BACKGROUND:Chronic neuropathic pain (CNP) is a debilitating condition, often refractory to currently available drugs. Understanding biochemical alterations in peripheral tissues such as blood will be useful for understanding underlying pathophysiological processes relating to CNP. METHODS:We collected blood from two independent cohorts of CNP and pain-free controls (CNP n = 129/Controls n = 127) in the UK and Ireland to investigate the relationship between CNP-associated molecular/biochemical alterations and a range of clinical and pain metric parameters. Multiple statistical comparisons were conducted on the data, with selected variables included in one or more of the intended inferential analyses (six models). RESULTS:Gene expression analysis showed that choline phosphotransferase (CHPT1) was increased (p < .001) in the CNP group compared to controls. The levels of phosphatidylcholine, a metabolite of CHPT1 in the Kennedy Pathway, were significantly (p = .008) decreased in the plasma of patients with CNP. Given the relationship between the Kennedy pathway and endocannabinoids, plasma endocannabinoids and related N-acylethanolamines were quantified in clinical samples by HPLC-Tandem Mass Spectrometry. Plasma levels of the endocannabinoid 2-arachidonoylglycerol were higher in CNP samples compared to controls, and in the statistical models applied, 2-arachidonoylglycerol significantly increased the odds of CNP (p < .001). The expression of genes related to the synthesis and catabolism of endocannabinoids also corroborated the increased plasma 2-arachidonoylglycerol levels in patients with CNP. CONCLUSIONS:Endocannabinoid levels, expression of genes related to endocannabinoid metabolism, age, sex, depression and anxiety state together were strong predictors of CNP. The observed molecular changes indicate that lipid metabolism is altered in CNP and thus may represent a viable target for novel analgesics or biomarker development.

Research methodology This case was developed through secondary sources in response to the environmental concerns being raised in legal actions, company documents, online forums, trade press articles and academic research relative to Li mining practices, a key material in Li-ion batteries. The case focuses on Tesla’s actual and potential response to the environmental and humanitarian concerns being raised with its battery supply chain Case overview/synopsis Tesla was one of the world’s leading producers of Li-ion batteries which were critical to its EV and battery offerings. Unfortunately, sourcing rare earth metals, such as Co and Li, which are key components in these batteries, raise several environmental and social concerns. This case highlights senior leadership considerations critical to environmental, social and governance (ESG) issues, including environmental tradeoffs and issue management. The case highlights the complexity of strategic decision-making in innovative and ESG contexts and challenges the students to contextualize the trade-offs behind each decision and the potential impact to associated stakeholders. Complexity academic level Level: Upper undergraduate and masters. Majors: Management; technology & innovation management; environmental science; science, technology & society; supply chain management; business ethics. Courses: Strategic management (social issues in management, strategic management, technological innovation); technology & society; ethics, supply chain management. Time: 60- or 90-minute class session. Supporting texts (depending on course context): Strategic Management of Technological Innovation. Schilling, M. McGraw Hill, 2017. Contemporary Strategy Analysis. Grant, R. Wiley, 2017. Society, Ethics & Technology. Winston, M., Edelbach, R. Cengage, 2014. Principles of Supply Chain Management. Wisner, J., Tan, K., Leong, G. Cengage, 2019.

Social media networks are expanding rapidly, increasing the spread and scale of information diffusion. Researchers have highlighted distinguishing features of social media network platforms: network structure transparency, public self-monitored digital profiles, homogenized network connections, and node-created digital content. These features, while adding utility to social media platform providers and users, can also be exploited to manipulate users' behavior and overall network outcomes. This paper posits the importance of network theory as critical foundational "laws" upon which the responsible innovation of social media can be built to minimize such manipulation, how such theory can be used to predict the potential impacts of new network innovations, and the resulting difficulty this framing suggests for self-governance on the part of platform providers. Through a case study analysis of Russian social media interference in the 2016 U.S. presidential election, the value of a network theoretic lens is highlighted. The concept of "supranodes", social media nodes empowered via theoretical knowledge and network awareness to socially engineer network structures and outcomes, is developed and the network theoretic features they exploit discussed.

Background: Skin regeneration from an injury without a scar is still a challenge. Methods: A murine model of a skin wound was treated with a combination of extract of astragalus and exosomes of mesenchymal stem cells (MSCs). CD11b+ and CD45 macrophages were detected and levels of cytokines were tested. Results: The expression of growth factors VEGF, FGF2 and EGF was elevated after treatment administered to MSCs. The administration of ethanolic extract of astragalus decreased the expression of TNF-α, IL-1β and IL-6 and simultaneously increased the levels of IL-10. The combination sped up the process of wound healing. A sustained-release gel with both ingredients was developed to enhance restoration from granulation. Conclusion: The extract of astragalus promotes the efficacy of MSC-derived exosomes in skin repair.

