Drug use, homelessness and health: responding to the opioid overdose crisis with housing and harm reduction services.

BACKGROUND: Canada is in the midst of an opioid overdose crisis and Alberta has one of the highest opioid use rates across the country. Populations made vulnerable through structural inequities who also use opioids, such as those who are unstably housed, are at an increased risk of experiencing harms associated with opioid use. The main purpose of this study was to explore if there was an association between unstable housing and hospital use for people who use opioids. METHODS: Analysis utilized self-reported data from the Alberta Health and Drug Use Survey which surveyed 813 Albertans in three cities. Hospital use was modeled using a logistic regression with our primary variable of interest being housing unstable status. Chi square tests were conducted between hospital use and variables associated with demographics, characteristics of drug use, health characteristics, and experiences of receiving services to establish model inclusion. RESULTS: Results revealed a significant association between housing instability and hospital use with unstably housed individuals twice as likely torequire hospital care. CONCLUSIONS: Results highlight the importance of concurrently addressing housing instability alongside the provision of harm reduction services such as safe supply and supervised consumption sites. These findings have significant implications for policy and policymakers during the opioid overdose epidemic, and provide a foundation for future areas of research.

PAF promotes stemness and radioresistance of glioma stem cells.

An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor (PAF) up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).

A systematic review of noninvasive and invasive sialorrhoea management.

AIMS AND OBJECTIVES: To review published literature pertaining to the management of sialorrhoea while also highlighting the significance of the multidisciplinary approach. BACKGROUND: Sialorrhoea is a common and troublesome problem among certain neurological patients. It is distressing for patients and caregivers, and can be challenging for healthcare professionals. Various sialorrhoea management approaches have been documented. However, there is no clear consensus on best management practices. Therefore, it is necessary to systematically review and synthesise various approaches so as to provide an understanding of the efficacy of management approaches. DESIGN: Systematic literature review using PRISMA checklist (see Appendix S1). METHOD: Five databases (ScienceDirect, Wiley Online Library, CINAHL, Cochrane Library and PubMed) were searched (years 2001-2018) following inclusion criteria. Out of 1,294 identified records, 29 studies met the inclusion criteria. RESULTS: Various management approaches identified, ranging from noninvasive, such as speech therapy aiming to enhance swallowing behaviour, to invasive treatment including anticholinergic medication, botulinum toxin injection and surgical techniques. However, in the majority of cases, there is no scientific evidence-based management protocol leading to favourable results, and the evidence base for intervention effectiveness remains weak. CONCLUSIONS: The multifactor nature of sialorrhoea and its associated complications presents challenges for the medical care team. None of the management strategies stand alone as the best modality; therefore, it is proposed that management strategies follow a multidisciplinary approach to meet the diverse needs of patients. RELEVANCE TO CLINICAL PRACTICE: A comprehensive understanding of different sialorrhoea management approaches will enable healthcare professionals to identify the signs and symptoms regarding sialorrhoea, and to assist in effective management implementation. This will help to improve the management of sialorrhoea, hence, to improve quality of life of patients and provide formative scope to the development of an integrated care pathway.

Colorectal cancer survivors: an investigation of symptom burden and influencing factors.

BACKGROUND: Colorectal cancer is a significant issue internationally, with over 1.3 million people diagnosed annually. Survival rates are increasing as treatments improve, although physical symptoms can persist despite eradication of the tumour. In order to optimize survivorship care, further research is warranted in relation to symptom burden. Therefore, the objectives of this study are to (i) investigate frequency of physical symptoms in colorectal cancer survivors (ii) identify which symptoms occur together (iii) examine the associations between demographic and clinical variables, and symptoms. METHODS: Participants nine months to three years post diagnosis were identified from the population-based National Cancer Registry Ireland. Respondents completed the EORTC QLQ-C30 and EORTC QLQ-CR29. Reported physical symptom frequencies were transformed into continuous scale variables, which were then analysed using one way analysis of variance, general linear modelling and Spearman rank correlations. RESULTS: There were 496 participants. Fatigue, insomnia and flatulence were the most frequent symptoms, with ≥20% of respondents reporting these to be often present in the previous week. Eight other symptoms were experienced often by 10-20% of respondents. At least one of these eleven most common symptoms was experienced frequently by almost every respondent (99%). 66% of respondents experienced at least two of these symptoms together, and 16% experienced five or more together. Current stoma was the single most common variable associated with increased symptom scores, although statistically significant relationships (p ≤ 0.05) between symptom frequency scores and clinical/demographic variables were generally weak (R-sq value ≤0.08). CONCLUSION: Findings may inform targeted interventions during the nine month to three year post diagnosis timeframe, which would enable supported self-management of symptoms.

