Effect of NKG2C absence on natural killer cell phenotype and function in human immunodeficiency virus/cytomegalovirus co-infection

Natural killer (NK) cells expressing NKG2C and CD57 expand following human cytomegalovirus (CMV) infection. This NK cell subset downregulates FcεR1γ and acquires enhanced capacity to mediate antibody-dependent cellular cytotoxicity (ADCC). Expansion of these differentiated NK cells is exaggerated in human immunodeficiency virus (HIV) infection. Individuals lacking the gene encoding NKG2C have diminished resistance to HIV, but it remains unclear whether differentiation into NK cells with superior ADCC is impaired in NKG2Cnull individuals. Therefore, our objective was to investigate if CMV-driven NK cell differentiation into enhanced killers is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD57⁺, FcεR1γ⁻) and functional (IFN-γ, TNF-α induction and cytotoxicity) NK cell responses were compared between NKG2Cnull and matched NKG2C-expressing individuals by flow cytometry following stimulation through natural cytotoxicity receptors (using K562 cells) or CD16 (using monoclonal antibody, 3G8). Cytotoxicity was measured in ⁵¹Chromium release assays against anti-CD16-coated P815 cells (redirected lysis) and anti-human leukocyte antigen (HLA) class I antibody-coated C1R cells (classical ADCC). Antibodies were titrated to determine concentrations producing half maximal responses (EC₅₀) to compare sensitivity. Our data indicate highly similar CMV-driven NK cell differentiation in terms of both general phenotype and function, regardless of NKG2C genotype. The observed equivalency between groups suggests alternate routes of CMV-driven NK cell differentiation, which are independent of NKG2C

\u27More of the Same, But Worse Than Before\u27: A Qualitative Study of the Challenges Encountered by People Who Use Drugs in Nova Scotia, Canada During COVID-19

Background To learn about the experiences of people who use drugs, specifically opioids, in the Halifax Regional Municipality (HRM), in Nova Scotia, Canada during the COVID-19 pandemic through qualitative interviews with people who use drugs and healthcare providers (HCP). This study took place within the HRM, a municipality of 448,500 people. During the pandemic many critical services were interrupted while overdose events increased. We wanted to understand the experiences of people who use drugs as well as their HCPs during the first year of the pandemic. Methodology We conducted a qualitative study using semi-structured interviews with 13 people who use drugs and 6 HCPs, including physicians who work in addiction medicine (3), a pharmacist, a nurse, and a community-based opioid agonist therapy (OAT) program staff member. Participants were recruited within HRM. Interviews were held via phone or videoconference due to social distancing directives. Interviews focused on the challenges people who use drugs and HCPs faced during the pandemic as well as elicited perspectives on a safe supply of drugs and the associated barriers and facilitators to the provision of a safe supply. Results Of the 13 people who use drugs who participated in this study, ages ranged from 21–55 years (mean 40). Individuals had spent on average 17 years in HRM. Most people who use drugs (85%, n = 11) utilized income assistance, the Canadian Emergency Response Benefit, or disability support. Many had experienced homelessness (85%, n = 11) and almost half (46%, n = 6) were currently precariously housed in the shelter system. The main themes among interviews (people who use drugs and HCPs) were housing, accessing healthcare and community services, shifts in the drug supply, and perspectives on safe supply. Conclusions We identified several challenges that people who use drugs face in general, but especially during the COVID-19 pandemic. Access to services, housing support, and interventions to use safely at home were limited. As many challenges faced by people who use drugs exist outside of COVID-19, we concluded that the formal and informal interventions and changes in practice that were made to support people who use drugs should be sustained well past the end of the pandemic. The need for enhanced community supports and a safe supply of drugs, despite its complicated nature, is essential for the health and safety of people who use drugs in HRM, especially during COVID-19

