Generating user-driven patient personas to support preventive health care activities of rural-living unattached patients.

Objective: This study created personas using quantitative segmentation and knowledge user enhancement to inform intervention and service design for rural patients to encourage preventive care uptake. Methods: This study comprised a cross-sectional survey of rural unattached patients and a co-design workshop for persona development. Cross-sectional survey data were analyzed for meaningful subgroups based on quartiles of preventive care completion. These quartiles informed "relevant user segments" grouped according to demographics (age, sex), length of unattachment, percentage of up-to-date preventive activities, health care visit frequency, preventive priorities, communication confidence with providers, and chronic health conditions, which were then used in the workshop to build the final personas. Results: 207 responses informed persona user segments, and five health care providers and 13 patients attended the workshop. The resulting four personas, included John (not up-to-date on preventive care activities), Terrance (few up-to-date preventive care activities), George (moderately up-to-date preventive care activities), and Anne (mostly up-to-date preventive care activities). Conclusion: Quantitative persona development with integrated knowledge user co-design/enhancement elevated and enriched final personas that achieved robust profiles for intervention design. Innovation: This project's use of a progressive methodology to build robust personas coupled with participant feedback on the co-design process offers a replicable approach for health researchers.

Transcriptionally-active "defective" HIV-1 proviruses and their association with immunological non-response to antiretroviral therapy.

A subset of antiretroviral therapy-treated persons with HIV, referred to as immunological non-responders (INRs), fails to normalize CD4+ T-cell numbers. In a case-control study involving 26 INRs (CD4<250 cells/µL) and 25 immunological responders (IRs, CD4≥250 cells/µL), we evaluated the potential contribution of transcriptionally-competent "defective" HIV-1 proviruses to poor CD4+ T-cell recovery. Compared to the responders, the INRs had higher levels of cell-associated HIV-RNA (p=0.034) and higher percentages of HLA-DR+CD4+ T-cells (p<0.001). While not encoding replication-competent viruses, the RNA transcripts frequently encoded HIV-1 Gag-p17 and Nef proteins. These transcripts and/or resulting proteins may activate pathway(s) leading to the immunological non-response phenotype.

Managing With Atrial Fibrillation: An Exploratory Model-Based Cluster Analysis of Clinical and Personal Patient Characteristics.

Background: Examining characteristics of patients with atrial fibrillation (AF) has the potential to help in identifying groups of patients who might benefit from different management approaches. Methods: Secondary analysis of online survey data was combined with clinic referral data abstraction from 196 patients with AF attending an AF specialty clinic. Cluster analyses were performed to identify distinct, homogeneous clusters of AF patients defined by 11 relevant variables: CHA2DS2-VASc score, age, AF symptoms, overall health, mental health, AF knowledge, perceived stress, household and recreation activity, overall AF quality of life, and AF symptom treatment satisfaction. Follow-up analyses examined differences between the cluster groups in additional clinical variables. Results: Evidence emerged for both 2- and 4-cluster solutions. The 2-cluster solution involved a contrast between patients who were doing well on all variables (n = 129; 66%) vs those doing less well (n = 67; 34%). The 4-cluster solution provided a closer-up view of the data, showing that the group doing less well was split into 3 meaningfully different subgroups of patients who were managing in different ways. The final 4 clusters produced were as follows: (i) doing well; (ii) stressed and discontented; (iii) struggling and dissatisfied; and (iv) satisfied and complacent. Conclusions: Patients with AF can be accurately classified into distinct, natural groupings that vary in clinically important ways. Among the patients who were not managing well with AF, we found 3 distinct subgroups of patients who may benefit from tailored approaches to AF management and support. The tailoring of treatment approaches to specific personal and/or behavioural patterns, alongside clinical patterns, holds potential to improve patient outcomes (eg, treatment satisfaction).

