Voretigene Neparvovec for Treating Inherited Retinal Dystrophies Caused by RPE65 Gene Mutations: An Evidence Review Group Perspective of a NICE Highly Specialised Technology Appraisal

The UK National Institute for Health and Care Excellence (NICE) considered evidence for voretigene neparvovec (VN; Luxturna®) for the treatment of RPE65-mediated inherited retinal dystrophies (IRD) within its highly specialised technology programme. This paper summarises the evidence provided by the company; the appraisal of the evidence by the Peninsula Technology Appraisal Group, who were commissioned to act as the independent evidence review group (ERG); and the development of the NICE guidance by the appraisal committee. The evidence presented by the company highlighted the significant lifelong burden of IRD for patients and carers. Evidence to support the effectiveness of VN was lacking, but the available evidence showed a modest, sustained improvement across a variety of vision-related outcomes. While patients would remain visually impaired, the committee considered that VN would prevent further deterioration in vision. The modelling approach used by the company had a number of limitations and relied heavily upon a large volume of clinical expert input to produce cost-effectiveness estimates with large uncertainty around long-term effectiveness. The ERG’s main concerns revolved around these long-term outcomes and the plausibility of utility values. The NICE committee were convinced that the clinical benefits of VN were important and an appropriate use of national health service resources within a specialised service. The committee concluded that a high unmet need existed in patients with RPE65-mediated IRD and that VN represents a step change in the management of this condition

Cytochrome p-450 gene expression in the functional units of the fetal liver

Hepatocytes of the right and left lobes of the fetal liver are surrounded by different microenvironments. The right and left lobes of the fetal liver are perfused by vascular systems carrying different concentrations of oxygen and constitute distinct functional units. The aim of this study was to assess the expression of the phenobarbital-inducible cytochrome P-450 b,e genes in hepatocytes of the right and left fetal liver lobes in mice. Northern-blot analysis using [ 32 P]cDNAs and quantitative dot-blot hybridization were performed to assess the size and levels of these mRNAs in the right and left fetal liver lobes. In fetal mice, the levels of cytochrome P-450, b,e mRNAs were higher in the left than in the right fetal liver lobe. During the last days of gestation and in the immediate postnatal period, the levels of liver cytochrome P-450 b,e mRNAs increased predominantly in the left liver lobe. In contrast, the levels of albumin and Α-fetoprotein mRNAs (genes studied to assess the specificity of these findings) were similar in each of functional units of the fetal liver. Phenobarbital induction of cytochromes P-450 b,e mRNAs was not observed in either of the fetal liver lobes. Postnatally, phenobarbital induced these cytochromes similarly in the right and left liver lobes. Therefore, the microenvironment surrounding fetal hepatocytes seems to influence the expression of the cytochrome P-450 b,e genes. This lobar heterogeneity of expression disappears as the pattern of adult liver circulation is attained.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/38336/1/1840080222_ftp.pd

Effects of castration and slaughter age on the fatty acid composition of ovine muscle and adipose tissue from two breeds

peer-reviewedFatty acids (g/100 g total fatty acids) in M. longissimus thoracis et lumborum (LTL) and total branched chain fatty acids (μg/g fat) in subcutaneous adipose tissue (SAT) of rams and castrates from Scottish Blackface (SB) or Texel × Scottish Blackface (T × SB) lambs, slaughtered at mean ages of 196, 242, 293, 344 or 385 days were determined. Lambs were fed pasture prior to a 36-day finishing period on a barley/maize-based concentrate ration. The intramuscular fat content (IMF; %) was higher (P < 0.001) in castrates than in rams and in SB compared to T × SB lambs (P < 0.001). The proportions of c9-C18:1 and total monounsaturated fatty acids (MUFA) were higher (P < 0.001) in LTL of castrates than rams. The proportions of C18:2n-6 and total n-6 polyunsaturated fatty acids (PUFA) were lower (P = 0.001) in LTL of castrates compared to rams related to differences in IMF content. The proportions of C14:0, C16:0, c9-C18:1 and total MUFA were higher (P < 0.05), while the proportions of C18:2n-6, C20:4n-6, C20:5n-3, total PUFA, n-6 and n-3 PUFA were lower (P < 0.05), in SB than in T × SB lambs, which was related to differences in IMF content. There was a higher (P < 0.001) proportion of conjugated linoleic acid (CLA) c9,t11-C18:2 in LTL from SB compared to T × SB. The effects of slaughter age on the proportions of fatty acids in LTL did not show a clear trend. The concentration of 4-methylnonanoic acid was higher (P = 0.002) in SAT of rams than castrates, particularly in older lambs. Despite the differences in the muscle fatty acid composition due to gender, slaughter age or breed of lambs, the ratio of n-6/n-3 PUFA (≤3.11) was within the dietary recommendation of <4.0 for human health