The impact of rheumatologist-performed ultrasound on diagnosis and management of inflammatory arthritis in routine clinical practice.

BACKGROUND: Rheumatologists increasingly perform ultrasound (US) imaging to aid diagnosis and management decisions. There is a need to determine the role of US in facilitating early diagnosis of inflammatory arthritis. This study describes the impact of US use by rheumatologists on diagnosis and management of inflammatory arthritis in routine UK clinical practice. METHODS: We conducted a prospective study in four secondary care rheumatology clinics, each with one consultant who routinely used US and one who did not. Consenting patients aged > 18, newly referred with suspected inflammatory arthritis were included. Data were collected both retrospectively from medical records and via a prospectively-completed physician questionnaire on US use. Analyses were stratified by US/non-US groups and by sub-population of rheumatoid arthritis (RA)-diagnosed patients. RESULTS: 258 patients were included; 134 US and 124 non-US. 42% (56/134) of US and 47% (58/124) of non-US were diagnosed with RA. Results described for US and non-US cohorts, respectively as follows. The proportion of patients diagnosed at their first clinic visit was 37% vs 19% overall (p = 0.004) and 41% vs 19% in RA-diagnosed patients (p = 0.01). The median time to diagnosis (months) was 0.85 vs 2.00 (overall, p = 0.0046) and 0.23 vs 1.38 (RA-diagnosed, p = 0.0016). Median time (months) to initiation on a DMARD (where initiated) was 0.62 vs 1.41 (overall, p = 0.0048) and 0.46 vs 1.81 (RA-diagnosed, p = 0.0007). CONCLUSION: In patients with suspected inflammatory arthritis, routine US use in newly referred patients seems to be associated with significantly earlier diagnosis and DMARD initiation.

Nursing implications: symptom presentation and quality of life in rectal cancer patients.

AIMS AND OBJECTIVES: To determine the changes in symptoms experienced by rectal cancer patients during preoperative chemoradiotherapy, with a specific focus on fatigue and to explore how symptoms impact the quality of life. BACKGROUND: Rectal cancer continues to be a healthcare issue internationally, despite advances in management strategies, which includes the administration of preoperative chemoradiotherapy to improve locoregional control. It is known that this treatment may cause adverse effects; however, there is a paucity of literature that specifically examines fatigue, symptoms and quality of life in this patient cohort. DESIGN: A prospective, quantitative correlational design using purposive sampling was adopted. METHODS: Symptoms and quality of life were measured with validated questionnaires in 35 patients at four time points. RESULTS: Symptoms that changed significantly over time as examined using rm-anova include fatigue, bowel function issues, nutritional issues, pain, dermatological issues and urinary function issues. Findings indicate that fatigue leads to poorer quality of life, with constipation, bloating, stool frequency, appetite loss, weight worry, nausea and vomiting, dry mouth and pain also identified as influencing factors on quality of life. CONCLUSION: Findings have highlighted the importance of thorough symptom assessment and management of patients receiving preoperative chemoradiotherapy, particularly midway through treatment, in order to optimise quality of life and minimise interruptions to treatment. RELEVANCE TO CLINICAL PRACTICE: Close monitoring of symptoms during preoperative chemoradiotherapy, particularly at week 4, will enable the implementation of timely interventions so that interruptions to treatment are prevented and the quality of life is optimised, which may hasten postoperative recovery times.

Literature review: preoperative radiotherapy and rectal cancer - impact on acute symptom presentation and quality of life.