Peri-conceptional environment can induce permanent changes in embryo phenotype which alter development and associate with later disease susceptibility. Thus, mouse maternal low protein diet (LPD) fed exclusively during preimplantation is sufficient to lead to cardiovascular, metabolic and neurological dysfunction in adult offspring. Embryonic stem cell (ESC) lines were generated from LPD and control NPD C57BL/6 blastocysts and characterised by transcriptomics, metabolomics, bioinformatics and molecular/cellular studies to assess early potential mechanisms in dietary environmental programming. Previously, we showed these lines retain cellular and epigenetic characteristics of LPD and NPD embryos after several passages. Here, three main changes were identified in LPD ESC lines. First, their derivation capacity was reduced but pluripotency marker expression was similar to controls. Second, LPD lines had impaired Mitogen-activated protein kinase (MAPK) pathway with altered gene expression of several regulators (e.g., Maff, Rassf1, JunD), reduced ERK1/2 signalling capacity and poorer cell survival characteristics which may contribute to reduced derivation. Third, LPD lines had impaired glucose metabolism comprising reduced upstream enzyme expression (e.g., Gpi, Mpi) and accumulation of metabolites (e.g., glucose-6-P, fructose-6-P) above the phosphofructokinase (PFK) gateway with PFK enzyme activity reduced. ESC lines may therefore permit investigation of peri-conceptional programming mechanisms with reduced need for animal experimentation.

The [3H]DNA product of the murine sarcoma-leukemia virus (MSV(MLV)) and viral 60–70 S [3H]RNA was annealed with cytological preparations of mouse and rat cells transformed by the Harvey and Moloney strains of MSV. With viral [3H]DNA as cytological probe, these in situ hybridization measurements detected from 25 to 30 autoradiographic grains per interphase nucleus of transformed cells and 1 to 3 grains per nucleus of uninfected rat and mouse cells. With viral 60–70 S [3H]RNA of lower specific radioactivity as cytological probe, 12 grains per transformed cell nucleus were detected. These findings indicate that transformation of cells with MSV(MLV) produces a several-fold increase in the content of some virus-specific DNA sequences. Virus-specific sequences in transformed mouse cells were localized in the chromocenters of interphase nuclei.

A 63-year-old woman presented with ulcerations of both lower legs. Symptom onset was 2006. In 2013 she saw a dermatologist and a biopsy suggested livedoid vasculopathy. In 2016 a whole food plant-based diet (WFPB) was advised as a potential treatment in the community setting. The patient changed her diet accordingly, but was not otherwise treated. The symptoms remitted completely with close adherence to the WFPB diet and recurred on multiple occasions associated with poor dietary adherence. There was a self-identified dose–response relationship with degree of adherence and number and intensity of flares. There were no known adverse side effects from the diet change, although the patient felt adherence to be difficult at times. The mechanism is not completely clear; we speculate that the dietary changes directly affect vascular endothelial health, which in turn affects propensity towards a prothrombotic state. More research is needed to elucidate potential mechanisms.

In this study, we recruited 50 chronic pain (neuropathic and nociceptive) and 43 pain-free controls to identify specific blood biomarkers of chronic neuropathic pain (CNP). Affymetrix microarray was carried out on a subset of samples selected 10 CNP and 10 pain-free control participants. The most significant genes were cross-validated using the entire dataset by quantitative real-time PCR (qRT-PCR). In comparative analysis of controls and CNP patients, WLS ( P = 4.80 × 10 –7 ), CHPT1 ( P = 7.74 × 10 –7 ) and CASP5 ( P = 2.30 × 10 –5 ) were highly significant, whilst FGFBP2 ( P = 0.00162), STAT1 ( P = 0.00223), FCRL6 ( P = 0.00335), MYC ( P = 0.00335), XCL2 ( P = 0.0144) and GZMA ( P = 0.0168) were significant in all CNP patients. A three-arm comparative analysis was also carried out with control as the reference group and CNP samples differentiated into two groups of high and low S-LANSS score using a cut-off of 12. STAT1 , XCL2 and GZMA were not significant but KIR3DL2 ( P = 0.00838), SH2D1B ( P = 0.00295) and CXCR31 ( P = 0.0136) were significant in CNP high S-LANSS group (S-LANSS score > 12), along with WLS (P = 8.40 × 10 –5 ), CHPT1 ( P = 7.89 × 10 –4 ) , CASP5 ( P = 0.00393) , FGFBP2 ( P = 8.70 × 10 –4 ) and FCRL6 ( P = 0.00199), suggesting involvement of immune pathways in CNP mechanisms. None of the genes was significant in CNP samples with low (< 12) S-LANSS score. The area under the receiver operating characteristic (AUROC) analysis showed that combination of MYC , STAT1 , TLR4 , CASP5 and WLS gene expression could be potentially used as a biomarker signature of CNP (AUROC − 0.852, (0.773, 0.931 95% CI)).

