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Presently, the world is considering the integration of small, medium and large-scale PV systems into both urban and remote rural electricity networks. This sees a transition towards a 100% renewable energy based electricity supply from the current conventional fossil fuel based electricity supply. Australia has a significant electricity generation potential from solar PV resources which also encourages the uptake of PV-battery hybrid systems. Australian utilities operating in the isolated and remote areas are now seriously considering the integration of solar PV systems as a long-term solution to reduce costs and facilitate sustainable electricity generation. This would also defer expensive grid extension to supply electricity to these dispersed remote communities. This study aims to model and optimise a remote Australian PV-diesel system incorporated with high levels of PV penetration and battery storage and investigate the system power quality issues. The study includes system component optimisation and techno-economic analysis which considers the outcomes regarding the cost of energy (AUD$/kWh), fuel savings potential and environmental impacts. Power quality issues have been explored by analysing the response of fast frequency-responsive (FFR) battery storage. The overall study has found that higher levels of PV penetration integrated with the current diesel operated system provides a comprehensive and efficient electricity supply and FFR Li-ion batteries can mitigate transient power quality issues and maintain system frequency within acceptable limits.

Australia and most other countries are adopting renewable energy generation as the dominant means of reducing dependence on fossil fuels. This has been made more feasible by the exponential take-up of solar photovoltaic (PV) systems and their concurrent production scale-up and cost decline. Rooftop solar PV, combined with battery storage, seems likely to be the dominant means of providing household electricity needs. In response to the technical challenges from rooftop PV, network utilities have implemented various low cost options to cope with PV’s impact on network voltages. However, if we want this clean energy technology to fully utilise the available roof space and eventually meet residential electricity needs, additional hardware, control and commercial options will need to be adopted by both network utilities and their customers to overcome the technical barriers, especially voltage rise. This paper presents the authors’ evaluations of options to mitigate voltage rise, including operating solar inverters with reactive power absorption (var absorbing), dependent only on solar power output or operating the solar inverters in a volt–var response mode (voltage droop control) where the inverter adjusts its reactive power (Q) in response to changes in its terminal voltage – Q(V). This paper also considers the fulltime Q(V) option, where an inverter’s reactive power capacity is independent of solar conditions – statcom mode. The network utility option of using line drop compensation (LDC – used on long rural MV feeders) on urban MV feeders during daylight hours is assessed to lessen voltage rise on LV feeders with low net loading or reverse power flow due to high solar PV generation. The paper concludes that a combination of solar inverters performing fast fulltime voltage droop control outside a voltage deadband (statcom mode) and HV/MV substation transformers with slow acting daytime LDC mitigates voltage rise, whilst limiting feeder reactive power requirements.

The integration of a high share of photovoltaic (PV) power generation in remote electricity networks is often limited by the networks’ capabilities to accommodate PV power fluctuations caused by passing clouds. Increasing the share of PV penetration in such networks is accompanied by an increased effort to achieve integration. In the absence of solar forecasting, sufficient spinning reserve must always be provided to cover unforeseen reductions. The expected ramp rates are magnified in small and centralised PV systems and can be in the order of a few seconds. In this study, we investigate the use of a low-cost sky camera for very short-term solar forecasting. Almost 2 months of sky camera data have been recorded in Perth, Western Australia and processed for to provide high-resolution irradiance forecasts based on visible sky images. For performance validation, the capability to provide reliable forecasts under constant clear sky conditions is investigated. During these times, PV generation is expected to be high and reliable, which provides an opportunity to reduce the online spinning reserve often enabling power station operation with one less operating diesel generation. For networks with disconnected diesel generators, we assume that clouds that could reduce the PV generation output have to be predicted at least 2 min before their arrival to have enough time for a diesel generator to start and synchronize with the grid. Therefore, we define an irradiance threshold discriminating between the persistent state of constant clear sky (stays clear) and the non-persistent state (cloud shading event) based on a 2–5 min time horizon. In a binary evaluation, we achieve an overall accuracy of 97% correct forecasts and low 3% false alarms of cloud events indicating a high potential for fuel savings. Focusing on the rare (2% of the time) but more critical non-persistent conditions, we found 8 out of 84 cloud events have not been predicted in advance. Reasons for erroneous forecasts and suggestions for model improvements are provided.

Competing Interests: Disclosures None.

