Missense mutations at homologous positions in the fourth and fifth laminin A G-like domains of eyes shut homolog cause autosomal recessive retinitis pigmentosa

Purpose: To describe two novel mutations in the eyes shut homolog (EYS) gene in two families with autosomal recessive retinitis pigmentosa (arRP) from Pakistan and Indonesia. Methods: Genome-wide linkage and homozygosity mapping were performed using single nucleotide polymorphism microarray analysis in affected members of the two arRP families. Sequence analysis was performed to identify genetic changes in protein coding exons of EYS. Results: In the Indonesian and Pakistani families, homozygous regions encompassing the EYS gene at 6q12 were identified, with maximum LOD scores of 1.8 and 3.6, respectively. Novel missense variants in the EYS gene (p.D2767Y and p.D3028Y) were found in the Pakistani and Indonesian families, respectively, that co-segregate with the disease phenotype. Interestingly, the missense variants are located at the same homologous position within the fourth and fifth laminin A G-like domains of EYS. Conclusions: To date, mostly protein-truncating mutations have been described in EYS, while only few patients have been described with pathogenic compound heterozygous missense mutations. The mutations p.D2767Y and p.D3028Y described in this study affect highly conserved residues at homologous positions in laminin A G-like domains and support the notion that missense mutations in EYS can cause arRP

Relaxation Height in Energy Landscapes: an Application to Multiple Metastable States

The study of systems with multiple (not necessarily degenerate) metastable states presents subtle difficulties from the mathematical point of view related to the variational problem that has to be solved in these cases. We introduce the notion of relaxation height in a general energy landscape and we prove sufficient conditions which are valid even in presence of multiple metastable states. We show how these results can be used to approach the problem of multiple metastable states via the use of the modern theories of metastability. We finally apply these general results to the Blume--Capel model for a particular choice of the parameters ensuring the existence of two multiple, and not degenerate in energy, metastable states

Trapping in complex networks

We investigate the trapping problem in Erdos-Renyi (ER) and Scale-Free (SF) networks. We calculate the evolution of the particle density $\rho(t)$ of random walkers in the presence of one or multiple traps with concentration $c$. We show using theory and simulations that in ER networks, while for short times $\rho(t) \propto \exp(-Act)$, for longer times $\rho(t)$ exhibits a more complex behavior, with explicit dependence on both the number of traps and the size of the network. In SF networks we reveal the significant impact of the trap's location: $\rho(t)$ is drastically different when a trap is placed on a random node compared to the case of the trap being on the node with the maximum connectivity. For the latter case we find \rho(t)\propto\exp\left[-At/N^\frac{\gamma-2}{\gamma-1}\av{k}\right] for all $\gamma>2$, where $\gamma$ is the exponent of the degree distribution $P(k)\propto k^{-\gamma}$.Comment: Appendix adde

Decreased exposure to sunitinib due to concomitant administration of ifosfamide: results of a phase I and pharmacokinetic study on the combination of sunitinib and ifosfamide in patients with advanced solid malignancies

Background:This study aimed to define the maximally tolerated dose (MTD) of sunitinib combined with two different infusion schedules of ifosfamide. Methods:Patients with advanced solid tumours, good performance score, good organ function, and no standard therapy available were eligible. Continuous once daily sunitinib, in escalating doses per cohort, was combined with ifosfamide, 9 g m-2 for 3 days or 6 g m-2 for 5 days, administered every 3 weeks. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were performed. Results:With growth-factor support, the MTD of sunitinib combined with either ifosfamide schedule was 12.5 mg in 32 patients enrolled. Neutropenia-related adverse events were dose-limiting toxicities. Sunitinib did not affect ifosfamide PK. Ifosfamide significantly decreased exposure to sunitinib and increased exposure to its metabolite, SU12662. No consistent changes in PD parameters were observed. Conclusion:With growth-factor support, the MTD of sunitinib with both ifosfamide schedules was 12.5 mg. Ifosfamide produced decreased sunitinib blood levels because of CYP3A induction. As PK interactions cannot explain the relatively low sunitinib doses that can be combined with ifosfamide, synergy in toxicity is likely. Whether this also holds true for anti-tumour activity needs to be further explored.British Journal of Cancer advance online publication, 18 May 2010; doi:10.1038/sj.bjc.6605696 www.bjcancer.com

A global perspective on collision and non-collision match characteristics in male rugby union: Comparisons by age and playing standard

This study quantified and compared the collision and non-collision match characteristics across age categories (i.e. U12, U14, U16, U18, Senior) for both amateur and elite playing standards from Tier 1 rugby union nations (i.e. England, South Africa, New Zealand). Two-hundred and one male matches (5911 min ball-in-play) were coded using computerised notational analysis, including 193,708 match characteristics (e.g. 83,688 collisions, 33,052 tackles, 13,299 rucks, 1006 mauls, 2681 scrums, 2923 lineouts, 44,879 passes, 5568 kicks). Generalised linear mixed models with post-hoc comparisons and cluster analysis compared the match characteristics by age category and playing standard. Overall significant differences (p &lt; 0.001) between age category and playing standard were found for the frequency of match characteristics, and tackle and ruck activity. The frequency of characteristics increased with age category and playing standard except for scrums and tries that were the lowest at the senior level. For the tackle, the percentage of successful tackles, frequency of active shoulder, sequential and simultaneous tackles increased with age and playing standard. For ruck activity, the number of attackers and defenders were lower in U18 and senior than younger age categories. Cluster analysis demonstrated clear differences in all and collision match characteristics and activity by age category and playing standard. These findings provide the most comprehensive quantification and comparison of collision and non-collision activity in rugby union demonstrating increased frequency and type of collision activity with increasing age and playing standard. These findings have implications for policy to ensure the safe development of rugby union players throughout the world.</p

