Planning with Information-Processing Constraints and Model Uncertainty in Markov Decision Processes

Information-theoretic principles for learning and acting have been proposed to solve particular classes of Markov Decision Problems. Mathematically, such approaches are governed by a variational free energy principle and allow solving MDP planning problems with information-processing constraints expressed in terms of a Kullback-Leibler divergence with respect to a reference distribution. Here we consider a generalization of such MDP planners by taking model uncertainty into account. As model uncertainty can also be formalized as an information-processing constraint, we can derive a unified solution from a single generalized variational principle. We provide a generalized value iteration scheme together with a convergence proof. As limit cases, this generalized scheme includes standard value iteration with a known model, Bayesian MDP planning, and robust planning. We demonstrate the benefits of this approach in a grid world simulation.Comment: 16 pages, 3 figure

EXOGEN ultrasound bone healing system for long bone fractures with non-union or delayed healing: a NICE medical technology guidance

Open Access. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.This article has been made available through the Brunel Open Access Publishing Fund.A routine part of the process for developing National Institute for Health and Care Excellence (NICE) medical technologies guidance is a submission of clinical and economic evidence by the technology manufacturer. The Birmingham and Brunel Consortium External Assessment Centre (EAC; a consortium of the University of Birmingham and Brunel University) independently appraised the submission on the EXOGEN bone healing system for long bone fractures with non-union or delayed healing. This article is an overview of the original evidence submitted, the EAC’s findings, and the final NICE guidance issued.The Birmingham and Brunel Consortium is funded by NICE to act as an External Assessment Centre for the Medical Technologies Evaluation Programme

AI-based structure-function correlation in age-related macular degeneration

Sensitive and robust outcome measures of retinal function are pivotal for clinical trials in age-related macular degeneration (AMD). A recent development is the implementation of artificial intelligence (AI) to infer results of psychophysical examinations based on findings derived from multimodal imaging. We conducted a review of the current literature referenced in PubMed and Web of Science among others with the keywords 'artificial intelligence' and 'machine learning' in combination with 'perimetry', 'best-corrected visual acuity (BCVA)', 'retinal function' and 'age-related macular degeneration'. So far AI-based structure-function correlations have been applied to infer conventional visual field, fundus-controlled perimetry, and electroretinography data, as well as BCVA, and patient-reported outcome measures (PROM). In neovascular AMD, inference of BCVA (hereafter termed inferred BCVA) can estimate BCVA results with a root mean squared error of ~7-11 letters, which is comparable to the accuracy of actual visual acuity assessment. Further, AI-based structure-function correlation can successfully infer fundus-controlled perimetry (FCP) results both for mesopic as well as dark-adapted (DA) cyan and red testing (hereafter termed inferred sensitivity). Accuracy of inferred sensitivity can be augmented by adding short FCP examinations and reach mean absolute errors (MAE) of ~3-5 dB for mesopic, DA cyan and DA red testing. Inferred BCVA, and inferred retinal sensitivity, based on multimodal imaging, may be considered as a quasi-functional surrogate endpoint for future interventional clinical trials in the future

SimHap GUI: An intuitive graphical user interface for genetic association analysis

<p>Abstract</p> <p>Background</p> <p>Researchers wishing to conduct genetic association analysis involving single nucleotide polymorphisms (SNPs) or haplotypes are often confronted with the lack of user-friendly graphical analysis tools, requiring sophisticated statistical and informatics expertise to perform relatively straightforward tasks. Tools, such as the <it>SimHap </it>package for the R statistics language, provide the necessary statistical operations to conduct sophisticated genetic analysis, but lacks a graphical user interface that allows anyone but a professional statistician to effectively utilise the tool.</p> <p>Results</p> <p>We have developed SimHap GUI, a cross-platform integrated graphical analysis tool for conducting epidemiological, single SNP and haplotype-based association analysis. SimHap GUI features a novel workflow interface that guides the user through each logical step of the analysis process, making it accessible to both novice and advanced users. This tool provides a seamless interface to the <it>SimHap </it>R package, while providing enhanced functionality such as sophisticated data checking, automated data conversion, and real-time estimations of haplotype simulation progress.</p> <p>Conclusion</p> <p>SimHap GUI provides a novel, easy-to-use, cross-platform solution for conducting a range of genetic and non-genetic association analyses. This provides a free alternative to commercial statistics packages that is specifically designed for genetic association analysis.</p

HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis

Penile verrucous carcinoma is a rare disease and little is known of its aetiology or pathogenesis. In this study we examined cell-cycle proteins expression and correlation with human papillomavirus infection in a series of 15 pure penile verrucous carcinomas from a single centre. Of 148 penile tumours, 15 (10%) were diagnosed as pure verrucous carcinomas. The expression of the cell-cycle-associated proteins p53, p21, RB, p16INK4A and Ki67 were examined by immunohistochemistry. Human papillomavirus infection was determined by polymerase chain reaction to identify a wide range of virus types. The expression of p16INK4A and Ki67 was significantly lower in verrucous carcinoma than in usual type squamous cell carcinoma, whereas the expression of p53, p21 and RB was not significantly different. p53 showed basal expression in contrast to usual type squamous cell carcinoma. Human papillomavirus infection was present in only 3 out of 13 verrucous carcinomas. Unique low-risk, high-risk and mixed viral infections were observed in each of the three cases. In conclusion, lower levels of p16INK4A and Ki67 expressions differentiate penile verrucous carcinoma from usual type squamous cell carcinoma. The low Ki67 index reflects the slow-growing nature of verrucous tumours. The low level of p16INK4A expression and human papillomavirus detection suggests that penile verrucous carcinoma pathogenesis is unrelated to human papillomavirus infection and the oncogenes and tumour suppressor genes classically altered by virus infection.Peer reviewedFinal Accepted Versio

Acute inhalation of hypertonic saline does not improve mucociliary clearance in all children with cystic fibrosis

<p>Abstract</p> <p>Background</p> <p>Little is known of how mucociliary clearance (MCC) in children with cystic fibrosis (CF) and normal pulmonary function compares with healthy adults, or how an acute inhalation of 7% hypertonic saline (HS) aerosol affects MCC in these same children.</p> <p>Methods</p> <p>We compared MCC in 12 children with CF and normal pulmonary function after an acute inhalation of 0.12% saline (placebo), or HS, admixed with the radioisotope ^{99 m}technetium sulfur colloid in a double-blind, randomized, cross-over study. Mucociliary clearance on the placebo day in the children was also compared to MCC in 10 healthy, non-CF adults. Mucociliary clearance was quantified over a 90 min period, using gamma scintigraphy, and is reported as MCC at 60 min (MCC60) and 90 min (MCC90).</p> <p>Results</p> <p>Median [interquartile range] MCC60 and MCC90 in the children on the placebo visit were 15.4 [12.4-24.5]% and 19.3 [17.3-27.8%]%, respectively, which were similar to the adults with 17.8 [6.4-28.7]% and 29.6 [16.1-43.5]%, respectively. There was no significant improvement in MCC60 (2.2 [-6.2-11.8]%) or MCC90 (2.3 [-1.2-10.5]%) with HS, compared to placebo. In addition, 5/12 and 4/12 of the children showed a decrease in MCC60 and MCC90, respectively, after inhalation of HS. A <it>post hoc </it>subgroup analysis of the change in MCC90 after HS showed a significantly greater improvement in MCC in children with lower placebo MCC90 compared to those with higher placebo MCC90 (p = 0.045).</p> <p>Conclusions</p> <p>These data suggest that percent MCC varies significantly between children with CF lung disease and normal pulmonary functions, with some children demonstrating MCC values within the normal range and others showing MCC values that are below normal values. In addition, although MCC did not improve in all children after inhalation of HS, improvement did occur in children with relatively low MCC values after placebo. This finding suggests that acute inhalation of hypertonic saline may benefit a subset of children with low MCC values.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov: <a href="http://www.clinicaltrials.gov/ct2/show/NCT01293084">NCT01293084</a></p

A methodology pruning the search space of six compiler transformations by addressing them together as one problem and by exploiting the hardware architecture details

Today’s compilers have a plethora of optimizations-transformations to choose from, and the correct choice, order as well parameters of transformations have a significant/large impact on performance; choosing the correct order and parameters of optimizations has been a long standing problem in compilation research, which until now remains unsolved; the separate sub-problems optimization gives a different schedule/binary for each sub-problem and these schedules cannot coexist, as by refining one degrades the other. Researchers try to solve this problem by using iterative compilation techniques but the search space is so big that it cannot be searched even by using modern supercomputers. Moreover, compiler transformations do not take into account the hardware architecture details and data reuse in an efficient way. In this paper, a new iterative compilation methodology is presented which reduces the search space of six compiler transformations by addressing the above problems; the search space is reduced by many orders of magnitude and thus an efficient solution is now capable to be found. The transformations are the following: loop tiling (including the number of the levels of tiling), loop unroll, register allocation, scalar replacement, loop interchange and data array layouts. The search space is reduced (a) by addressing the aforementioned transformations together as one problem and not separately, (b) by taking into account the custom hardware architecture details (e.g., cache size and associativity) and algorithm characteristics (e.g., data reuse). The proposed methodology has been evaluated over iterative compilation and gcc/icc compilers, on both embedded and general purpose processors; it achieves significant performance gains at many orders of magnitude lower compilation time