Effect of castration and age at slaughter on sensory perception of lamb meat

peer-reviewedThis study assessed the effect of castration and slaughter age (196–385 days old) on sensory quality of lamb meat from two sheep breeds (Scottish Blackface, SB; Texel x Scottish Blackface, TxSB). Results obtained using a trained sensory panel showed small but statistically significant differences due to castration, with rams having higher scores for Intensity of Lamb Aroma, Animal Smell/Farm Smell, Woolly Aroma, Rancid Aroma, Manure/Faecal Aroma, Sweaty Aroma and Off-flavours. SB lamb had higher scores for Intensity of Lamb Aroma, Lamb Flavour, Lamb Aftertaste, Tenderness and Juiciness. Age effects on sensory attributes were not linear and significant age × gender interactions were observed. The number of samples considered “extreme” in undesirable flavour attributes was higher among rams and T × SB animals. The impact of the sensory differences on consumer acceptability of lamb remains to be established

Effect of finishing diet and duration on the sensory quality and volatile profile of lamb meat

peer-reviewedAnimal production factors can affect the sensory quality of lamb meat. The study investigated the effect of diet composition and duration of consumption on the proximate analysis, volatile profile and sensory quality of lamb meat. Ninety-nine male Texel × Scottish Blackface lambs were raised at pasture for 10 months before being assigned in groups of 11 to one of the following treatments: 100% Silage (S) for 36 (S36), 54 (S54) or 72 (S72) days; 50% Silage - 50% Concentrate (SC) for 36 (SC36), 54 (SC54) or 72 (SC72) days; 100% Concentrate (C) for 36 (C36) or 54 (C54) or 72 (C72) days. A trained sensory panel found Intensity of Lamb Aroma, Dry Aftertaste and Astringent Aftertaste to be higher in meat from lambs on the concentrate diet. Discriminant analysis showed that the volatile profile enabled discrimination of lamb based on dietary treatment but the volatile differences were insufficient to impact highly on sensory quality. Muscle from animals in the S54 group had higher Manure/Faecal Aroma and Woolly Aroma than the SC54 and C54 groups, possibly related to higher levels of indole and skatole. Further research is required to establish if these small differences would influence consumer acceptability.The financial support of the Irish Department of Agriculture, Food and the Marine (project 11/SF/310) and of the Teagasc Walsh Fellowship Programme (award 2013058) is gratefully acknowledged

Levels of Reconstruction as Complementarity in Mixed Methods Research: A Social Theory-Based Conceptual Framework for Integrating Qualitative and Quantitative Research

Like other areas of health research, there has been increasing use of qualitative methods to study public health problems such as injuries and injury prevention. Likewise, the integration of qualitative and quantitative research (mixed-methods) is beginning to assume a more prominent role in public health studies. Likewise, using mixed-methods has great potential for gaining a broad and comprehensive understanding of injuries and their prevention. However, qualitative and quantitative research methods are based on two inherently different paradigms, and their integration requires a conceptual framework that permits the unity of these two methods. We present a theory-driven framework for viewing qualitative and quantitative research, which enables us to integrate them in a conceptually sound and useful manner. This framework has its foundation within the philosophical concept of complementarity, as espoused in the physical and social sciences, and draws on Bergson’s metaphysical work on the ‘ways of knowing’. Through understanding how data are constructed and reconstructed, and the different levels of meaning that can be ascribed to qualitative and quantitative findings, we can use a mixed-methods approach to gain a conceptually sound, holistic knowledge about injury phenomena that will enhance our development of relevant and successful interventions

Isometric Exercise Training and Arterial Hypertension: An Updated Review

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research

Rare copy number variants: a point of rarity in genetic risk for bipolar disorder and schizophrenia

Context: Recent studies suggest that copy number variation in the human genome is extensive and may play an important role in susceptibility to disease, including neuropsychiatric disorders such as schizophrenia and autism. The possible involvement of copy number variants (CNVs) in bipolar disorder has received little attention to date. Objectives: To determine whether large (>100 000 base pairs) and rare (found in <1% of the population) CNVs are associated with susceptibility to bipolar disorder and to compare with findings in schizophrenia. Design: A genome-wide survey of large, rare CNVs in a case-control sample using a high-density microarray. Setting: The Wellcome Trust Case Control Consortium. Participants: There were 1697 cases of bipolar disorder and 2806 nonpsychiatric controls. All participants were white UK residents. Main Outcome Measures: Overall load of CNVs and presence of rare CNVs. Results: The burden of CNVs in bipolar disorder was not increased compared with controls and was significantly less than in schizophrenia cases. The CNVs previously implicated in the etiology of schizophrenia were not more common in cases with bipolar disorder. Conclusions: Schizophrenia and bipolar disorder differ with respect to CNV burden in general and association with specific CNVs in particular. Our data are consistent with the possibility that possession of large, rare deletions may modify the phenotype in those at risk of psychosis: those possessing such events are more likely to be diagnosed as having schizophrenia, and those without them are more likely to be diagnosed as having bipolar disorder

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level