Functional expression of CD73 on human natural killer cells.

The production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73- NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.

Selecting implementation models, theories, and frameworks in which to integrate intersectional approaches.

BACKGROUND: Models, theories, and frameworks (MTFs) provide the foundation for a cumulative science of implementation, reflecting a shared, evolving understanding of various facets of implementation. One under-represented aspect in implementation MTFs is how intersecting social factors and systems of power and oppression can shape implementation. There is value in enhancing how MTFs in implementation research and practice account for these intersecting factors. Given the large number of MTFs, we sought to identify exemplar MTFs that represent key implementation phases within which to embed an intersectional perspective. METHODS: We used a five-step process to prioritize MTFs for enhancement with an intersectional lens. We mapped 160 MTFs to three previously prioritized phases of the Knowledge-to-Action (KTA) framework. Next, 17 implementation researchers/practitioners, MTF experts, and intersectionality experts agreed on criteria for prioritizing MTFs within each KTA phase. The experts used a modified Delphi process to agree on an exemplar MTF for each of the three prioritized KTA framework phases. Finally, we reached consensus on the final MTFs and contacted the original MTF developers to confirm MTF versions and explore additional insights. RESULTS: We agreed on three criteria when prioritizing MTFs: acceptability (mean = 3.20, SD = 0.75), applicability (mean = 3.82, SD = 0.72), and usability (median = 4.00, mean = 3.89, SD = 0.31) of the MTF. The top-rated MTFs were the Iowa Model of Evidence-Based Practice to Promote Quality Care for the 'Identify the problem' phase (mean = 4.57, SD = 2.31), the Consolidated Framework for Implementation Research for the 'Assess barriers/facilitators to knowledge use' phase (mean = 5.79, SD = 1.12), and the Behaviour Change Wheel for the 'Select, tailor, implement interventions' phase (mean = 6.36, SD = 1.08). CONCLUSIONS: Our interdisciplinary team engaged in a rigorous process to reach consensus on MTFs reflecting specific phases of the implementation process and prioritized each to serve as an exemplar in which to embed intersectional approaches. The resulting MTFs correspond with specific phases of the KTA framework, which itself may be useful for those seeking particular MTFs for particular KTA phases. This approach also provides a template for how other implementation MTFs could be similarly considered in the future. TRIAL REGISTRATION: Open Science Framework Registration: osf.io/qgh64.

Differentiation of natural killer cells from induced pluripotent stem cells under defined, serum- and feeder-free conditions.

BACKGROUND AIMS: Traditionally, natural killer (NK) cells are sourced from the peripheral blood of donors-a laborious and highly donor-specific process. Processes for generating NK cells from induced pluripotent stem cells (iPSCs) have demonstrated that it is possible to successfully generate renewable alloreactive NK cells that are not only functional in vivo but can also be genetically engineered for enhanced function. However, poor standardization and cumbersome differentiation procedures suggest that further improvements in the control of the differentiation process are necessary. METHODS: Here the authors evaluated the potential of differentiating NK cells from centrally authenticated iPSCs under entirely chemically defined and serum-free conditions as well as their immunotherapeutic potential, after expansion in feeder-free media, against solid tumors targets. To address limitations of current differentiation approaches, the authors did not utilize feeder or stromal cell layers, TrypLE adaptation or peripheral blood during the differentiation process. The authors also evaluated the feasibility of utilizing centrally authenticated iPSC lines, thus circumventing protocol- and donor-induced variability associated with reprogramming approaches, and characterized these iPSC-NK cells in terms of cytotoxicity, cytokine production and degranulation potential against solid tumor cell lines and patient-derived targets. RESULTS: Differentiation of iPSCs generated NK cells that were predominantly CD56+/CD16+/CD3- and expressed NK activation markers NKG2D, NKp30, NKp44, NKp46 and DNAM-1. These iPSC-NK cells mediated effector functions, including cytotoxicity, degranulation and IFN-γ production, in response to solid tumor targets, including patient-derived cancer cells, and could be cryopreserved and expanded in culture. CONCLUSIONS: The ability to produce NK cells under defined conditions and the functional responses elicited by these iPSC-NK cells suggest that they could represent promising effectors in clinical adoptive transfer settings as a renewable source of donor-independent NK cells for immunotherapy of solid tumors.