Colonialism underlies the commodification of health care in the United States and continues to harm well-being among Black Americans. We present four recommendations for addressing its health consequences: (1) Investments in epigenetic research to improve our understanding of how systemic oppression becomes biology. (2) Centering Black experiences and knowledge traditions in education, practice, and policy. (3) Support for Black scholars, trainees, and practitioners when they critic disciplinary tenets and practices. (4) Expansion of preventive care. Our health care system is a for-profit industry that exploits workers and harms the most marginalized, much like colonialism. Advancing health equity requires dismantling colonial legacies., Competing Interests: No competing financial interests exist., (© Sirry M. Alang et al., 2023; Published by Mary Ann Liebert, Inc.)

Dryden (2023) highlights how the COVID-19 pandemic anchored on anti-Black racism within the Canadian healthcare system to cause disproportionate suffering and death among Black people. We extend this argument by situating both COVID-19 and healthcare within broader racialized landscapes- the weather of anti-Blackness in the US - and argue that from sports and education to healthcare, Black bodies are weathering precisely because of intentional interconnected systems of oppression grounded in white supremacy, racial capitalism and patriarchy. Because oppression does not exist in a vacuum, health equity and liberation require us to engender new lexicons that decisively expose racism to (1) evaluate data differently, relationally and more critically through different disciplinary lenses and (2) centre the liberation of those at the intersection of multiple systems of oppression, such as Black women; Black queer and transgender people; Black people with disabilities; and unhoused, unemployed, uninsured and incarcerated Black people., (Copyright © 2023 Longwoods Publishing.)

Gaucher disease (GD) is an autosomal recessive disorder resulting from glucocerebrosidase deficiency due to pathologic variants in GBA1. While clinically heterogeneous, GD encompasses three types, non-neuronopathic (GD1), acute neuronopathic (GD2), and chronic neuronopathic (GD3). Newborn screening (NBS), which has made remarkable inroads in detecting certain diseases before detrimental health consequences and fatality ensues, is now being piloted for GD in several states and countries. Early on, clinical features of GD2 can overlap with GD3; hence, predicting outcome is challenging. As NBS for GD becomes more available, the increased detection of GD in neonates is inevitable. As a result, health care providers and families will be faced with uncertainty with respect to clinical management. Since more severe GBA1 variants are generally associated with neuronopathic GD, there has been an increased dependence on genotypic information. We present an infant detected by NBS with genotype D409H(p.Asp448His)/RecNciI (p.Leu483Pro; p.Ala495Pro;p.Val499=). To assist in genetic counseling, we performed a retrospective review of other patients in our cohort carrying D409H and reviewed the literature. The study illustrates the challenges faced in counseling for infants with neuronopathic GD, even with known GBA1 variants, and the tough management decisions that can ensue from detection in newborns., (© 2023 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background. Sociodemographically diverse study samples are critical for research related to health decision making. However, not all researchers have the training, capacity, and funding to engage research methods that recruit the most diverse populations. Objective and Methods. We used participant-generated data, staff salary data, and participant observation to examine the effectiveness and cost of strategies that we used for screening, enrolling, and retaining a sociodemographically diverse sample for a risk communication and behavior change randomized controlled trial. Results. It took approximately 646 hours to contact 1,626 individuals and enroll 554 participants (505 of whom completed the baseline survey; 45.2% were members of a underrepresented racial/ethnic group, 19.4% had no college education, 49.5% were age 30-49 y). Retention at 90-d follow-up was 93%. The total cost was USD$19,898.50. The average cost was $35.92 per participant enrolled. In-person recruitment was most successful in identifying the largest proportion of screened and eligible participants who were members of underrepresented racial/ethnic populations (32.8% and 27.8%, respectively) and with no college experience (39.7% and 33.5%, respectively); it also had the highest total cost ($8,079.17). Existing research pools identified the largest proportion of younger participants (ages 30-49 y; 39.3% and 43.4% for screened and eligible, respectively). Existing listservs yielded the smallest proportion of individuals with no college experience and the fewest members of underrepresented racial/ethnic populations but had the lowest total cost ($290.33). Newspaper ads identified the fewest younger individuals and also had the highest cost per participant enrolled ($166.21). Word of mouth had the lowest cost per participant enrolled ($10.47). Conclusion. Results help medical decision-making researchers formulate recruitment plans that increase sociodemographic diversity in study samples. We also ask funders to accommodate increased costs required to maximize sociodemographic diversity in medical decision-making research., Highlights: We provide concrete strategies for recruiting, enrolling, and retaining a sociodemographically diverse study sample.We offer cost estimates for all stages of study recruitment and found that in-person recruitment was the most effective, but also the most expensive, way to identify Black participants and participants with no college experience.It is critical for investigators to have access to institutional infrastructure and resources to support conducting research that is inclusive of diverse sociodemographic groups.An intentionally diverse recruitment staff supports a diverse study sample., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Research reported in this publication was supported by funding from the National Cancer Institute of the National Institutes of Health (R01CA190391). Funding was also provided by the Washington University in St. Louis Institute of Clinical and Translational Sciences grant UL1TR002345 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health. Redcap was supported by Clinical and Translational Science Award (CTSA) grant (UL1 TR000448) and the Siteman Comprehensive Cancer Center and NCI Cancer Center Support Grant P30 CA091842. The content is solely the responsibility of the authors and does not necessarily represent the official view of the NIH., (© The Author(s) 2023.)