Contexte: L'examen des caractéristiques des patients atteints de fibrillation auriculaire (FA) pourrait permettre de mieux cerner les groupes qui pourraient bénéficier de différentes approches de prise en charge. Méthodologie: Nous avons combiné une analyse secondaire de données issues d'un sondage en ligne et les données issues de l'orientation clinique de 196 patients atteints de FA d'une clinique spécialisée en FA. Des analyses par grappes ont été réalisées pour cerner des groupes homogènes et distincts de patients atteints de FA, définis grâce à 11 variables pertinentes : score CHA2DS2-VASc, âge, symptômes de FA, état de santé général, état de santé mentale, niveau de connaissances sur la FA, niveau de stress perçu, activités récréatives et domestiques, qualité de vie générale avec la FA, et satisfaction concernant le traitement des symptômes de FA. Des ana-lyses ultérieures ont permis de se pencher sur les différences entre les groupes pour d'autres variables cliniques. Résultats: Deux solutions de regroupement des patients sont apparues possibles à l'analyse : en 2 groupes ou en 4 groupes. Le regroupement en 2 groupes mettait en relief le contraste entre les patients qui avaient des résultats favorables pour tous les paramètres (n = 129; 66 %) et ceux qui avaient des résultats moins favorables (n = 67; 34 %). Le regroupement en 4 groupes permettait d'observer les données plus en détail, et démontrait que le groupe avec des résultats moins favorables se subdivisait en 3 sous-groupes avec des distinctions pertinentes, qui vivaient leur maladie de façon différente. Les 4 groupes finaux étaient les suivants : (i) patients avec une expérience positive; (ii) patients vivant du stress et du mécontentement; (iii) patients vivant des difficultés et une insatisfaction; et (iv) patients vivant une satisfaction complaisante. Conclusions: Les patients atteints de FA peuvent être classés avec exactitude dans des groupes naturels distincts dont les différences sont d'intérêt clinique. Parmi les patients chez qui la prise en charge de la FA n'est pas optimale, il existe 3 sous-groupes différents qui pourraient tirer profit d'une approche de soutien et de prise en charge adaptée à leur profil. La personnalisation des approches thérapeutiques selon le type de comportements et de traits de personnalité, en plus du tableau clinique, pourrait permettre d'améliorer les résultats des patients (p. ex. la satisfaction par rapport au traitement).

Quality of life among patients with atrial fibrillation: A theoretically-guided cross-sectional study.

BACKGROUND: Patients with atrial fibrillation (AF) have significantly lower health-related quality of life (HRQoL) compared to the general population and patients with other heart diseases. The research emphasis on the influence of AF symptoms on HRQoL overshadows the role of individual characteristics. To address this gap, this study's purpose was to test an incremental predictive model for AF-related HRQoL following an adapted HRQoL conceptual model that incorporates both symptoms and individual characteristics. METHODS: Patients attending an AF specialty clinic were invited to complete an online survey. Hierarchical regression analyses were conducted to examine whether individual characteristics (overall mental health, perceived stress, sex, age, AF knowledge, household and recreational physical activity) incremented prediction of HRQoL and AF treatment satisfaction beyond AF symptom recency and overall health. RESULTS: Of 196 participants (mean age 65.3 years), 63% were male and 90% were Caucasian. Most reported 'excellent' or 'good' overall and mental health, had high overall AF knowledge scores, had low perceived stress scores, and had high household and recreation physical activity. The mean overall AF Effect On Quality-Of-Life Questionnaire (AFEQT) and AF treatment satisfaction scores were 70.62 and 73.84, respectively. Recency of AF symptoms and overall health accounted for 29.6% of the variance in overall HRQoL and 20.2% of the variance in AF treatment satisfaction. Individual characteristics explained an additional 13.6% of the variance in overall HRQoL and 7.6% of the variance in AF treatment satisfaction. Perceived stress and household physical activity were the largest contributors to overall HRQoL, whereas age and AF knowledge made significant contributions to AF treatment satisfaction. CONCLUSIONS: Along with AF symptoms and overall health, individual characteristics are important predictors of HRQoL and AF treatment satisfaction in AF patients. In particular, perceived stress and household physical activity could further be targeted as potential areas to improve HRQoL.

Telehealth Satisfaction in Patients Receiving Virtual Atrial Fibrillation Care: Quantitative Exploratory Study.

