Ab Initio Neutrinoless Double-Beta Decay Matrix Elements for

We calculate basis-space converged neutrinoless ßß-decay nuclear matrix elements for the lightest candidates: ^{48}Ca, ^{76}Ge, and ^{82}Se. Starting from initial two- and three-nucleon forces, we apply the ab initio in-medium similarity renormalization group to construct valence-space Hamiltonians and consistently transformed ßß-decay operators. We find that the tensor component is non-negligible in ^{76}Ge and ^{82}Se, and the resulting nuclear matrix elements are overall 25%-45% smaller than those obtained from the phenomenological shell model. While a final matrix element with uncertainties still requires substantial developments, this work nevertheless opens a path toward a true first-principles calculation of neutrinoless ßß decay in all nuclei relevant for ongoing large-scale searches.

The discovery and optimization of benzimidazoles as selective NaV1.8 blockers for the treatment of pain.

The voltage gated sodium channel NaV1.8 has been postulated to play a key role in the transmission of pain signals. Core hopping from our previously reported phenylimidazole leads has allowed the identification of a novel series of benzimidazole NaV1.8 blockers. Subsequent optimization allowed the identification of compound 9, PF-06305591, as a potent, highly selective blocker with an excellent preclinical in vitro ADME and safety profile.

Malignant transformation of tailgut cysts is significantly higher than previously reported: systematic review of cases in the literature.

AIM: The best treatment for tailgut cysts has not been firmly established. We report a systematic review of the cases in the available literature in order to provide an evidence base for treatment. METHOD: A systematic search of articles wholly or partly in English was made of PubMed, Embase and Google Scholar; additional studies were discovered by searching reference lists and contacting authors directly. Search terms 'tailgut cyst', 'tail gut cyst', 'retrorectal hamartoma' and 'retrorectal tumour' were used for case reports or case series; no publication date restrictions were imposed. Only studies with histological confirmation of diagnosis and reporting the age and gender of patients were included. Papers were excluded by consensus between the first two authors. RESULTS: A total of 196 individual cases were analysed in detail including 51 cases of neoplasia. The overall rate of neoplastic transformation was 26.6%. Although the male:female cyst incidence ratio was 1:4, men over 18 had a significantly greater relative risk of neoplasm at 1.94 (P = 0.0055). Radiological evidence of nodular thickening of the cyst wall significantly increased the relative risk of the presence of cancer (P = 0.0023). CONCLUSIONS: Current orthodoxy that these are not dangerous embryological remnants is unfounded and may be false. The available data suggest the risk of malignant transformation is high and will apply to any residual tissue after excision. The same rationale behind total mesorectal excision in rectal cancer applies to tailgut cysts. Consequently they should be resected with similar oncological margins.

Understanding and managing fish populations: keeping the toolbox fit for purpose.

Wild fish populations are currently experiencing unprecedented pressures, which are projected to intensify in the coming decades. Developing a thorough understanding of the influences of both biotic and abiotic factors on fish populations is a salient issue in contemporary fish conservation and management. During the 50th Anniversary Symposium of The Fisheries Society of the British Isles at the University of Exeter, UK, in July 2017, scientists from diverse research backgrounds gathered to discuss key topics under the broad umbrella of 'Understanding Fish Populations'. Below, the output of one such discussion group is detailed, focusing on tools used to investigate natural fish populations. Five main groups of approaches were identified: tagging and telemetry; molecular tools; survey tools; statistical and modelling tools; tissue analyses. The appraisal covered current challenges and potential solutions for each of these topics. In addition, three key themes were identified as applicable across all tool-based applications. These included data management, public engagement, and fisheries policy and governance. The continued innovation of tools and capacity to integrate interdisciplinary approaches into the future assessment and management of fish populations is highlighted as an important focus for the next 50 years of fisheries research.

Highly potent and selective NaV1.7 inhibitors for use as intravenous agents and chemical probes.

The discovery and selection of a highly potent and selective NaV1.7 inhibitor PF-06456384, designed specifically for intravenous infusion, is disclosed. Extensive in vitro pharmacology and ADME profiling followed by in vivo preclinical PK and efficacy model data are discussed. A proposed protein-ligand binding mode for this compound is also provided to rationalise the high levels of potency and selectivity over inhibition of related sodium channels. To further support the proposed binding mode, potent conjugates are described which illustrate the potential for development of chemical probes to enable further target evaluation.

