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Sarcoidosis is a systemic inflammatory condition causing increased immune system activity and manifesting as noncaseating granulomatous disease with the ability to affect multiple organ systems. Neurosarcoidosis is an uncommon presentation, with just 5–10% of patients with sarcoidosis experiencing intracranial disease. The diagnosis of neurosarcoidosis can be difficult, especially given the overlap of imaging findings with more common intracranial lesions. This case presents trigeminal neuralgia as the initial symptom of neurosarcoidosis and emphasizes the importance of a high clinical index of suspicion for neurosarcoidosis in patients with otherwise unexplained neurological symptoms.

Objectives: To evaluate interobserver variability for diagnosis of disease presence and extent of small bowel and colonic Crohn’s disease using MR enterography (MRE) Methods: Data from the first 73 consecutive patients (mean age 32, 33F, 28 new diagnosis, 45 suspected relapse) recruited to a multicentre, prospective diagnostic accuracy trial evaluating MRE for small bowel Crohn’s disease were each read independently by three (from a pool of 20) radiologists. Radiologists documented presence and segmental location of small bowel Crohn’s disease and recorded morphological mural/extramural parameters for involved segments. Per patient percentage agreement for disease presence and extent were calculated against an outcome-based construct reference standard (averaged between pairs of readers). Prevalence-adjusted bias-adjusted κ (PABAK) was calculated. Results: Agreement for small bowel disease presence for new diagnosis/relapsed patients was 68%(κ = 0.36)/ 78% (κ = 0.56) and 43%(κ = 0.14)/ 53% for disease extent (κ = 0.07), respectively. For disease presence, all three radiologists agreed correctly with the reference standard in 41/59 (69%) of patients with small bowel involvement, and in 8/14 (57%) cases of without small bowel disease. Agreement was highest for multisegment disease, greater than 5 cm in length, with mural thickness>6 mm, and increased mural T2 signal. Agreement for colonic disease presence was 61% (κ = 0.21 fair agreement) for new diagnosis/ 60% (κ = 0.20, slight agreement) for relapsed patients. Conclusion: There is a reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed Crohn’s disease, and patients with suspected relapse, respectively. Agreement is lower for disease extent. Advances in knowledge: There is reasonable agreement between radiologists for small bowel disease presence using MRE for newly diagnosed (68%) Crohn’s disease, and patients with suspected relapse (78%). Agreement is lower for disease extent (43% new diagnosis and 53% suspected relapse).

To compare the distention quality and patient experience of oral mannitol and polyethylene glycol (PEG) for MRE.This study is a retrospective, observational study of a subset of patients enrolled in a multicentre, prospective trial evaluating the diagnostic accuracy of MRE for small bowel Crohn's. Overall and segmental MRE small bowel distention, from 105 patients (64 F, mean age 37) was scored from 0 = poor to 4 = excellent by two experienced observers (68 [65%] mannitol and 37 [35%] PEG). Additionally, 130 patients (77 F, mean age 34) completed a questionnaire rating tolerability of various symptoms immediately and 2 days after MRE (85 [65%] receiving mannitol 45 [35%] receiving PEG). Distension was compared between agents and between those ingesting ≤ 1 L or1 L of mannitol using the test of proportions. Tolerability grades were collapsed into "very tolerable," "moderately tolerable," and "not tolerable."Per patient distension quality was similar between agents ("excellent" or "good" in 54% [37/68] versus 46% [17/37]) with mannitol and PEG respectively. Jejunal distension was significantly better with mannitol compared to PEG (40% [27/68] versus 14% [5/37] rated as excellent or good respectively). There was no significant difference according to the volume of mannitol ingested. Symptom tolerability was comparable between agents, although fullness following MRE was graded as "very tolerable" in 27% (12/45) of patients ingesting PEG, verses 44% (37/84) ingesting mannitol, difference 17% (95% CI 0.6 to 34%).Mannitol-based solutions and PEG generally achieve comparable distension quality and side effect profiles, although jejunal distension is better quality with mannitol. Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol.• Mannitol-based and PEG-based oral preparation agents generally achieve comparable distension quality for MRE with the exception of the jejunum which is better distended with mannitol. • Mannitol-based and PEG-based oral preparation agents used for MRE have similar side effect profiles. • Neither distension quality nor side-effect profile is altered by ingestion of more than 1 L of mannitol.