BACKGROUND: Telehealth can optimize access to specialty care for patients with atrial fibrillation (AF). Virtual AF care, however, may not fit with the complex needs of patients with AF. OBJECTIVE: This study aims to explore the correlation among attitudes toward health care technologies, self-efficacy, and telehealth satisfaction as part of the future planning of virtual AF clinic care. METHODS: Patients with AF older than 18 years from an urban-based, highly specialized AF clinic who had an upcoming telehealth visit were invited to participate in a web-based survey. The survey asked about demographic characteristics; use of technology; general, computer, and health care technology self-efficacy (HTSE) and health care technology attitudes, using a validated 30-item tool; and telehealth satisfaction questionnaire using a validated 14-item questionnaire. Data were analyzed with descriptive statistics, correlational analyses, and linear regression modeling. RESULTS: Participants (n=195 of 579 invited, for a 34% response rate) were primarily older, male, and White, had postsecondary schooling or more, and had high self-reported overall and mental health ratings. A variety of technologies were used in their daily lives and for health care, with the majority of technologies comprising desktop and laptop computers, smartphones, and tablets. Self-efficacy and telehealth satisfaction questionnaire scores were high overall, with male participants having higher general self-efficacy, computer self-efficacy, HTSE, and technology attitude scores. After controlling for age and sex, only HTSE was significantly related to individuals' attitudes toward health care technology. Both general self-efficacy and attitude toward health care technology were positively related to telehealth satisfaction. CONCLUSIONS: Consistent with a previous study, only HTSE significantly influenced attitudes toward health care technology. This finding confirms that, in this regard, self-efficacy is not a general perception but is domain specific. Considering participants' predominant use of the telephone for virtual care, it follows that general self-efficacy and attitude toward health care technology were significant contributors to telehealth satisfaction. Given our patients' frequent use of technology and high computer self-efficacy and HTSE scores, the use of video for telehealth appointments could be supported.

Long-term persistence of transcriptionally active 'defective' HIV-1 proviruses: implications for persistent immune activation during antiretroviral therapy.

OBJECTIVES: People with HIV-1 (PWH) on effective antiretroviral therapy (ART) continue to exhibit chronic systemic inflammation, immune activation, and persistent elevations in markers of HIV-1 infection [including HIV-DNA, cell-associated HIV-RNA (CA HIV-RNA), and antibodies to HIV-1 proteins] despite prolonged suppression of plasma HIV-RNA levels less than 50 copies/ml. Here, we investigated the hypothesis that nonreplicating but transcriptionally and translationally competent 'defective' HIV-1 proviruses may be one of drivers of these phenomena. DESIGN: A combined cohort of 23 viremic and virologically suppressed individuals on ART were studied. METHODS: HIV-DNA, CA HIV-RNA, western blot score (measure of anti-HIV-1 antibodies as a surrogate for viral protein expression in vivo ), and key biomarkers of inflammation and coagulation (IL-6, hsCRP, TNF-alpha, tissue factor, and D-dimer) were measured in peripheral blood and analyzed using a combined cross-sectional and longitudinal approaches. Sequences of HIV-DNA and CA HIV-RNA obtained via 5'-LTR-to-3'-LTR PCR and single-genome sequencing were also analyzed. RESULTS: We observed similar long-term persistence of multiple, unique, transcriptionally active 'defective' HIV-1 provirus clones (average: 11 years., range: 4-20 years) and antibody responses against HIV-1 viral proteins among all ART-treated participants evaluated. A direct correlation was observed between the magnitude of HIV-1 western blot score and the levels of transcription of 'defective' HIV-1 proviruses ( r  = 0.73, P  < 0.01). Additional correlations were noted between total CD8 + T-cell counts and HIV-DNA ( r  = 0.52, P  = 0.01) or CA HIV-RNA ( r  = 0.65, P  < 0.01). CONCLUSION: These findings suggest a novel interplay between transcription and translation of 'defective' HIV-1 proviruses and the persistent immune activation seen in the setting of treated chronic HIV-1 infection.

A flow-cytometry-based assay to assess granule exocytosis and GZB delivery by human CD8 T cells and NK cells.

