Minimum target prices for production of direct acting antivirals and associated diagnostics to combat Hepatitis C Virus

Combinations of direct-acting antivirals (DAAs) can cure hepatitis C virus (HCV) in the majority of treatment-naïve patients. Mass treatment programs to cure HCV in developing countries are only feasible if the costs of treatment and laboratory diagnostics are very low. This analysis aimed to estimate minimum costs of DAA treatment and associated diagnostic monitoring. Clinical trials of HCV DAAs were reviewed to identify combinations with consistently high rates of sustained virological response across hepatitis C genotypes. For each DAA, molecular structures, doses, treatment duration, and components of retrosynthesis were used to estimate costs of large-scale, generic production. Manufacturing costs per gram of DAA were based upon treating at least 5 million patients per year and a 40% margin for formulation. Costs of diagnostic support were estimated based on published minimum prices of genotyping, HCV antigen tests plus full blood count/clinical chemistry tests. Predicted minimum costs for 12-week courses of combination DAAs with the most consistent efficacy results were: US$122 per person for sofosbuvir+daclatasvir; US$152 for sofosbuvir+ribavirin; US$192 for sofosbuvir+ledipasvir; and US$115 for MK-8742+MK-5172. Diagnostic testing costs were estimated at US$90 for genotyping US$34 for two HCV antigen tests and US$22 for two full blood count/clinical chemistry tests. Conclusions: Minimum costs of treatment and diagnostics to cure hepatitis C virus infection were estimated at US$171-360 per person without genotyping or US$261-450 per person with genotyping. These cost estimates assume that existing large-scale treatment programs can be established. (Hepatology 2015;61:1174–1182

Mycoprotein reduces energy intake and postprandial insulin release without altering glucagon-like peptide-1 and peptide tyrosine-tyrosine concentrations in healthy overweight and obese adults: a randomised-controlled trial

Dietary mycoprotein decreases energy intake in lean individuals. The effects in overweight individuals are unclear, and the mechanisms remain to be elucidated. This study aimed to investigate the effect of mycoprotein on energy intake, appetite regulation, and the metabolic phenotype in overweight and obese volunteers. In two randomised-controlled trials, fifty-five volunteers (age: 31 (95 % CI 27, 35) years), BMI: 28·0 (95 % CI 27·3, 28·7) kg/m2) consumed a test meal containing low (44 g), medium (88 g) or high (132 g) mycoprotein or isoenergetic chicken meals. Visual analogue scales and blood samples were collected to measure appetite, glucose, insulin, peptide tyrosine-tyrosine (PYY) and glucagon-like peptide-1 (GLP-1). Ad libitum energy intake was assessed after 3 h in part A (n 36). Gastric emptying by the paracetamol method, resting energy expenditure and substrate oxidation were recorded in part B (n 14). Metabonomics was used to compare plasma and urine samples in response to the test meals. Mycoprotein reduced energy intake by 10 % (280 kJ (67 kcal)) compared with chicken at the high content (P=0·009). All mycoprotein meals reduced insulin concentrations compared with chicken (incremental AUClow (IAUClow): -8 %, IAUCmedium: -12 %, IAUChigh: -21 %, P=0·004). There was no significant difference in glucose, PYY, GLP-1, gastric emptying rate and energy expenditure. Following chicken intake, paracetamol-glucuronide was positively associated with fullness. After mycoprotein, creatinine and the deamination product of isoleucine, α-keto-β-methyl-N-valerate, were inversely related to fullness, whereas the ketone body, β-hydroxybutyrate, was positively associated. In conclusion, mycoprotein reduces energy intake and insulin release in overweight volunteers. The mechanism does not involve changes in PYY and GLP-1. The metabonomics analysis may bring new understanding to the appetite regulatory properties of food.</p

Timing the Kilohertz Quasi-Periodic Oscillations in Low-mass X-ray Binaries

I describe a new technique that we have been using in the past few years to get precise measurements of the frequency separation of the kHz QPOs in some Low-mass X-ray binaries. I show how this technique (that we call "shift-and-add") works, and I present some of the results we obtained using it.Comment: To appear in the Proceedings of the NATO ASI School "The Neutron Star - Black Hole Connection" (Kluwer Academic Publishers), C. Kouveliotou, J. van Paradijs, J. Ventura (eds.). (6 pages; 4 figures