Interactive E-Texts and Students: A Scoping Review

The purpose of this article is to explore the scope of available evidence regarding the use of interactive e-texts and their relationship to student learning experiences in post-secondary education. Following the framework of Arksey and O’Malley, this scoping review identified and reported on 33 articles. Study characteristics are presented alongside four themes that were found across the included articles: (1) the effect of interactive e-texts on student learning experiences; (2) the relationship between interactive e-texts and academic performance; (3) factors influencing student adoption and experience of interactive e-texts; and (4) roles, responsibilities, and recommendations. While the adoption of interactive e-texts is becoming increasingly common in post-secondary education, their effect on student learning experiences remains complex. This review emphasizes the importance of user-friendliness, affordability, accessibility, portability, and the role of educators. Using interactive e-texts shows promise, though future research should explore how barriers might be minimized and benefits might be maximized to have the strongest impact on student learning experiences. Keywords: interactive e-text, student experience, scoping review, post-secondary educationL’objectif de cet article était d’explorer l’étendue des connaissances disponibles sur l’utilisation des documents numériques interactifs et leur relation avec les expériences d’apprentissage des étudiants à l’enseignement supérieur. Suivant le cadre de l’étude d’Arksey et O’Malley (2005), cet examen de l’étendue des connaissances nous a permis de repérer et d’analyser 33 articles. Les caractéristiques de l’étude sont présentées selon quatre thèmes retrouvés dans les articles consultés : (1) l’impact des documents numériques interactifs sur les expériences d’apprentissage des étudiants; (2) la relation entre les documents numériques interactifs et les résultats scolaires; (3) les facteurs influençant l’adoption des documents numériques interactifs et les expériences d’utilisation par les étudiants; et (4) les rôles, les responsabilités et les recommandations. Tandis que l’utilisation des documents numériques interactifs devient de plus en plus fréquente au postsecondaire, leur impact sur les expériences d’apprentissage des étudiants demeure complexe. Cet article souligne l’importance de la convivialité, du coût, de l’accessibilité, de la portabilité et du rôle des enseignants. Puisque l’utilisation de documents numériques interactifs est prometteuse, de futures recherches devraient explorer comment les obstacles pourraient être réduits au minimum et les avantages maximisés pour permettre le meilleur impact possible sur les expériences d’apprentissage des étudiants. Mots-clés : documents numériques interactifs, expérience étudiante, étendue des connaissances, éducation postsecondair

Social and structural determinants of injection drug use-associated bacterial and fungal infections: a qualitative systematic review and thematic synthesis

BACKGROUND AND AIMS: Injection drug use-associated bacterial and fungal infections are increasingly common, and social contexts shape individuals' injecting practices and treatment experiences. We sought to synthesize qualitative studies of social-structural factors influencing incidence and treatment of injecting-related infections. METHODS: We searched PubMed, EMBASE, Scopus, CINAHL, and PsycINFO from January 1, 2000, to February 18, 2021. Informed by Rhodes' "risk environment" framework, we performed thematic synthesis in three stages: (1) line-by-line coding; (2) organizing codes into descriptive themes, reflecting interpretations of study authors; (3) consolidating descriptive themes into conceptual categories to identify higher-order analytic themes. RESULTS: We screened 4,841 abstracts and included 26 qualitative studies on experiences of injecting-related bacterial and fungal infections. We identified six descriptive themes organized into two analytic themes. The first analytic theme, social production of risk, considered macro-environmental influences. Four descriptive themes highlighted pathways through which this occurs: (1) unregulated drug supply, leading to poor drug quality and solubility; (2) unsafe spaces, influenced by policing practices and insecure housing; (3) health care policies and practices, leading to negative experiences that discourage access to care; and (4) restrictions on harm reduction programs, including structural barriers to effective service provision. The second analytic theme, practices of care among people who use drugs, addressed protective strategies people employ within infection risk environments. Associated descriptive themes were: (5) mutual care, including assisted-injecting and sharing sterile equipment; and (6) self-care, including vein health and self-treatment. Within constraining risk environments, some protective strategies for bacterial infections precipitated other health risks (e.g., HIV transmission). CONCLUSIONS: Injecting-related bacterial and fungal infections are shaped by modifiable social-structural factors, including poor quality unregulated drugs, criminalization and policing enforcement, insufficient housing, limited harm reduction services, and harmful health care practices. People who inject drugs navigate these barriers while attempting to protect themselves and their community

Securing Safe Supply During COVID-19 and Beyond: Scoping Review and Knowledge Mobilization