Whakarongorau Aotearoa/New Zealand Telehealth Services, formerly known as Homecare Medical, is New Zealand's largest digital healthcare service. It originated as a house call doctor service about 20 years ago and now delivers free 24/7 telehealth services to the New Zealand public 365 days a year. Whakarongorau Aotearoa changed its name in April 2021 to reflect the growing kaupapa and was gifted this whakataukī: He reo mārohirohi ka taringa rongohia-A brave voice deserves a listening ear. This viewpoint sets out to address a number of public and professional misconceptions about Whakarongorau Aotearoa and provide a more detailed description of the depth, breadth and complexity of the organisation, how it is structured, the range of services available to the public and its clinical governance, leadership and oversight.

Summary Background Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. Methods TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8–10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. Findings Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months’ follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. Interpretation Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. Funding Cancer Research UK.

Background: While a shift to minimally invasive techniques in rectal cancer surgery has occurred, non-inferiority of laparoscopy in terms of oncological outcomes has not been definitely demonstrated. Transanal total mesorectal excision (TaTME) has been pioneered to potentially overcome difficulties experienced when operating with a pure abdominal approach deep down in the pelvis. This study aimed to compare short-term oncological results of TaTME versus laparoscopic TME (lapTME), based on a strict anatomical definition for low rectal cancer on MRI. Methods: From June 2013, all consecutive TaTME cases were included and compared to lapTME in a single institution. Propensity score-matching was performed for nine relevant factors. Primary outcome was resection margin involvement (R1), secondary outcomes included intra- and post-operative outcomes. Results: After matching, forty-one patients were included in each group; no significant differences were observed in patient and tumor characteristics. The resection margin was involved in 5 cases (12.2%) in the laparoscopic group, versus 2 (4.9%) TaTME cases (P = 0.432). The TME specimen quality was complete in 84.0% of the laparoscopic cases and in 92.7% of the TaTME cases (P = 0.266). Median distance to the circumferential resection margin (CRM) was 5 mm in lapTME and 10 mm in TaTME (P = 0.065). Significantly more conversions took place in the laparoscopic group, 9 (22.0%) compared to none in the TaTME group (P < 0.001). Other clinical outcomes did not show any significant differences between the two groups. Conclusion: This is the first study to compare results of TaTME with lapTME in a highly selected patient group with MRI-defined low rectal tumors. A significant decrease in R1 rate could not be demonstrated, although conversion rate was significantly lower in this TaTME cohort.

BACKGROUND: There remains a lack of international consensus on the appropriate management of lateral nodal disease. Although the East manages this more aggressively with lateral lymph node dissections, the West aims to eradicate small-volume disease with neoadjuvant chemoradiotherapy and lateral nodal disease is not considered for routine surgical treatment. However, recent studies have shown that, despite neoadjuvant treatment, a significant number of patients with lateral nodal disease develop local recurrence in the lateral compartment after total mesorectal excision. OBJECTIVE: The aim of this study is to assess the role of the pretreatment features of lateral nodes on MRI in regard to local recurrence. DESIGN: All patients operated on for low locally advanced rectal cancer over a 5-year period were evaluated retrospectively. SETTINGS: This study was conducted at a single expert center. PATIENTS: The MRIs of a total of 313 patients were reviewed, and only those with rectal cancers up to 8 cm from the anorectal junction, measured on MRI, were selected. This left 185 patients; of these, 58 patients had clinical T1 or T2 tumors as assessed on MRI, identifying 127 patients who had cT3/T4 tumors that were included in this study. MAIN OUTCOME MEASURES: The primary outcomes measured were lateral local recurrence and multivariate analyses. RESULTS: The lateral local recurrence rate was significantly higher (33.3% 4-year rate) in patients with nodes larger than 10 mm than in patients with smaller nodes (10.1%, p = 0.03), despite patients being irradiated in the lateral compartment. LIMITATIONS: Because this is a relatively uncommon disease, patient numbers are low, and a multicenter study is needed to further address lateral nodal disease in low rectal cancer. CONCLUSIONS: Chemoradiotherapy with total mesorectal excision might not be sufficient in a selected group of patients. Further research is needed about which pretreatment features of the lateral nodes predict local recurrence and what is needed to prevent these from developing. See Video Abstract at http://links.lww.com/DCR/A338.

