Liver toxicity and risk of discontinuation in HIV/hepatitis C virus-coinfected patients receiving an etravirine-containing antiretroviral regimen: influence of liver fibrosis

Short communication[Abstract] Objectives. The aim of the study was to establish the risk of liver toxicity in HIV/hepatitis C virus (HCV)-coinfected patients receiving etravirine, according to the degree of liver fibrosis. Methods. A prospective cohort study of 211 HIV-infected patients initiating an etravirine-containing regimen was carried out. HCV coinfection was defined as a positive HCV RNA test, and baseline liver fibrosis was assessed by transient elastography. Hepatotoxicity was defined as clinical symptoms, or an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value > 5-fold higher than the upper limit of normal if baseline values were normal, or 3.5-fold higher if values were altered at baseline. Results. Overall, 145 patients (69%) were HCV coinfected, with a lower nadir (165 versus 220 cells/μL, respectively; p = 0.03) and baseline (374 versus 498 cells/μL, respectively; p = 0.04) CD4 count than monoinfected patients. Etravirine was mainly used with two nucleoside reverse transcriptase inhibitors (129; 61%) or with a boosted protease inhibitor (PI) (28%), with no significant differences according to HCV serostatus. Transient elastography in 117 patients (81%) showed a median (range) stiffness value of 8.25 (3.5–69) kPa, with fibrosis stage 1 in 43 patients (37%) and fibrosis stage 4 in 28 patients (24%). During an accumulated follow-up time of 449.3 patient-years (median 548 days), only one patient with advanced fibrosis (50.8 kPa) had grade 3–4 liver toxicity (0.7%). Transaminases changed slightly, with no significant differences compared with baseline fibrosis, and nine and six patients had grade 1 and 2 transaminase increases, respectively. Also, HCV coinfection was not associated with a higher risk of discontinuation (25% discontinued versus 21% of monoinfected patients; p = 0.39, log-rank test) or virological failure (8% versus 12%, respectively; p = 0.4). Conclusions. Our data suggest that etravirine is a safe option for HIV/HCV-coinfected patients, including those with significant liver fibrosis

O Processo de coloração a seco de porcelanato. Parte 1: Variáveis envolvidas e influência sobre as propriedades das peças

Dentre as tipologias de revestimentos cerâmicos atualmente produzidos o porcelanato tem se destacado pela grande expansão em sua produção, observada nos últimos anos. O sucesso do produto se deve pelas propriedades técnicas e estéticas oferecidas. Dentro deste contexto a técnica de coloração a seco surge como alternativa a ser adotada no processamento da massa do material, pois confere ao produto características estéticas que podem ser obtidas através de uma simples mistura de pigmentos e grânulos atomizados. Entretanto, pouco se conhece sobre as variáveis envolvidas neste processo de mistura e a real interferência de cada uma delas nas propriedades apresentadas pelo produto queimado. Este trabalho apresenta o resultado de um estudo que revela o efeito das principais variáveis relacionadas à mistura do pigmento com os grânulos atomizados sobre as propriedades apresentadas pelo produto fina

Novel Somatic Genetic Variants as Predictors of Resistance to EGFR-Targeted Therapies in Metastatic Colorectal Cancer Patients

Background: About 40% of RAS/BRAF wild-type metastatic colorectal cancer (mCRC) patients undergoing anti-EGFR-based therapy have poor outcomes. Treatment failure is not only associated with poorer prognosis but higher healthcare costs. Our aim was to identify novel somatic genetic variants in the primary tumor and assess their effect on anti-EGFR response. Patients and Methods: Tumor (somatic) and blood (germline) DNA samples were obtained from two well-defined cohorts of mCRC patients, those sensitive and those resistant to EGFR blockade. Genetic variant screening of 43 EGFR-related genes was performed using targeted next-generation sequencing (NGS). Relevant clinical data were collected through chart review to assess genetic results. Results: Among 61 patients, 38 were sensitive and 23 were resistant to treatment. We identified eight somatic variants that predicted non-response. Three were located in insulin-related genes (I668N and E1218K in IGF1R, T1156M in IRS2) and three in genes belonging to the LRIG family (T152T in LRIG1, S697L in LRIG2 and V812M in LRIG3). The remaining two variants were found in NRAS (G115Efs*46) and PDGFRA (T301T). We did not identify any somatic variants related to good response. Conclusions: This study provides evidence that novel somatic genetic variants along the EGFR-triggered pathway could modulate the response to anti-EGFR drugs in mCRC patients. It also highlights the influence of insulin-related genes and LRIG genes on anti-EGFR efficacy. Our findings could help characterize patients who are resistant to anti-EGFR blockade despite harboring RAS/BRAF wild-type tumors

Macrophage-induced blood vessels guide Schwann cell-mediated regeneration of peripheral nerves