Comparing the effectiveness of the 0.018-inch versus the 0.022-inch bracket slot system in orthodontic treatment:study protocol for a randomized controlled trial

BACKGROUND: Edgewise fixed orthodontic appliances are available in two different bracket slot sizes (0.018 and 0.022 inch). Both systems are used by clinicians worldwide with some orthodontists claiming the superiority and clinical advantages of one system over the other. However, the scientific evidence supporting this area is scarce and weak. This leaves the clinician’s choice of bracket slot system to clinical preference. We aim to compare the 0.018-inch and 0.022-inch pre-adjusted bracket slot systems in terms of the effectiveness of orthodontic treatment. METHODS/DESIGN: This is a prospective, multicenter, randomized clinical trial, undertaken in the secondary care hospital environment in the NHS Tayside region of Scotland (United Kingdom). A total of 216 orthodontic patients will be recruited in three centers in secondary care hospitals in NHS Tayside. The participants will be randomly allocated to treatment with either the 0.018-inch or 0.022-inch bracket slot systems (n = 108 for each group) using Victory series™ conventional pre-adjusted bracket systems (3 M Unitek, Monrovia, United States). Baseline records and outcome data collected during and at the end of orthodontic treatment will be assessed. The primary outcome measures will be the duration of orthodontic treatment in the maxillary and mandibular arches. The secondary outcome measures will be the number of scheduled appointments for orthodontic treatment in the maxillary and mandibular arches, treatment outcome using Peer Assessment Rating index (PAR), orthodontically induced inflammatory root resorption (as measured using periapical radiographs) and the patient’s perception of wearing orthodontic appliances. DISCUSSION: The results from the current study will serve as evidence to guide the clinician in deciding whether the difference in bracket slot size has a significant impact on the effectiveness of orthodontic treatment. TRIAL REGISTRATION: Registered with ClinicalTrials.gov on 5 March 2014, registration number: NCT02080338

Complete loss of TP53 and RB1 is associated with complex genome and low immune infiltrate in pleomorphic rhabdomyosarcoma

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. Lower immune infiltrate was associated with complete loss of both TP53 and RB1. This comprehensive characterization of the genetic, epigenetic, and immune landscape of PRMS provides a roadmap for improved prognostications and therapeutic exploration

Improved healing response in delayed unions of the tibia with low-intensity pulsed ultrasound: results of a randomized sham-controlled trial

<p>Abstract</p> <p>Background</p> <p>We compared the healing response of tibial delayed unions between subjects treated with low-intensity pulsed ultrasound (LIPUS) (n = 51) and subjects treated with a sham device (n = 50). Fracture age was ≥ 4 months in all cases. Study personnel and participants were blinded to random treatment assignment throughout the study.</p> <p>Methods</p> <p>This multi-center randomized sham-controlled trial was undertaken at six hospitals in Germany. Adult patients who had sustained a tibial shaft fracture that subsequently showed inadequate progress toward healing (i.e., delayed union) were enrolled and randomized to receive either LIPUS (Exogen 2000/2000+, Smith & Nephew GmbH, Schenefeld, Germany) or an identical nonoperative sham device. The daily treatment duration was 20 minutes, for a period of 16 weeks. Subjects randomly assigned to active treatment had the ultrasound pressure wave signal set at the following parameters: 1.5 MHz frequency, 1 kHz repetition rate, 200 μs pulse duration, 30 mW/cm²spatial intensity. Progress toward healing was estimated from changes in bone mineral density (BMD) and gap area as determined from computed tomography scans. Intention-to-treat analysis was conducted using a multiple imputation methodology.</p> <p>Results</p> <p>Based on log-transformed data, mean improvement in BMD was 1.34 (90% confidence interval (CI) 1.14 to 1.57) times greater for LIPUS-treated subjects compared to sham (p = 0.002). A mean reduction in bone gap area also favored LIPUS treatment (p = 0.014).</p> <p>Conclusions</p> <p>These findings demonstrate significantly greater progress toward bone healing after LIPUS treatment compared to no LIPUS treatment in subjects with established delayed unions of the tibia.</p