Objectives: (1) Test whether a mental imagery-based self-regulation intervention increases physical activity behaviour over 90 days; (2) Examine cognitive and affective precursors of change in physical activity behaviour., Design: A randomized control trial with participants (N = 500) randomized to one of six intervention conditions in a 3 (risk communication format: bulleted list, table, risk ladder) x 2 (mental imagery behaviour: physical activity, active control [sleep hygiene]) factorial design., Methods: After receiving personalized risk estimates via a website on a smartphone, participants listened to an audiorecording that guided them through a mental imagery activity related to improving physical activity (intervention group) or sleep hygiene behaviour (active control). Participants received text message reminders to complete the imagery for 3 weeks post-intervention, 4 weekly text surveys to assess behaviour and its cognitive and affective precursors, and a mailed survey 90 days post-baseline., Results: Physical activity increased over 90 days by 19.5 more minutes per week (95%CI: 2.0, 37.1) in the physical activity than the active control condition. This effect was driven by participants in the risk ladder condition, who exercised 54.8 more minutes (95%CI 15.6, 94.0) in the physical activity condition than participants in the active control sleep hygiene group. Goal planning positively predicted physical activity behaviour (b = 12.2 minutes per week, p = 0.002), but self-efficacy, image clarity, and affective attitudes towards behaviours did not (p > 0.05)., Conclusions: Mental imagery-based self-regulation interventions can increase physical activity behaviour, particularly when supported by personalized disease risk information presented in an easy-to-understand format., (© 2021 The British Psychological Society.)

Recent health policy in the United States encourages an outsourcing of labor from professional practice into domestic spaces, where in theory, medical professionals supply the training, technologies, and guidance needed to discharge responsibility for care to patients or caregivers. Mattingly et al. (2011) term this labor "chronic homework," describing the relationship between the assigning and undertaking of medical care at the borders of professional and domestic domains. This is a system predicated on relationships between professional and caregiver. However, in our research with families and providers in two U.S. sites, we observed a "disarticulation" of asthma care from professional medicine. Caregivers may undertake routine asthma management with little physician oversight, transforming chronic homework into what we term "disarticulated homework." We argue that expanding the concept of chronic homework to theorize disarticulation processes can help elucidate how health disparities are reproduced in the gap between medical systems and domestic life. [asthma, self-management, caregiving pharmaceuticalization, health disparities]., (© 2021 by the American Anthropological Association.)

Background: Personalized medicine may increase the amount of probabilistic information patients encounter. Little guidance exists about communicating risk for multiple diseases simultaneously or about communicating how changes in risk factors affect risk (hereafter "risk reduction")., Purpose: To determine how to communicate personalized risk and risk reduction information for up to 5 diseases associated with insufficient physical activity in a way laypeople can understand and that increases intentions., Methods: We recruited 500 participants with <150 min weekly of physical activity from community settings. Participants completed risk assessments for diabetes, heart disease, stroke, colon cancer, and breast cancer (women only) on a smartphone. Then, they were randomly assigned to view personalized risk and risk reduction information organized as a bulleted list, a simplified table, or a specialized vertical bar graph ("risk ladder"). Last, they completed a questionnaire assessing outcomes. Personalized risk and risk reduction information was presented as categories (e.g., "very low"). Our analytic sample ( N = 372) included 41.3% individuals from underrepresented racial/ethnic backgrounds, 15.9% with vocational-technical training or less, 84.7% women, 43.8% aged 50 to 64 y, and 71.8% who were overweight/obese., Results: Analyses of covariance with post hoc comparisons showed that the risk ladder elicited higher gist comprehension than the bulleted list ( P = 0.01). There were no significant main effects on verbatim comprehension or physical activity intentions and no moderation by sex, race/ethnicity, education, numeracy, or graph literacy ( P > 0.05). Sequential mediation analyses revealed a small beneficial indirect effect of risk ladder versus list on intentions through gist comprehension and then through perceived risk ( b IndirectEffect = 0.02, 95% confidence interval: 0.00, 0.04)., Conclusion: Risk ladders can communicate the gist meaning of multiple pieces of risk information to individuals from many sociodemographic backgrounds and with varying levels of facility with numbers and graphs.

