The bifurcation and topography of the posterior tibial artery within the tarsal tunnel.

PURPOSE: The tarsal tunnel (TT) is a fibro-osseous anatomical space coursing from the medial ankle to the medial midfoot. This tunnel acts as a passage for both tendinous and neurovascular structures, including the neurovascular bundle containing the posterior tibial artery (PTA), posterior tibial veins (PTVs) and tibial nerve (TN). Tarsal tunnel syndrome (TTS) is the entrapment neuropathy that describes the compression and irritation of the TN within this space. Iatrogenic injury to the PTA plays a significant role in both the onset and exacerbation of TTS symptoms. The current study aims to produce a method to allow clinicians and surgeons to easily and accurately predict the bifurcation of the PTA, to avoid iatrogenic injury during treatment of TTS. METHODS: Fifteen embalmed cadaveric lower limbs were dissected at the medial ankle region to expose the TT. Various measurements regarding the location of the PTA within the TT were recorded and multiple linear regression analysis performed using RStudio. RESULTS: Analysis provided a clear correlation (p < 0.05) between the length of the foot (MH), length of hind-foot (MC) and location of bifurcation of the PTA (MB). Using these measurements, this study developed an equation (MB = 0.3*MH + 0.37*MC - 28.24 mm) to predict the location of bifurcation of the PTA within a 23° arc inferior to the medial malleolus. CONCLUSIONS: This study successfully developed a method whereby clinicians and surgeons can easily and accurately predict the bifurcation of the PTA, to avoid iatrogenic injury that would previously lead to an exacerbation of TTS symptoms.

Exact Solutions of Interacting Dissipative Systems via Weak Symmetries.

We demonstrate how the presence of continuous weak symmetry can be used to analytically diagonalize the Liouvillian of a class of Markovian dissipative systems with strong interactions or nonlinearity. This enables an exact description of the full dynamics and dissipative spectrum. Our method can be viewed as implementing an exact, sector-dependent mean-field decoupling, or alternatively, as a kind of quantum-to-classical mapping. We focus on two canonical examples: a nonlinear bosonic mode subject to incoherent loss and pumping, and an inhomogeneous quantum Ising model with arbitrary connectivity and local dissipation. In both cases, we calculate and analyze the full dissipation spectrum. Our method is applicable to a variety of other systems, and could provide a powerful new tool for the study of complex driven-dissipative quantum systems.

Bayesian approach for sample size determination, illustrated with Soil Health Card data of Andhra Pradesh (India).

A crucial decision in designing a spatial sample for soil survey is the number of sampling locations required to answer, with sufficient accuracy and precision, the questions posed by decision makers at different levels of geographic aggregation. In the Indian Soil Health Card (SHC) scheme, many thousands of locations are sampled per district. In this paper the SHC data are used to estimate the mean of a soil property within a defined study area, e.g., a district, or the areal fraction of the study area where some condition is satisfied, e.g., exceedence of a critical level. The central question is whether this large sample size is needed for this aim. The sample size required for a given maximum length of a confidence interval can be computed with formulas from classical sampling theory, using a prior estimate of the variance of the property of interest within the study area. Similarly, for the areal fraction a prior estimate of this fraction is required. In practice we are uncertain about these prior estimates, and our uncertainty is not accounted for in classical sample size determination (SSD). This deficiency can be overcome with a Bayesian approach, in which the prior estimate of the variance or areal fraction is replaced by a prior distribution. Once new data from the sample are available, this prior distribution is updated to a posterior distribution using Bayes' rule. The apparent problem with a Bayesian approach prior to a sampling campaign is that the data are not yet available. This dilemma can be solved by computing, for a given sample size, the predictive distribution of the data, given a prior distribution on the population and design parameter. Thus we do not have a single vector with data values, but a finite or infinite set of possible data vectors. As a consequence, we have as many posterior distribution functions as we have data vectors. This leads to a probability distribution of lengths or coverages of Bayesian credible intervals, from which various criteria for SSD can be derived. Besides the fully Bayesian approach, a mixed Bayesian-likelihood approach for SSD is available. This is of interest when, after the data have been collected, we prefer to estimate the mean from these data only, using the frequentist approach, ignoring the prior distribution. The fully Bayesian and mixed Bayesian-likelihood approach are illustrated for estimating the mean of log-transformed Zn and the areal fraction with Zn-deficiency, defined as Zn concentration <0.9 mg kg -1, in the thirteen districts of Andhra Pradesh state. The SHC data from 2015-2017 are used to derive prior distributions. For all districts the Bayesian and mixed Bayesian-likelihood sample sizes are much smaller than the current sample sizes. The hyperparameters of the prior distributions have a strong effect on the sample sizes. We discuss methods to deal with this. Even at the mandal (sub-district) level the sample size can almost always be reduced substantially. Clearly SHC over-sampled, and here we show how to reduce the effort while still providing information required for decision-making. R scripts for SSD are provided as supplementary material.