Agreement between an online dietary assessment tool (myfood24) and an interviewer-administered 24-h dietary recall in British adolescents aged 11–18 years

myfood24 Is an online 24-h dietary assessment tool developed for use among British adolescents and adults. Limited information is available regarding the validity of using new technology in assessing nutritional intake among adolescents. Thus, a relative validation of myfood24 against a face-to-face interviewer-administered 24-h multiple-pass recall (MPR) was conducted among seventy-five British adolescents aged 11–18 years. Participants were asked to complete myfood24 and an interviewer-administered MPR on the same day for 2 non-consecutive days at school. Total energy intake (EI) and nutrients recorded by the two methods were compared using intraclass correlation coefficients (ICC), Bland–Altman plots (using between and within-individual information) and weighted κ to assess the agreement. Energy, macronutrients and other reported nutrients from myfood24 demonstrated strong agreement with the interview MPR data, and ICC ranged from 0·46 for Na to 0·88 for EI. There was no significant bias between the two methods for EI, macronutrients and most reported nutrients. The mean difference between myfood24 and the interviewer-administered MPR for EI was −230 kJ (−55 kcal) (95 % CI −490, 30 kJ (−117, 7 kcal); P=0·4) with limits of agreement ranging between 39 % (3336 kJ (−797 kcal)) lower and 34 % (2874 kJ (687 kcal)) higher than the interviewer-administered MPR. There was good agreement in terms of classifying adolescents into tertiles of EI (κ w =0·64). The agreement between day 1 and day 2 was as good for myfood24 as for the interviewer-administered MPR, reflecting the reliability of myfood24. myfood24 Has the potential to collect dietary data of comparable quality with that of an interviewer-administered MPR

Justification of the symmetric damping model of the dynamical Casimir effect in a cavity with a semiconductor mirror

A "microscopic" justification of the "symmetric damping" model of a quantum oscillator with time-dependent frequency and time-dependent damping is given. This model is used to predict results of experiments on simulating the dynamical Casimir effect in a cavity with a photo-excited semiconductor mirror. It is shown that the most general bilinear time-dependent coupling of a selected oscillator (field mode) to a bath of harmonic oscillators results in two equal friction coefficients for the both quadratures, provided all the coupling coefficients are proportional to a single arbitrary function of time whose duration is much shorter than the periods of all oscillators. The choice of coupling in the rotating wave approximation form leads to the "mimimum noise" model of the quantum damped oscillator, introduced earlier in a pure phenomenological way.Comment: 9 pages, typos corrected, corresponds to the published version, except for the reference styl

Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases

Training teachers in classroom management to improve mental health in primary school children: the STARS cluster RCT

