Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

First evidence for the two-body charmless baryonic decay

The results of a search for the rare two-body charmless baryonic decays TeX and TeX are reported. The analysis uses a data sample, corresponding to an integrated luminosity of 0.9 fb−1, of pp collision data collected by the LHCb experiment at a centre-of-mass energy of 7 TeV. An excess of TeX candidates with respect to background expectations is seen with a statistical significance of 3.3 standard deviations. This is the first evidence for a two-body charmless baryonic B 0 decay. No significant TeX signal is observed, leading to an improvement of three orders of magnitude over previous bounds. If the excess events are interpreted as signal, the 68.3% confidence level intervals on the branching fractions are $ TeX $ where the first uncertainty is statistical and the second is systematic.

The Total Deviation Index estimated by Tolerance Intervals to evaluate the concordance of measurement devices

Background In an agreement assay, it is of interest to evaluate the degree of agreement between the different methods (devices, instruments or observers) used to measure the same characteristic. We propose in this study a technical simplification for inference about the total deviation index (TDI) estimate to assess agreement between two devices of normally-distributed measurements and describe its utility to evaluate inter- and intra-rater agreement if more than one reading per subject is available for each device. Methods We propose to estimate the TDI by constructing a probability interval of the difference in paired measurements between devices, and thereafter, we derive a tolerance interval (TI) procedure as a natural way to make inferences about probability limit estimates. We also describe how the proposed method can be used to compute bounds of the coverage probability. Results The approach is illustrated in a real case example where the agreement between two instruments, a handle mercury sphygmomanometer device and an OMRON 711 automatic device, is assessed in a sample of 384 subjects where measures of systolic blood pressure were taken twice by each device. A simulation study procedure is implemented to evaluate and compare the accuracy of the approach to two already established methods, showing that the TI approximation produces accurate empirical confidence levels which are reasonably close to the nominal confidence level. Conclusions The method proposed is straightforward since the TDI estimate is derived directly from a probability interval of a normally-distributed variable in its original scale, without further transformations. Thereafter, a natural way of making inferences about this estimate is to derive the appropriate TI. Constructions of TI based on normal populations are implemented in most standard statistical packages, thus making it simpler for any practitioner to implement our proposal to assess agreement.

On the bicanonical map of irregular varieties

From the point of view of uniform bounds for the birationality of pluricanonical maps, irregular varieties of general type and maximal Albanese dimension behave similarly to curves. In fact Chen-Hacon showed that, at least when their holomorphic Euler characteristic is positive, the tricanonical map of such varieties is always birational. In this paper we study the bicanonical map. We consider the natural subclass of varieties of maximal Albanese dimension formed by primitive varieties of Albanese general type. We prove that the only such varieties with non-birational bicanonical map are the natural higher-dimensional generalization to this context of curves of genus $2$: varieties birationally equivalent to the theta-divisor of an indecomposable principally polarized abelian variety. The proof is based on the (generalized) Fourier-Mukai transform.

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.

On Short Exponential Sums Involving Fourier Coefficients of Holomorphic Cusp Forms

By an exponential sum of the Fourier coefficients of a holomorphic cusp form we mean the sum which is formed by first taking the Fourier series of the said form,then cutting the beginning and the tail away and considering the remaining sum on the real axis. For simplicity’s sake, typically the coefficients are normalized. However, this isn’t so important as the normalization can be done and removed simply by using partial summation. We improve the approximate functional equation for the exponential sums of the Fourier coefficients of the holomorphic cusp forms by giving an explicit upper bound for the error term appearing in the equation. The approximate functional equation is originally due to Jutila [9] and a crucial tool for transforming sums into shorter sums. This transformation changes the point of the real axis on which the sum is to be considered. We also improve known upper bounds for the size estimates of the exponential sums. For very short sums we do not obtain any better estimates than the very easy estimate obtained by multiplying the upper bound estimate for a Fourier coefficient (they are bounded by the divisor function as Deligne [2] showed) by the number of coefficients. This estimate is extremely rough as no possible cancellation is taken into account. However, with small sums, it is unclear whether there happens any remarkable amounts of cancellation.

