Incorporating multiparametric MRI staging and the new histological Grade Group system improves risk-stratified detection of bone metastasis in prostate cancer

$\textbf{BACKGROUND}$: There remains uncertainty on the need for bone staging in men with intermediate-risk prostate cancer. Current guidelines do not use mpMRI-staging information and rely on historic pathology grading. $\textbf{METHODS}$: We investigated the ability of mpMRI and the new Grade Group system to better predict bone metastasis status in a retrospective cohort study of 438 men with prostate cancer undergoing baseline mpMRI and isotope bone scintigraphy (BS). $\textbf{RESULTS}$: Including mpMRI-staging information significantly increased the specificity of bone metastasis detection from 3.0% to 24.2% (P<0.01) and sensitivity from 89.2% to 97.3%. The new Grade Group score demonstrated progressive increase in bone metastasis rates (P<0.001). A novel risk-stratification model combining Grade Groups, PSA and mpMRI staging shows promise in predicting bone metastasis and could potentially reduce BS usage by 22.4%-34.7%. $\textbf{CONCLUSIONS}$: Incorporating the new Grade Group system and mpMRI staging more accurately identified bone metastatic risk and suggests men with Grade Group ⩽2 and/or without radiological T3 disease could safely avoid routine bone staging.We thank research support from the National Institute of Health Research, Cambridge Biomedical Research Centre, Cancer Research UK, Cancer Research UK and the Engineering and Physical Sciences Research Council Imaging Centre in Cambridge and Manchester and the Cambridge Experimental Cancer Medicine Centre

Removing rician bias in diffusional kurtosis of the prostate using real-data reconstruction.

Purpose To compare prostate diffusional kurtosis imaging (DKI) metrics generated using phase-corrected real data with those generated using magnitude data with and without noise compensation (NC).Methods Diffusion-weighted images were acquired at 3T in 16 prostate cancer patients, measuring 6 b-values (0-1500 s/mm2 ), each acquired with 6 signal averages along 3 diffusion directions, with noise-only images acquired to allow NC. In addition to conventional magnitude averaging, phase-corrected real data were averaged in an attempt to reduce rician noise-bias, with a range of phase-correction low-pass filter (LPF) sizes (8-128 pixels) tested. Each method was also tested using simulations. Pixelwise maps of apparent diffusion (D) and apparent kurtosis (K) were calculated for magnitude data with and without NC and phase-corrected real data. Average values were compared in tumor, normal transition zone (NTZ), and normal peripheral zone (NPZ).Results Simulations indicated LPF size can strongly affect K metrics, where 64-pixel LPFs produced accurate metrics. Relative to metrics estimated from magnitude data without NC, median NC K were lower (P < 0.0001) by 6/11/8% in tumor/NPZ/NTZ, 64-LPF real-data K were lower (P < 0.0001) by 4/10/7%, respectively.Conclusion Compared with magnitude data with NC, phase-corrected real data can produce similar K, although the choice of phase-correction LPF should be chosen carefully

Adequate debridement and drainage of the mediastinum using open thoracotomy or video-assisted thoracoscopic surgery for Boerhaave’s syndrome

Background Boerhaave's syndrome has a high mortality rate (14-40%). Surgical treatment varies from a minimal approach consisting of adequate debridement with drainage of the mediastinum and pleural cavity to esophageal resection. This study compared the results between a previously preferred open minimal approach and a video-assisted thoracoscopic surgery (VATS) procedure currently considered the method of choice. Methods In this study, 12 consecutive patients treated with a historical nonresectional drainage approach (1985-2001) were compared with 12 consecutive patients treated prospectively after the introduction of VATS during the period 2002-2009. Baseline characteristics were equally distributed between the two groups. Results In the prospective group, 2 of the 12 patients had the VATS procedure converted to an open thoracotomy, and 2 additional patients were treated by open surgery. In the prospective group, 8 patients experienced postoperative complications compared with all 12 patients in the historical control group. Four patients (17%), two in each group, underwent reoperation. Six patients, three in each group, were readmitted to the hospital. The overall in-hospital mortality was 8% (1 patient in each group), which compares favorably with other reports (7-27%) based on drainage alone. Conclusions Adequate surgical debridement with drainage of the mediastinum and pleural cavity resulted in a low mortality rate. The results for VATS in this relatively small series were comparable with those for an open thoracotomy

An Ethical Façade? Medical Students' Miscomprehensions of Substituted Judgment

Background: We studied how well first-year medical students understand and apply the concept of substituted judgment, following a course on clinical ethics. Method: Students submitted essays on one of three ethically controversial scenarios presented in class. One scenario involved a patient who had lost decisional capacity. Through an iterative process of textual analysis, the essays were studied and coded for patterns in the ways students misunderstood or misapplied the principle of substituted judgment. Results: Students correctly articulated course principles regarding patient autonomy, substituted judgment, and nonimposition of physician values. However, students showed misunderstanding by giving doctors the responsibility of balancing the interests of the patient against the interests of the family, by stating doctors and surrogates should be guided primarily by a best-interest standard, and by suggesting that patient autonomy becomes the guiding principle only when patients can no longer express their wishes. Conclusion: Students did not appear to internalize or correctly apply the substituted judgment standard, even though they could describe it accurately. This suggests the substituted judgment standard may run counter to students ’ moral intuitions

Sympatric Speciation: When Is It Possible in Bacteria?

This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping.Ellison Medical FoundationSwiss National Science Foundation (PA00P1_131448/1

The Higher-Order Prover Leo-II.