The Tudor domain of human PHF1 recognizes trimethylated lysine 36 on histone H3 (H3K36me3). PHF1 relies on this interaction to regulate PRC2 methyltransferase activity, localize to DNA double strand breaks and mediate nucleosome accessibility. Here, we investigate the impact of the PHF1 N-terminal domain (NTD) on the Tudor domain interaction with the nucleosome. We show that the NTD is partially ordered when it is natively attached to the Tudor domain. Through a combination of FRET and single molecule studies, we find that the increase of DNA accessibility within the H3K36me3-containing nucleosome, instigated by the Tudor binding to H3K36me3, is dramatically enhanced by the NTD. We demonstrate that this nearly order of magnitude increase is due to preferential binding of PHF1 to partially unwrapped nucleosomes, and that PHF1 alters DNA–protein binding within the nucleosome by decreasing dissociation rates. These results highlight the potency of a PTM-binding protein to regulate DNA accessibility and underscores the role of the novel mechanism by which nucleosomes control DNA–protein binding through increasing protein dissociation rates.

Summary Background Closure of an abdominal stoma, a common elective operation, is associated with frequent complications; one of the commonest and impactful is incisional hernia formation. We aimed to investigate whether biological mesh (collagen tissue matrix) can safely reduce the incidence of incisional hernias at the stoma closure site. Methods In this randomised controlled trial (ROCSS) done in 37 hospitals across three European countries (35 UK, one Denmark, one Netherlands), patients aged 18 years or older undergoing elective ileostomy or colostomy closure were randomly assigned using a computer-based algorithm in a 1:1 ratio to either biological mesh reinforcement or closure with sutures alone (control). Training in the novel technique was standardised across hospitals. Patients and outcome assessors were masked to treatment allocation. The primary outcome measure was occurrence of clinically detectable hernia 2 years after randomisation (intention to treat). A sample size of 790 patients was required to identify a 40% reduction (25% to 15%), with 90% power (15% drop-out rate). This study is registered with ClinicalTrials.gov, NCT02238964. Findings Between Nov 28, 2012, and Nov 11, 2015, of 1286 screened patients, 790 were randomly assigned. 394 (50%) patients were randomly assigned to mesh closure and 396 (50%) to standard closure. In the mesh group, 373 (95%) of 394 patients successfully received mesh and in the control group, three patients received mesh. The clinically detectable hernia rate, the primary outcome, at 2 years was 12% (39 of 323) in the mesh group and 20% (64 of 327) in the control group (adjusted relative risk [RR] 0·62, 95% CI 0·43–0·90; p=0·012). In 455 patients for whom 1 year postoperative CT scans were available, there was a lower radiologically defined hernia rate in mesh versus control groups (20 [9%] of 229 vs 47 [21%] of 226, adjusted RR 0·42, 95% CI 0·26–0·69; p

Observations of daily surface solar or shortwave radiation data from over 4000 stations have been gathered, covering much of the continental United States as well as portions of Alberta and British Columbia, Canada. The quantity of data increases almost linearly from 1998, when only several hundred stations had data. A quality-control procedure utilizing threshold values along with computing the clear-sky radiation envelope for individual stations was implemented to both screen bad data and rescue informative data. Over two-thirds of the observations are seen as acceptable. There are 15 different surface solar radiation products assessed relative to observations, including reanalyses [Twentieth-Century Reanalysis (20CR), CFS Reanalysis and Reforecast (CFSRR), ERA-Interim, Japanese 55-year Reanalysis Project (JRA-55), MERRA, NARR, and NCEP–NCAR Reanalysis 1 (NCEP-1)], derived products [observations from the CRU and NCEP-1 (CRU–NCEP); Daily Surface Weather and Climatological Summaries (Daymet); Global Land Data Assimilation System, version 1 (GLDAS-1); Global Soil Wetness Project Phase 3 (GSWP3); Multiscale Synthesis and Terrestrial Model Intercomparison Project (MsTMIP); and phase 2 of the North American Land Data Assimilation System (NLDAS-2)], and two satellite products (CERES and GOES). All except the CERES product have daily or finer temporal resolution. The RMSE of spatial biases is greater than 18 W m−2 for 13 of the 15 products over the summer season (June–August). None of the daily resolution products fulfill all three desirable criteria of low (

Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488–97. ©2016 AACR.