Scherzando

Simananniemen käsikirjoituskokoelma.

Severity and burden of partial-onset seizures in a phase III trial of eslicarbazepine acetate.

OBJECTIVE: The objective of this study was to compare posttreatment seizure severity in a phase III clinical trial of eslicarbazepine acetate (ESL) as adjunctive treatment of refractory partial-onset seizures. METHODS: The Seizure Severity Questionnaire (SSQ) was administered at baseline and posttreatment. The SSQ total score (TS) and component scores (frequency and helpfulness of warning signs before seizures [BS]; severity and bothersomeness of ictal movement and altered consciousness during seizures [DS]; cognitive, emotional, and physical aspects of postictal recovery after seizures [AS]; and overall severity and bothersomeness [SB]) were calculated for the per-protocol population. Analysis of covariance, adjusted for baseline scores, estimated differences in posttreatment least square means between treatment arms. RESULTS: Out of 547 per-protocol patients, 441 had valid SSQ TS both at baseline and posttreatment. Mean posttreatment TS for ESL 1200mg/day was significantly lower than that for placebo (2.68 vs 3.20, p<0.001), exceeding the minimal clinically important difference (MCID: 0.48). Mean DS, AS, and SB were also significantly lower with ESL 1200mg/day; differences in AS and SB exceeded the MCIDs. The TS, DS, AS, and SB were lower for ESL 800mg/day than for placebo; only SB was significant (p=0.013). For both ESL arms combined versus placebo, mean scores differed significantly for TS (p=0.006), DS (p=0.031), and SB (p=0.001). CONCLUSIONS: Therapeutic ESL doses led to clinically meaningful, dose-dependent reductions in seizure severity, as measured by SSQ scores. CLASSIFICATION OF EVIDENCE: This study presents Class I evidence that adjunctive ESL (800 and 1200mg/day) led to clinically meaningful, dose-dependent seizure severity reductions, measured by the SSQ.

Tomografia computadorizada na avaliação da distribuição do tecido adiposo abdominal de ratos alimentados com rações hiperlipídicas após desnutrição neonatal

OBJETIVO: Descrever repercussões da ração suplementada com óleo de soja ou óleo de canola, por meio da tomografia computadorizada, na distribuição do tecido adiposo abdominal, após desmame de ratos desnutridos durante a lactação. MATERIAIS E MÉTODOS: Ratas lactantes submetidas a restrição alimentar (RA) em 50%, de acordo com o consumo das lactantes controles (C). Após o desmame, filhotes desnutridos receberam ração contendo 19% de óleo de soja (RA-soja 19%) ou óleo de canola (RA-canola 19%). Os filhotes do grupo controle receberam ração contendo 7% de óleo de soja (C-soja 7%). Aos 60 dias de idade, foram realizadas medidas corporais e das áreas de tecido adiposo abdominal por meio de tomografia computadorizada. Após sacrifício, tecido adiposo abdominal foi excisado e pesado. Os dados foram expressos como média ± erro-padrão da média, considerando o nível de significância de p < 0,05. RESULTADOS: Os grupos RA 19% desenvolveram similares comprimento, massa corporal e depósito de tecido adiposo visceral. Todas as avaliações realizadas foram significantemente menores em relação ao grupo C-soja 7%. Entretanto, na tomografia computadorizada, os grupos RA-soja 19% e RA-canola 19% apresentaram diferenças significativas da distribuição do tecido adiposo abdominal. CONCLUSÃO: A tomografia computadorizada mostrou que a distribuição de tecido adiposo, na cavidade abdominal, pode ser dependente do tipo de óleo vegetal na dieta.

Grand sonata Piano Forte and Violoncello Op 17

Sello, piano

Grand sonata Piano forte and Violoncello No 1 Op 5

Museokokoelma: 005.

Grand sonata Piano forte and Violoncello No 2 Op 5

Sello, piano

Grand sonata Piano forte and Violoncello No 1 Op102

Museokokoelma: 005.

Grand sonata Piano forte and Violoncello No 2 Op 102

Museokokoelma: 005.

Sonate für Pianoforte & Violoncello, Op121

Museokokoelma: 052.