Diverging trends in the incidence of occupational and nonoccupational injury in Ontario, 2004-2011.

OBJECTIVES: We describe trends in occupational and nonoccupational injury among working-age adults in Ontario. METHODS: We conducted an observational study of adults aged 15 to 64 over the period 2004 through 2011, estimating the incidence of occupational and nonoccupational injury from emergency department (ED) records and, separately, from survey responses to 5 waves of a national health interview survey. RESULTS: Over the observation period, the annual percentage change (APC) in the incidence of work-related injury was -5.9% (95% confidence interval [CI] = -7.3, -4.6) in ED records and -7.4% (95% CI=-11.1, -3.5) among survey participants. In contrast, the APC in the incidence of nonoccupational injury was -0.3% (95% CI=-0.4, 0.0) in ED records and 1.0% (95% CI=0.4, 1.6) among survey participants. Among working-age adults, the percentage of all injuries attributed to work exposures declined from 20.0% in 2004 to 15.2% in 2011 in ED records and from 27.7% in 2001 to 16.9% in 2010 among survey participants. CONCLUSIONS: Among working-age adults in Ontario, nearly all of the observed decline in injury incidence over the period 2004 through 2011 is attributed to reductions in occupational injury.

Time trends in musculoskeletal disorders attributed to work exposures in Ontario using three independent data sources, 2004-2011.

OBJECTIVE: Work-related musculoskeletal disorders (MSDs) are the leading cause of work disability in the developed economies. The objective of this study was to describe trends in the incidence of MSDs attributed to work exposures in Ontario over the period 2004-2011. METHODS: An observational study of work-related morbidity obtained from three independent sources for a complete population of approximately six million occupationally active adults aged 15-64 in the largest Canadian province. We implemented a conceptually concordant case definition for work-related non-traumatic MSDs in three population-based data sources: emergency department encounter records, lost-time workers' compensation claims and representative samples of Ontario workers participating in consecutive waves of a national health interview survey. RESULTS: Over the 8-year observation period, the annual per cent change (APC) in the incidence of work-related MSDs was -3.4% (95% CI -4.9% to -1.9%) in emergency departments' administrative records, -7.2% (-8.5% to -5.8%) in lost-time workers' compensation claims and -5.3% (-7.2% to -3.5%) among participants in the national health interview survey. Corresponding APC measures for all other work-related conditions were -5.4% (-6.6% to -4.2%), -6.0% (-6.7% to -5.3%) and -5.3% (-7.8% to -2.8%), respectively. Incidence rate declines were substantial in the economic recession following the 2008 global financial crisis. CONCLUSIONS: The three independent population-based data sources used in this study documented an important reduction in the incidence of work-related morbidity attributed to non-traumatic MSDs. The results of this study are consistent with an interpretation that the burden of non-traumatic MSDs arising from work exposures is declining among working-age adults.

The development of a framework to integrate evidence into a national injury prevention strategy.

BACKGROUND: Injury is the leading cause of death from birth to age 34 in Canada (Statistics Canada, 2008). In 2013, a national injury prevention organization in Canada initiated a research-practitioner collaboration to establish a framework for incorporating evidence in the organization's decision-making. In this study, we outline the development process and provide an overview of the framework. METHODS: The process of development of the evidence-synthesis framework included consultation with national and international injury prevention experts, a review of the research literature to identify existing models for incorporating research evidence into public health practice and extensive interactions with the organization's leadership and staff. RESULTS: A framework emphasizing four types of research evidence was recommended: (i) epidemiologic evidence describing the burden and cause of injury, (ii) evidence concerning the effectiveness of interventions, (iii) evidence on effective methods for implementing promising interventions at a population level, and (iv) evidence and theory from the behavioral sciences. Through the evidence-synthesis process the framework prioritizes highly synthesized evidence-based strategies and draws attention to important research gaps. CONCLUSIONS: This study describes a novel opportunity to operationalize an organization's commitment to integrate evidence into practice. The framework provides guidance on how to use evidence strategically to maximize the potential impact of prevention efforts. Opportunities for further evaluation and dissemination are discussed.