This is the final version. Available from NIHR Journals Library via the DOI in this record.Background Poor mental health in childhood is common, persistent and associated with a range of adverse outcomes that include persistent psychopathology, as well as risk-taking behaviour, criminality and educational failure, all of which may also compromise health. There is a growing policy focus on children’s mental health and the role of schools in particular in addressing this. Objectives To evaluate whether or not the Incredible Years® (IY) Teacher Classroom Management (TCM) training improved children’s mental health, behaviour, educational attainment and enjoyment of school, improved teachers’ mental health and relationship with work, and was cost-effective in relation to potential improvements. Design A two-arm, pragmatic, parallel-group, superiority, cluster randomised controlled trial. Setting A total of 80 UK schools (clusters) were recruited in three distinct cohorts between 2012 and 2014 and randomised to TCM (intervention) or teaching as usual [(TAU) control] with follow-ups at 9, 18 and 30 months. Schools and teachers were not masked to allocation. Participants Eighty schools (n = 2075 children) were randomised: 40 (n = 1037 children) to TCM and 40 (n = 1038 children) to TAU. Interventions TCM was delivered to teachers in six whole-day sessions, spread over 6 months. The explicit goals of TCM are to enhance classroom management skills and improve teacher–student relationships. Main outcome measures The primary planned outcome was the teacher-reported Strengths and Difficulties Questionnaire Total Difficulties (SDQ-TD) score. Random-effects linear regression and marginal logistic regression models using generalized estimating equations were used to analyse outcomes. Results The intervention reduced the SDQ-TD score at 9 months [adjusted mean difference (AMD) –1.0, 95% confidence interval (CI) –1.9 to –0.1; p = 0.03] but there was little evidence of effects at 18 months (AMD –0.1, 95% CI –1.5 to 1.2; p = 0.85) and 30 months (AMD –0.7, 95% CI –1.9 to 0.4; p = 0.23). Planned subgroup analyses suggested that TCM is more effective than TAU for children with poor mental health. Cost-effectiveness analysis using the SDQ-TD suggested that the probability of TCM being cost-effective compared with TAU was associated with some uncertainty (range of 40% to 80% depending on the willingness to pay for a unit improvement in SDQ-TD score). In terms of quality-adjusted life-years (QALYs), there was evidence to suggest that TCM was cost-effective compared with TAU at the National Institute for Health and Care Excellence thresholds of £20,000–30,000 per QALY at 9- and 18-month follow-up, but not at 30-month follow-up. There was evidence of reduced disruptive behaviour (p = 0.04) and reductions in inattention and overactivity (p = 0.02) at the 30-month follow-up. Despite no main effect on educational attainment, subgroup analysis indicated that the intervention’s effect differed between those who did and those who did not have poor mental health for both literacy (interaction p = 0.04) and numeracy (interaction p = 0.03). Independent blind observations and qualitative feedback from teachers suggested that teachers’ behaviour in the classroom changed as a result of attending TCM training. Limitations Teachers were not masked to allocation and attrition was marked for parent-reported data. Conclusions Our findings provide tentative evidence that TCM may be an effective universal child mental health intervention in the short term, particularly for primary school children who are identified as struggling, and it may be a cost-effective intervention in the short term. Future work Further research should explore TCM as a whole-school approach by training all school staff and should evaluate the impact of TCM on academic progress in a more thorough and systematic manner.National Institute for Health Research (NIHR

Viral population estimation using pyrosequencing

The diversity of virus populations within single infected hosts presents a major difficulty for the natural immune response as well as for vaccine design and antiviral drug therapy. Recently developed pyrophosphate based sequencing technologies (pyrosequencing) can be used for quantifying this diversity by ultra-deep sequencing of virus samples. We present computational methods for the analysis of such sequence data and apply these techniques to pyrosequencing data obtained from HIV populations within patients harboring drug resistant virus strains. Our main result is the estimation of the population structure of the sample from the pyrosequencing reads. This inference is based on a statistical approach to error correction, followed by a combinatorial algorithm for constructing a minimal set of haplotypes that explain the data. Using this set of explaining haplotypes, we apply a statistical model to infer the frequencies of the haplotypes in the population via an EM algorithm. We demonstrate that pyrosequencing reads allow for effective population reconstruction by extensive simulations and by comparison to 165 sequences obtained directly from clonal sequencing of four independent, diverse HIV populations. Thus, pyrosequencing can be used for cost-effective estimation of the structure of virus populations, promising new insights into viral evolutionary dynamics and disease control strategies.Comment: 23 pages, 13 figure

Validation of the Oxford WebQ online 24-hour dietary questionnaire using biomarkers

Oxford WebQ is an online dietary questionnaire covering 24 hours, appropriate for repeated administration in large-scale prospective studies including UK Biobank and the Million Women Study. We compared performance of the Oxford WebQ and a traditional interviewer-administered multi-pass 24-hour recall against biomarkers for protein, potassium and total sugar intake, and total energy expenditure estimated by accelerometry. 160 participants were recruited between 2014 and 2016 in London, UK, and measured at 3 non-consecutive time-points. The measurement error model simultaneously compared all 3 methods. Attenuation factors for protein, potassium, sugars and total energy intake estimated by the mean of 2 Oxford WebQs were 0.37, 0.42, 0.45, and 0.31 respectively, with performance improving incrementally for the mean of more measures. Correlation between the mean of 2 Oxford WebQs and estimated true intakes, reflecting attenuation when intake is categorised or ranked, was 0.47, 0.39, 0.40, and 0.38 respectively, also improving with repeated administration. These were similar to the more administratively burdensome interviewer-based recall. Using objective biomarkers as the standard, Oxford WebQ performs well across key nutrients in comparison with more administratively burdensome interviewer-based 24-hour recalls. Attenuation improves when the average is taken over repeated administration, reducing measurement error bias in assessment of diet-disease associations