CD8 T and NK cells mediate killing by delivery of perforin and granzyme B (GZB) stored in lysosome-like granules. We present a flow-cytometry-based protocol combined with a redirected killing assay to evaluate granule exocytosis and the cytotoxic potential of human CD8 T cells and NK cells. We describe the assessment of the delivered GZB inside the target cells. We then detail the detection of lysosome membrane protein CD107a exposed on the cell surface of the effector cells upon degranulation. For complete details on the use and execution of this protocol, please refer to Chen et al. (2021).1.

A cross-sectional study of the preventive health care activities of western Canadian rural-living patients unattached to primary care providers.

Prevention services, such as screening tests and vaccination, are underutilized, especially by rural populations and patients without a usual primary care provider. Little is known about the compounding impacts on preventive care of being unattached and living in a rural area and there has been no comprehensive exploration of this highly vulnerable population's prevention activities. The twofold purpose of this research was to examine rural unattached patients' prevention activity self-efficacy and completion and to explore their experiences accessing healthcare, including COVID-19 impacts. Two thirds of patients had been unattached for over one year, and over 20 % had been unattached for over 5 years; males experienced longer unattachment compared to females. Completion rates of prevention activities were relatively low, ranging from 5.9 % (alcohol screening) to 59 % (vision test). Most participants did not complete their prevention care activities in line with the Lifetime Prevention Schedule timeline: 65 % of participants had less than half of their activities up-to-date and only 6.7 % of participants were up to date on 75 % or more of their prevention activities. Participants with higher prevention self-efficacy scores were more likely to be up-to-date on associated prevention activities but the longer patients had been unattached, the fewer their up-to-date prevention activities. Patients expressed negative impacts of COVID-19 including walk-in clinics shutting down limiting access to care. These results suggest serious gaps in rural unattached patients' preventive care and highlight the need for support when they are without a usual primary care provider, which can be lengthy.

Has Virtual Care Arrived? A Survey of Rural Canadian Providers During the Early Stages of the COVID-19 Pandemic.

We investigated the uptake and perceptions of virtual care solutions by rural Canadian primary and specialist providers during the early phase (May-June 2020) of the COVID-19 pandemic. A web-based, cross-sectional survey of rural primary and specialty care providers examined types of virtual care platforms used (eg, phone, video), appointment length, experience and satisfaction with the solution used, plans for future use of virtual care, and patients' use of virtual care services. Targeted participants were actively-practicing providers in rural Western Canada who were emailed an invitation for the study and its survey link. Fifty-nine providers (26% response rate) completed the survey. During the pandemic, 78% of providers reported using virtual care for more than 60% of their appointments, while only 3% did so frequently pre-pandemic. Most providers used phone consultations, despite believing that video provided a better virtual visit. Key barriers included workflow interruptions, unique concerns about quality of care, remuneration and sustainability, or poor internet access and bandwidth for both providers and patients. The key opportunity noted was improved access to care. While most virtual care visits were not conducted using video technologies, overall virtual care resulted in high provider satisfaction, while not increasing workload. Virtual care will continue to play an important role in future rural care practice; however, sustainability will require both provider-level and system-level changes.

Empowering Patients Through Virtual Care Delivery: Qualitative Study With Micropractice Clinic Patients and Health Care Providers.