Trends in needlestick injury incidence following regulatory change in Ontario, Canada (2004-2012): an observational study.

BACKGROUND: A number of jurisdictions have used regulation to promote the adoption of safety-engineered needles as a primary solution to reduce the risk of needlestick injuries among healthcare workers. Regulatory change has not been complemented by ongoing efforts to monitor needlestick injury trends which limits opportunities to evaluate the need for additional investment in this area. The objective of this study was to describe trends in the incidence of needlestick injuries in Ontario prior to and following the establishment of regulation to promote the adoption of safety-engineered needles. METHODS: An observational study of needlestick injuries obtained from two independent administrative data sources (emergency department records for the treatment of work-related disorders and workers' compensation claims) for a population of occupationally-active adults over the period 2004-2012. RESULTS: Comparing the year prior to the regulation being established (2006) to three years after the regulation came into effect (2011), needlestick injury rates in the health and social services sector that were captured by workers' compensation claims declined by 31% and by 43% in the work-related emergency department records. Rates of workers' compensation claims associated with needlestick injuries declined by 31% in the hospital sector, by 67% in the long-term care sector and have increased by approximately 1% in nursing services over the period 2004-2012. CONCLUSIONS: Two independent administrative data sources documented an overall reduction in needlestick injuries in the province of Ontario following a regulatory requirement to adopt safety-engineered needles; however, a substantial burden of occupational needlestick injuries persists in this setting.

Paediatric pain management practice and policies across Alberta emergency departments.

BACKGROUND: Many children requiring acute care receive suboptimal analgesia. OBJECTIVES: To describe paediatric pain management practices and policies in emergency departments (EDs) in Alberta. METHODS: A descriptive survey was distributed to each of the EDs in Alberta. RESULTS: A response rate of 67% (72 of 108) was obtained. Seventy-one percent (42 of 59) of EDs reported the use of a pain tool, 29.3% (17 of 58) reported mandatory pain documentation and 16.7% (10 of 60) had nurse-initiated pain protocols. Topical anesthetics were reported to be used for intravenous line insertion by 70.4% of respondents (38 of 54) and for lumbar puncture (LP) by 30.8% (12 of 39). According to respondents, infiltrated anesthetic was used for LP by 69.2% (27 of 39) of respondents, and oral sucrose was used infrequently for urinary catheterization (one of 46 [2.2%]), intravenous line insertion (zero of 54 [0%]) and LP (one of 39 [2.6%]). CONCLUSIONS: Few Alberta EDs use policies and protocols to manage paediatric pain. Noninvasive methods to limit procedural pain are underutilized. Canadian paediatricians must advocate for improved analgesia to narrow this knowledge-to-practice gap.

HISTORIQUE: De nombreux enfants qui ont besoin de soins aigus reçoivent une analgésie sous-optimale. OBJECTIFS: Décrire les pratiques et politiques de gestion de la douleur en pédiatrie dans les salles d'urgence (SU) albertaines. MÉTHODOLOGIE: Chaque SU de l'Alberta a reçu un sondage descriptif. RÉSULTATS: Les chercheurs ont obtenu un taux de réponse de 67 % (72 sur 108). Au total, 71 % des SU (42 sur 59) ont déclaré utiliser un outil de gestion de la douleur, 29,3 % (17 sur 58) ont déclaré exiger de consigner la douleur et 16,7 % (dix sur 60) disposaient de protocoles de gestion de la douleur initiés par les infirmières. Ainsi, 70,4 % des répondants (38 sur 54) recouraient à l'anesthésie topique pour insérer un cathéter intraveineux et 30,8 % (12 sur 39), pour effectuer une ponction lombaire (PL). De plus, 69,2 % des répondants (27 sur 39) utilisaient des injections d'anesthésique pour les PL et, rarement, du saccharose par voie orale pour un cathétérisme urinaire (un cas sur 46 [2,2 %]), l'insertion d'un cathéter intraveineux (zéro sur 54 [0 %]) et une PL (un sur 39 [2,6 %]). CONCLUSIONS: Un petit nombre de SU albertaines sont dotées des politiques et protocoles pour gérer la douleur en pédiatrie. Les méthodes non invasives sont sous-utilisées pour limiter la douleur liée à des interventions. Les pédiatres canadiens doivent prôner une meil-leure analgésie pour réduire cet écart entre le savoir et la pratique.