Background Safe supply is defined as the legal and regulated provision of drugs with mind and/or body altering properties that have been typically accessible only through the illegal drug market. In response to the coronavirus disease 2019 (COVID-19) pandemic and related social/physical distancing measures, efforts have been made to scale up and increase access to safe supply programs in an effort to reduce overdose and other drug- and drug policy-related risks. However, it remains unclear whether these efforts taken thus far have meaningfully mitigated the barriers to safe supply experienced by People Who Use Drugs (PWUD), both during and beyond the context of COVID-19. We thus undertook a scoping review to identify key concepts, strategies and gaps in evidence with respect to the provision of safe supply during pandemics and other emergencies. Methods We conducted three searches across Scopus, Medline, Embase, CINAHL, and The Cochrane Central Register of Controlled Trials (CENTRAL) for peer-reviewed and grey literature articles to understand barriers/facilitators to both accessing and prescribing legal, pharmaceutical-grade drugs, including opioids, benzodiazepines, and/or stimulants during public health emergencies from January 1 2002 to June 30 2020. We also included opioid agonist therapies (OAT) during emergency conditions. All potential sources underwent title/abstract screening and duplicate full- text review to determine eligibility for inclusion. Three reviewers extracted characteristics and barriers/facilitators to accessing or prescribing drugs for each study, and these were then inductively analyzed to identify common themes. Key stakeholders (PWUD, prescribers, and policymakers/regulators) informed the search strategy and validated findings and interpretations. Input from PWUD and prescribers was gathered through Advisory Committee meetings and one-on-one consultations, respectively. Results We screened 9,839 references and included 169 studies (135 peer-reviewed articles and 36 grey literature reports). From 119 articles, we identified 35 themes related to barriers/facilitators to prescribing safe supply or OAT. Few studies (n=24) focused on emergency or pandemic contexts. Among the most frequently reported barriers were restrictive laws or policies (n= 33; 28%). The most frequently cited facilitator was temporary legal or regulatory exemptions (n= 16; 13%). Further stakeholder consultation identified barriers/facilitators to safe supply absent in the reviewed literature: PWUD reported barriers including lack of access to desired substances, concerns about child apprehension, and a lack of cultural competency within safe supply/OAT programs; prescribers reported barriers including regional differences in service delivery, colleague support, and a lack of, or disagreement between, clinical guidance documents. Conclusion We identified multiple barriers and facilitators to accessing and/or prescribing safe supply or OAT. With few peer-reviewed studies on safe supply models, particularly in the context of emergencies, input from PWUD and other stakeholders offered crucial insights not reflected in the existing literature. To address the overdose epidemic stemming from the criminalization of an unregulated drug supply, prescribers, regulators, and public health authorities should focus on scaling up, and then evaluating, diverse safe supply frameworks that address the facilitators and barriers we have identified

Social and structural determinants of injection drug use-associated bacterial and fungal infections: A qualitative systematic review and thematic synthesis

BACKGROUND AND AIMS: Injection drug use-associated bacterial and fungal infections are increasingly common, and social contexts shape individuals' injecting practices and treatment experiences. We sought to synthesize qualitative studies of social-structural factors influencing incidence and treatment of injecting-related infections. METHODS: We searched PubMed, EMBASE, Scopus, CINAHL and PsycINFO from 1 January 2000 to 18 February 2021. Informed by Rhodes' 'risk environment' framework, we performed thematic synthesis in three stages: (1) line-by-line coding; (2) organizing codes into descriptive themes, reflecting interpretations of study authors; and (3) consolidating descriptive themes into conceptual categories to identify higher-order analytical themes. RESULTS: We screened 4841 abstracts and included 26 qualitative studies on experiences of injecting-related bacterial and fungal infections. We identified six descriptive themes organized into two analytical themes. The first analytical theme, social production of risk, considered macro-environmental influences. Four descriptive themes highlighted pathways through which this occurs: (1) unregulated drug supply, leading to poor drug quality and solubility; (2) unsafe spaces, influenced by policing practices and insecure housing; (3) health-care policies and practices, leading to negative experiences that discourage access to care; and (4) restrictions on harm reduction programmes, including structural barriers to effective service provision. The second analytical theme, practices of care among people who use drugs, addressed protective strategies that people employ within infection risk environments. Associated descriptive themes were: (5) mutual care, including assisted-injecting and sharing sterile equipment; and (6) self-care, including vein health and self-treatment. Within constraining risk environments, some protective strategies for bacterial infections precipitated other health risks (e.g. HIV transmission). CONCLUSIONS: Injecting-related bacterial and fungal infections are shaped by modifiable social-structural factors, including poor quality unregulated drugs, criminalization and policing enforcement, insufficient housing, limited harm reduction services and harmful health-care practices. People who inject drugs navigate these barriers while attempting to protect themselves and their community