AIMS AND OBJECTIVES: This paper presents a critical review of published literature detailing side effects of preoperative radiotherapy in patients with rectal cancer and the impact of their treatment on their quality of life which will assist in guiding nursing management in the future. BACKGROUND: Preoperative radiotherapy for rectal cancer leads to a number of side effects that have a negative influence on patients' quality of life. Although studies have investigated the various adverse effects that can occur, these have not yet been critically appraised and synopsised to form a comprehensive review of their prevalence and effects on the quality of life of patients with rectal cancer. DESIGN: This literature review study addresses the aims and objectives. METHODS: Following a literature search of electronic databases, 23 articles were retrieved that met the selection criteria with papers discussed in relation to symptoms that present due to this treatment, with six of these 23 studies also referring to health-related quality of life. RESULTS: Preoperative radiotherapy leads to a number of common adverse effects including diarrhoea, dermatological problems, micturition problems, fatigue, sexual dysfunction and pain. Some can lead to a decline in quality of life during treatment and cause prolonged surgical recovery times, but there appears to be no long-term deterioration in quality of life. CONCLUSIONS: There is a paucity of literature that specifically examines fatigue and quality of life in relation to patients with rectal cancer during preoperative radiotherapy treatment. RELEVANCE TO CLINICAL PRACTICE: Awareness of the prevalence and severity of the acute side effects of preoperative radiotherapy will enable nurses to thoroughly assess these symptoms, plan and implement appropriate interventions and evaluate outcomes. This will assist in optimising the quality of life of patients with rectal cancer and may hasten postoperative recovery times.

Stratification of biological therapies by pathobiology in biologic-naive patients with rheumatoid arthritis (STRAP and STRAP-EU): two parallel, open-label, biopsy-driven, randomised trials.

BACKGROUND: Despite highly effective targeted therapies for rheumatoid arthritis, about 40% of patients respond poorly, and predictive biomarkers for treatment choices are lacking. We did a biopsy-driven trial to compare the response to rituximab, etanercept, and tocilizumab in biologic-naive patients with rheumatoid arthritis stratified for synovial B cell status. METHODS: STRAP and STRAP-EU were two parallel, open-label, biopsy-driven, stratified, randomised, phase 3 trials done across 26 university centres in the UK and Europe. Biologic-naive patients aged 18 years or older with rheumatoid arthritis based on American College of Rheumatology (ACR)-European League Against Rheumatism classification criteria and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (DMARDs) were included. Following ultrasound-guided synovial biopsy, patients were classified as B cell poor or B cell rich according to synovial B cell signatures and randomly assigned (1:1:1) to intravenous rituximab (1000 mg at week 0 and week 2), subcutaneous tocilizumab (162 mg per week), or subcutaneous etanercept (50 mg per week). The primary outcome was the 16-week ACR20 response in the B cell-poor, intention-to-treat population (defined as all randomly assigned patients), with data pooled from the two trials, comparing etanercept and tocilizumab (grouped) versus rituximab. Safety was assessed in all patients who received at least one dose of study drug. These trials are registered with the EU Clinical Trials Register, 2014-003529-16 (STRAP) and 2017-004079-30 (STRAP-EU). FINDINGS: Between June 8, 2015, and July 4, 2019, 226 patients were randomly assigned to etanercept (n=73), tocilizumab (n=74), and rituximab (n=79). Three patients (one in each group) were excluded after randomisation because they received parenteral steroids in the 4 weeks before recruitment. 168 (75%) of 223 patients in the intention-to-treat population were women and 170 (76%) were White. In the B cell-poor population, ACR20 response at 16 weeks (primary endpoint) showed no significant differences between etanercept and tocilizumab grouped together and rituximab (46 [60%] of 77 patients vs 26 [59%] of 44; odds ratio 1·02 [95% CI 0·47-2·17], p=0·97). No differences were observed for adverse events, including serious adverse events, which occurred in six (6%) of 102 patients in the rituximab group, nine (6%) of 108 patients in the etanercept group, and three (4%) of 73 patients in the tocilizumab group (p=0·53). INTERPRETATION: In this biologic-naive population of patients with rheumatoid arthrtitis, the dichotomic classification into synovial B cell poor versus rich did not predict treatment response to B cell depletion with rituximab compared with alternative treatment strategies. However, the lack of response to rituximab in patients with a pauci-immune pathotype and the higher risk of structural damage progression in B cell-rich patients treated with rituximab warrant further investigations into the ability of synovial tissue analyses to inform disease pathogenesis and treatment response. FUNDING: UK Medical Research Council and Versus Arthritis.

Characterization of Key Odorants in Cumberland Rosemary, Conradina verticillata.