Airy light-sheet Raman imaging.

Light-sheet fluorescence microscopy has greatly improved the speed and overall photostability of optically sectioning cellular and multi-cellular specimens. Similar gains have also been conferred by light-sheet Raman imaging; these schemes, however, rely on diffraction limited Gaussian beams that hinder the uniformity and size of the imaging field-of-view, and, as such, the resulting throughput rates. Here, we demonstrate that a digitally scanned Airy beam increases the Raman imaging throughput rates by more than an order of magnitude than conventional diffraction-limited beams. Overall, this, spectrometer-less, approach enabled 3D imaging of microparticles with high contrast and 1 µm axial resolution at 300 msec integration times per plane and orders of magnitude lower irradiation density than coherent Raman imaging schemes. We detail the apparatus and its performance, as well as its compatibility with fluorescence light-sheet and quantitative-phase imaging towards rapid and low phototoxicity multimodal imaging.

Metallization of Porous Polyethylene Using a Wire-Arc Spray Process for Heat Transfer Applications.

Metallization of polyethylene (PE) using thermal spray techniques has proved difficult due to its low melting point and softness. In this study, metallic coatings were applied on porous polyethylene substrates using a twin wire-arc spray process. Commercially available polyethylene sheets, 3 mm in thickness, were used as substrates. Copper (Cu), aluminum (Al), and zinc (Zn) were successfully deposited on the porous polymer, without prior surface preparation, to form coatings with thickness of about 400 µm. Coating surface morphology and cross-sections were examined using a scanning electron microscope. Individual metal splats on the porous and non-porous substrates were observed to study the differences in the bonding mechanisms. The adhesion strength and electrical resistivity of the coatings on porous PE were evaluated. It was found that the bond strength of all three metallic coatings was found to be higher than the ultimate fracture strength of the porous. These results suggest that porosity in the polymer helps to overcome the challenges of metallizing polyethylene and provides a significant reduction in the weight of the polymer. Therefore, all these properties aided in fabricating an extremely lightweight, composite material with potential use in thermal management applications.

Mesh inlay, mesh kit or native tissue repair for women having repeat anterior or posterior prolapse surgery: randomised controlled trial (PROSPECT).

OBJECTIVE: To compare standard (native tissue) repair with synthetic mesh inlays or mesh kits. DESIGN: Randomised controlled trial. SETTING: Thirty-three UK hospitals. POPULATION: Women having surgery for recurrent prolapse. METHODS: Women recruited using remote randomisation. MAIN OUTCOME MEASURES: Prolapse symptoms, condition-specific quality-of-life and serious adverse effects. RESULTS: A Mean Pelvic Organ Prolapse Symptom Score at 1 year was similar for each comparison (standard 6.6 versus mesh inlay 6.1, mean difference [MD] -0.41, 95% CI -2.92 to 2.11: standard 6.6 versus mesh kit 5.9, MD -1.21 , 95% CI -4.13 to 1.72) but the confidence intervals did not exclude a minimally important clinical difference. There was no evidence of difference in any other outcome measure at 1 or 2 years. Serious adverse events, excluding mesh exposure, were similar at 1 year (standard 7/55 [13%] versus mesh inlay 5/52 [10%], risk ratio [RR] 1.05 [0.66-1.68]: standard 3/25 [12%] versus mesh kit 3/46 [7%], RR 0.49 [0.11-2.16]). Cumulative mesh exposure rates over 2 years were 7/52 (13%) in the mesh inlay arm, of whom four women required surgical revision; and 4/46 in the mesh kit arm (9%), of whom two required surgical revision. CONCLUSIONS: We did not find evidence of a difference in terms of prolapse symptoms from the use of mesh inlays or mesh kits in women undergoing repeat prolapse surgery. Although the sample size was too small to be conclusive, the results provide a substantive contribution to future meta-analysis. TWEETABLE ABSTRACT: There is not enough evidence to support use of synthetic mesh inlay or mesh kits for repeat prolapse surgery.