'More of the same, but worse than before': A qualitative study of the challenges encountered by people who use drugs in Nova Scotia, Canada during COVID-19.

BackgroundTo learn about the experiences of people who use drugs, specifically opioids, in the Halifax Regional Municipality (HRM), in Nova Scotia, Canada during the COVID-19 pandemic through qualitative interviews with people who use drugs and healthcare providers (HCP). This study took place within the HRM, a municipality of 448,500 people [1]. During the pandemic many critical services were interrupted while overdose events increased. We wanted to understand the experiences of people who use drugs as well as their HCPs during the first year of the pandemic.MethodologyWe conducted a qualitative study using semi-structured interviews with 13 people who use drugs and 6 HCPs, including physicians who work in addiction medicine (3), a pharmacist, a nurse, and a community-based opioid agonist therapy (OAT) program staff member. Participants were recruited within HRM. Interviews were held via phone or videoconference due to social distancing directives. Interviews focused on the challenges people who use drugs and HCPs faced during the pandemic as well as elicited perspectives on a safe supply of drugs and the associated barriers and facilitators to the provision of a safe supply.ResultsOf the 13 people who use drugs who participated in this study, ages ranged from 21-55 years (mean 40). Individuals had spent on average 17 years in HRM. Most people who use drugs (85%, n = 11) utilized income assistance, the Canadian Emergency Response Benefit, or disability support. Many had experienced homelessness (85%, n = 11) and almost half (46%, n = 6) were currently precariously housed in the shelter system. The main themes among interviews (people who use drugs and HCPs) were housing, accessing healthcare and community services, shifts in the drug supply, and perspectives on safe supply.ConclusionsWe identified several challenges that people who use drugs face in general, but especially during the COVID-19 pandemic. Access to services, housing support, and interventions to use safely at home were limited. As many challenges faced by people who use drugs exist outside of COVID-19, we concluded that the formal and informal interventions and changes in practice that were made to support people who use drugs should be sustained well past the end of the pandemic. The need for enhanced community supports and a safe supply of drugs, despite its complicated nature, is essential for the health and safety of people who use drugs in HRM, especially during COVID-19

\u27More of the Same, But Worse Than Before\u27: A Qualitative Study of the Challenges Encountered by People Who Use Drugs in Nova Scotia, Canada During COVID-19

Background To learn about the experiences of people who use drugs, specifically opioids, in the Halifax Regional Municipality (HRM), in Nova Scotia, Canada during the COVID-19 pandemic through qualitative interviews with people who use drugs and healthcare providers (HCP). This study took place within the HRM, a municipality of 448,500 people. During the pandemic many critical services were interrupted while overdose events increased. We wanted to understand the experiences of people who use drugs as well as their HCPs during the first year of the pandemic. Methodology We conducted a qualitative study using semi-structured interviews with 13 people who use drugs and 6 HCPs, including physicians who work in addiction medicine (3), a pharmacist, a nurse, and a community-based opioid agonist therapy (OAT) program staff member. Participants were recruited within HRM. Interviews were held via phone or videoconference due to social distancing directives. Interviews focused on the challenges people who use drugs and HCPs faced during the pandemic as well as elicited perspectives on a safe supply of drugs and the associated barriers and facilitators to the provision of a safe supply. Results Of the 13 people who use drugs who participated in this study, ages ranged from 21–55 years (mean 40). Individuals had spent on average 17 years in HRM. Most people who use drugs (85%, n = 11) utilized income assistance, the Canadian Emergency Response Benefit, or disability support. Many had experienced homelessness (85%, n = 11) and almost half (46%, n = 6) were currently precariously housed in the shelter system. The main themes among interviews (people who use drugs and HCPs) were housing, accessing healthcare and community services, shifts in the drug supply, and perspectives on safe supply. Conclusions We identified several challenges that people who use drugs face in general, but especially during the COVID-19 pandemic. Access to services, housing support, and interventions to use safely at home were limited. As many challenges faced by people who use drugs exist outside of COVID-19, we concluded that the formal and informal interventions and changes in practice that were made to support people who use drugs should be sustained well past the end of the pandemic. The need for enhanced community supports and a safe supply of drugs, despite its complicated nature, is essential for the health and safety of people who use drugs in HRM, especially during COVID-19