Environmental enrichment (EE), a housing condition providing complex physical, social, and cognitive stimulation, leads to improved metabolic health and resistance to diet-induced obesity and cancer. One underlying mechanism is the activation of the hypothalamic-sympathoneural-adipocyte axis with hypothalamic brain-derived neurotrophic factor (BDNF) as the key mediator. VGF, a peptide precursor particularly abundant in the hypothalamus, was up-regulated by EE. Overexpressing BDNF or acute injection of BDNF protein to the hypothalamus up-regulated VGF, whereas suppressing BDNF signaling down-regulated VGF expression. Moreover, hypothalamic VGF expression was regulated by leptin, melanocortin receptor agonist, and food deprivation mostly paralleled to BDNF expression. Recombinant adeno-associated virus-mediated gene transfer of Cre recombinase to floxed VGF mice specifically decreased VGF expression in the hypothalamus. In contrast to the lean and hypermetabolic phenotype of homozygous germline VGF knockout mice, specific knockdown of hypothalamic VGF in male adult mice led to increased adiposity, decreased core body temperature, reduced energy expenditure, and impaired glucose tolerance, as well as disturbance of molecular features of brown and white adipose tissues without effects on food intake. However, VGF knockdown failed to block the EE-induced BDNF up-regulation or decrease of adiposity indicating a minor role of VGF in the hypothalamic-sympathoneural-adipocyte axis. Taken together, our results suggest hypothalamic VGF responds to environmental demands and plays an important role in energy balance and glycemic control likely acting in the melanocortin pathway downstream of BDNF. (Endocrinology 157: 983-996, 2016)

Permafrost is a characteristic aspect of the terrestrial Arctic and the fate of near-surface permafrost over the next century is likely to exert strong controls on Arctic hydrology and biogeochemistry. Using output from the fifth phase of the Coupled Model Intercomparison Project (CMIP5), the authors assess its ability to simulate present-day and future permafrost. Permafrost extent diagnosed directly from each climate model's soil temperature is a function of the modeled surface climate as well as the ability of the land surface model to represent permafrost physics. For each CMIP5 model these two effects are separated by using indirect estimators of permafrost driven by climatic indices and compared to permafrost extent directly diagnosed via soil temperatures. Several robust conclusions can be drawn from this analysis. Significant air temperature and snow depth biases exist in some model's climates, which degrade both directly and indirectly diagnosed permafrost conditions. The range of directly calculated present-day (1986–2005) permafrost area is extremely large (~4–25 × 106 km2). Several land models contain structural weaknesses that limit their skill in simulating cold region subsurface processes. The sensitivity of future permafrost extent to temperature change over the present-day observed permafrost region averages (1.67 ± 0.7) × 106 km2 °C−1 but is a function of the spatial and temporal distribution of climate change. Because of sizable differences in future climates for the representative concentration pathway (RCP) emission scenarios, a wide variety of future permafrost states is predicted by 2100. Conservatively, the models suggest that for RCP4.5, permafrost will retreat from the present-day discontinuous zone. Under RCP8.5, sustainable permafrost will be most probable only in the Canadian Archipelago, Russian Arctic coast, and east Siberian uplands.

To assess the cross-centre consistency of iodine enhancement, contrast-to-noise ratio and radiation dose in a multicentre perfusion CT trial of colorectal cancer. A cylindrical water phantom containing different iodine inserts was examined on seven CT models in 13 hospitals. The relationship between CT number (Hounsfield units, HU) and iodine concentration (milligrams per millilitre) was established and contrast-to-noise ratios (CNRs) calculated. Radiation doses (CTDIvol, DLP) were compared across all sites. There was a linear relationship between CT number and iodine density. Iodine enhancement varied by a factor of at most 1.10, and image noise by at most 1.5 across the study sites. At an iodine concentration of 1 mg ml−1 and 100 kV, CNRs ranged from 3.6 to 4.8 in the 220-mm phantom and from 1.4 to 1.9 in the 300-mm phantom. Doses varied by a factor of at most 2.4, but remained within study dose constraints. Iterative reconstruction algorithms did not alter iodine enhancement but resulted in reduced image noise by a factor of at most 2.2, allowing a potential dose decrease of at most 80 % compared to filtered back projection (FBP). Quality control of CT performance across centres indicates that CNR values remain relatively consistent across all sites, giving acceptable image quality within the agreed dose constraints. • Quality control is essential in a multicentre setting to enable CT quantification. • CNRs in a body-sized phantom had the recommended value of at least 1.5. • CTDIs and DLPs varied by factors of 1.8 and 2.4 respectively.