AIMS:The Rural Hospital Medicine Training Programme (RHMTP) was established in 2008 to develop New Zealand's rural hospital medical workforce. This study evaluates the RHMTP's first 10-year outcomes.METHODS:A mixed-methods descriptive study. Database interrogation of: the Royal New Zealand College of General Practitioners records; University of Otago's e-Vision; the Medical Council of New Zealand's register of doctors. A survey of trainees who had graduated or withdrew from the programme. Survey questions included: current scope and place of employment; undergraduate rural experience; and trainee experiences.RESULTS:From 2009-2018, 98 doctors entered the RHMTP: 29 graduated, 20 withdrew and 49 are active registrars. Of the graduates, more than half (17/29) also completed GP training. Overall survey response rate: 80% (39/49). Graduate response rate: 97% (28/29). 92% (24/26) of currently practising graduates are working in rural New Zealand, mostly (22/24) in rural hospitals. Trainees value the RHMTP's flexibility and breadth of clinical exposure. The main challenges relate to a lack of alignment of training requirements and funding.CONCLUSIONS:In its first decade, the RHMTP has been successful in generating a rural hospital workforce and the programme is steadily growing. Attention to existing barriers is needed to ensure the RHMTP can reach its potential to benefit all of New Zealand's rural communities.

No external funding was received for this study. This research has not previously been published. There are no conflicts of interest.

The definition of a “tipping point” suggests a moment in time when a series of small changes creates a disproportionately large effect. In its original scientific reference, a tipping point implies a change that is irreversible and beyond our control - such as the spread of an epidemic. Following Gladwell’s popular book “ The tipping point: How little things can make a big difference” (2000), the phrase has become a catch-all sensemaking device to reference complex social phenomena that trigger our epidemiological imagination – from the idea that something is “going viral” to innovative changes in business models. In this article, we seek to better understand the defining features of the phenomena that individuals perceive as tipping points in social science. We conduct an experiment with 178 subjects analyzing 32 potential tipping points; we utilize advanced machine learning methods as we enlighten the dynamic relationship between the characteristics of the perceiver and their perceptions of the phenomena in defining when a tipping point is believed to occur. This is the first empirical study to the authors’ knowledge designed to investigate the concept of tipping points and what they mean to the individuals who perceive them. The implications of this preliminary effort conclude this article.

Faculty approaches successfully used in traditional classroom settings do not necessarily translate smoothly into online environments and new methods are required to be effective. In this paper we explore teacher presence in online environments. With online teacher presence less can be more and therefore must be consciously managed. Through the use of a single longitudinal case study, we track the evolution of an online MBA course from its initial offering through major revisions made to improve faculty performance. Changes to improve faculty presence are discussed and the importance of contextual factor considerations are proposed

Maternal immune activation (mIA) in rodents is rapidly emerging as a key model for neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. Here, we optimise a mIA model in rats, aiming to address certain limitations of current work in this field. Specifically, the lack of clear evidence for methodology chosen, identification of successful induction of mIA in the dams and investigation of male offspring only. We focus on gestational and early juvenile changes in offspring following mIA, as detailed information on these critical early developmental time points is sparse. Following strain (Wistar, Lister Hooded, Sprague Dawley) comparison and selection, and polyriboinosinicpolyribocytidylic acid (poly I:C) dose selection (2.5-15 mg/kg single or once daily for 5 days), mIA was induced in pregnant Wistar rats with 10 mg/kg poly I:C i.p. on gestational day (GD) 15. Early morphometric analysis was conducted in male and female offspring at GD21 and postnatal day (PD) 21, eight dams for each treatment at each time point were used, 32 in total. Subsequent microglia analysis was conducted at PD21 in a small group of offspring. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C at 10 mg/kg i.p. induced a robust, but variable, plasma IL-6 response 3 h post-injection and reduced body weight at 6 h and 24 h post-injection in two separate cohorts of Wistar rats at GD15. Plasma IL-6 was not elevated at PD21 in offspring or dams. Poly I:C-induced mIA did not affect litter numbers, but resulted in PD21 pup, and GD21 placenta growth restriction. Poly I:C significantly increased microglial activation at PD21 in male hippocampi. We have identified 10 mg/kg poly I:C i.p on GD15 as a robust experimental approach for inducing mIA in Wistar rats and used this to identify early neurodevelopmental changes. This work provides a framework to study the developmental trajectory of disease-relevant, sex-specific phenotypic changes in rats.

