Biallelic Loss-of-Function NDUFA12 Variants Cause a Wide Phenotypic Spectrum from Leigh/Leigh-Like Syndrome to Isolated Optic Atrophy

BACKGROUND: Biallelic loss-of-function NDUFA12 variants have hitherto been linked to mitochondrial complex I deficiency presenting with heterogeneous clinical and radiological features in nine cases only. OBJECTIVES: To fully characterize, both phenotypically and genotypically, NDUFA12-related mitochondrial disease. METHODS: We collected data from cases identified by screening genetic databases of several laboratories worldwide and systematically reviewed the literature. RESULTS: Nine unreported NDUFA12 cases from six pedigrees were identified, with presentation ranging from movement disorder phenotypes (dystonia and/or spasticity) to isolated optic atrophy. MRI showed basal ganglia abnormalities (n = 6), optic atrophy (n = 2), or was unremarkable (n = 1). All carried homozygous truncating NDUFA12 variants, three of which are novel. CONCLUSIONS: Our case series expands phenotype–genotype correlations in NDUFA12-associated mitochondrial disease, providing evidence of intra- and inter-familial clinical heterogeneity for the same variant. It confirms NDUFA12 variants should be included in the diagnostic workup of Leigh/Leigh-like syndromes – particularly with dystonia – as well as isolated optic atrophy

Rapid virological response of telaprevir and boceprevir in a Brazilian cohort of HCV genotype 1 patients: A multicenter longitudinal study

© 2017 Borba et al. Background: Chronic hepatitis C is a major public health issue, but there is a gap in the literature regarding the effectiveness and safety of direct-acting antiviral agents in the Brazilian population. The main aim of this study was to describe the effectiveness of boceprevir and telaprevir in patients treated at public health care institutions in Brazil. Materials and methods: A prospective longitudinal and multicenter study was conducted in five centers in the State of Paraná between September 2014 and June 2016. Data regarding effectiveness and safety were collected from medical records of patients treated with boceprevir or telaprevir. The effectiveness outcome comprised the rapid virological response (RVR). Multivariate analysis was performed to verify the influence of independent variables (ie, age, gender, baseline viral load) on RVR achievement. Results: Data were collected from 117 patients with chronic hepatitis C virus (HCV) genotype 1 infection. Fifteen patients received treatment with boceprevir and 102 received telaprevir. The mean age was 51.6 years, 64.1% were male, 44.4% were infected with HCV subtype 1a, 62.4% had a high baseline viral load (≥800,000 IU/mL) and 33% were cirrhotic. Furthermore, 79.5% of patients achieved RVR (26.7% in the boceprevir group and 87.3% in the telaprevir group). Multivariate analysis demonstrated that the type of protease inhibitor (boceprevir or telaprevir) and the baseline viral load had an influence on the RVR rate (odds ratio [OR] =0.011; 95% confidence interval [CI]: 0.001–0.119; P<0.001/OR =13.004; 95% CI: 1.522–111.115; P=0.019, respectively). Conclusion: In this longitudinal multicenter cohort study conducted from the Brazilian perspective, differences were found in the RVR rates, favoring telaprevir over boceprevir for genotype 1 HCV-infected patients. In addition, the baseline viral load was associated with RVR achievement in both evaluated groups. As RVR is also reported in the literature as a predictor of the sustained virological response (SVR), further analyses of RVR as predictor of SVR outcomes should be further evaluated in Brazil

Network meta-analysis of first- and second-generation protease inhibitors for chronic hepatitis C genotype 1: efficacy based on RVR and SVR 24

© 2016, Springer-Verlag Berlin Heidelberg. Purpose: This study aimed to compare the efficacy among direct-acting antiviral agents (first and second-generation direct-acting antiviral agents (DAAs)) with placebo and with standard dual therapy (pegylated interferon + ribavirin (Peg-IFN + RBV)) in terms of rapid virologic response (RVR) and sustained virologic response (SVR) in chronic hepatitis C genotype 1 treatment. Methods: We performed a systematic review of randomized controlled trials (RCTs) in MEDLINE, International Pharmaceutical Abstracts, Cochrane Library, SCIELO, and Scopus and conducted a network meta-analysis to compare the efficacy of boceprevir (BOC), daclatasvir (DCV), grazoprevir, simeprevir (SMV) and telaprevir (TVR), in treatment-naive and treatment-experienced patients. Results: Sixteen studies encompassing 7171 patients were analysed. Associations between DAAs therapies (IFN-free regimens) could not be addressed since no common comparator was found in the RCTs among these associations and the other agents included in the present analysis. All agents were more efficacious than placebo or Peg-IFN + RBV in terms of RVR, while only BOC and SMV showed statistically significant superiority for the SVR outcome when compared to placebo or standard dual therapy. No significant differences between the DAAs were observed. The analysis prioritized treatment with DCV for both efficacy outcomes. Node-splitting analysis showed that our networks are robust (p > 0.05). Conclusions: The superiority of DAAs over placebo or standard dual therapy with Peg-IFN + RBV was confirmed, indicating the greater efficacy of DCV. This study is the first network meta-analysis that included RVR as an outcome in the evaluation of these agents via indirect comparison. Further investigation should be carried out addressing safety and tolerability outcomes