Achieving assessor accuracy on the International Standards for Neurological Classification of Spinal Cord Injury.

STUDY DESIGN: A retrospective audit of assessor accuracy using the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) in three multicentre randomised controlled trials (SCIPA: Spinal Cord Injury and Physical Activity) spanning 2010-2014 with standards revised in 2011. OBJECTIVES: To investigate assessor accuracy of neurological classification after spinal cord injury. SETTING: Australia and New Zealand. METHODS: ISNCSCI examinations were undertaken by trained clinicians prior to randomisation. Data were recorded manually and ISNCSCI worksheets circulated to panels, consensus reached and worksheets corrected. An audit team used a 2014 computerised ISNCSCI algorithm to check manual worksheets. A second audit team assessed whether the 2014 computerised algorithm accurately reflected pre- and post-2011 ISNCSCI standards. RESULTS: Of the 208 ISNCSCI worksheets, 24 were excluded. Of the remaining 184 worksheets, 47 (25.5%) were consistent with the 2014 computerised algorithm and 137 (74.5%) contained one or more errors. Errors were in motor (30.1%) or sensory (12.4%) levels, zone of partial preservation (24.0%), motor/sensory scoring (21.5%), ASIA Impairment Scale (AIS, 8.3%) and complete/incomplete classification (0.8%). Other difficulties included classification when anal contraction/sensation was omitted, incorrect neurological levels and violation of the 'motor follows sensory rule in non-testable myotomes' (7.4%). Panel errors comprised corrections that were incorrect or missed or incorrect changes to correct worksheets. CONCLUSION: Given inaccuracies in the manual ISNCSCI worksheets in this long-term clinical trial setting, continued training and a computerised algorithm are essential to ensure accurate scoring, scaling and classification of the ISNCSCI and confidence in clinical trials.

Cognitive representations of peripheral neuropathy and self-reported foot-care behaviour of people at high risk of diabetes-related foot complications.

AIM: The aim of this study was to explore the cognitive representations of peripheral neuropathy and self-reported foot-care behaviour in an Australian sample of people with diabetes and peripheral neuropathy. METHODS: This cross-sectional study was undertaken with 121 participants with diabetes and peripheral neuropathy. Cognitive representations of peripheral neuropathy were measured by the Patients' Interpretation of Neuropathy questionnaire and two aspects of self-foot-care behaviour were measured using a self-report questionnaire. Hierarchical cluster analysis using the average linkage method was used to identify distinct illness schemata related to peripheral neuropathy. RESULTS: Three clusters of participants were identified who exhibited distinct illness schemata related to peripheral neuropathy. One cluster had more misperceptions about the nature of peripheral neuropathy, one cluster was generally realistic about the nature of their condition and the final cluster was uncertain about their condition. The cluster with high misperceptions of their condition undertook more potentially damaging foot-care behaviours than the other clusters (F = 4.98; P < 0.01). CONCLUSIONS: People with diabetes and peripheral neuropathy have different illness schemata that may influence health-related behaviour. Education aimed at improving foot-care behaviour and foot-health outcomes should be tailored to specific illness schemata related to peripheral neuropathy.

What are the costs and benefits of patient notification exercises following poor infection control practices in dentistry?

BACKGROUND: Allegations of serious failures in infection control practice were made against a dentist practicing in the South West of England. The dentist (who tested negative for Blood Borne Viruses (BBVs)) was immediately suspended. METHODS: Because inadequate infection control presents a potential risk of transmitting BBVs between patients, a notification exercise was undertaken. Of 7625 patients contacted, 2780 (37%) were tested. RESULTS: Nine cases of Hepatitis B (HBV) and four cases of Hepatitis C (HCV) were identified, of which seven were previously diagnosed. None of these were children. All of the six newly diagnosed cases had recognized risk factors for BBVs. The costs of the notification exercise were estimated at £311,500 of which £165,000 was staff costs, (£51,916 per newly diagnosed case). CONCLUSION: This study did not demonstrate any patient-to-patient transmission of blood-borne viruses but the response rate was relatively low. There are significant costs associated with undertaking notification exercises. These findings should inform future recommendations and practice in this area.

