated cardiomyopathy before and 6 months after undergoing CRT. We evaluated the effect of reverse remodelling (reduction ≥ 10% in end-systolic volume) according to the presence or absence of important FMR, defined as a regurgitant orifice area (ROA) of ≥ 0.20 cm2. Of the 20 patients (mean age, 64.7 ± 8.2 years, eight women), 9 had marked FMR (ROA 0.40 ± 0.12 cm2), 6 mild FMR (ROA 0.15 ± 0.02 cm2), and 5 had trivial or no FMR. CRT reduced the presence of mitral regurgitation by 33.3% and induced reverse remodelling in 60% of the patients. A ROA ≥ 0.20 cm2 was associated with a lack of reverse remodelling, despite presenting similar baseline characteristics and a reduction in asynchrony to the other patients. Reverse remodelling was produced in all the other patients, with a significant reduction in end-systolic volume (41.7 ± 21%; P = 0.003), accompanied by improvement in the ejection fraction ( P = 0.003) and myocardial performance index ( P = 0.027). Conclusion CRT improved FMR, although the baseline presence of important mitral regurgitation, with a ROA ≥ 0.20 cm2, in patients undergoing CRT was associated with a lack of response in reverse remodelling.