NKG2C+CD57+ Natural Killer Cell Expansion Parallels Cytomegalovirus-Specific CD8+ T Cell Evolution towards Senescence

Objective. Measuring NKG2C+CD57+ natural killer (NK) cell expansion to investigate NK responses against human cytomegalovirus (HCMV) and assessing relationships with adaptive immunity against HCMV. Methods. Expansion of NKG2C+CD57+ NK was measured in peripheral blood mononuclear cells (PBMC) from groups distinguished by HCMV and human immunodeficiency virus (HIV) infection status. Anti-HCMV antibody levels against HCMV-infected MRC-5 cell lysate were assessed by ELISA and HCMV-specific CD8+ T cell responses characterized by intracellular flow cytometry following PBMC stimulation with immunodominant HCMV peptides. Results. Median NK, antibody, and CD8+ T cell responses against HCMV were significantly greater in the HCMV/HIV coinfected group than the group infected with CMV alone. The fraction of CMV-specific CD8+ T cells expressing CD28 correlated inversely with NKG2C+CD57+ NK expansion in HIV infection. Conclusion. Our data reveal no significant direct relationships between NK and adaptive immunity against HCMV. However, stronger NK and adaptive immune responses against HCMV and an inverse correlation between NKG2C+CD57+ NK expansion and proliferative reserve of HCMV-specific CD8+ T cells, as signified by CD28 expression, indicate parallel evolution of NK and T cell responses against HCMV in HIV infection. Similar aspects of chronic HCMV infection may drive both NK and CD8+ T cell memory inflation

Cytomegalovirus-Driven Adaption of Natural Killer Cells in NKG2Cnull Human Immunodeficiency Virus-Infected Individuals

Expansion of natural killer (NK) cells expressing NKG2C occurs following human cytomegalovirus (HCMV) infection and is amplified by human immunodeficiency virus (HIV) co-infection. These NKG2C-expressing NK cells demonstrate enhanced CD16-dependent cytokine production and downregulate FcεRIγ and promyelocytic leukemia zinc finger protein (PLZF). Lacking NKG2C diminishes resistance to HIV infection, but whether this affects NK cell acquisition of superior antibody-dependent function is unclear. Therefore, our objective was to investigate whether HCMV-driven NK cell differentiation is impaired in NKG2Cnull HIV-infected individuals. Phenotypic (CD2, CD16, CD57, NKG2A, FcεRIγ, and PLZF expression) and functional (cytokine induction and cytotoxicity) properties were compared between HIV–infected NKG2Cnull and NKG2C-expressing groups. Cytokine production was compared following stimulation through natural cytotoxicity receptors or through CD16. Cytotoxicity was measured by anti-CD16-redirected lysis and by classical antibody-dependent cell-mediated cytotoxicity (ADCC) against anti-class I human leukocyte antigen (HLA) antibody-coated cells. Our data indicate highly similar HCMV-driven NK cell differentiation in HIV infection with or without NKG2C. While the fraction of mature (CD57pos) NK cells expressing CD2 (p = 0.009) or co-expressing CD2 and CD16 (p = 0.03) was significantly higher in NKG2Cnull HIV-infected individuals, there were no significant differences in NKG2A, FcεRIγ, or PLZF expression. The general phenotypic and functional equivalency observed suggests NKG2C-independent routes of HCMV-driven NK cell differentiation, which may involve increased CD2 expression