Conradina verticillata Jennison, commonly known as Cumberland Rosemary, is an endangered plant from the mint family Lamiaceae. This species is a flowering, perennial shrub found only in a few counties in Kentucky and Tennessee. Although the odorants responsible for Cumberland Rosemary's unique aroma have not been previously characterized, in this study, a total of 32 odorants were identified using gas chromatography-olfactometry (GC-O) and gas chromatography-mass spectrometry (GC-MS). Odorant flavor dilution (FD) factors were determined through the application of aroma extract dilution analysis (AEDA). Seven odorants with FD factors ≥64 were quantitated by stable isotope dilution assays (SIDA), and their odor activity values (OAV) were calculated. Odorants with OAV ≥1 included 1-octen-3-one (earthy-mushroom, OAV 2,900,000), 1,8-cineole (eucalyptus, OAV 510,000), borneol (earthy, OAV 10,000), bornyl acetate (earthy-fruity, OAV 3,700), eugenol (spicy, OAV 2,200), menthone (mint, OAV 130), and camphor (herbaceous, OAV 72). Sensory analysis revealed that an odor simulation model based on the quantitative data was a close match to the aroma of the plant. Omission studies determined that 1-octen-3-one, 1,8-cineole, and eugenol were the key odorants critical to Cumberland Rosemary's distinct aroma profile. The stereochemistry of selected odorants was also determined by chiral chromatography. This study established a foundation for future experiments on the aroma chemistry of C. verticillata and the other six members of the Conradina genus.

Resilience and active inference.

In this article, we aim to conceptualize and formalize the construct of resilience using the tools of active inference, a new physics-based modeling approach apt for the description and analysis of complex adaptive systems. We intend this as a first step toward a computational model of resilient systems. We begin by offering a conceptual analysis of resilience, to clarify its meaning, as established in the literature. We examine an orthogonal, threefold distinction between meanings of the word "resilience": (i) inertia, or the ability to resist change (ii) elasticity, or the ability to bounce back from a perturbation, and (iii) plasticity, or the ability to flexibly expand the repertoire of adaptive states. We then situate all three senses of resilience within active inference. We map resilience as inertia onto high precision beliefs, resilience as elasticity onto relaxation back to characteristic (i.e., attracting) states, and resilience as plasticity onto functional redundancy and structural degeneracy.

A scoping review of opioid harm reduction interventions for equity-deserving populations.

Background: Morbidity and mortality associated with opioid use has become a North American crisis. Harm reduction is an evidence-based approach to substance use. Targeted harm reduction strategies that consider the needs of specific populations are required. The objective of this scoping review was to document the range of opioid harm reduction interventions across equity-deserving populations including racialized groups, Indigenous peoples, LGBTQIA2S+, people with disabilities, and women. Methods: Ten databases were searched from inception to July 5th, 2021. Terms for harm reduction and opioid use formed the central concepts of the search. We included studies that: (1) assessed the development, implementation, and/or evaluation of harm reduction interventions for opioid use, and (2) reported health-related outcomes or presented perspectives that directly related to experiences receiving or administering harm reduction interventions, (3) were completed within an equity-deserving population and (4) were completed in New Zealand, Australia, Canada or the US. A knowledge map was developed a-priori based on literature outlining different types of harm reduction interventions and supplemented by the expertise of the research team. Findings: 12,958 citations were identified and screened, with 1373 reviewed in full-text screening. Of these, 15 studies were included in the final dataset. The most common harm reduction program was opioid agonist treatment (OAT) (n = 11, 73%). The remaining four studies included: overdose prevention; drug testing equipment; and outreach, peer support, and educational programs for safer use. Nine studies focused on women, primarily pregnant/post-partum women, three focused on Indigenous peoples, and three studies included racialized groups. No studies were identified that provided any information on persons with a disability or members of the LGBTQIA2S+ population. Interpretation: The scant opioid specific harm reduction literature on equity-deserving populations to date has primarily focused on OAT programs and is focused primarily on women. There is a need for more targeted research to address the diverse social experiences of people who use drugs and the spectrum of harm reduction interventions that are needed. There is also a need to acknowledge the history of harm reduction as a drug-user activist movement aimed at challenging bio-medical paradigms of drug use. Further, there is a need to recognize that academic research may be contributing to health inequity by not prioritizing research with this lens. Funding: This research was funded by the Canadian Institutes of Health Research.