Indian agriculture, air pollution, and public health in the age of COVID.

Emerging evidence supports the intuitive link between chronic health conditions associated with air pollution and the vulnerability of individuals and communities to COVID-19. Poor air quality already imposes a highly significant public health burden in Northwest India, with pollution levels spiking to hazardous levels in November and early December when rice crop residues are burned. The urgency of curtailing the COVID-19 pandemic and mitigating a potential resurgence later in the year provides even more justification for accelerating efforts to dramatically reduce open agricultural burning in India.

Temporal changes in soil microbial properties and nutrient dynamics under climate smart agriculture practices.

Climate smart agriculture (CSA) practices are emerging as sustainable alternative to conventional rice-wheat system to pull up natural resources degradation across south Asia. After five years of continuous CSA based experiment, a two years study was conducted to evaluate changes in microbial biomasses (microbial biomass carbon and nitrogen), enzyme activities (alkaline phosphatase, dehydrogenase and ß-glucosidase), nutrient release and uptake (N, P and K) at different wheat crop growth stages. Effect of CSA practices was also studied for carbon mineralization in an incubation experiment. Four scenarios (Sc) were included in this study- conventional tillage (CT) based rice-wheat system (Sc1), partial CSA based rice-wheat-mungbean system (Sc2), full CSA based rice-wheat-mungbean system (Sc3), and full CSA based maize-wheat-mungbean system (Sc4). Soil samples were collected from scenarios at 0-15 and 15-30 cm depth at different growth stages of wheat crop namely sowing, crown root initiation (CRI), active tillering, panicle initiation, and harvesting. Analysis of soil was done for chemical properties viz. pH, electrical conductivity, available N, P, K, NPK uptake and mineralizable carbon and biological properties viz., microbial biomass carbon (MBC), microbial biomass nitrogen (MBN), dehydrogenase activity (DHA), alkaline phosphatase activity (APA) and ß-glucosidase. Significantly higher microbial biomass carbon (42 %) and nitrogen (79 %) were found in surface soil (0-15 cm depth) under CSA based scenarios (Sc2, Sc3 and Sc4) at harvest stage of wheat over CT based/ conventional scenario (Sc1). At surface soil, alkaline phosphatase, dehydrogenase and ß-glucosidase activity was 58, 14 and 13 % higher in CSA based scenarios, respectively than CT based scenario. CSA based scenarios showed significantly higher C mineralization after 3 days of the incubation experiment at harvest. An increase of respectively 15, 48 and 17 % of N, P and K uptake was observed with CSA based scenarios than CT based scenario. At harvest stage, 7 % higher amount of dry matter was reported with full CSA based scenarios (mean of Sc2 to Sc4) compared to Sc1. Higher wheat grain yield of ∼10 % was recorded with CSA based scenarios over CT based scenario. Therefore, CSA based scenarios with improved biological properties and nutrient availability and uptake at different wheat growth stages resulted in higher yields and hence need to be popularized among the farmers.

Agricultural labor, COVID-19, and potential implications for food security and air quality in the breadbasket of India.