The peripheral nervous system has remarkable regenerative capacities in that it can repair a fully cut nerve. This requires Schwann cells to migrate collectively to guide regrowing axons across a 'bridge' of new tissue, which forms to reconnect a severed nerve. Here we show that blood vessels direct the migrating cords of Schwann cells. This multicellular process is initiated by hypoxia, selectively sensed by macrophages within the bridge, which via VEGF-A secretion induce a polarized vasculature that relieves the hypoxia. Schwann cells then use the blood vessels as "tracks" to cross the bridge taking regrowing axons with them. Importantly, disrupting the organization of the newly formed blood vessels in vivo, either by inhibiting the angiogenic signal or by re-orienting them, compromises Schwann cell directionality resulting in defective nerve repair. This study provides important insights into how the choreography of multiple cell-types is required for the regeneration of an adult tissue

Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

This article belongs to the Special Issue Genetic Advances in Neuromuscular Disorders: From Gene Identification to Gene Therapy.The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.This study was granted by FIS PI15/01898, funded by ISCIII and FEDER, ‘Una manera de hacer Europa’ and by Fundación Mutua Madrileña in the “Convocatoria de ayudas a la Investigación en Salud 2015”. It was also funded by an ACCI grant from CIBERER. Daniel Natera-de Benito is the recipient of a grant from the Instituto de Salud Carlos III (Contrato Rio Hortega, CM17/00044)

Pituitary tumor transforming gene-1 haplotypes and risk of pituitary adenoma: a case-control study

<p>Abstract</p> <p>Background</p> <p>It has been suggested that pituitary adenoma results from accumulation of multiple genetic and/or epigenetic aberrations, which may be identified through association studies. As pituitary tumor transforming gene-1 (<it>PTTG1</it>)/securin plays a critical role in promoting genomic instability in pituitary neoplasia, the present study explored the association of <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma.</p> <p>Methods</p> <p>We genotyped five <it>PTTG1 </it>haplotype-tagging SNPs (htSNP) by PCR-RFLP assays in a case-control study, which included 280 Han Chinese patients diagnosed with pituitary adenoma and 280 age-, gender- and geographically matched Han Chinese controls. Haplotypes were reconstructed according to the genotyping data and linkage disequilibrium status of the htSNPs.</p> <p>Results</p> <p>No significant differences in allele and genotype frequencies of the htSNPs were observed between pituitary adenoma patients and controls, indicating that none of the individual <it>PTTG1 </it>SNPs examined in this study is associated with the risk of pituitary adenoma. In addition, no significant association was detected between the reconstructed <it>PTTG1 </it>haplotypes and pituitary adenoma cases or the controls.</p> <p>Conclusions</p> <p>Though no significant association was found between <it>PTTG1 </it>haplotypes and the risk of pituitary adenoma, this is the first report on the association of individual <it>PTTG1 </it>SNPs or <it>PTTG1 </it>haplotypes with the risk of pituitary adenoma based on a solid study; it will provide an important reference for future studies on the association between genetic alterations in <it>PTTG1 </it>and the risk of pituitary adenoma or other tumors.</p

Real-time PCR detection of Human Herpesvirus 1-5 in patients lacking clinical signs of a viral CNS infection

<p>Abstract</p> <p>Background</p> <p>Infections of the central nervous system (CNS) with herpes- or enterovirus can be self-limiting and benign, but occasionally result in severe and fatal disease. The polymerase chain reaction (PCR) has revolutionized the diagnostics of viral pathogens, and by multiple displacement amplification (MDA) prior to real-time PCR the sensitivity might be further enhanced. The aim of this study was to investigate if herpes- or enterovirus can be detected in cerebrospinal fluid (CSF) from patients without symptoms.</p> <p>Methods</p> <p>Cerebrospinal fluid (CSF) samples from 373 patients lacking typical symptoms of viral CNS infection were analysed by real-time PCR targeting herpesviruses or enteroviruses with or without prior MDA.</p> <p>Results</p> <p>In total, virus was detected in 17 patients (4%). Epstein-Barr virus (EBV) was most commonly detected, in general from patients with other conditions (e.g. infections, cerebral hemorrhage). MDA satisfactorily amplified viral DNA in the absence of human nucleic acids, but showed poor amplification capacity for viral DNA in CSF samples, and did not increase the sensitivity for herpes virus-detection with our methodology.</p> <p>Conclusions</p> <p>Viral pathogens are rarely detected in CSF from patients without signs of CNS infection, supporting the view that real-time PCR is a highly specific method to detect symptomatic CNS-infection caused by these viruses. However, EBV may be subclinically reactivated due to other pathological conditions in the CNS.</p

Zebrafish usp39 Mutation Leads to rb1 mRNA Splicing Defect and Pituitary Lineage Expansion