Exercise and nutrition interventions in advanced lung cancer: a systematic review.

UNLABELLED: In this systematic review, we sought to evaluate the effect of physical activity or nutrition interventions (or both) in adults with advanced non-small-cell lung cancer (nsclc). METHODS: A systematic search for relevant clinical trials was conducted in 6 electronic databases, by hand searching, and by contacting key investigators. No limits were placed on study language. Information about recruitment rates, protocol adherence, patient-reported and clinical outcome measures, and study conclusions was extracted. Methodologic quality and risk of bias in each study was assessed using validated tools. MAIN RESULTS: Six papers detailing five studies involving 203 participants met the inclusion criteria. Two of the studies were single-cohort physical activity studies (54 participants), and three were controlled nutrition studies (149 participants). All were conducted in an outpatient setting. None of the included studies combined physical activity with nutrition interventions. CONCLUSIONS: Our systematic review suggests that exercise and nutrition interventions are not harmful and may have beneficial effects on unintentional weight loss, physical strength, and functional performance in patients with advanced nsclc. However, the observed improvements must be interpreted with caution, because findings were not consistent across the included studies. Moreover, the included studies were small and at significant risk of bias. More research is required to ascertain the optimal physical activity and nutrition interventions in advanced inoperable nsclc. Specifically, the potential benefits of combining physical activity with nutrition counselling have yet to be adequately explored in this population.

Pediatric neurogenic bowel dysfunction: ICCS review document.

INTRODUCTION: The International Children's Continence Society (ICCS) aims to improve the quality of life in children with lower urinary tract dysfunction. A substantial portion of children also have problems with bowel dysfunction. There is a lack of evidence-based information on managing neurogenic bowel dysfunction (NBD) in children. OBJECTIVE/METHODS: The ICCS aimed to provide an up-to-date, selective, non-systematic review of NBD's definitions, assessment, and treatment. RESULTS: Specific definitions and terminology are defined within the document. Recommendations and considerations for physical assessment, history taking, and diagnostic studies are made. Management updates, both surgical and non-surgical, are provided as well as recommendations for follow-up and monitoring of individuals with NBD. CONCLUSION: This review of the current literature will help guide NBD management and research to improve NBD care.

Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness.

PURPOSE: We determined the efficacy and safety of pelvic floor myofascial physical therapy compared to global therapeutic massage in women with newly symptomatic interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A randomized controlled trial of 10 scheduled treatments of myofascial physical therapy vs global therapeutic massage was performed at 11 clinical centers in North America. We recruited women with interstitial cystitis/painful bladder syndrome with demonstrable pelvic floor tenderness on physical examination and a limitation of no more than 3 years' symptom duration. The primary outcome was the proportion of responders defined as moderately improved or markedly improved in overall symptoms compared to baseline on a 7-point global response assessment scale. Secondary outcomes included ratings for pain, urgency and frequency, the O'Leary-Sant IC Symptom and Problem Index, and reports of adverse events. We compared response rates between treatment arms using the exact conditional version of the Mantel-Haenszel test to control for clustering by clinical center. For secondary efficacy outcomes cross-sectional descriptive statistics and changes from baseline were calculated. RESULTS: A total of 81 women randomized to the 2 treatment groups had similar symptoms at baseline. The global response assessment response rate was 26% in the global therapeutic massage group and 59% in the myofascial physical therapy group (p=0.0012). Pain, urgency and frequency ratings, and O'Leary-Sant IC Symptom and Problem Index decreased in both groups during followup, and were not significantly different between the groups. Pain was the most common adverse event, occurring at similar rates in both groups. No serious adverse events were reported. CONCLUSIONS: A significantly higher proportion of women with interstitial cystitis/painful bladder syndrome responded to treatment with myofascial physical therapy than to global therapeutic massage. Myofascial physical therapy may be a beneficial therapy in women with this syndrome.

Risk stratification scores in elective open abdominal aortic aneurysm repair: are they suitable for preoperative decision making?