BACKGROUND: Prior to the wider adoption of digital health technologies during the COVID-19 pandemic, applications of virtual care were largely limited to specialist visits and remote care using telehealth (phone or video) applications. Data sharing approaches using tethered patient portals were mostly built around hospitals and larger care systems. These portals offer opportunities for improved communication, but despite a belief that care has improved, they have so far shown few outcome improvements beyond medication adherence. Less is known about use of virtual care and related tools in the outpatient context and particularly in rural community contexts. OBJECTIVE: This study aims to reflect on the opportunities and barriers for sustainable virtual care through an example of a digitally enabled rural micropractice, which has provided 10%-15% virtual care since 2016 and 70% virtual care since March 2020. METHODS: Three focus groups, 1 with providers (physician and medical office manager) and 2 with a total of 8 patients from a rural micropractice in British Columbia, were conducted in November 2020 and December 2020. Virtual care delivery was explored through the topics of communication approach, mixing virtual and in-person care, the practice team's journey in developing these approaches, and provider and patient satisfaction with the care model. Interviews were transcribed, checked for accuracy against recordings, and thematically analyzed. RESULTS: Both patients and providers reported ease of communication and high satisfaction. Either could initiate communication, and patients found the ability to share health information asynchronously through the portal allowed time to reflect and prepare their thoughts. Patients were highly engaged and reported feeling empowered and true partners in their health care, although they noted limited care coordination with specialists. The mix of virtual and in-person visits was highly regarded by patients and providers, and patients reported feeling safe and cared for 24/7, although both expressed concern about work spilling into the provider's home life. The physician worried about missed diagnoses with virtual care. With respect to establishing the micropractice, solutions took about 5 years to optimize, with providers noting a learning curve requiring technical support for both themselves and their patients and a willingness to respond to patient feedback to identify the best solutions. Despite a mature virtual practice, patients reported deferred care due to COVID-19. CONCLUSIONS: The micropractice's hybrid care model encouraged patients to be true partners in their care and resulted in high patient engagement and satisfaction; yet, success may rely on the patient population being willing to engage and being comfortable with technology. Barriers lie in gaps in care coordination and provider fear that signs or symptoms more evident with an in-person exam could be missed. Even in this setting, deferral of care in light of COVID-19 was present, and opportunities to address care gaps should be sought.

Paving the Way for Electronic Patient-Centered Measurement in Team-Based Primary Care: Integrated Knowledge Translation Approach.

BACKGROUND: Patient-centered measurement (PCM) aims to improve the overall quality of care through the collection and sharing of patient values, outcomes, and perspectives. However, the use of PCM in care team decisions remains limited. Integrated knowledge translation (IKT) offers a collaborative, adaptive approach to explore best practices for incorporating PCM into primary care practices by involving knowledge users, including patients and providers, in the exploratory process. OBJECTIVE: This study aims to test the feasibility of using patient-generated data in team-based care; describe the use of these data for team-based mental health care; and summarize patient and provider care experiences with PCM. METHODS: We conducted a multi-method exploratory study in a rural team-based primary care clinic using IKT to co-design, implement, and evaluate the use of PCM in team-based mental health care. Care pathways, workflows, and quality improvement activities were adjusted iteratively to improve integration efforts. Patient and provider experiences were evaluated using individual interviews relating to the use of PCM and patient portals in practice. All meeting notes, interview summaries, and emails were analyzed to create a narrative evaluation. RESULTS: During co-design, a care workflow was developed to incorporate electronically collected patient-generated data from the patient portal into the electronic medical record, and customized educational tools and resources were added. During implementation, care pathways and patient workflows for PCM were developed. Patients found portal use easy, educational, and validating, but data entries were not used during care visits. Providers saw the portal as extra work, and the lack of portal and electronic medical record integration was a major barrier. The IKT approach was invaluable for addressing workflow changes and understanding the ongoing barriers to PCM use and quality improvement. CONCLUSIONS: Although the culture toward using PCM is changing, the use of PCM during care has not been successful. Patients felt validated and supported through portal use and could be empowered to bring these data to their visits. Training, modeling, and adaptable PCM methods are required before PCM can be integrated into routine care.

Advancing digital patient-centered measurement methods for team-based care.

Objectives: To conceptualize new methods for integrating patient-centered measurement into team-based care. Methods: A standalone portal was introduced into a rural clinic to support conceptualization of new methods for integration of patient-centered measurement in team-based care. The portal housed mental health-related online resources, three patient-reported measures and a self-action plan. Six providers and four patients used the portal for four months. Our data collection techniques included clinic discussions, one-on-one interviews, workflow diagrams and data generated through the portal. Analysis was supported through coding interview transcripts, looking across multiple sources of research data and research team discussions. Results: Our research team conceptualized five team-based patient-centered measurement methods through this study. Patient-centered measurement Team Mapping offfers a technique to provide greater clarity of care-team roles and responsibilities in data collected through patient-centered measurement. Longitudinal Care Alignment can guide the care-team on incorporating patient-centered measurement into ongoing provider-patient interactions. Digital Tool Exploration can be used to evaluate a team's readiness toward digital tool adoption, and the impact of these tools. Team-based quality improvement serves as a framework for engaging teams in patient-centered quality improvement. Shared learning is a method that promotes patientprovider interactions that validate patient's perspectives of their care. Conclusion: The portal illuminated new methods for the integration of patient-centered measurement in team-based care. The first three proposed patient-centered measurement methods provides ways to assess how a clinic can incorporate patient-centered measurement methods into team-based care. The latter two methods focus on the aim of patient-generated data in which patient's values and perspectives are represented and quality of patient-centered care can be evaluated. Further testing is needed to assess the utility of these patient-centered measurement methods across different clinical settings and domains.

