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The current paper revisits and builds upon task demonstrability, which defines the criteria necessary for groups to choose a correct response if any member prefers that response. We identify boundary conditions of the current conceptualization of task demonstrability with respect to its use in understanding modern organizational teams. Specifically, we argue that, in its current form, task demonstrability is not optimally suited to studying ongoing teams in which member expertise varies and teams work to complete complex multifaceted tasks. To address this issue, we provide a revisited perspective on demonstrability. We specify the nomological network of revisited demonstrability and recast each of its criteria in a form that preserves the original intent of the construct, but has broader applicability, particularly to organizational contexts. We then discuss theoretical implications and managerial applications of the construct. Finally, noting that there is no standard assessment tool for demonstrability (original or revisited), we develop and validate a measure to facilitate future research.

Understanding chronic pain and disability requires a consideration of the lived experience of the patient. There is limited evaluation of the content validity of patient-reported outcome measures (PROMs) in chronic pain using a comprehensive biopsychosocial view of the patient's experience. To address this gap, this study aimed to evaluate the content validity of PROMs for patients with chronic pain. A literature review was performed to identify PROMs for patients with chronic pain. Concepts from PROMs were linked to the International Classification of Functioning, Disability, and Health (ICF); the ICF Core Set for Chronic Widespread Pain; and the International Classification of Diseases-11 Functioning Properties of Chronic Pain (FP). Concepts were compared with published "attributes'' of chronic pain. 62 PROMs (1336 items total) were identified and linked to 560 unique second-level ICF categories. The greatest number of items across PROMs were represented in the activities and participation category (44% of all total items), followed by body functions (41%), environmental factors (9%), personal factors (5%), and body structures (0.3%). There was a 41% to 78% match with the Core Set for Chronic Widespread Pain and the International Classification of Diseases-11 FP, respectively. 20% of items reflected the pain-experience attributes with the most items reflecting the concept of "control over pain." Content validity analysis suggests chronic widespread pain patient-reported outcome measures poorly address attributes of living with chronic pain that matter most to patients. Future development or refinement should consider a more comprehensive view of the patients' lived experience.

The importance of Ca2+ signaling, and particularly Ca2+ channels, in key events of cancer cell function such as proliferation, metastasis, autophagy and angiogenesis, has recently begun to be appreciated. Of particular note are two-pore channels (TPCs), a group of recently identified Ca2+-channels, located within the endolysosomal system. TPC2 has recently emerged as an intracellular ion channel of significant pathophysiological relevance, specifically in cancer, and interest in its role as an anti-cancer drug target has begun to be explored. Herein, an overview of the cancer-related functions of TPC2 and a discussion of its potential as a target for therapeutic intervention, including a summary of clinical trials examining the TPC2 inhibitors, naringenin, tetrandrine, and verapamil for the treatment of various cancers is provided.

This research aims to understand the content and nature, and to explore the harm potential, of suspected 3,4-methylenedioxymethamphetamine (MDMA) substances circulating at music festivals in New South Wales.Across 19 music festivals held between October 2019 and March 2020, 302 substances detected and suspected by police to contain MDMA were selected for quantitative analysis.Five percent of substances contained a drug other than MDMA (n = 13) or no drug (n = 2). The remaining 95.0% (n = 287) contained MDMA. Of this sub-sample, capsule was the commonest form (83.3%), followed by tablet (7.7%), crystal (6.3%) and powder (2.8%). The median MDMA base-purity of non-tablet forms ranged between 73.5% and 75.0%. The median MDMA base-dose per tablet (116 mg) was higher than per capsule (68 mg). The dose range varied substantially for capsules (14-146 mg) and tablets (24-201 mg). A higher dose (130 mg or greater) was found in 3.5% of MDMA tablets or capsules. Adulterants were identified in 14.1% of MDMA substances but only 1.6% contained a psychoactive adulterant and none presented as dangerous due to their nature or low concentration.Dangerous MDMA adulterants or new psychoactive substances in tablet, capsule, powder or crystal forms (whether misrepresented as MDMA or not) were unlikely to be in circulation during the study period. Harm reduction messaging should inform that a key risk-factor for MDMA-related harm is the high and wide variation of purity and dose across forms. Market changes may have occurred since COVID-19, but continued monitoring will ensure messaging remains current.