Loss of retinoblastoma (Rb) tumor suppressor function is associated with human malignancies. Molecular and genetic mechanisms responsible for tumorigenic Rb downregulation are not fully defined. Through a forward genetic screen and positional cloning, we identified and characterized a zebrafish ubiquitin specific peptidase 39 (usp39) mutation, the yeast and human homolog of which encodes a component of RNA splicing machinery. Zebrafish usp39 mutants exhibit microcephaly and adenohypophyseal cell lineage expansion without apparent changes in major hypothalamic hormonal and regulatory signals. Gene expression profiling of usp39 mutants revealed decreased rb1 and increased e2f4, rbl2 (p130), and cdkn1a (p21) expression. Rb1 mRNA overexpression, or antisense morpholino knockdown of e2f4, partially reversed embryonic pituitary expansion in usp39 mutants. Analysis of pre-mRNA splicing status of critical cell cycle regulators showed misspliced Rb1 pre-mRNA resulting in a premature stop codon. These studies unravel a novel mechanism for rb1 regulation by a neuronal mRNA splicing factor, usp39. Zebrafish usp39 regulates embryonic pituitary homeostasis by targeting rb1 and e2f4 expression, respectively, contributing to increased adenohypophyseal sensitivity to these altered cell cycle regulators. These results provide a mechanism for dysregulated rb1 and e2f4 pathways that may result in pituitary tumorigenesis

Eligibility criteria for Menopausal Hormone Therapy (MHT): a position statement from a consortium of scientific societies for the use of MHT in women with medical conditions. MHT Eligibility Criteria Group

This project aims to develop eligibility criteria for menopausal hormone therapy (MHT). The tool should be similar to those already established for contraception A consortium of scientific societies coordinated by the Spanish Menopause Society met to formulate recommendations for the use of MHT by women with medical conditions based on the best available evidence. The project was developed in two phases. As a first step, we conducted 14 systematic reviews and 32 metanalyses on the safety of MHT (in nine areas: age, time of menopause onset, treatment duration, women with thrombotic risk, women with a personal history of cardiovascular disease, women with metabolic syndrome, women with gastrointestinal diseases, survivors of breast cancer or of other cancers, and women who smoke) and on the most relevant pharmacological interactions with MHT. These systematic reviews and metanalyses helped inform a structured process in which a panel of experts defined the eligibility criteria according to a specific framework, which facilitated the discussion and development process. To unify the proposal, the following eligibility criteria have been defined in accordance with the WHO international nomenclature for the different alternatives for MHT (category 1, no restriction on the use of MHT; category 2, the benefits outweigh the risks; category 3, the risks generally outweigh the benefits; category 4, MHT should not be used). Quality was classified as high, moderate, low or very low, based on several factors (including risk of bias, inaccuracy, inconsistency, lack of directionality and publication bias). When no direct evidence was identified, but plausibility, clinical experience or indirect evidence were available, "Expert opinion" was categorized. For the first time, a set of eligibility criteria, based on clinical evidence and developed according to the most rigorous methodological tools, has been defined. This will provide health professionals with a powerful decision-making tool that can be used to manage menopausal symptoms

Epidemiological trends of HIV/HCV coinfection in Spain, 2015-2019

Altres ajuts: Spanish AIDS Research Network; European Funding for Regional Development (FEDER).Objectives: We assessed the prevalence of anti-hepatitis C virus (HCV) antibodies and active HCV infection (HCV-RNA-positive) in people living with HIV (PLWH) in Spain in 2019 and compared the results with those of four similar studies performed during 2015-2018. Methods: The study was performed in 41 centres. Sample size was estimated for an accuracy of 1%. Patients were selected by random sampling with proportional allocation. Results: The reference population comprised 41 973 PLWH, and the sample size was 1325. HCV serostatus was known in 1316 PLWH (99.3%), of whom 376 (28.6%) were HCV antibody (Ab)-positive (78.7% were prior injection drug users); 29 were HCV-RNA-positive (2.2%). Of the 29 HCV-RNA-positive PLWH, infection was chronic in 24, it was acute/recent in one, and it was of unknown duration in four. Cirrhosis was present in 71 (5.4%) PLWH overall, three (10.3%) HCV-RNA-positive patients and 68 (23.4%) of those who cleared HCV after anti-HCV therapy (p = 0.04). The prevalence of anti-HCV antibodies decreased steadily from 37.7% in 2015 to 28.6% in 2019 (p < 0.001); the prevalence of active HCV infection decreased from 22.1% in 2015 to 2.2% in 2019 (p < 0.001). Uptake of anti-HCV treatment increased from 53.9% in 2015 to 95.0% in 2019 (p < 0.001). Conclusions: In Spain, the prevalence of active HCV infection among PLWH at the end of 2019 was 2.2%, i.e. 90.0% lower than in 2015. Increased exposure to DAAs was probably the main reason for this sharp reduction. Despite the high coverage of treatment with direct-acting antiviral agents, HCV-related cirrhosis remains significant in this population