To contain the COVID-19 pandemic, India imposed a national lockdown at the end of March 2020, a decision that resulted in a massive reverse migration as many workers across economic sectors returned to their home regions. Migrants provide the foundations of the agricultural workforce in the 'breadbasket' states of Punjab and Haryana in Northwest India.There are mounting concerns that near and potentially longer-term reductions in labor availability may jeopardize agricultural production and consequently national food security. The timing of rice transplanting at the beginning of the summer monsoon season has a cascading influence on productivity of the entire rice-wheat cropping system. To assess the potential for COVID-related reductions in the agriculture workforce to disrupt production of the dominant rice-wheat cropping pattern in these states, we use a spatial ex ante modelling framework to evaluate four scenarios representing a range of plausible labor constraints on the timing of rice transplanting. Averaged over both states, results suggest that rice productivity losses under all delay scenarios would be low as compare to those for wheat, with total system productivity loss estimates ranging from 9%, to 21%, equivalent to economic losses of USD $674 m to $1.48 billion. Late rice transplanting and harvesting can also aggravate winter air pollution with concomitant health risks. Technological options such as direct seeded rice, staggered nursery transplanting, and crop diversification away from rice can help address these challenges but require new approaches to policy and incentives for change.

'We've made the best of it. But we do not have a normal life': families' experiences of tuberous sclerosis complex and seizure management.

BACKGROUND: Tuberous sclerosis complex (TSC) is a complex multisystem genetic disorder. Approximately 84% of people with TSC have epilepsy. However, there is little literature available regarding families' experiences with TSC and seizure management. Therefore, the aim of the current study was to explore families' positive and negative experiences, and attitudes towards TSC, epilepsy and medical management of seizures. METHODS: Framework analysis informed an open exploration of families' experiences with TSC, epilepsy and medical management of seizures. Using structured interviews, 11 parents of people with TSC and 2 people with TSC were interviewed, providing the data set for transcription and thematic analysis. RESULTS: 'TSC rules our life' overarched three subordinate themes: 'Our normal', 'Burnout' and 'Seizure management has given us our life back'. Families had to adapt to the normality of needing to constantly supervise their child even as they become an adult. They express a feeling of fear particularly of seizures, and this has impact throughout the family. There are frequent expressions of exhaustion and struggling to fight for access and support. There are some positives and cautious hope with the gaining of control from seizures as being able to predict or plan improves activity and participation. These interviews provided a rich insight into the lives of those with TSC and their families. CONCLUSION: There are exciting developments with respect to scientific understanding of the pathophysiology of TSC, which opens opportunity for new treatments. Holistic family centred health care and practical support (e.g. opportunities for parental respite) is as important as medical intervention. As TSC is such a complex condition, there is a need for specialist clinics and TSC-specific research.

Taking the climate risk out of transplanted and direct seeded rice: Insights from dynamic simulation in Eastern India.

Rice productivity in Eastern Indo-Gangetic plains (EIGP) is extremely low, in part due to the prevailing practice of cultivating long-duration transplanted rice under rainfed conditions which leads to water stress and significant yield losses in many seasons. Rice establishment alternatives such as direct seeded rice (DSR) require less water at planting but also are accompanied by climate risks that constrain adoption. For both conventional transplanted and DSR systems, successfully addressing climate-based production risks may provide a strong basis for sustainable rice intensification in EIGP. In this ex ante study of rice yield and yield variability, the APSIM cropping system model was used to evaluate the efficacy of risk-reducing management practices in both transplanted and DSR systems. Simulations were conducted with 44 years (1970-2013) of historical weather data from central Bihar, India. Results confirm that the prevailing farmer practice of transplanting long-duration cultivars under rainfed conditions (fTR) often results in delayed transplanting and the use of older seedlings, leading to low (median 1.6 t ha-1) and variable (Standard deviation (SD) 2.1 t ha-1) rice yields. To improve the fTR system, simulations suggest that adoption of medium-duration hybrid rice (3.2 t ha-1), provision of supplemental post-establishment irrigation (3.2 t ha-1), or transplanting appropriately aged seedlings (3.4 t ha -1) can double yields as single interventions while, in the case of supplemental irrigation, significantly reducing inter-annual production variability. Additional gains are achievable when interventions are layered: supplemental irrigation paired with medium-duration hybrids increased median rice yields to 4.6 t ha-1 with much lower variability (SD 1.0 t ha-1). In these improved systems where irrigation is used to transplant the crop, simulations revealed the importance of timely planting: high and stable yields are achievable for long-duration cultivars when transplanting is completed by 2 August with this window of opportunity extending to 16 August for medium-duration hybrids. In rainfed DSR systems, the potential pay-offs from single interventions were even higher with medium-duration hybrids resulting in a median yield of 4.5 t ha-1 against 1.8 t ha-1 with long-duration cultivars. For irrigated DSR systems, an optimum sowing window of early to mid-June was identified which resulted in higher and more stable yields with lower water requirements. Simulation results suggest several risk-reducing intensification pathways that can be selectively matched to farmer risk preferences and investment capabilities within the target region in EIGP.