The role of protease-activated receptor 1 signaling in CD8 T cell effector functions.

CD8 T cells are essential for adaptive immunity against viral infections. Protease activated receptor 1 (PAR1) is expressed by CD8 T cells; however, its role in T cell effector function is not well defined. Here we show that in human CD8 T cells, PAR1 stimulation accelerates calcium mobilization. Furthermore, PAR1 is involved in cytotoxic T cell function by facilitating granule trafficking via actin polymerization and repositioning of the microtubule organizing center (MTOC) toward the immunological synapse. In vivo, PAR1-/- mice have reduced cytokine-producing T cells in response to a lymphocytic choriomeningitis virus (LCMV) infection and fail to efficiently control the virus. Specific deletion of PAR1 in LCMV GP33-specific CD8 T cells results in reduced expansion and diminished effector function. These data demonstrate that PAR1 plays a role in T cell activation and function, and this pathway could represent a new therapeutic strategy to modulate CD8 T cell effector function.

Preferred Functions of Personal Health Records in Rural Primary Health Clinics in Canada: Health Care Team Perspectives.

BACKGROUND: Personal health records (PHR) provide opportunities for improved patient engagement, collection of patient-generated data, and overcome health-system inefficiencies. While PHR use is increasing, uptake in rural populations is lower than in urban areas. OBJECTIVES: The study aimed to identify priorities for PHR functionality and gain insights into meaning, value, and use of patient-generated data for rural primary care providers. METHODS: We performed PHR preimplementation focus groups with rural providers and their health care teams from five primary care clinics in a sparsely populated mountainous region of British Columbia, Canada to obtain their understanding of PHR functionality, needs, and perceived challenges. RESULTS: Eight general practitioners (GP), five medical office assistants, two nurse practitioners (NP), and two registered nurses (14 females and 3 males) participated in focus groups held at their respective clinics. Providers (GPs, NPs, and RNs) had been practicing for a median of 9.5 (range = 1-38) years and had used an electronic medical record for 7.0 (1-20) years. Participants expressed interest in incorporating functionality around two-way communication and appointment scheduling, previsit data gathering, patient and provider data sharing, virtual care including visits using videoconferencing tools, and postvisit sharing of educational materials. Three further themes emerged from the focus groups: (1) the context in which the providers' practice matters, (2) the need for providing patients and providers with choice (e.g., which data to share, who gets to initiate/respond in communications, and processes around virtual care visits), and (3) perceived risks of system use (e.g., increased complexity for older patients and workload barriers for the health care team). CONCLUSION: Rural primary care teams perceived PHR opportunities for increased patient engagement and access to patient-generated data, while worries about changes in workflow were the biggest perceived risk. Recommendations for PHR adoption in a rural primary health network include setting provider-patient expectations about response times, ability to share notes selectively, and automatically augmented note-taking from virtual-care visits.

News Article Portrayal of Virtual Care for Health Care Delivery in the First 7 Months of the COVID-19 Pandemic.