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system., (© 2020 by The American Society of Hematology.)

Objective: We aimed to define preoperative clinical and molecular characteristics that would allow better patient selection for operative resection., Background: Although we use molecular selection methods for systemic targeted therapies, these principles are not applied to surgical oncology. Improving patient selection is of vital importance for the operative treatment of pancreatic cancer (pancreatic ductal adenocarcinoma). Although surgery is the only chance of long-term survival, 80% still succumb to the disease and approximately 30% die within 1 year, often sooner than those that have unresected local disease., Method: In 3 independent pancreatic ductal adenocarcinoma cohorts (total participants = 1184) the relationship between aberrant expression of prometastatic proteins S100A2 and S100A4 and survival was assessed. A preoperative nomogram based on clinical variables available before surgery and expression of these proteins was constructed and compared to traditional measures, and a postoperative nomogram., Results: High expression of either S100A2 or S100A4 was independent poor prognostic factors in a training cohort of 518 participants. These results were validated in 2 independent patient cohorts (Glasgow, n = 198; Germany, n = 468). Aberrant biomarker expression stratified the cohorts into 3 distinct prognostic groups. A preoperative nomogram incorporating S100A2 and S100A4 expression predicted survival and nomograms derived using postoperative clinicopathological variables., Conclusions: Of those patients with a poor preoperative nomogram score, approximately 50% of patients died within a year of resection. Nomograms have the potential to improve selection for surgery and neoadjuvant therapy, avoiding surgery in aggressive disease, and justifying more extensive resections in biologically favorable disease.

Purpose: Breast cancer tumour-infiltrating lymphocytes associate with clinico-pathological factors, including survival, although the literature includes many conflicting findings. Our aim was to assess these associations for key lymphocyte subtypes and in different tumour compartments, to determine whether these provide differential correlations and could, therefore, explain published inconsistencies. Uniquely, we also examine whether infiltrating levels merely reflect systemic lymphocyte levels or whether local factors are predominant in recruitment., Methods: Immunohistochemistry was used to detect tumour-infiltrating CD20+ (B), CD4+ (helper T), CD8+ (cytotoxic T) and FoxP3+ (regulatory T) cells in breast cancers from 62 patients, with quantification in tumour stroma, tumour cell nests, and tumour margins. Levels were analysed with respect to clinico-pathological characteristics and matched circulating levels (determined by flow-cytometry)., Results: CD4+ lymphocytes were the most prevalent subtype in tumour stroma and at tumour edge and CD8+ lymphocytes were most prevalent in tumour nests; FoxP3+ lymphocytes were rarest in all compartments. High grade or hormone receptor negative tumours generally had significantly increased lymphocytes, especially in tumour stroma. Only intra-tumoural levels of CD8+ lymphocytes correlated significantly with matched circulating levels (p < 0.03), suggesting that recruitment is mainly unrelated to systemic activity. High levels of stromal CD4+ and CD20+ cells associated with improved survival in hormone receptor negative cases (p < 0.04), while tumour nest CD8+ and FoxP3+ cells associated with poor survival in hormone receptor positives (p < 0.005)., Conclusions: Lymphocyte subtype and location define differential impacts on tumour biology, therefore, roles of tumour-infiltrating lymphocytes will only be unravelled through thorough analyses that take this into account.

Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC.