Tetrahydrobiopterin (BH4) is a cofactor in the production of various signaling molecules including nitric oxide, dopamine, adrenaline, and noradrenaline. BH4 levels are critical for processes associated with cardiovascular function, inflammation, mood, pain, and neurotransmission. Increasing pieces of evidence suggest that BH4 is upregulated in chronic pain. Sepiapterin reductase (SPR) catalyzes both the reversible reduction of sepiapterin to dihydrobiopterin (BH2) and 6-pyruvoyl-tetrahydrobiopterin to BH4 within the BH4 pathway. Therefore, inhibition of SPR by small molecules can be used to control BH4 production and ultimately alleviate chronic pain. Here, we have used various in silico and in vitro experiments to show that tranilast, licensed for use in bronchial asthma, can inhibit sepiapterin reduction by SPR. Docking and molecular dynamics simulations suggest that tranilast can bind to human SPR (hSPR) at the same site as sepiapterin including S157, one of the catalytic triad residues of hSPR. Colorimetric assays revealed that tranilast was nearly twice as potent as the known hSPR inhibitor, N-acetyl serotonin. Tranilast was able to inhibit hSPR activity both intracellularly and extracellularly in live cells. Triple quad mass spectrophotometry of cell lysates showed a proportional decrease of BH4 in cells treated with tranilast. Our results suggest that tranilast can act as a potent hSPR inhibitor and therefore is a valid candidate for drug repurposing in the treatment of chronic pain.

Despite an ever-increasing burden of non-communicable diseases and overwhelming evidence that good nutrition improves outcomes it is difficult to know whether this evidence is reaching the general population. The purpose of this study was to investigate whether health professionals in Tairāwhiti have sufficient nutrition education for their roles in health education and promotion and whether nutrition beliefs held by health professionals were consistent with current literature. A particular interest was to enlist views on the harms, benefits, and possible barriers to following plant-based diets. A mixed-methods study involving health professionals completing a questionnaire and a subsequent focus group to collect data was used. Survey data were analysed using spreadsheet software, and thematic content analysis of focus group data was undertaken. Participants provided nutrition advice 2.4 times per day. Almost half of practitioners considered their nutrition knowledge to be inadequate, and most made poor use of references for provision of information. Plant-based diets were generally viewed as beneficial to health, improve quality of life, be filling, but were perceived as not as easy to follow. This study is in keeping with previous research that the health workforce would benefit from more formalised nutrition education and competencies to address common chronic disease.

Chronic neuropathic pain (CNP) is one of the most significant unmet clinical needs in modern medicine. Alongside the lack of effective treatments, there is a great deficit in the availability of objective diagnostic methods to reliably facilitate an accurate diagnosis. We therefore aimed to determine the feasibility of a simple diagnostic test by analysing differentially expressed genes in the blood of patients diagnosed with CNP of the lower back and compared to healthy human controls. Refinement of microarray expression data was performed using correlation analysis with 3900 human 2-colour microarray experiments. Selected genes were analysed in the dorsal horn of Sprague–Dawley rats after L5 spinal nerve ligation (SNL), using qRT-PCR and ddPCR, to determine possible associations with pathophysiological mechanisms underpinning CNP and whether they represent translational biomarkers of CNP. We found that of the 15 potential biomarkers identified, tissue inhibitor of matrix metalloproteinase-1 ( TIMP1 ) gene expression was upregulated in chronic neuropathic lower back pain (CNBP) ( p = 0.0049) which positively correlated ( R = 0.68, p = ≤0.05) with increased plasma TIMP1 levels in this group ( p = 0.0433). Moreover, plasma TIMP1 was also significantly upregulated in CNBP than chronic inflammatory lower back pain ( p = 0.0272). In the SNL model, upregulation of the Timp1 gene was also observed ( p = 0.0058) alongside a strong trend for the upregulation of melanocortin 1 receptor ( p = 0.0847). Our data therefore highlights several genes that warrant further investigation, and of these, TIMP1 shows the greatest potential as an accessible and translational CNP biomarker.