Work injury risk by time of day in two population-based data sources.

OBJECTIVE: To estimate the rate of work injury over the 24 h clock in Ontario workers over 5 years (2004-2008). METHODS: A cross-sectional, observational study of work-related injury and illness was conducted for a population of occupationally active adults using two independent data sources (lost-time compensation claims and emergency department encounter records). Hours worked annually by the Ontario labour force by time of day, age, gender and occupation were estimated from population-based surveys. RESULTS: There was an approximately 40% higher incidence of emergency department visits for work-related conditions than of lost-time workers' compensation claims (707 933 emergency department records and 457 141 lost-time claims). For men and women and across all age groups, there was an elevated risk of work-related injury or illness in the evening, night and early morning periods in both administrative data sources. This elevated risk was consistently observed across manual, mixed and non-manual occupational groups. The fraction of lost-time compensation claims that can be attributed to elevated risk of work injury in evening or night work schedules is 12.5% for women and 5.8% for men. CONCLUSIONS: Despite the high prevalence of employment in non-daytime work schedules in developed economies, the work injury hazards associated with evening and night schedules remain relatively invisible. This study has demonstrated the feasibility of using administrative data sources to enhance capacity to conduct surveillance of work injury risk by time of day. More sophisticated aetiological research is needed to understand the specific mechanisms of hazards associated with non-regular work hours.

Lessons learned from implementing a surge capacity support program for COVID-19 contact management in Ontario.

SETTING: In Ontario, local public health units (PHUs) are responsible for leading case investigations, contact tracing, and follow-up. The workforce capacity and operational requirements needed to maintain this public health strategy during the COVID-19 pandemic were unprecedented. INTERVENTION: Public Health Ontario's Contact Tracing Initiative (CTI) was established to provide a centralized workforce. This program was unique in leveraging existing human resources from federal and provincial government agencies and its targeted focus on initial and follow-up phone calls to high-risk close contacts of COVID-19 cases. By setting criteria for submissions to the program, standardizing scripts, and simplifying the data management process, the CTI was able to support a high volume of calls. OUTCOMES: During its 23 months of operation, the CTI was used by 33 of the 34 PHUs and supported over a million calls to high-risk close contacts. This initiative was able to meet its objectives while adapting to the changing dynamics of the pandemic and the implementation of a new COVID-19 provincial information system. Core strengths of the CTI were timeliness, volume, and efficient use of resources. The CTI was found to be useful for school exposures, providing support when public health measures were lifted, and in supporting PHU's reallocation of resources during the vaccine roll-out. IMPLICATIONS: When considering future use of this model, it is important to take note of the program strengths and limitations to ensure alignment with future needs for surge capacity support. Lessons learned from this initiative could provide practice-relevant knowledge for surge capacity planning.

RéSUMé: CONTEXTE: En Ontario, ce sont les bureaux de santé publique qui s'occupent des enquêtes de cas, de la recherche des contacts et des suivis. Pendant la pandémie de COVID-19, les besoins opérationnels et de capacité de la main-d'œuvre à combler pour conserver cette stratégie de santé publique ont atteint une ampleur jamais vue. INTERVENTION: L'Initiative de recherche des contacts dans le cadre de la lutte contre la COVID-19 de Santé publique Ontario a été mise sur pied dans l'objectif de centraliser l'effectif. Mobilisant des ressources humaines d'organisations fédérales et provinciales, ce programme a permis de faire les appels initiaux et de suivi aux contacts étroits de cas de COVID-19 exposés à un risque élevé. Grâce à des critères bien établis pour les soumissions au programme, à l'uniformisation des scripts et à la simplification du processus de gestion des données, un grand volume d'appels a pu être traité. RéSULTATS: Durant les 23 mois de l'Initiative, 33 des 34 bureaux de santé publique y ont eu recours. Ce sont ainsi plus d'un million d'appels à des contacts étroits qui ont pu être faits. L'Initiative a permis d'atteindre les objectifs en s'adaptant au contexte pandémique en constante évolution et de mettre en œuvre un nouveau système de gestion des renseignements provinciaux sur la COVID-19. Ses grandes forces sont la rapidité, le volume et l'efficacité de l'utilisation des ressources. Elle a été particulièrement utile dans les cas d'exposition en milieu scolaire, permettant d'offrir du soutien à la levée des mesures sanitaires et d'aider à la réaffectation des ressources des bureaux de santé publique pendant la campagne de vaccination. CONSéQUENCES: Si l'on envisage de réutiliser ce modèle, il importe de tenir compte des forces et des faiblesses du programme pour qu'il cadre avec les besoins futurs de soutien en matière de capacité de mobilisation. Les leçons tirées de cette initiative pourraient s'avérer pertinentes pour la planification de cette capacité.