Activation of the hypothalamus-adipocyte axis is associated with an antiobesity and anticancer phenotype in animal models of melanoma and colon cancer. Brain-derived neurotrophic factor (BDNF) is a key mediator in the hypothalamus leading to preferential sympathoneural activation of adipose tissue and the ensuing resistance to obesity and cancer. Here, we generated middle age obese mice by high fat diet feeding for a year and investigated the effects of hypothalamic gene transfer of BDNF on a hormone receptor-positive mammary tumor model. The recombinant adeno-associated viral vector-mediated overexpression of BDNF led to marked weight loss and decrease of adiposity without change of food intake. BDNF gene therapy improved glucose tolerance, alleviated steatosis, reduced leptin level, inhibited mouse breast cancer EO771 growth, and prevented the metastasis. The reduced tumor growth in BDNF-treated mice was associated with reduced angiogenesis, decreased proliferation, increased apoptosis, and reduced adipocyte recruitment and lipid accumulation. Moreover, BDNF gene therapy reduced inflammation markers in the hypothalamus, the mammary gland, the subcutaneous fat, and the mammary tumor. Our results suggest that manipulating a single gene in the brain may influence multiple mechanisms implicated in obesity-cancer association and provide a target for the prevention and treatment of both obesity and cancer.

The UK conurbation of Birmingham and the Black Country has recently been surveyed for a new Flora, on the basis of a 1 km square grid. The present paper uses the data to describe the ecological network of the conurbation. The total number of taxa per 1 km squares is shown to be moderately but significantly correlated, and the number of native taxa more strongly correlated, with the area of the previously-established network of protected sites. Nevertheless coincidence maps of total numbers or numbers of native species per 1 km square give only poor representations of the ecological network compared with maps of protected sites. Axiophytes are defined as plant species 90% restricted to conservation habitats and recorded in fewer than 25% of 2km × 2km squares in a county. Applying the concept to 1 km squares in Birmingham and the Black Country creates a list of 256 axiophytes. Numbers of axiophytes are shown to be more strongly correlated with areas of protected sites than total taxa or native taxa and a coincidence map of the axiophytes is found to provide a useful quantitative assessment of the ecological network. Maps of axiophytes are used to divide the network into core and linking areas and their use in consolidating and improving the botanical ecological network is explored.

Background: Crohn’s disease (CD) is a lifelong, relapsing and remitting inflammatory condition of the intestine. Medical imaging is crucial for diagnosis, phenotyping, activity assessment and detecting complications. Diverse small bowel imaging tests are available but a standard algorithm for deployment is lacking. Many hospitals employ tests that impart ionising radiation, of particular concern to this young patient population. Magnetic resonance enterography (MRE) and small bowel ultrasound (USS) are attractive options, as they do not use ionising radiation. However, their comparative diagnostic accuracy has not been compared in large head to head trials. METRIC aims to compare the diagnostic efficacy, therapeutic impact and cost effectiveness of MRE and USS in newly diagnosed and relapsing CD. Methods: METRIC (ISRCTN03982913) is a multicentre, non-randomised, single-arm, prospective comparison study. Two patient cohorts will be recruited; those newly diagnosed with CD, and those with suspected relapse. Both will undergo MRE and USS in addition to other imaging tests performed as part of clinical care. Strict blinding protocols will be enforced for those interpreting MRE and USS. The Harvey Bradshaw index, C-reactive protein and faecal calprotectin will be collected at recruitment and 3 months, and patient experience will be assessed via questionnaires. A multidisciplinary consensus panel will assess all available clinical and imaging data up to 6 months after recruitment of each patient and will define the standard of reference for the presence, localisation and activity of disease against which the diagnostic accuracy of MRE and USS will be judged. Diagnostic impact of MRE and USS will be evaluated and cost effectiveness will be assessed. The primary outcome measure is the difference in per patient sensitivity between MRE and USS for the correct identification and localisation of small bowel CD. Discussion: The trial is open at 5 centres with 46 patients recruited. We highlight the importance of stringent blinding protocols in order to delineate the true diagnostic accuracy of both imaging tests and discuss the difficulties of diagnostic accuracy studies in the absence of a single standard of reference, describing our approach utilising a consensus panel whilst minimising incorporation bias. Trial registration: METRIC - ISRCTN03982913 – 05.11.13.