Pancreatic cancer is a leading cause of cancer related deaths in the UK. However, public knowledge and understanding of the pancreas is generally poor, therefore pancreatic cancer patients often have to contend with understanding large quantities of new information at a pivotal time in their lives.Despite utilisation of digital visualisation techniques in medical education, very rarely are they being used to help clinicians communicate information to their patients. Specifically, there is no literature describing use of an interactive digital application for use by healthcare professionals to aid discussions specific to pancreatic cancer.Therefore, we developed a workflow methodology, and created an interactive application, thus creating a tool that could help clinicians explain pancreatic cancer anatomy, and staging, to their patients. Three-dimensional (3D) digital models were created using ZBrush and Autodesk 3DS Max, and exported into the Unity game engine. Within Unity, the interactivity of models was maximally utilised, and a simple user interface created.The application centres on anatomically accurate, visually simple, 3D digital models, demonstrating a variety of common scenarios that arise in pancreatic cancer. The design of the application is such that the clinician can select which model is relevant to the patient, and can give an explanation of the anatomy and disease process at a speed and level appropriate to that person. This simple, robust and effective workflow methodology for the development of an application could be useful in any clinical setting that needs visual and interactive tools to enhance patient understanding of a clinical condition.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Human transitional B cells express relatively high IL-10 and low TNF-α levels, which correlate with B regulatory activity in vitro. Herein, we aim to further define B regulatory phenotype and determine whether B regulatory activity can serve as a prognostic marker for renal allograft dysfunction (graft loss or 2-fold fall in estimated glomerular filtration rate). Transitional B cells can be divided into T1 and T2 subsets based on surface phenotype. T1 cells express a significantly higher ratio of IL-10 to TNF-α than T2 cells or other B subsets. When analyzed in 45 kidney transplant recipients at the time of late for-cause biopsy, the T1/T2 ratio was independently associated with allograft dysfunction over the next 5 years. Next, the T1/T2 ratio was examined in an independent set of 97 clinically stable kidney transplant recipients 2 years after transplant. Again, the T1/T2 ratio was strongly and independently associated with allograft dysfunction over the ensuing 5 years. In these clinically quiescent patients, a low T1/T2 ratio identified a 41-patient subgroup in which 35% developed allograft dysfunction, with 25% losing their allografts. However, none of the 56 patients with a high ratio developed graft dysfunction. In both the initial study and validation groups, the T1/T2 ratio was a much stronger predictor of graft dysfunction than donor-specific antibodies or the estimated glomerular filtration rate. Thus, the T1/T2 ratio, a relative measure of expressing an anti-inflammatory cytokine profile, is a novel prognostic marker that might inform individualized immunosuppression., (Copyright © 2016 International Society of Nephrology. All rights reserved.)

CXCR2 has been suggested to have both tumor-promoting and tumor-suppressive properties. Here we show that CXCR2 signaling is upregulated in human pancreatic cancer, predominantly in neutrophil/myeloid-derived suppressor cells, but rarely in tumor cells. Genetic ablation or inhibition of CXCR2 abrogated metastasis, but only inhibition slowed tumorigenesis. Depletion of neutrophils/myeloid-derived suppressor cells also suppressed metastasis suggesting a key role for CXCR2 in establishing and maintaining the metastatic niche. Importantly, loss or inhibition of CXCR2 improved T cell entry, and combined inhibition of CXCR2 and PD1 in mice with established disease significantly extended survival. We show that CXCR2 signaling in the myeloid compartment can promote pancreatic tumorigenesis and is required for pancreatic cancer metastasis, making it an excellent therapeutic target., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

Preclinical modelling studies are beginning to aid development of therapies targeted against key regulators of pancreatic cancer progression. Pancreatic cancer is an aggressive, stromally-rich tumor, from which few people survive. Within the tumor microenvironment cellular and extracellular components exist, shielding tumor cells from immune cell clearance, and chemotherapy, enhancing progression of the disease. The cellular component of this microenvironment consists mainly of stellate cells and inflammatory cells. New findings suggest that manipulation of the cellular component of the tumor microenvironment is possible to promote immune cell killing of tumor cells. Here we explore possible immunogenic therapeutic strategies. Additionally extracellular stromal elements play a key role in protecting tumor cells from chemotherapies targeted at the pancreas. We describe the experimental findings and the pitfalls associated with translation of stromally targeted therapies to clinical trial. Finally, we discuss the key inflammatory signal transducers activated subsequent to driver mutations in oncogenic Kras in pancreatic cancer. We present the preclinical findings that have led to successful early trials of STAT3 inhibitors in pancreatic adenocarcinoma.

Background: Pancreas-specific complications (PSCs), comprising postoperative pancreatic fistula, haemorrhage and intra-abdominal collections, are drivers of morbidity and mortality after pancreaticoduodenectomy (PD). A serum amylase concentration of 130 units/l or more on postoperative day (POD) 0 has been shown to be an objective surrogate of pancreatic texture, a determinant of PSCs. This study evaluated serial measurements of C-reactive protein (CRP) to refine PSC risk stratification., Methods: Consecutive patients undergoing PD between 2008 and 2014, with vascular resection if required and without preoperative chemoradiotherapy, had serum investigations from the day before operation until discharge. Receiver operating characteristic (ROC) curve analysis was used to identify a threshold value of serum CRP with clinically relevant PSCs for up to 30 days after discharge as outcome measure., Results: Of 230 patients, 95 (41·3 per cent) experienced a clinically relevant PSC. A serum CRP level of 180 mg/l or higher on POD 2 was associated with PSCs, prolonged critical care stay and relaparotomy (all P < 0·050). Patients with a serum amylase concentration of 130 units/l or more on POD 0 who developed a serum CRP level of at least 180 mg/l on POD 2 had a higher incidence of morbidity. Patients were stratified into high-, intermediate- and low-risk groups using these markers. The low-risk category was associated with a negative predictive value of 86·5 per cent for development of clinically relevant PSCs. There were no deaths among 52 patients in the low-risk group, but seven deaths among 79 (9 per cent) in the high-risk group., Conclusion: A serum amylase level below 130 units/l on POD 0 combined with a serum CRP level under 180 mg/l on POD 2 constitutes a low-risk profile following PD, and may help identify patients suitable for early discharge., (© 2016 BJS Society Ltd Published by John Wiley & Sons Ltd.)