Antenatal identification of major depressive disorder: a cohort study.

OBJECTIVE: The purpose of this study was to estimate the frequency of identification of major depressive disorder by providers during prenatal care. STUDY DESIGN: A cohort of pregnant women who were participating in a randomized controlled trial and who had received a diagnosis of major depressive disorder was examined. Women were included in the current study if prenatal clinic records were available and legible. RESULTS: Clinical depression was noted in 56% of prenatal charts and on 24% of problem lists. Physicians and certified nurse midwives noted depression equally (P = .935); physicians more frequently noted mental health referral (23% vs 0%; P = .01), and midwives more frequently included depression on the problem list (P = .01). Recent medication use, which was stopped before conception or study participation, predicted notation of depression in the chart (P = .001). CONCLUSION: Depression frequently is missed during pregnancy and, when identified, is underacknowledged as a problem. Women who have not recently used antidepressant medication are more likely to be missed. Better screening and acknowledgment are needed.

Comparison of data sources for the surveillance of work injury.

OBJECTIVE: The objective of this study was to compare the incidence of work-related injury and illness presenting to Ontario emergency departments to the incidence of worker's compensation claims reported to the Ontario Workplace Safety & Insurance Board over the period 2004-2008. METHODS: Records of work-related injury were obtained from two administrative data sources in Ontario for the period 2004-2008: workers' compensation lost-time claims (N=435,336) and records of non-scheduled emergency department visits where the main problem was attributed to a work-related exposure (N=707,963). Denominator information required to compute the risk of work injury per 2,000,000 work hours, stratified by age and gender was estimated from labour force surveys conducted by Statistics Canada. RESULTS: The frequency of emergency department visits for all work-related conditions was approximately 60% greater than the incidence of accepted lost-time compensation claims. When restricted to injuries resulting in fracture or concussion, gender-specific age differences in injury incidence were similar in the two data sources. Between 2004 and 2008, there was a 14.5% reduction in emergency department visits attributed to work-related causes and a 17.8% reduction in lost-time compensation claims. There was evidence that younger workers were more likely than older workers to seek treatment in an emergency department for work-related injury. CONCLUSIONS: In this setting, emergency department records available for the complete population of Ontario residents are a valid source of surveillance information on the incidence of work-related disorders. Occupational health and safety authorities should give priority to incorporating emergency department records in the routine surveillance of the health of workers.

Engineered natural killer cells impede the immunometabolic CD73-adenosine axis in solid tumors.

Immunometabolic reprogramming due to adenosine produced by CD73 (encoded by the 5'-ectonucleotidase gene NT5E) is a recognized immunosuppressive mechanism contributing to immune evasion in solid tumors. Adenosine is not only known to contribute to tumor progression, but it has specific roles in driving dysfunction of immune cells, including natural killer (NK) cells. Here, we engineered human NK cells to directly target the CD73-adenosine axis by blocking the enzymatic activity of CD73. In doing so, the engineered NK cells not only impaired adenosinergic metabolism driven by the hypoxic uptake of ATP by cancer cells in a model of non-small-cell lung cancer, but also mediated killing of tumor cells due to the specific recognition of overexpressed CD73. This resulted in a 'single agent' immunotherapy that combines antibody specificity, blockade of purinergic signaling, and killing of targets mediated by NK cells. We also showed that CD73-targeted NK cells are potent in vivo and result in tumor arrest, while promoting NK cell infiltration into CD73+ tumors and enhancing intratumoral activation.