Background: Screening of populations at risk for colorectal cancer (CRC) allows the detection and successful treatment of tumours and their precursor polyps. The current UK CRC screening programme is faecal occult blood testing (FOBT), despite evidence from modelling studies to suggest that more cost-effective technologies exist. Objective: To assess the cost effectiveness of CT colonography (CTC) for colorectal cancer screening from the perspective of the UK NHS. Methods: A state-transition Markov model was constructed to estimate lifetime costs and health outcomes of a cohort of individuals screened at age 60-69 years using four different CRC screening technologies: FOBT, flexible sigmoidoscopy, optical colonoscopy and CTC. Results: CTC screening offered every 10 years was cost saving compared with the current UK programme of biennial FOBT screening. This strategy also yielded greater health benefits (QALYs and life-years) than biennial FOBT screening. The model fit observed CRC epidemiology data well and was robust to changes in underlying parameter values. CTC remained cost effective under a range of assumptions in the univariate sensitivity analysis. However, in the probabilistic sensitivity analysis, CTC dominated FOBT in only 5.9% of simulations and was cost effective at a threshold of £30 000 per QALY gained in 48% of simulations. Conclusions: CTC has the potential to provide a cost-effective option for CRC screening in the UK NHS and may be cost saving compared with the current programme of biennial FOBT. Further analysis is required to assess the impact of introducing CTC to the UK CRC screening programme on the NHS budget and capacity.

Environmental enrichment (EE) is a housing environment for mice that boosts mental and physical health compared to standard laboratory housing. Our recent studies demonstrate that environmental enrichment decreases adiposity, increases energy expenditure, resists diet induced obesity, and causes cancer remission and inhibition in mice. EE typically consists of larger living space, a variety of ‘toys’ to interact with, running wheels, and can include a number of other novel environmental changes. All of this fosters a more complex social engagement, cognitive and physical stimulations. Importantly, the toy location and type of toy is changed regularly, which encourages the mice to adapt to a frequently changing and novel environment. Many variables can be manipulated in EE to promote health effects in mice. Thus these approaches are difficult to control and must be properly managed to successfully replicate the associated phenotypes. Therefore, the goal of this video is to demonstrate how EE is properly set up and maintained to assure a complex, challenging, and controlled environment so that other researchers can easily reproduce the protective effects of EE against obesity and cancer.

Living in an enriched environment (EE) decreases adiposity, increases energy expenditure, causes resistance to diet induced obesity, and induces brown-like (beige) cells in white fat via activating a hypothalamic-adipocyte axis. Here we report that EE stimulated vascular endothelial growth factor (VEGF) expression in a fat depot-specific manner prior to the emergence of beige cells. The VEGF up-regulation was independent of hypoxia but required intact sympathetic tone to the adipose tissue. Targeted adipose overexpression of VEGF reproduced the browning effect of EE. Adipose-specific VEGF knockout or pharmacological VEGF blockade with antibodies abolished the induction of beige cell by EE. Hypothalamic brain-derived neurotrophic factor stimulated by EE regulated the adipose VEGF expression, and VEGF signaling was essential to the hypothalamic brain-derived neurotrophic factor-induced white adipose tissue browning. Furthermore, VEGF signaling was essential to the beige cells induction by exercise, a β3-adrenergic agonist, and a peroxisome proliferator-activated receptor-γ ligand, suggesting a common downstream pathway integrating diverse upstream mechanisms. Exploiting this pathway may offer potential therapeutic interventions to obesity and metabolic diseases.

This case illustrates an unusual associated pathology in a patient with gastric adenocarcinoma. A 79-year-old male with biopsy-proven gastric cancer was found intra-operatively to have a hard mass in the mesentery involving proximal jejunum. A segment of small bowel was resected and a frozen section was requested to confirm disseminated malignancy. After a benign diagnosis was rendered, a total gastrectomy for adenocarcinoma was then performed. The jejunum contained two diverticula, one of which had perforated and this was the cause of the intra-abdominal mesenteric pathology. Jejunal diverticular disease is highlighted and reviewed.

This chapter assesses the scientific literature describing expectations for near-term climate (present through mid-century). Unless otherwise stated, 'near-term' change and the projected changes below are for the period 2016-2035 relative to the reference period 1986-2005. Atmos- pheric composition (apart from CO2; see Chapter 12) and air quality projections through to 2100 are also assessed.

This article focuses primarily on the challenges of one multicultural classroom. The underlying intentions of the exercise are, however, somewhat wider than this may suggest. The article initially notes that some urban teachers have felt undervalued in recent years and then seeks to identify how the demands of complex urban classrooms can be explained effectively. It is in pursuit of this objective that attention turns to a multicultural class taught for one year. Factors which made the task of teaching the class both complex and rewarding are identified and analysed. Use of the concept of ‘complexity’ is then clarified through brief reference to wider reading. This paves the way for consideration of the potential value of the approach adopted at a time when some urban teachers are vulnerable to unfair criticism rooted in ignorance and arrogance. It is hoped that the article may help to combat the prejudice which far too many urban teachers continue to face.