Rapid virological response of telaprevir and boceprevir in a Brazilian cohort of HCV genotype 1 patients: a multicenter longitudinal study

Helena HL Borba,1 Astrid Wiens,1 Laiza M Steimbach,1 Fernanda S Tonin,1 Maria LA Pedroso,2 Cl&aacute;udia AP Ivantes,3 Fernando Fernandez-Llimos,4 Roberto Pontarolo1 1Pharmaceutical Sciences Postgraduate Research Program, Department of Pharmacy, 2Gastroenterology Service, Hospital de Cl&iacute;nicas, Federal University of Paran&aacute;, 3Guidance and Counseling Center, Curitiba City Hall, Curitiba, Paran&aacute;, Brazil; 4Department of Social Pharmacy, Faculty of Pharmacy, Research Institute for Medicines, University of Lisboa, Lisbon, Portugal Background: Chronic hepatitis C is a major public health issue, but there is a gap in the literature regarding the effectiveness and safety of direct-acting antiviral agents in the Brazilian population. The main aim of this study was to describe the effectiveness of boceprevir and telaprevir in patients treated at public health care institutions in Brazil.Materials and methods: A prospective longitudinal and multicenter study was conducted in five centers in the State of Paran&aacute; between September 2014 and June 2016. Data regarding effectiveness and safety were collected from medical records of patients treated with boceprevir or telaprevir. The effectiveness outcome comprised the rapid virological response (RVR). Multivariate analysis was performed to verify the influence of independent variables (ie, age, gender, baseline viral load) on RVR achievement.Results: Data were collected from 117 patients with chronic hepatitis C virus (HCV) genotype 1 infection. Fifteen patients received treatment with boceprevir and 102 received telaprevir. The mean age was 51.6&nbsp;years, 64.1% were male, 44.4% were infected with HCV subtype 1a, 62.4% had a high baseline viral load (&ge;800,000&nbsp;IU/mL) and 33% were cirrhotic. Furthermore, 79.5% of patients achieved RVR (26.7% in the boceprevir group and 87.3% in the telaprevir group). Multivariate analysis demonstrated that the type of protease inhibitor (boceprevir or telaprevir) and the baseline viral load had an influence on the RVR rate (odds ratio [OR] =0.011; 95% confidence interval [CI]: 0.001&ndash;0.119; P&lt;0.001/OR =13.004; 95% CI: 1.522&ndash;111.115; P=0.019, respectively).Conclusion: In this longitudinal multicenter cohort study conducted from the Brazilian perspective, differences were found in the RVR rates, favoring telaprevir over boceprevir for genotype 1 HCV-infected patients. In addition, the baseline viral load was associated with RVR achievement in both evaluated groups. As RVR is also reported in the literature as a predictor of the sustained virological response (SVR), further analyses of RVR as predictor of SVR outcomes should be further evaluated in Brazil. Keywords: hepatitis C, rapid virological response, protease inhibitors, telaprevir, boceprevir, multicente

Association between dynamic asymmetry of the newborn's head and intrauterine factors Associação entre a assimetria dinâmica da cabeça do recém-nascido e fatores intra-uterinos

A non-comparable, individual, observational and contemporary cross-sectional study in newborns was made to determine the dynamic lateralization in the head turning after release from the midline and its relationship with obstetric variables. From October to December of 2005, 320 newborns were admitted to the Adjacent Lodgings of the University Hospital of Santa Maria. From those, 89 were selected for assessment of the vestibular function since they have had previously fetal static control through ultrasound. Our results show that the right-sided head lateralization was significantly greater than the left-sided. The predominancy of the lateralization towards the right side also occurred in cephalic presentations and left-sided back, however these were not significant. Results corroborate with the existing literature and suggest an association between fetal static and vestibular function.<br>Com o objetivo determinar a lateralização dinâmica na prova da queda da cabeça e sua associação com variáveis obstétricas, foi realizado um estudo transversal no recém-nascido, não comparado, individual, observacional e contemporâneo. No período de outubro a dezembro de 2005, 320 recém-nascidos foram admitidos no Alojamento Conjunto do Hospital Universitário de Santa Maria, e destes 89 foram selecionados para avaliação da função vestibular, por terem feito controle da estática fetal através do ultrasom. Nossos resultados mostram que a lateralização da cabeça para a direita foi significativamente maior do que para esquerda. Também este predomínio da lateralização para a direita ocorreu nas apresentações cefálicas e com o dorso para esquerda, no entanto estes não foram significativos. Nossos resultados corroboram com a literatura existente, e sugerem uma associação entre a estática fetal e a função vestibular