Virtual learning collaboratives to improve urine culturing and antibiotic prescribing in long-term care: controlled before-and-after study.

BACKGROUND: Urine culturing practices are highly variable in long-term care and contribute to overprescribing of antibiotics for presumed urinary tract infections. The purpose of this study was to evaluate the use of virtual learning collaboratives to support long-term care homes in implementing a quality improvement programme focused on reducing unnecessary urine culturing and antibiotic overprescribing. METHODS: Over a 4-month period (May 2018-August 2018), 45 long-term care homes were self-selected from five regions to participate in virtual learning collaborative sessions, which provided an orientation to a quality improvement programme and guidance for implementation. A process evaluation complemented the use of a controlled before-and-after study with a propensity score matched control group (n=127) and a difference-in-difference analysis. Primary outcomes included rates of urine cultures performed and urinary antibiotic prescriptions. Secondary outcomes included rates of emergency department visits, hospital admission and mortality. An 18-month baseline period was compared with a 16-month postimplementation period with the use of administrative data sources. RESULTS: Rates of urine culturing and urinary antibiotic prescriptions per 1000 resident days decreased significantly more among long-term care homes that participated in learning collaboratives compared with matched controls (differential reductions of 19% and 13%, respectively, p<0.0001). There was no statistically significant changes to rates of emergency department visits, hospital admissions or mortality. These outcomes were observed with moderate adherence to the programme model. CONCLUSIONS: Rates of urine culturing and urinary antibiotic prescriptions declined among long-term care homes that participated in a virtual learning collaborative to support implementation of a quality improvement programme. The results of this study have refined a model to scale this programme in long-term care.

Evaluation of evidence-based literature and formulation of recommendations for the clinical preventive guidelines for immigrants and refugees in Canada.

BACKGROUND: This article describes the evidence review and guideline development method developed for the Clinical Preventive Guidelines for Immigrants and Refugees in Canada by the Canadian Collaboration for Immigrant and Refugee Health Guideline Committee. METHODS: The Appraisal of Guidelines for Research and Evaluation (AGREE) best-practice framework was combined with the recently developed Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to produce evidence-based clinical guidelines for immigrants and refugees in Canada. RESULTS: A systematic approach was designed to produce the evidence reviews and apply the GRADE approach, including building on evidence from previous systematic reviews, searching for and comparing evidence between general and specific immigrant populations, and applying the GRADE criteria for making recommendations. This method was used for priority health conditions that had been selected by practitioners caring for immigrants and refugees in Canada. INTERPRETATION: This article outlines the 14-step method that was defined to standardize the guideline development process for each priority health condition.

An exposure-response curve for copper excess and deficiency.

There is a need to define exposure-response curves for both Cu excess and deficiency to assist in determining the acceptable range of oral intake. A comprehensive database has been developed where different health outcomes from elevated and deficient Cu intakes were assigned ordinal severity scores to create common measures of response. A generalized linear model for ordinal data was used to estimate the probability of response associated with dose, duration and severity. The model can account for differences in animal species, the exposure medium (drinking water and feed), age, sex, and solubility. Using this model, an optimal intake level of 2.6 mg Cu/d was determined. This value is higher than the current U.S. recommended dietary intake (RDI; 0.9 mg/d) that protects against toxicity from Cu deficiency. It is also lower than the current tolerable upper intake level (UL; 10 mg/d) that protects against toxicity from Cu excess. Compared to traditional risk assessment approaches, categorical regression can provide risk managers with more information, including a range of intake levels associated with different levels of severity and probability of response. To weigh the relative harms of deficiency and excess, it is important that the results be interpreted along with the available information on the nature of the responses that were assigned to each severity score.

The use of categorical regression in modeling copper exposure-response relationships.