[1] The current distribution and future projections of permafrost are examined in a fully coupled global climate model, the Community Climate System Model, version 3 (CCSM3) with explicit treatment of frozen soil processes. The spatial extent of simulated present-day permafrost in CCSM3 agrees well with observational estimates – an area, excluding ice sheets, of 10.5 million km2. By 2100, as little as 1.0 million km2 of near-surface permafrost remains. Freshwater discharge to the Arctic Ocean rises by 28% over the same period, largely due to increases in precipitation that outpace increases in evaporation, with about 15% of the rise directly attributable to melting ground ice. Such large changes in permafrost may provoke feedbacks such as activation of the soil carbon pool and a northward expansion of shrubs and forests.

Some surgical interventions carried out on pregnant women could harm the fetus. If a previously unknown pregnancy is detected before a procedure, such risks can be discussed with the patient. Where necessary, surgery can be postponed or anaesthetic and surgical approaches modified. At present, despite national guidelines,1 it seems that pregnancy status is not always being checked routinely before surgery. Although robust processes have been established to check for pregnancy before gynaecological procedures and those involving ionising radiation,2 the same precautions seem not to be in place for general surgery. This is important given the scale of the problem—although no major study has been done in the United Kingdom, estimates from the United States suggest a 0.15-2.2% incidence of previously undiagnosed pregnancy at the point of surgery.3 4 Between October 2003 and November 2009, healthcare staff in England and Wales reported 42 serious incidents in which no documented pregnancy check was carried out before a planned procedure. Three of these cases resulted in spontaneous abortion. A typical incident report reads: “Patient informed me that she had been admitted post-op with PV [vaginal] bleeding and a miscarriage diagnosed therefore pregnant during surgery. …

Purpose: To determine the diagnostic accuracy of ultrasound in the diagnosis of pneumothorax in patients with COPD with particular regard to false-positive diagnoses. Materials and methods: This was a single-center, prospective, blinded study. Nine patients with pneumothorax, 9 patients with cystic fibrosis, 17 patients with COPD, and 6 control subjects were studied. Ultrasound clips were recorded at three positions in both hemithoraces of each patient and then reviewed by two observers blinded to patient status. Each clip was scored for the presence or absence of pneumothorax and the degree of observer confidence. Results: The sensitivity and specificity for a pneumothorax were 100% and 84% for the experienced observer and 78% and 81% for the inexperienced observer, respectively. In the COPD patient group, specificity was 71% for the experienced observer and 65% for the inexperienced observer. There were no false-positive diagnoses in the cystic fibrosis or the control group. Conclusion: Patients with COPD commonly show signs on ultrasound mimicking a pneumothorax, but this was not seen in patients with cystic fibrosis. In patients with COPD, ultrasound may be used to exclude the presence of a pneumothorax, but it cannot be used to confidently diagnose pneumothorax without using other imaging modalities.

UNLABELLED: PURPOSE OF REPORT: To determine the usefulness of SPECT imaging over planar imaging for the detection of parathyroid adenomas using dual-phase Tc-99m sestamibi. MATERIALS AND METHODS: The records of patients referred for dual-phase sestamibi scintigraphy for detection of parathyroid adenomas were reviewed retrospectively. The images were reviewed blindly and planar images were compared with SPECT. The imaging results were compared with the operative results to determine the sensitivity, accuracy of localization, and confidence of the reporting radiologist. RESULTS: The records of 37 patients were reviewed. Sensitivity was 62% for planar imaging and 73% for SPECT. There was one false positive. The side of the adenoma was correctly identified in all other patients. Confidence of detection was higher for SPECT than for planar imaging. CONCLUSION: SPECT imaging increased the sensitivity and confidence of the detection of parathyroid adenomas. The results indicate that SPECT should be used for all preoperative parathyroid localization.