OBJECTIVES: Risk indices help quantify the risk of cardiovascular events and death prior to making decisions about prophylactic AAA repair. This paper aims to study the predictive capabilities of 5 validated indices. DESIGN AND METHODS: A prospective observational multi-centre cohort study from August 2005 to September 2007 in Glasgow recruited 106 consecutive patients undergoing elective open AAA repair. The Glasgow Aneurysm Score (GAS), Vascular physiology only Physiological and Operative Severity Score for enUmeration of Mortality (V(p)-POSSUM), Vascular Biochemical and Haematological Outcome Model (VBHOM), Revised Cardiac Risk Index (RCRI) and Preoperative Risk Score of the Estimation of Physiological Ability and Surgical Stress Score (PRS of E-PASS) were calculated. Indices were compared using receiver operating characteristic (ROC) analysis and area under the curve (AUC) estimates. End points were all-cause mortality, Major Adverse Cardiac Events (MACE) and cardiac death. RESULTS: GAS, VBHOM and RCRI did not predict outcome. V(p)-POSSUM predicted MACE (AUC = 0.681), cardiac death (AUC = 0.762) and all-cause mortality (AUC = 0.780), as did E-PASS (AUC = 0.682, 0.821, 0.703 for MACE, cardiac death and all-cause mortality respectively). CONCLUSION: Whilst V(p)-POSSUM and E-PASS predicted outcome, the less complex RCRI and GAS performed poorly which questions the utility of decision making based on these surgical risk indices.

Bone mineral concentration predicted by dual energy X-ray absorptiometry and its relationship with lamb eating quality.

Lumbar bone mineral concentration, as predicted by dual energy x-ray absorptiometry (DEXA), may reflect changes in lamb maturity and eating quality. New season (n = 60) and old season (n = 60) lambs were slaughtered and DEXA scanned at a commercial abattoir across 2 kill groups. The second lumbar vertebra was isolated from the spine for determination of calcium, phosphorus, and magnesium concentration (mg/g). The loin and rack cuts were collected for consumer sensory grilling and roasting analyses. Mineral concentration was significantly higher in old season lambs within kill group 1 (P < 0.05). DEXA was a positive predictor of phosphorus and calcium concentration, but only when DEXA lean % (P < 0.05) was included in the model. Calcium and phosphorus were significant positive predictors of overall liking scores (P < 0.05), but only for the rack roast. These effects became insignificant when DEXA lean % was included. These results suggest that DEXA values likely reflect changes in both DEXA lean % and bone minerals, and that DEXA lean % was the driver of eating quality, rather than maturity.

B-type natriuretic peptide predicts long-term survival after major non-cardiac surgery.

BACKGROUND: The prediction of long-term survival after surgery is complex. Natriuretic peptides can predict short-term postoperative cardiac morbidity and mortality. This study aims to determine the long-term prognostic significance of preoperative B-type natriuretic peptide (BNP) concentration after major non-cardiac surgery. METHODS: We conducted a prospective single-centre observational cohort study in a West of Scotland teaching hospital. Three hundred and forty-five patients undergoing major non-cardiac surgery were included. The primary endpoint was long-term all-cause mortality. RESULTS: Overall survival was 67.8% (234/345), with 27 postoperative deaths (within 42 days) and 84 deaths at subsequent follow-up (median follow-up 953 days). A BNP concentration of >87.5 pg ml(-1) best predicted mortality, and the mean survival of patients with an elevated BNP (>87.5 pg ml(-1)) was 731.9 (95% CI 613.6-850.2) days compared with 1284.6 days [(95% CI 1219.3-1350.0), P<0.001] in patients with a BNP<87.5 pg ml(-1). BNP was an independent predictor of survival. CONCLUSIONS: BNP is an independent predictor of long-term survival after major non-cardiac surgery. A simple preoperative blood test can provide predictive information on future risk of death, and potentially has a role in preoperative risk assessment.

The potential for dual energy X-ray absorptiometry to predict lamb eating quality.