Characterization of the exposure-response relationship for copper (Cu) is an essential step in identifying a range of exposures that can prevent against toxicity from either excess or deficiency. Categorical regression is a exposure-response modeling technique that can be used to model data from multiple studies with diverse endpoints simultaneously by organizing the toxicity data into ordered categories of severity. This study describes how categorical regression can be used to model the exposure-response relationship for Cu and presents a preliminary analysis of the comprehensive database on Cu-induced toxicity due to either excess or deficiency. Categorical regression provides a useful tool for summarizing and describing the available data on Cu excess and deficiency, as well as in identifying data gaps in Cu exposure-response. This methodology also allows for a diverse database with considerable variability in animal species, strain, age, and study design to be analyzed in its entirety. The present application of the Cu toxicity database suggests that there is a lack of information on the potential adverse health effects from chronic exposure to Cu; there are also a limited number of studies using marginally excess and deficient levels of Cu. The database presently includes insufficient data to create a complex model that accounts for a large proportion of the heterogeneity in toxicity seen among the available studies on Cu-induced toxicity. The current Cu database is presently being updated in order to permit more comprehensive categorical regression analyses with finer stratification options. The resulting exposure-response model could be used to provide information in the determination of an acceptable range of oral intake for Cu.

Development of a copper database for exposure-response analysis.

While its precise form has not yet been defined, it is assumed that the exposure-response curve for copper (Cu) is U-shaped, as both Cu deficiency and excess can produce adverse health effects. Exposure-response relationships provide the foundation for setting recommended levels of exposure to essential and nonessential substances. A group of toxicologists, biologists, and epidemiologists formed a working group in 2002 to review the literature on Cu excess and deficiency as well as possible exposure-response modeling strategies. It was decided that in order to conduct more complex modeling exercises with studies on Cu, the information had to be organized into a database for application of emerging analytical approaches in exposure-response assessment. The database would support both current as well as proposed methods for exposure-response assessment and accommodate a variety of reporting methods found in the literature. As there are multiple studies looking at a wide range of adverse health effects attributed to excess and deficiency, data were organized into ordered categories of severity to create a common measure of response. The present study (1) outlines the approach used to identify studies for the Cu database based on their quality and usefulness for exposure-response analyses; (2) provides an overview of the process used to define a common dose metric; and (3) describes the process used to categorize a diverse number of responses from Cu excess and deficiency to an ordinal severity score. Efforts are underway to use this database to define the exposure-response curve for Cu excess and deficiency; however, the comprehensive database can be used to carry out other in-depth analyses on Cu toxicity.

Insomnia and depression: a multifaceted interplay.

Historically, insomnia has been viewed as a symptom of depressive illness that is expected to resolve with adequate treatment of the depressive disorder. This article reviews the evidence that increasingly challenges this simplistic view and summarizes research demonstrating the multifaceted interplay between insomnia and depression. It discusses the prevalence, clinical significance, and time course of insomnia, distinguishing between poor sleep and an insomnia disorder. The article also discusses abnormalities in sleep architecture in major depressive disorder and theories about the pathways connecting sleep and depression. It concludes with a discussion of issues related to treatment, including the effects of antidepressants on sleep and new evidence of the utility of adding an insomnia-specific therapy for improved management of depressed patients with comorbid insomnia.

Immunometabolic Dysfunction of Natural Killer Cells Mediated by the Hypoxia-CD73 Axis in Solid Tumors.

NK cell infiltration into solid tumors is often low and is largely represented by the poorly-cytotoxic CD56bright subset. Numerous studies have demonstrated that CD73, overexpressed under conditions of hypoxia, is involved in a variety of physiological processes, while its overexpression has been correlated with tumor invasiveness, metastasis and poorer patient survival in many cancers. Hypoxia itself favors aggressive glycolytic fueling of cancer cells, in turn driving reprogramming of NK cell metabolism. In addition, the hypoxia-driven activity of CD73 immunometabolically impairs NK cells in tumors, due to its catalytic role in the generation of the highly immunosuppressive metabolite adenosine. Adenosinergic signaling was shown to alter NK cell metabolic programs, leading to tumor-promoting environments characterized by NK cell dysfunction. Despite the demonstrated role of NK cell responses in the context of CD73 targeting, the engagement of NK cells in the setting of hypoxia/CD73 signaling has not been extensively studied or exploited. Here, we discuss available evidence on the role of hypoxic signaling on CD73-mediated activity, and how this relates to the immunometabolic responses of NK cells, with a particular focus on the therapeutic targeting of these pathways.