The 1+1-dimensional Kardar-Parisi-Zhang equation and its universality class

We explain the exact solution of the 1+1 dimensional Kardar-Parisi-Zhang equation with sharp wedge initial conditions. Thereby it is confirmed that the continuum model belongs to the KPZ universality class, not only as regards to scaling exponents but also as regards to the full probability distribution of the height in the long time limit.Comment: Proceedings StatPhys 2

Consensus on a video analysis framework of descriptors and definitions by the Rugby Union Video Analysis Consensus group

Using an expert consensus-based approach, a rugby union Video Analysis Consensus (RUVAC) group was formed to develop a framework for video analysis research in rugby union. The aim of the framework is to improve the consistency of video analysis work in rugby union and help enhance the overall quality of future research in the sport. To reach consensus, a systematic review and Delphi method study design was used. After a systematic search of the literature, 17 articles were used to develop the final framework that described and defined key actions and events in rugby union (rugby). Thereafter, a group of researchers and practitioners with experience and expertise in rugby video analysis formed the RUVAC group. Each member of the group examined the framework of descriptors and definitions and rated their level of agreement on a 5-point agreement Likert scale (1: strongly disagree; 2: disagree; 3: neitheragree or disagree; 4: agree; 5: strongly agree). The mean rating of agreement on the five-point scale (1: strongly disagree; 5: strongly agree) was 4.6 (4.3–4.9), 4.6 (4.4–4.9), 4.7 (4.5–4.9), 4.8 (4.6–5.0) and 4.8 (4.6–5.0) for the tackle, ruck, scrum, line-out and maul, respectively. The RUVAC group recommends using this consensus as the starting framework when conducting rugby video analysis research. Which variables to use (if not all) depends on the objectives of the study. Furthermore, the intention of this consensus is to help integrate video data with other data (eg, injury surveillance)

A clinical and molecular characterisation of CRB1-associated maculopathy

To date, over 150 disease-associated variants in CRB1 have been described, resulting in a range of retinal disease phenotypes including Leber congenital amaurosis and retinitis pigmentosa. Despite this, no genotype–phenotype correlations are currently recognised. We performed a retrospective review of electronic patient records to identify patients with macular dystrophy due to bi-allelic variants in CRB1. In total, seven unrelated individuals were identified. The median age at presentation was 21 years, with a median acuity of 0.55 decimalised Snellen units (IQR = 0.43). The follow-up period ranged from 0 to 19 years (median = 2.0 years), with a median final decimalised Snellen acuity of 0.65 (IQR = 0.70). Fundoscopy revealed only a subtly altered foveal reflex, which evolved into a bull’s-eye pattern of outer retinal atrophy. Optical coherence tomography identified structural changes—intraretinal cysts in the early stages of disease, and later outer retinal atrophy. Genetic testing revealed that one rare allele (c.498_506del, p.(Ile167_Gly169del)) was present in all patients, with one patient being homozygous for the variant and six being heterozygous. In trans with this, one variant recurred twice (p.(Cys896Ter)), while the four remaining alleles were each observed once (p.(Pro1381Thr), p.(Ser478ProfsTer24), p.(Cys195Phe) and p.(Arg764Cys)). These findings show that the rare CRB1 variant, c.498_506del, is strongly associated with localised retinal dysfunction. The clinical findings are much milder than those observed with bi-allelic, loss-of-function variants in CRB1, suggesting this in-frame deletion acts as a hypomorphic allele. This is the most prevalent disease-causing CRB1 variant identified in the non-Asian population to date

Priorities and preferences of advanced soft tissue sarcoma patients starting palliative chemotherapy:baseline results from the HOLISTIC study

INTRODUCTION: Palliative chemotherapy is the principal treatment of patients with advanced soft tissue sarcomas (STS); however prognosis is limited (median overall survival 12-19 months). In this setting, patient values and priorities are central to personalised treatment decisions. PATIENTS AND METHODS: The prospective HOLISTIC study was conducted in the UK and the Netherlands assessing health-related quality of life in STS patients receiving palliative chemotherapy. Participants completed a questionnaire before starting chemotherapy, including attitudes towards quality of life (QoL) versus length of life (LoL), decisional control preferences, and decisional conflict. Chi-square and Fisher’s exact tests were used to evaluate associations between patient characteristics and preferences. RESULTS: One hundred and thirty-seven patients with advanced STS participated (UK: n = 72, the Netherlands: n = 65). Median age was 62 (27-79) years. Preference for extended LoL (n = 66, 48%) was slightly more common than preference for QoL (n = 56, 41%); 12 patients (9%) valued LoL and QoL equally (missing: n = 3). Younger patients (age <40 years) prioritised LoL, whereas two-thirds of older patients (aged ≥65 years) felt that QoL was equally or more important than LoL (P = 0.020). Decisional conflict was most common in patients who prioritised QoL (P = 0.024). Most patients preferred an active (n = 45, 33%) or collaborative (n = 59, 44%) role in treatment decisions. Gender, performance status, and country were significantly associated with preferred role. Concordance between preferred and actual role in chemotherapy decision was high (n = 104, 76%). CONCLUSIONS: Heterogeneous priorities and preferences among advanced STS patients support personalised decisions about palliative treatment. Considering individual differences during treatment discussions may enhance communication and optimise patient-centred care