"I Feel Like Less of a Mom": Experiences of Weight Stigma by Association among Mothers of Children with Overweight and Obesity.

Background: Parents of children with higher weight are blamed and shamed for their children's weight. However, parents' experiences of this form of stigma, termed weight stigma by association, are poorly understood. The objective of this study was to investigate the sources, forms, and impacts of weight stigma by association among mothers of children with overweight or obesity. Methods: In this qualitative study, mothers who reported concern about their children's weight participated in semistructured interviews administered by the research team. A coding scheme was developed and reliably applied to interview transcripts. Mothers' self-reported sociodemographic information, and height and weight were measured. Results: Thirty-four mothers (Mage: 43.4 years; 26.5% non-Hispanic Black or African American, 70.6% with obesity) participated in the study. Mothers reported that family members were a common source of negative comments about their children's weight; these comments were often critical of mothers' parenting and in some cases contributed to negative affect among mothers. Many mothers also reported negative experiences during children's physicians' visits as a result of their children's weight. Almost all mothers expressed guilt and sadness for their perceived role in their children's weight status, expressing regret that they did not parent differently. Conclusions: Mothers of children with overweight and obesity are frequently the target of weight stigma by association and experience negative cognitions and emotions regarding their perceived role in their children's weight. Continued research is needed to elucidate the impacts of stigma by association due to child weight on parents' health, the parent/child relationship, and children's health.

Multi-omics of the esophageal microenvironment identifies signatures associated with progression of Barrett's esophagus.

BACKGROUND: The enrichment of Gram-negative bacteria of oral origin in the esophageal microbiome has been associated with the development of metaplasia. However, to date, no study has comprehensively assessed the relationships between the esophageal microbiome and the host. METHODS: Here, we examine the esophageal microenvironment in gastro-esophageal reflux disease and metaplasia using multi-omics strategies targeting the microbiome and host transcriptome, followed by targeted culture, comparative genomics, and host-microbial interaction studies of bacterial signatures of interest. RESULTS: Profiling of the host transcriptome from esophageal mucosal biopsies revealed profound changes during metaplasia. Importantly, five biomarkers showed consistent longitudinal changes with disease progression from reflux disease to metaplasia. We showed for the first time that the esophageal microbiome is distinct from the salivary microbiome and the enrichment of Campylobacter species as a consistent signature in disease across two independent cohorts. Shape fitting and matrix correlation identified associations between the microbiome and host transcriptome profiles, with a novel co-exclusion relationship found between Campylobacter and napsin B aspartic peptidase. Targeted culture of Campylobacter species from the same cohort revealed a subset of isolates to have a higher capacity to survive within primary human macrophages. Comparative genomic analyses showed these isolates could be differentiated by specific genomic features, one of which was validated to be associated with intracellular fitness. Screening for these Campylobacter strain-specific signatures in shotgun metagenomics data from another cohort showed an increase in prevalence with disease progression. Comparative transcriptomic analyses of primary esophageal epithelial cells exposed to the Campylobacter isolates revealed expression changes within those infected with strains with high intracellular fitness that could explain the increased likelihood of disease progression. CONCLUSIONS: We provide a comprehensive assessment of the esophageal microenvironment, identifying bacterial strain-specific signatures with high relevance to progression of metaplasia.

Cups for COVID: rapid implementation of a harm reduction initiative to support populations experiencing homelessness during the COVID-19 pandemic.

SETTING: As of June 10, 2020, 37 people experiencing homelessness or unstable housing in Calgary, Alberta, had developed lab-confirmed COVID-19. Spread occurred despite standard outbreak controls at affected shelter and supportive housing sites. Among these 37 cases, drink sharing was frequently identified as a modifiable mode of possible transmission. We collaborated with emergency shelters, a supportive housing site, and street and encampment outreach groups, using mixed service delivery by health staff, non-profits, and peers with lived experience with homelessness. INTERVENTION: To empower individuals to decrease COVID-19 transmission using a harm reduction approach, we provided disposable paper cups to service providers for distribution to clients. Service providers tracked the number of cups distributed. To assess effectiveness, we interviewed staff and peers who distributed the cups. OUTCOMES: Cup distribution was highest among populations with higher rates of alcohol use, and the intervention was well received by people who drink alcohol regularly, providing unique opportunities to promote COVID-19 awareness and safer drinking practices. Providers to these populations reported enthusiastic client engagement and repeat requests for cups for safer drinking. Intervention usefulness was limited in contexts with low alcohol consumption and in the absence of paired COVID-19 education. Provider reports suggest appropriate disposal of these cups after use. IMPLICATIONS: Disposable cups are a novel, rapidly implementable, low-cost harm reduction tool to empower people experiencing homelessness to reduce the risk of COVID-19 transmission due to drink sharing, ideally as part of a larger harm reduction and community education strategy.