491 Background: Nelfinavir, an inhibitor of AKT in the PI3-kinase pathway, is a radiosensitizer which increases tumor blood flow and reduces hypoxia in preclinical models. We conducted a pilot study of nelfinavir before and during hypofractionated pelvic radiotherapy (RT) in patients with rectal cancer to evaluate the safety of the combination, changes in tumor perfusion and a tissue biomarker of radiosensitization, tumor cell density (TCD). Methods: Eight patients with T3-4 N1-2 M1 rectal cancer received 7 days of oral nelfinavir (1250 mg bd) and a further 7 days of nelfinavir during pelvic RT (25 Gy/5 fractions/7 days). Safety was evaluated by CTCAE v 4.0. Dynamic contrast enhanced (DCE) CT and MRI scans were performed pre-treatment, after 7 days nelfinavir and prior to last fraction of RT. TCD was performed in biopsies taken pre-treatment and 7 days post-radiotherapy (West N et al. Br J Cancer. 2010, 102; 1519-23). Radiological response and tumor regression grade (TRG) was assessed on MRI 8 weeks from end of RT (Patel UB et al. J Clin Oncol. 2011, 29:3753-60). Results: This was the first clinical trial to combine nelfinavir with hypofractionated RT. There were 3 grade 3 adverse events (diarrhea, rash, lymphopenia). After 7 days of nelfinavir, there was a 40% increase in mean Ktrans on DCE-MRI (p = 0.029, paired t test). On DCE-CT, there was a 30% increase in mean blood flow from before RT to the last day of RT (p = 0.028). The median TCD in biopsies decreased from 41.2% (IQR = 23.5, 53.0%) at baseline to 9.2% (IQR = 2.8, 18.2%) after RT (p = 0.007, paired t test). By RECIST criteria, 3/8 patients treated had complete radiological responses and 4/8 had partial responses. TRG was associated with the magnitude of decrease in TCD measured in paired biopsies for individual patients (p = 0.029, Fisher’s Exact Test). Conclusions: These data suggest that the radiosensitizing drug, nelfinavir, can increase blood flow to rectal cancer when given prior to RT. Nelfinavir added to hypofractionated pelvic radiotherapy has acceptable toxicity and is associated with radiological and tissue biomarker responses. Funded by Oxford NIHR BRC, OCIC, Yorkshire Cancer Research, Oxford and Leeds ECMCs. Clinical trial information: 2010-020621-40.

We present the first implementation of a theorem prover running on a smart card. The prover is written in Java and implements a dual tableau calculus. Due to the limited resources available on current smart cards, the prover is restricted to prepositional classical logic. It can be easily extended to full first-order logic.

The export of cytochrome c from mitochondria to the cytoplasm has been detected during apoptosis. Addition of cytochrome c to cytosolic extracts can activate the caspases, suggesting that this export could be an important intracellular signal for initiating the apoptotic programme. We have investigated the mechanism of caspase activation by cytochrome c. Mitochondrial cytochrome c normally shuttles electrons between complexes III and IV of the electron transport chain. Interaction with these complexes is dependent on electrostatic interactions via a polylysine binding pocket. Cytosolic caspase activation was only observed with intact holocytochrome c, and increasing the ionic composition of the extracts prevented activation, suggesting that stringent allosteric interactions between cytochrome c and other cytoplasmic factors are necessary. Cytochrome c was fully reduced within 5 min of addition to the cytosolic extracts. Potassium ferricyanide could maintain cytochrome c in an oxidized state, but care was taken to use ferricyanide at concentrations where its polyanion effect did not cause interference. The oxidized form of cytochrome c was able to activate the caspases. We conclude that reduced cytochrome c will function in the cytoplasm; however, its reduction is not a critical step, and electron transfer from cytochrome c to its cytoplasmic-binding partner(s) is not necessary in the pathway leading to apoptosis.

We present the first implementation of a theorem prover which runs on a smart card. The prover is written in Java and implements a dual tableau calculus. Due to the limited resources available on current smart cards, the prover is restricted to propositional classical logic. It can be easily extended to full first-order logic. The potential applications for our prover lie within the context of security related functions based on trusted devices such as smart cards.

Formant‐based synthetic speech is less robust in noise than natural speech and is often criticized as ‘‘robot‐like.’’ One reason may be the failure to model nonlocal spectral variation induced by segments in other syllables. This study investigates how a single consonant can affect vowel formant frequencies in nonadjacent as well as adjacent syllables. Sequences of /schwa u i schwa/ with intervening consonants were embedded in carrier phrases to give quasimeaningful sentences. The medial consonant was /z/ or /r/. Flanking consonants were either all /b/, or /d/ in the syllables before and after the medial consonant (/bschwabu{zr}ibschwab/, /bschwadu{zr}idschwab/). Primary stress was on either the second syllable, or the first and third. Steady‐state or mid‐point frequencies of F1–F3 were measured from LPC spectra. Preliminary results confirm expectations: /r/ engenders lower formant frequencies than /z/ in less‐stressed, all‐b contexts, even in nonadjacent syllables. Vowel stress and /d/ contexts tend to b...