Background and Purpose: Colorectal cancer (CRC) is a major health problem worldwide. Dicarbonyl electrophiles, such as iso-levuglandins (isoLGs), are generated from lipid peroxidation and form covalent adducts with amine-containing macromolecules. We have shown high levels of adducts of isoLGs in colonic epithelial cells from patients with CRC. We thus investigated the role of these reactive aldehydes on colon cancer development. Experimental Approach: We investigated the effect of oral treatment with 2-hydroxybenzylamine (2-HOBA), a natural compound derived from buckwheat seeds that acts as a potent scavenger of electrophiles, on colon carcinogenesis using the azoxymethane-dextran sulfate sodium model of colitis-associated carcinogenesis and mice with epithelial-specific deletion of the adenomatous polyposis coli gene, as a model of sporadic cancer. We also tested 2-HOBA in a murine xenograft of human HCT116 CRC cells implanted into the flank of nude mice. Key Results: 2-HOBA is bioavailable in the colon of mice after supplementation in the drinking water and does affect the colonic microbiome. However, it reduced the level of isoLG adducts to lysine as well as tumorigenesis in both models of CRC. In parallel, we found that NRF2 activation and signaling was decreased in the colon of 2-HOBA-treated mice. Last, the growth of human tumors is significantly attenuated by 2-HOBA supplementation. Conclusion and Implications: 2-HOBA, which has been shown to be safe in humans, reduces colon tumorigenesis and growth of tumor cells in three distinct models of CRC. Thus, 2-HOBA represents a promising natural compound for the prevention and treatment of CRC.

INTRODUCTION Aconitate decarboxylase 1 (ACOD1; also known as IRG1) is highly expressed in activated macrophages and converts cis-aconitate to itaconate, which contributes to the antimicrobial activity of macrophages. The role of ACOD1 in intestinal inflammation remains unknown. Therefore, we investigated the role of ACOD1 during colitis induced by Citrobacter rodentium (C. rodentium), a murine bacterial pathogen used to model the pathogenesis of enteropathogenic Escherichia coli, and dextran sulfate sodium (DSS) a model of epithelial injury-mediated inflammation. METHODS The GEO database was utilized to examine ACOD1 mRNA levels in ulcerative colitis (UC) and Crohn’s disease (CD) patients, and normal controls. C57BL/6 wild-type (WT) and Acod1–/– mice were infected with C. rodentium for 14 days or given 4% DSS for 5 days and then normal drinking water for 5 days. Mice were weighed daily. Histology was analyzed by H&E staining on colon Swiss rolls using a 0-21 scale for C. rodentium infection and a 0-40 scale for DSS. DNA was extracted from stool to use for 16S microbiome analysis from 5 naïve WT and 5 Acod1–/– mice. RESULTS ACOD1 expression is increased in the colon of UC and CD patients compared to normal controls (GEO GSE16879). Further ACOD1 is significantly increased in active UC compared to inactive (P=0.0256) (GEO GSE75214). C. rodentium-infected Acod1–/– mice lost significantly more body weight compared to infected WT mice (P CONCLUSION While ACOD1 is increased in human IBD tissues, our data indicates that this enzyme has a protective role in experimental colitis. Notably, Acod1 deletion is associated with an altered microbiome. Together our findings suggest that enhancement of ACOD1 activity may represent a new therapeutic strategy for IBD.

Established simulation methods generally require from the modeller a broad and detailed knowledge of the system under study. This paper proposes the application of Reinforcement Learning in an Agent-Based Simulation model to enable agents to define the necessary interaction rules. The model is applied to queue network systems, which are a proxy for broader applications, in order to be validated. Simulation tests compare results obtained from learning agents and results obtained from known good rules. The comparison shows that the learning model is able to learn efficient policies on the go, providing an interesting framework for simulation.