RéSUMé: LIEU: Au 10 juin 2020, trente-sept (37) personnes sans abri ou vivant en logement instable à Calgary (Alberta) avaient contracté une infection par la COVID-19 confirmée en laboratoire. La maladie s'est propagée malgré les mesures types de contrôle des éclosions dans les refuges et les logements supervisés touchés. Parmi ces 37 cas, le partage de boissons a souvent été défini comme un mode de transmission modifiable possible. En collaboration avec des refuges d'urgence, un complexe de logements supervisés et des groupes menant des activités de proximité dans la rue et les campements, nous avons assuré une prestation de services mixte par des personnels de santé, des organisations sans but lucratif et des pairs ayant une expérience vécue de sans-abrisme. INTERVENTION: Pour donner à chaque personne les moyens de réduire la transmission de la COVID-19 selon une approche de réduction des méfaits, nous avons fourni aux dispensateurs de services des gobelets en papier jetables à distribuer à leurs usagers. Les dispensateurs ont fait un suivi du nombre de gobelets distribués. Pour évaluer l'efficacité de l'initiative, nous avons interviewé le personnel et les pairs ayant distribué les gobelets. RéSULTATS: Le nombre de gobelets distribués a été le plus élevé dans les populations ayant des taux élevés de consommation d'alcool, et l'intervention a été bien accueillie par les personnes qui consomment régulièrement de l'alcool; elle a offert des occasions uniques de faire de la sensibilisation à la COVID-19 et de promouvoir une pratique de consommation de boissons à moindre risque. Les intervenants auprès de ces populations ont fait état d'une participation enthousiaste des usagers et de demandes répétées de gobelets pour boire sans s'exposer au risque de contracter la maladie. L'utilité de l'intervention a été limitée dans les contextes de faible consommation d'alcool et en l'absence d'une sensibilisation conjointe à la COVID-19. Selon les rapports des dispensateurs de services, les gobelets ont été correctement éliminés après usage. CONSéQUENCES: Les gobelets jetables sont un nouvel outil de réduction des méfaits à prix abordable qui peut être mis en œuvre rapidement pour donner aux personnes aux prises avec le sans-abrisme les moyens de réduire le risque de transmission de la COVID-19 lorsqu'elles partagent des boissons, idéalement dans le cadre d'une stratégie de réduction des méfaits et de sensibilisation de proximité.

Expansion of T-cell receptor zeta dim effector T cells in acute coronary syndromes.

OBJECTIVE: The T-cell receptor zeta (TCR zeta)-chain is a master sensor and regulator of lymphocyte responses. Loss of TCR zeta-chain expression has been documented during infectious and inflammatory diseases and defines a population of effector T cells (TCR zeta(dim) T cells) that migrate to inflamed tissues. We assessed the expression and functional correlates of circulating TCR zeta(dim) T cells in coronary artery disease. METHODS AND RESULTS: We examined the expression of TCR zeta-chain by flow cytometry in 140 subjects. Increased peripheral blood CD4(+) TCR zeta(dim) T cells were found in patients with acute coronary syndromes (ACS, n=66; median 5.3%, interquartile 2.6 to 9.1% of total CD4(+) T cells; P<0.0001) compared to chronic stable angina (CSA, n=32; 1.6%; 1.0 to 4.1%) and controls (n=42; 1.5%; 0.5 to 2.9%). Such increase was significantly greater in ACS patients with elevated levels of C-reactive protein, and it persisted after the acute event. Moreover, TCR zeta(dim) cells were also more represented within CD8(+) T cell, NK, and CD4(+)CD28(null) T cell subsets in ACS compared to CSA and controls. Finally, CD4(+) and CD8(+) TCR zeta(dim) T cells isolated from ACS displayed an enhanced transendothelial migratory capacity. CONCLUSIONS: TCR zeta(dim) T cells, an effector T-cell subset with transendothelial migratory ability, are increased in ACS, and may be implicated in coronary instability.