Effects of tillage, crop establishment and diversification on soil organic carbon, aggregation, aggregate associated carbon and productivity in cereal systems of semi-arid Northwest India.

Intensive tillage based management practices are threatening soil quality and systems sustainability in the rice-wheat belt of Northwest India. Furthermore, it is accentuated with puddling of soil, which disrupts soil aggregates. Conservation agriculture (CA) practices involving zero tillage, crop residue management and suitable crop rotation can serve as better alternative to conventional agriculture for maintaining soil quality. Soil organic carbon is an important determinant of soil quality, playing critical role in food production, mitigation and adaptation to climate change as well as performs many ecosystem functions. To understand the turnover of soil carbon in different forms (Total organic carbon-TOC; aggregate associated carbon-AAC; particulate organic carbon- POC), soil aggregation and crop productivity with different management practices, one conventional agriculture based scenario and three CA based crop management scenarios namely conventional rice-wheat system (Sc1), partial CA based rice-wheat-mungbean system (Sc2), full CA-based rice-wheat-mungbean system (Sc3) and maize-wheat-mungbean system (Sc4) were evaluated. TOC was increased by 71%, 68% and 25% after 4 years of the experiment and 75%, 80% and 38% after 6 years of the experiment in Sc4, Sc3 and Sc2, respectively, over Sc1 at 0-15 cm soil depth. After 4 years of the experiment, 38.5% and 5.0% and after 6 years 50.8% and 24.4% improvement in total water stable aggregates at 0-15 and 15-30 cm soil depth, respectively was observed in CA-based scenarios over Sc1. Higher aggregate indices were associated with Sc3 at 0-15 cm soil depth than others. Among the size classes of aggregates, highest aggregate associated C (8.94 g kg-1) was retained in the 1-0.5 mm size class under CA-based scenarios. After 6 years, higher POC was associated with Sc4 (116%). CA-based rice/maize system (Sc3 and Sc4) showed higher productivity than Sc1. Therefore, CA could be a potential management practice in rice-wheat cropping system of Northwest India to improve the soil carbon pools through maintaining soil aggregation and productivity.

Protocol for a Randomised controlled trial to Evaluate the effectiveness and cost benefit of prescribing high dose FLuoride toothpaste in preventing and treating dEntal Caries in high-risk older adulTs (reflect trial).

BACKGROUND: Dental caries in the expanding elderly, predominantly-dentate population is an emerging public health concern. Elderly individuals with heavily restored dentitions represent a clinical challenge and significant financial burden for healthcare systems, especially when their physical and cognitive abilities are in decline. Prescription of higher concentration fluoride toothpaste to prevent caries in older populations is expanding in the UK, significantly increasing costs for the National Health Services (NHS) but the effectiveness and cost benefit of this intervention are uncertain. The Reflect trial will evaluate the effectiveness and cost benefit of General Dental Practitioner (GDP) prescribing of 5000 ppm fluoride toothpaste and usual care compared to usual care alone in individuals 50 years and over with high-risk of caries. METHODS/DESIGN: A pragmatic, open-label, randomised controlled trial involving adults aged 50 years and above attending NHS dental practices identified by their dentist as having high risk of dental caries. Participants will be randomised to prescription of 5000 ppm fluoride toothpaste (frequency, amount and duration decided by GDP) and usual care only. 1200 participants will be recruited from approximately 60 dental practices in England, Scotland and Northern Ireland and followed up for 3 years. The primary outcome will be the proportion of participants receiving any dental treatment due to caries. Secondary outcomes will include coronal and root caries increments measured by independent, blinded examiners, patient reported quality of life measures, and economic outcomes; NHS and patient perspective costs, willingness to pay, net benefit (analysed over the trial follow-up period and modelled lifetime horizon). A parallel qualitative study will investigate GDPs' practises of and beliefs about prescribing the toothpaste and patients' beliefs and experiences of the toothpaste and perceived impacts on their oral health-related behaviours. DISCUSSION: The Reflect trial will provide valuable information to patients, policy makers and clinicians on the costs and benefits of an expensive, but evidence-deficient caries prevention intervention delivered to older adults in general dental practice. TRIAL REGISTRATION: ISRCTN: 2017-002402-13 registered 02/06/2017, first participant recruited 03/05/2018. Ethics Reference No: 17/NE/0329/233335. Funding Body: Health Technology Assessment funding stream of National Institute for Health Research. Funder number: HTA project 16/23/01. Trial Sponsor: Manchester University NHS Foundation Trust, Oxford Road, Manchester, M13 9WL. The Trial was prospectively registered.

Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer.

BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy.

BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

Early barriers to neonatal porcine islet engraftment in a dual transplant model.

Porcine islet xenografts have the potential to provide an inexhaustible source of islets for ß cell replacement. Proof-of-concept has been established in nonhuman primates. However, significant barriers to xenoislet transplantation remain, including the poorly understood instant blood-mediated inflammatory reaction and a thorough understanding of early xeno-specific immune responses. A paucity of data exist comparing xeno-specific immune responses with alloislet (AI) responses in primates. We recently developed a dual islet transplant model, which enables direct histologic comparison of early engraftment immunobiology. In this study, we investigate early immune responses to neonatal porcine islet (NPI) xenografts compared with rhesus islet allografts at 1 hour, 24 hours, and 7 days. Within the first 24 hours after intraportal infusion, we identified greater apoptosis (caspase 3 activity and TUNEL [terminal deoxynucleotidyl transferase dUTP nick end labeling])-positive cells) of NPIs compared with AIs. Macrophage infiltration was significantly greater at 24 hours compared with 1 hour in both NPI (wild-type) and AIs. At 7 days, IgM and macrophages were highly specific for NPIs (α1,3-galactosyltransferase knockout) compared with AIs. These findings demonstrate an augmented macrophage and antibody response toward xenografts compared with allografts. These data may inform future immune or genetic manipulations required to improve xenoislet engraftment.

Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging.

A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (∼2 nm), and detected with a statistical significance of 12.9σ over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers.

Runx1 Orchestrates Sphingolipid Metabolism and Glucocorticoid Resistance in Lymphomagenesis.

The three-membered RUNX gene family includes RUNX1, a major mutational target in human leukemias, and displays hallmarks of both tumor suppressors and oncogenes. In mouse models, the Runx genes appear to act as conditional oncogenes, as ectopic expression is growth suppressive in normal cells but drives lymphoma development potently when combined with over-expressed Myc or loss of p53. Clues to underlying mechanisms emerged previously from murine fibroblasts where ectopic expression of any of the Runx genes promotes survival through direct and indirect regulation of key enzymes in sphingolipid metabolism associated with a shift in the "sphingolipid rheostat" from ceramide to sphingosine-1-phosphate (S1P). Testing of this relationship in lymphoma cells was therefore a high priority. We find that ectopic expression of Runx1 in lymphoma cells consistently perturbs the sphingolipid rheostat, whereas an essential physiological role for Runx1 is revealed by reduced S1P levels in normal spleen after partial Cre-mediated excision. Furthermore, we show that ectopic Runx1 expression confers increased resistance of lymphoma cells to glucocorticoid-mediated apoptosis, and elucidate the mechanism of cross-talk between glucocorticoid and sphingolipid metabolism through Sgpp1. Dexamethasone potently induces expression of Sgpp1 in T-lymphoma cells and drives cell death which is reduced by partial knockdown of Sgpp1 with shRNA or direct transcriptional repression of Sgpp1 by ectopic Runx1. Together these data show that Runx1 plays a role in regulating the sphingolipid rheostat in normal development and that perturbation of this cell fate regulator contributes to Runx-driven lymphomagenesis. J. Cell. Biochem. 118: 1432-1441, 2017. © 2016 Wiley Periodicals, Inc.