Leo-II is an automated theorem prover for classical higher-order logic. The prover has pioneered cooperative higher-order-first-order proof automation, it has influenced the development of the TPTP THF infrastructure for higher-order logic, and it has been applied in a wide array of problems. Leo-II may also be called in proof assistants as an external aid tool to save user effort. For this it is crucial that Leo-II returns proof information in a standardised syntax, so that these proofs can eventually be transformed and verified within proof assistants. Recent progress in this direction is reported for the Isabelle/HOL system.The Leo-II project has been supported by the following grants: EPSRC grant EP/D070511/1 and DFG grants BE/2501 6-1, 8-1 and 9-1.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s10817-015-9348-y

Staff understanding of recovery-orientated mental health practice: a systematic review and narrative synthesis

Background: Mental health policy is for staff to transform their practice towards a recovery orientation. Staff understanding of recovery-orientated practice will influence the implementation of this policy. The aim of this study was to conduct a systematic review and narrative synthesis of empirical studies identifying clinician and manager conceptualisations of recovery-orientated practice. Methods: A systematic review of empirical primary research was conducted. Data sources were online databases (n = 8), journal table of contents (n = 5), internet, expert consultation (n = 13), reference lists of included studies and references to included studies. Narrative synthesis was used to integrate the findings. Results: A total of 10,125 studies were screened, 245 full papers were retrieved, and 22 were included (participants, n = 1163). The following three conceptualisations of recovery-orientated practice were identified: clinical recovery, personal recovery and service-defined recovery. Service-defined recovery is a new conceptualisation which translates recovery into practice according to the goals and financial needs of the organisation. Conclusions: Organisational priorities influence staff understanding of recovery support. This influence is leading to the emergence of an additional meaning of recovery. The impact of service-led approaches to operationalising recovery-orientated practice has not been evaluated. Trial Registration: The protocol for the review was pre-registered (PROSPERO 2013: CRD42013005942)

Templating hydrogels

Templating processes for creating polymerized hydrogels are reviewed. The use of contact photonic crystals and of non-contact colloidal crystalline arrays as templates are described and applications to chemical sensing and device fabrication are illustrated. Emulsion templating is illustrated in the formation of microporous membranes, and templating on reverse emulsions and double emulsions is described. Templating in solutions of macromolecules and micelles is discussed and then various applications of hydrogel templating on surfactant liquid crystalline mesophases are illustrated, including a nanoscale analogue of colloidal crystalline array templating, except that the bead array in this case is a cubic array of nonionic micelles. The use of particles as templates in making core-shell and hollow microgel beads is described, as is the use of membrane pores as another illustration of confinement templating

In Vivo Tumor Targeting and Imaging with Engineered Trivalent Antibody Fragments Containing Collagen-Derived Sequences

There is an urgent need to develop new and effective agents for cancer targeting. In this work, a multivalent antibody is characterized in vivo in living animals. The antibody, termed “trimerbody”, comprises a single-chain antibody (scFv) fragment connected to the N-terminal trimerization subdomain of collagen XVIII NC1 by a flexible linker. As indicated by computer graphic modeling, the trimerbody has a tripod-shaped structure with three highly flexible scFv heads radially outward oriented. Trimerbodies are trimeric in solution and exhibited multivalent binding, which provides them with at least a 100-fold increase in functional affinity than the monovalent scFv. Our results also demonstrate the feasibility of producing functional bispecific trimerbodies, which concurrently bind two different ligands. A trimerbody specific for the carcinoembryonic antigen (CEA), a classic tumor-associated antigen, showed efficient tumor targeting after systemic administration in mice bearing CEA-positive tumors. Importantly, a trimerbody that recognizes an angiogenesis-associated laminin epitope, showed excellent tumor localization in several cancer types, including fibrosarcomas and carcinomas. These results illustrate the potential of this new antibody format for imaging and therapeutic applications, and suggest that some laminin epitopes might be universal targets for cancer targeting

Identification of the Pangenome and Its Components in 14 Distinct Aggregatibacter actinomycetemcomitans Strains by Comparative Genomic Analysis

Aggregatibacter actinomycetemcomitans is genetically heterogeneous and comprises distinct clonal lineages that may have different virulence potentials. However, limited information of the strain-to-strain genomic variations is available.The genome sequences of 11 A. actinomycetemcomitans strains (serotypes a-f) were generated de novo, annotated and combined with three previously sequenced genomes (serotypes a-c) for comparative genomic analysis. Two major groups were identified; serotypes a, d, e, and f, and serotypes b and c. A serotype e strain was found to be distinct from both groups. The size of the pangenome was 3,301 genes, which included 2,034 core genes and 1,267 flexible genes. The number of core genes is estimated to stabilize at 2,060, while the size of the pangenome is estimated to increase by 16 genes with every additional strain sequenced in the future. Within each strain 16.7-29.4% of the genome belonged to the flexible gene pool. Between any two strains 0.4-19.5% of the genomes were different. The genomic differences were occasionally greater for strains of the same serotypes than strains of different serotypes. Furthermore, 171 genomic islands were identified. Cumulatively, 777 strain-specific genes were found on these islands and represented 61% of the flexible gene pool.Substantial genomic differences were detected among A. actinomycetemcomitans strains. Genomic islands account for more than half of the flexible genes. The phenotype and virulence of A. actinomycetemcomitans may not be defined by any single strain. Moreover, the genomic variation within each clonal lineage of A. actinomycetemcomitans (as defined by serotype grouping) may be greater than between clonal lineages. The large genomic data set in this study will be useful to further examine the molecular basis of variable virulence among A. actinomycetemcomitans strains