Data were obtained from 120 lambs which were slaughtered, scanned using dual energy X-ray absorptiometry (DEXA) and underwent eating quality assessment. DEXA images were used to determine R values, reflecting atomic mass, to predict carcass lean %. Additionally, bone regions (humerus, lumbar, femur and "all carcass bone") were isolated from images to determine bone specific R values (DEXA R Mean and SDev). Prediction of overall liking of cuts across the carcass (scored between 0 and 100) using lean % and bone DEXA was variable. Loin grill overall liking demonstrated significant associations with lumbar DEXA R Mean and SDev, decreasing by 8.6 and 7.6 units across the increasing range of these bone DEXA measures. This association is somewhat independent of carcass lean % and intramuscular fat % of the loin. Given the association of DEXA with eating quality, there are potential benefits for the lamb industry with respect to carcass sorting and marketing during routine processing and DEXA scanning.

Structural development of cortical lobes during the first 6 months of life in infant macaques.

This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2-24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20-24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2-24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2-12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.

Pharmacokinetics and pharmacodynamics of prasugrel in subjects with moderate liver disease.

BACKGROUND AND OBJECTIVE: Prasugrel is a thienopyridine antiplatelet agent under investigation for the prevention of atherothrombotic events in patients with acute coronary syndrome who undergo percutaneous coronary intervention. Patients with chronic liver disease are among those in the target population for prasugrel. As hepatic enzymes play a key role in formation of prasugrel's active metabolite, hepatic impairment could affect the safety and/or efficacy of prasugrel in such patients. METHODS: This was a parallel-design, open-label, multiple dose study of 30 subjects, 10 with moderate hepatic impairment (Child-Pugh Class B) and 20 with normal hepatic function. Prasugrel was administered orally as a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MDs) for 5 days. Pharmacokinetic parameters (AUC(0-t), C(max) and t(max)) and maximal platelet aggregation (MPA) by light transmission aggregometry were assessed after the LD and final MD. RESULTS AND DISCUSSION: Exposure to prasugrel's active metabolite was comparable between healthy subjects and those with moderate hepatic impairment. Point estimates for the ratios of geometric least square means for AUC(0-t) and C(max) after the LD and last MD ranged from 0.91 to 1.14. MPA to 20 microm ADP was similar between subjects with moderate hepatic impairment and healthy subjects for both the LD and MD. Prasugrel was well tolerated by all subjects, and adverse events were mild in severity. CONCLUSION: Moderate hepatic impairment appears to have no effect on exposure to prasugrel's active metabolite. Furthermore, MPA results suggest that moderate hepatic impairment has little or no effect on platelet aggregation relative to healthy controls. Overall, these results suggest that a dose adjustment would not be required in moderately hepatically impaired patients taking prasugrel.

Prasugrel pharmacokinetics and pharmacodynamics in subjects with moderate renal impairment and end-stage renal disease.

OBJECTIVE: The pharmacokinetic (PK) and pharmacodynamic (PD) responses to prasugrel were compared in three studies of healthy subjects vs. those with moderate or end-stage renal impairment. METHODS: Two of the three protocols were parallel-design, open-label, single dose (60-mg prasugrel) studies in subjects with end-stage renal disease (ESRD; n = 12) or moderate renal impairment (n = 10) and matched healthy subjects with normal renal function (n = 10). The third protocol was an open-label, single-dose escalation (5, 10, 30 and 60 mg prasugrel) study in subjects with ESRD (n = 16) and matched healthy subjects with normal renal function (n = 16). Plasma concentrations of prasugrel's active metabolite were determined and pharmacokinetic parameter estimates were derived. Maximum platelet aggregation (MPA) was measured by light transmission aggregometry using 20 mum adenosine diphosphate as agonist. RESULTS: Across all studies, prasugrel's C(max) and AUC(0-t) were 51% and 42% lower in subjects with ESRD than in healthy subjects. AUC(0-t) did not differ between healthy subjects and subjects with moderate renal impairment. The magnitude of change and time-course profiles of MPA was similar for healthy subjects compared with subjects with moderate renal impairment and those with ESRD. Prasugrel was well-tolerated in all subjects. CONCLUSION: There was no difference in pharmacokinetics or PD responses between subjects with moderate renal impairment and healthy subjects. Despite significantly lower exposure to prasugrel's active metabolite in subjects with ESRD, MPA did not differ between healthy subjects and those with ESRD.