The concept that motor disorders of the gallbladder, cystic duct and sphincter of Oddi can cause painful syndromes is attractive and popular, at least in the USA. However, the results of commonly performed ablative treatments (cholecystectomy and sphincterotomy) are not uniformly good. The predictive value of tests that are often used to diagnose dysfunction (dynamic gallbladder scintigraphy and sphincter manometry) is controversial. Evaluation and management of these patients is made difficult by the fluctuating symptoms and the placebo effect of invasive interventions. A recent stringent study has shown that sphincterotomy is no better than sham treatment in patients with post-cholecystectomy pain and little or no objective abnormalities on investigation, so that the old concept of sphincter of Oddi dysfunction (SOD) type III is discarded. ERCP approaches are no longer appropriate in that context. There is a pressing need for similar prospective studies to provide better guidance for clinicians dealing with these patients. We need to clarify the indications for cholecystectomy in patients with Functional Gallbladder Disorder (FGBD) and the relevance of sphincter dysfunction in patients with some evidence for biliary obstruction (previously SOD type II, now called "Functional Biliary Sphincter Disorder - FBSD") and with idiopathic acute recurrent pancreatitis., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background: Approximately 30 % of breast cancer patients receive chemotherapy, yet little is known about influences of current regimens on circulating lymphocyte levels and phenotypes. Similarly, clinico-pathological factors that modify these influences, and implications for future immune health remain mainly unexplored., Methods: We used flow-cytometry to assess circulating lymphocyte levels and phenotypes in 88 primary breast cancer patients before chemotherapy and at time-points from 2 weeks to 9 months after chemotherapy completion. We examined circulating titres of antibodies against pneumococcal and tetanus antigens using ELISAs., Results: Levels of B, T and NK cells were significantly reduced 2 weeks after chemotherapy (p < 0.001). B cells demonstrated particularly dramatic depletion, falling to 5.4 % of pre-chemotherapy levels. Levels of all cells recovered to some extent, although B and CD4(+) T cells remained significantly depleted even 9 months post-chemotherapy (p < 0.001). Phenotypes of repopulating B and CD4(+) T cells were significantly different from, and showed no sign of returning to pre-chemotherapy profiles. Repopulating B cells were highly depleted in memory cells, with proportions of memory cells falling from 38 % to 10 % (p < 0.001). Conversely, repopulating CD4(+) T cells were enriched in memory cells, which increased from 63 % to 75 % (p < 0.001). Differences in chemotherapy regimen and patient smoking were associated with significant differences in depletion extent or repopulation dynamics. Titres of anti-pneumococcal and anti-tetanus antibodies were both significantly reduced post-chemotherapy and did not recover during the study (p < 0.001)., Conclusion: Breast cancer chemotherapy is associated with long-term changes in immune parameters that should be considered during clinical management.

The effects of storage time and temperature on blood alcohol concentration were evaluated in this two-part study involving 34 ethanol-negative and 21 ethanol-positive volunteers. Multiple 10-mL Vacutainer(®) blood tubes containing 100 mg of sodium fluoride and 20 mg of potassium oxalate were collected from living persons and subjected to various storage conditions. The time from collection to analysis ranged from 0 to 60 days and storage temperatures ranged from 3 to 20°C. Regardless of the storage conditions, all ethanol-negative samples remained negative (<0.0025 g/100 mL) throughout the study. There was no increase in the concentration of ethanol-positive samples beyond the expected variability of the method, regardless of storage time or temperature. Many ethanol-positive samples demonstrated decreases in concentration during storage compared with the original immediate analysis. The findings from this study support previous research, which demonstrates that microbial formation of ethanol in properly collected antemortem blood is unlikely., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild-type and Cxcr2(-/-) mice. Strikingly, Cxcr2(-/-) mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2(-/-) mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non-neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild-type mice replicated the protection seen in Cxcr2(-/-) mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis., (© 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre Kras(G12D/+) Trp53(R172H/+) (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease., (© 2015 Cancer Research UK Beatson Institute. Published under the terms of the CC BY 4.0 license.)