Nitric oxide production of T lymphocytes is increased in rheumatoid arthritis.

Experimental and clinical evidence for T cell involvement in the pathology of rheumatoid arthritis (RA) is compelling, and points to a local dysregulation of T cell function in the inflamed joint. Nitric oxide (NO) has been shown to regulate T cell function under physiological conditions, but overproduction of NO may contribute to lymphocyte dysfunction characteristic of RA. Several investigations in patients with RA have documented evidence of increased NO synthesis, but these studies have focused largely on macrophage-derived NO and its impact on innate immune and inflammatory responses. In this study, we set out to explore the contribution that T cells make to NO production. We find that T cells from RA patients produce >2.5 times more NO than healthy donor T cells (p<0.001). Although NO is an important physiological mediator of mitochondrial biogenesis, mitochondrial mass is similar in RA and control T cells. In contrast, increased NO production is associated with increased cytoplasmic Ca(2+) concentrations in RA T cells (p<0.001). In vitro treatment of human peripheral blood lymphocytes, or Jurkat cells with TNF increases NO production (p=0.006 and p=0.001, respectively), whilst infliximab treatment in RA patients decreases T cell derived NO production within 6 weeks of the first infusion (p=0.005). Together, these data indicate that TNF induced NO production in T lymphocytes may contribute to perturbations of immune homeostasis in RA.

Immune-mediated pathways in chronic inflammatory arthritis.

Rheumatoid arthritis (RA) is the prototype chronic inflammatory arthropathy; its precise aetiology is unknown. Over recent years, a number of crucial advances in our understanding of the disease have had a major impact on the treatment of patients with RA.

Nitric oxide, chronic inflammation and autoimmunity.

Whilst many physiological functions of nitric oxide (NO) have been revealed so far, recent evidence proposes an essential role for NO in T lymphocyte activation and signal transduction. NO acts as a second messenger, activating soluble guanyl cyclase and participating in signal transduction pathways involving cyclic GMP. NO modulates mitochondrial events that are involved in apoptosis and regulates mitochondrial biogenesis in many cell types, including lymphocytes. Several studies undertaken on patients with RA and SLE have documented increased endogenous NO synthesis, although the effects of NO may be distinct. Here, we discuss recent evidence that NO contributes to T cell dysfunction in both SLE and RA by altering multiple signaling pathways in T cells. Although NO may play a physiological role in lymphocyte cell signaling, its overproduction may perturb T cell activation, differentiation and effector responses, each of which may contribute in different ways to the pathogenesis of autoimmunity.

Alberta's provincial take-home naloxone program: A multi-sectoral and multi-jurisdictional response to overdose.

SETTING: Alberta is a prairie province located in western Canada, with a population of approximately 4.3 million. In 2016, 363 Albertans died from apparent drug overdoses related to fentanyl, an opioid 50-100 times more toxic than morphine. This surpassed the number of deaths from motor vehicle collisions and homicides combined. INTERVENTION: Naloxone is a safe, effective, opioid antagonist that may quickly reverse an opioid overdose. In July 2015, a committee of community-based harm reduction programs in Alberta implemented a geographically restricted take-home naloxone (THN) program. The successes and limitations of this program demonstrated the need for an expanded, multi-sectoral, multi-jurisdictional response. The provincial health authority, Alberta Health Services (AHS), used previously established incident command system processes to coordinate implementation of a provincial THN program. OUTCOMES: Alberta's provincial THN program was implemented on December 23, 2015. This collaborative program resulted in a coordinated response across jurisdictional levels with wide geographical reach. Between December 2015 and December 2016, 953 locations, including many community pharmacies, registered to dispense THN kits, 9572 kits were distributed, and 472 reversals were reported. The provincial supply of THN kits more than tripled from 3000 to 10 000. IMPLICATIONS: Alberta was uniquely poised to deliver a large, province-wide, multi-sectoral and multi-jurisdictional THN program as part of a comprehensive response to increasing opioid-related morbidity and mortality. The speed at which AHS was able to roll out the program was made possible by work done previously and the willingness of multiple jurisdictions to work together to build on and expand the program.