Long-term results and recurrence patterns from SCALOP: a phase II randomised trial of gemcitabine- or capecitabine-based chemoradiation for locally advanced pancreatic cancer.

BACKGROUND: SCALOP, a randomised, phase II trial, tested the activity and safety of gemcitabine (GEM)-based and capecitabine (CAP)-based chemoradiation (CRT) for locally advanced pancreatic cancer (LAPC). Here we present the long-term outcomes. METHODS: Eligibility: histologically proven LAPC ⩽7 cm. Following 12 weeks of induction GEMCAP chemotherapy (three cycles: GEM 1000 mg m-2 days 1, 8, 15; CAP 830 mg m-2 days 1-21 q28 days) patients with stable/responding disease, tumour ⩽6 cm, and WHO Performance Status 0-1 were randomised to receive one cycle GEMCAP followed by CAP (830 mg m-2 b.d. on weekdays only) or GEM (300 mg m-2 weekly) with radiation (50.4 Gy per 28 fractions). RESULTS: One-hundred fourteen patients (28 UK centres) were registered between 24 December 2009 and 25 October 2011, and 74 were randomised (CAP-RT=36; GEM-RT=38). At the time of this analysis, 105 of the 114 patients had died and the surviving 9 patients had been followed up for a median of 10.9 months (IQR: 2.9-18.7). Updated median OS was 17.6 months (95% CI: 14.6-22.7) in the CAP-CRT arm and 14.6 months (95% CI: 11.1-16.0) in the GEM-CRT arm (intention-to-treat adjusted hazard ratio (HR): 0.68 (95% CI: 0.38-1.21, P=0.185)); median progression-free survival (PFS) was 12.0 months (95% CI: 10.0-15.2) in the CAP-CRT arm and 10.4 months (95% CI: 8.8-12.7) in the GEM-CRT arm (intention-to-treat adjusted HR: 0.60 (95% CI: 0.32-1.14, P=0.120)). In baseline multivariable model, age ⩾65 years, better performance status, CA19.9<613 IU l-1, and shorter tumour diameter predicted improved OS. CAP-CRT, age ⩾65 years, better performance status, CA19.9 <46 IU ml-1 predicted improved OS and PFS in the pre-radiotherapy model. Nine-month PFS was highly predictive of OS. CONCLUSIONS: CAP-CRT remains the superior regimen. SCALOP showed that patients with CA19.9 <46 IU ml-1 after induction chemotherapy are more likely to benefit from CRT.

Carbon dating cancer: defining the chronology of metastatic progression in colorectal cancer.

Background: Patients often ask oncologists how long a cancer has been present before causing symptoms or spreading to other organs. The evolutionary trajectory of cancers can be defined using phylogenetic approaches but lack of chronological references makes dating the exact onset of tumours very challenging. Patients and methods: Here, we describe the case of a colorectal cancer (CRC) patient presenting with synchronous lung metastasis and metachronous thyroid, chest wall and urinary tract metastases over the course of 5 years. The chest wall metastasis was caused by needle tract seeding, implying a known time of onset. Using whole genome sequencing data from primary and metastatic sites we inferred the complete chronology of the cancer by exploiting the time of needle tract seeding as an in vivo 'stopwatch'. This approach allowed us to follow the progression of the disease back in time, dating each ancestral node of the phylogenetic tree in the past history of the tumour. We used a Bayesian phylogenomic approach, which accounts for possible dynamic changes in mutational rate, to reconstruct the phylogenetic tree and effectively 'carbon date' the malignant progression. Results: The primary colon cancer emerged between 5 and 8 years before the clinical diagnosis. The primary tumour metastasized to the lung and the thyroid within a year from its onset. The thyroid lesion presented as a tumour-to-tumour deposit within a benign Hurthle adenoma. Despite rapid metastatic progression from the primary tumour, the patient showed an indolent disease course. Primary cancer and metastases were microsatellite stable and displayed low chromosomal instability. Neo-antigen analysis suggested minimal immunogenicity. Conclusion: Our data provide the first in vivo experimental evidence documenting the timing of metastatic progression in CRC and suggest that genomic instability might be more important than the metastatic potential of the primary cancer in dictating CRC fate.