ATP-sensitive K(+) (KATP) channels play an important role in insulin secretion. KATP channels possess intrinsic MgATPase activity that is important in regulating channel activity in response to metabolic changes, although the precise structural determinants are not clearly understood. Furthermore, the sulfonylurea receptor 1 (SUR1) S1369A diabetes risk variant increases MgATPase activity, but the molecular mechanisms remain to be determined. Therefore, we hypothesized that residue-residue interactions between 1369 and 1372, predicted from in silico modelling, influence MgATPase activity, as well as sensitivity to the clinically used drug diazoxide that is known to increase MgATPase activity. We employed a point mutagenic approach with patch-clamp and direct biochemical assays to determine interaction between residues 1369 and 1372. Mutations in residues 1369 and 1372 predicted to decrease the residue interaction elicited a significant increase in MgATPase activity, whereas mutations predicted to possess similar residue interactions to wild-type (WT) channels elicited no alterations in MgATPase activity. In contrast, mutations that were predicted to increase residue interactions resulted in significant decreases in MgATPase activity. We also determined that a single S1369K substitution in SUR1 caused MgATPase activity and diazoxide pharmacological profiles to resemble those of channels containing the SUR2A subunit isoform. Our results provide evidence, at the single residue level, for a molecular mechanism that may underlie the association of the S1369A variant with type 2 diabetes. We also show a single amino acid difference can account for the markedly different diazoxide sensitivities between channels containing either the SUR1 or SUR2A subunit isoforms., (© 2015 Authors.)

Purpose: The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome., Material and Methods: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome., Results: Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis., Conclusions: Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years.

Consensus advocating a principle of early organ support, nutritional optimisation, followed ideally by delayed minimally invasive intervention within a "step-up" framework where possible has radically changed the surgical approach to complications of acute pancreatitis in the last 20 years. The 2012 revision of the Atlanta Classification incorporates these changes, and provides a background which underpins the complexities of individual patient management decisions. This paper discusses the place for delayed minimally invasive surgical intervention (percutaneous necrosectomy, video-assisted retroperitoneal debridement (VARD)), and the rationale for opting to adopt a percutaneous approach over endoscopic or laparoscopic approaches in different clinical situations.

Objective: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease., Design: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition., Results: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours., Conclusions: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens., Methods: Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0-300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve., Results: The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off., Conclusion: A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.

Human B cells with immunoregulatory properties in vitro (Bregs) have been defined by the expression of IL-10 and are enriched in various B-cell subsets. However, proinflammatory cytokine expression in B-cell subsets is largely unexplored. We examined the cytokine profiles of human PBMCs and found that subsets of CD24(hi)CD38(hi) transitional B cells (TrBs), CD24(hi)CD27(+) memory B cells, and naïve B cells express IL-10 and the proinflammatory cytokine TNF-α simultaneously. TrBs had the highest IL-10/TNF-α ratio and suppressed proinflammatory helper T cell 1 (Th1) cytokine expression by autologous T cells in vitro more potently than memory B cells did, despite similar IL-10 expression. Whereas neutralization of IL-10 significantly inhibited TrB-mediated suppression of autologous Th1 cytokine expression, blocking TNF-α increased the suppressive capacity of both memory and naïve B-cell subsets. Thus, the ratio of IL-10/TNF-α expression, a measure of cytokine polarization, may be a better indicator of regulatory function than IL-10 expression alone. Indeed, compared with TrB cells from patients with stable kidney graft function, TrBs from patients with graft rejection displayed similar IL-10 expression levels but increased TNF-α expression (i.e., reduced IL-10/TNF-α ratio), did not inhibit in vitro expression of Th1 cytokines by T cells, and abnormally suppressed expression of Th2 cytokines. In patients with graft dysfunction, a low IL-10/TNF-α ratio in TrBs associated with poor graft outcomes after 3 years of follow-up. In summary, these results indicate that B cell-mediated immune regulation is best characterized by the cytokine polarization profile, a finding that was confirmed in renal transplant patients., (Copyright © 2014 by the American Society of Nephrology.)