background/Introduction The Covid-19 pandemic created immense unexpected pressure on postgraduate health care professional students undertaking academic study. The role of a community of practice within an international cohort of postgraduate students became apparent as the pandemic progressed. Needing a supported space away from social media in which to discuss developing issues, and a forum in which useful resources could be shared swiftly became apparent. A closed ‘Discussion board’ facility was used within the virtual learning platform in which themes and collections of support, ideas and materials were developed. Methods Qualitative thematic analysis of anonymised contributions to the Discussion board 25th March 2020 - 31st July 2020. Permission was sought retrospectively from all participants on the Discussion Board; any information from those not willing for their content to be included was deleted from the transcripts before review. The transcripts were reviewed by 2 independent researchers for content and context. Results 13 themes developed. Sharing resources (March); ethical issues, communication skills (including virtual communication), symptom control, team support and leadership, the challenge of covid 19 in remote communities, the collateral damage of the pandemic for children, involving the family remotely and maintaining one’s own wellbeing in a pandemic ( April); Developing services, moving forward and quality improvement ( May); moral courage and managing the symptom of breathlessness (June). Conclusions The generation of themes reflected the unprecedented challenges of the phase of the pandemic being experienced. Symptom control, communication skills and ethics leading to their application in different settings and the need after the first few weeks for team support, mental resilience and leadership. Valuable reflections and resources have been developed to help support future surges.

With exascale computing forthcoming, performance metrics such as memory traffic and arithmetic intensity are increasingly important for codes that heavily utilize numerical kernels. Performance metrics in different CPU architectures can be monitored by reading the occurrences of various hardware events. However, from architecture to architecture, it becomes more and more unclear which native performance events are indexed by which event names, making it difficult for users to understand what specific events actually measure. This ambiguity seems particularly true for events related to hardware that resides beyond the compute core, such as events related to memory traffic. Still, traffic to memory is a necessary characteristic for determining arithmetic intensity. To alleviate this difficulty, PAPI’s Counter Analysis Toolkit measures the occurrences of events through a series of benchmarks, allowing its users to discover the high-level meaning of native events. We (i) leverage the capabilities of the Counter Analysis Toolkit to identify the names of hardware events for reading and writing bandwidth utilization in addition to floating-point operations, (ii) measure the occurrences of the events they index during the execution of important numerical kernels, and (iii) verify their identities by comparing these occurrence patterns to the expected arithmetic intensity of the numerical kernels.

Bilio-enteric fistulization is the aberrant connection between the biliary and luminal digestive tracts. The cholecystocolonic fistula (CCF) is the second most common bilio-enteric fistula (comprising 20% of cases), after the cholocystoduodenal fistula (comprising 70% of all cases). A CCF may result from malignancy or more benign etiologies, such as gallstones, and is thought to arise from a chronic inflammatory cadence of tissue necrosis, tissue perforation, and fistula creation. The combination of chronic watery diarrhea, vitamin K malabsorption, and radiological evidence of pneumobilia in a patient with history of gallstone disease has been suggested as a pathognomonic triad of CCF. Here, we present a case of a 62-year-old woman exhibiting this triad, who was found to have a CCF as a result of chronic gallstone-related disease. Recognition of this rare etiology of chronic diarrhea can enhance clinicians' diagnostic appraisal and management of this common chief complaint.

Maternal diabetes impairs fetal development and increases the risk of metabolic diseases in the offspring. Previously, we showed maternal dietary supplementation with 6% of olive oil prevents diabetes-induced embryo and fetal defects, in part, through the activation of peroxisome proliferator-activated receptors (PPARs). In this study we examined the effects of this diet on neonatal and adult pancreatic development in both male and female offspring. A mild diabetic model was developed by injecting neonatal rats with streptozotocin (90 mg/kg). During pregnancy these dams were fed a chow diet supplemented or not with 6% olive oil. Dual immunohistochemistry was performed to detect α and β cells in islets at post-natal day 2 and at 5 months of age. Morphometric analysis was carried out to determine the number of islets, α and β cell clusters and β-cell mass. At 5 months, male offspring of diabetic mothers had reduced β-cell mass. Moreover, this β-cell pancreatic deficit was prevented by the maternal supplementation with olive oil. While no changes in PPARα expression was detected in the pancreas, both PPARβ/δ and PPARγ expression were reduced in 5-month-old male offspring of diabetic rats. Interestingly, the reduction in PPAR β/δ expression was prevented by maternal olive-oil supplementation. To further explore the direct effects on PPARs, INS-1E (β) and αTC1-6 (α) cell lines were treated with oleic acid. Interestingly PPARβ/δ expression is highly expressed in INS-1E. Collectively, these findings suggest that olive oil supplementation in utero may prevent diabetes-induced β cell loss in postnatal life by modulating pancreatic PPARs.