Objectives: Drainage after pancreaticoduodenectomy (PD) remains controversial because the risk for uncontrolled postoperative pancreatic fistula (POPF) must be balanced against the potential morbidity associated with prolonged and possibly unnecessary drainage. This study investigated the utility of the level of serum amylase on the night of surgery [postoperative day (PoD) 0 serum amylase] to predict POPF., Methods: A total of 185 patients who underwent PD were studied. Occurrences of POPF were graded using the International Study Group on Pancreatic Fistula (ISGPF) classification. Receiver operating characteristic (ROC) analysis identified a threshold value of PoD 0 serum amylase associated with clinically significant POPF (ISGPF Grades B and C) in a test cohort (n = 45). The accuracy of this threshold value was then tested in a validation cohort (n = 140)., Results: Overall, 43 (23.2%) patients developed clinically significant POPF. The threshold value of PoD 0 serum amylase for the identification of clinically significant POPF was ≥ 130 IU/l (P = 0.003). Serum amylase of <130 IU/l had a negative predictive value of 88.8% for clinically significant POPF (P < 0.001). Serum amylase of ≥ 130 IU/l on PoD 0 and a soft pancreatic parenchyma were independent risk factors for clinically significant POPF., Conclusions: Postoperative day 0 serum amylase of <130 IU/l allows for the early and accurate categorization of patients at least risk for clinically significant POPF and may identify patients suitable for early drain removal., (© 2013 International Hepato-Pancreato-Biliary Association.)

TRPV1 channels are an important class of membrane proteins that play an integral role in the regulation of intracellular cations such as calcium in many different tissue types. The anionic phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) is a known positive modulator of TRPV1 channels and the negatively charged phosphate groups interact with several basic amino acid residues in the proximal C-terminal TRP domain of the TRPV1 channel. We and other groups have shown that physiological sub-micromolar levels of long-chain acyl CoAs (LC-CoAs), another ubiquitous anionic lipid, can also act as positive modulators of ion channels and exchangers. Therefore, we investigated whether TRPV1 channel activity is similarly regulated by LC-CoAs. Our results show that LC-CoAs are potent activators of the TRPV1 channel and interact with the same PIP2-binding residues in TRPV1. In contrast to PIP2, LC-CoA modulation of TRPV1 is independent of Ca2+i, acting in an acyl side-chain saturation and chain-length dependent manner. Elevation of LC-CoAs in intact Jurkat T-cells leads to significant increases in agonist-induced Ca2+i levels. Our novel findings indicate that LC-CoAs represent a new fundamental mechanism for regulation of TRPV1 channel activity that may play a role in diverse cell types under physiological and pathophysiological conditions that alter fatty acid transport and metabolism such as obesity and diabetes.

Background & Aims: Pancreatic ductal adenocarcinoma (PDAC) is often lethal because it is highly invasive and metastasizes rapidly. The actin-bundling protein fascin has been identified as a biomarker of invasive and advanced PDAC and regulates cell migration and invasion in vitro. We investigated fascin expression and its role in PDAC progression in mice., Methods: We used KRas(G12D) p53(R172H) Pdx1-Cre (KPC) mice to investigate the effects of fascin deficiency on development of pancreatic intraepithelial neoplasia (PanIn), PDAC, and metastasis. We measured levels of fascin in PDAC cell lines and 122 human resected PDAC samples, along with normal ductal and acinar tissues; we associated levels with patient outcomes., Results: Pancreatic ducts and acini from control mice and early-stage PanINs from KPC mice were negative for fascin, but approximately 6% of PanIN3 and 100% of PDAC expressed fascin. Fascin-deficient KRas(G12D) p53(R172H) Pdx1-Cre mice had longer survival times, delayed onset of PDAC, and a lower PDAC tumor burdens than KPC mice; loss of fascin did not affect invasion of PDAC into bowel or peritoneum in mice. Levels of slug and fascin correlated in PDAC cells; slug was found to regulate transcription of Fascin along with the epithelial-mesenchymal transition. In PDAC cell lines and cells from mice, fascin concentrated in filopodia and was required for their assembly and turnover. Fascin promoted intercalation of filopodia into mesothelial cell layers and cell invasion. Nearly all human PDAC samples expressed fascin, and higher fascin histoscores correlated with poor outcomes, vascular invasion, and time to recurrence., Conclusions: The actin-bundling protein fascin is regulated by slug and involved in late-stage PanIN and PDAC formation in mice. Fascin appears to promote formation of filopodia and invasive activities of PDAC cells. Its levels in human PDAC correlate with outcomes and time to recurrence, indicating it might be a marker or therapeutic target for pancreatic cancer., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)