Objectives: The onset of the 2020 coronavirus pandemic resulted in rapid implementation of virtual care solutions at an unprecedented pace. The news media, as a trusted source for many Canadians, plays a vital role during emergencies by reporting on changes in health care protocols, policies, and technologies. This article presents the results of a qualitative analysis of Canadian news articles between February and August of 2020 to identify critical themes with respect to virtual care. Methods: A full-text search of the database Canadian Newsstream resulted in 1542 articles (708 duplicates), of which 294 articles were included in the final analysis. Inductive analysis was used to generate themes and identify voices, contradictions, and tensions in the articles. Results: Analysis generated four themes: coronavirus disease (COVID-19) as a catalyst for virtual care, safety and protection, economic impacts, and telehealth as a model of care. Media portrayals represented some voices (e.g., physicians) while limiting others (e.g., patients), reflected some contradictory messaging with respect to safety and protection, and raised key issues and concerns about virtual health care delivery during the first 7 months of COVID-19. Conclusions: Our findings of successful and rapid uptake, uses and concerns around funding, and privacy and virtual care adoption reported in the news media can be used to inform longer term implementation and sustainability. Policy makers could benefit from crafting messages that balance information and reassurance. Public/patient perspectives, which were largely missing from news media, are needed to gauge receptivity and sustainability.

Defective HIV-1 proviruses produce viral proteins.

HIV-1 proviruses persist in the CD4+ T cells of HIV-infected individuals despite years of combination antiretroviral therapy (cART) with suppression of HIV-1 RNA levels <40 copies/mL. Greater than 95% of these proviruses detected in circulating peripheral blood mononuclear cells (PBMCs) are referred to as "defective" by virtue of having large internal deletions and lethal genetic mutations. As these defective proviruses are unable to encode intact and replication-competent viruses, they have long been thought of as biologically irrelevant "graveyard" of viruses with little significance to HIV-1 pathogenesis. Contrary to this notion, we have recently demonstrated that these defective proviruses are not silent, are capable of transcribing novel unspliced forms of HIV-RNA transcripts with competent open reading frames (ORFs), and can be found in the peripheral blood CD4+ T cells of patients at all stages of HIV-1 infection. In the present study, by an approach of combining serial dilutions of CD4+ T cells and T cell-cloning technologies, we are able to demonstrate that defective proviruses that persist in HIV-infected individuals during suppressive cART are translationally competent and produce the HIV-1 Gag and Nef proteins. The HIV-RNA transcripts expressed from these defective proviruses may trigger an element of innate immunity. Likewise, the viral proteins coded in the defective proviruses may form extracellular virus-like particles and may trigger immune responses. The persistent production of HIV-1 proteins in the absence of viral replication helps explain persistent immune activation despite HIV-1 levels below detection, and also presents new challenges to HIV-1 eradication.

Comparison of xylazine and detomidine in combination with midazolam/ketamine for field castration in Quarter Horses.

BACKGROUND: The ideal field anaesthetic protocol for castration will offer an adequate duration and depth of anaesthesia using a single injection without compromising safety or recovery quality. OBJECTIVES: The objective of this study was to compare intravenous (IV) xylazine and detomidine as sedatives in combination with midazolam and ketamine for induction of anaesthesia in horses undergoing field castration. STUDY DESIGN: Randomised, blinded, clinical study. METHODS: Fifty-seven male Quarter Horses were randomly assigned to receive xylazine (group X) (1.1 mg/kg bwt) or detomidine (group D) (0.03 mg/kg bwt) as premedication with midazolam (0.05 mg/kg bwt) and ketamine (2.2 mg/kg bwt) anaesthesia. Using simple descriptive scales, quality of sedation, induction, surgical conditions and recovery were scored by blinded observers. Induction, surgery, recovery time and time from induction to standing were recorded. RESULTS: There were a greater number of horses with lower sedation score in group D when compared with horses in group X at 5 minutes after the first dose of sedation (11.1%, 66.7% and 2.2% of horses from group D with sedation scores of 1, 2 and 3, vs 0%, 52% and 48% from group X, respectively, P = .05). A significant (P < .01) difference was found between surgical condition scores for group D (63%, 14.8%, 11.1% and 11.1% with surgery scores of 1, 2, 3 and 4, respectively) and group X (28%, 4%, 28% and 40%). Horses in Group D were less likely to require maintenance doses of ketamine (P = .05) with only 26% (7 of 27 horses) in this group requiring additional doses compared to 68% (17 of 25 horses) in group X. Recovery time in minutes (Group D: 24.74 ± 14.80, Group X: 13.08 ± 8.00; P < .01) and induction to standing time in minutes (Group D: 42.2 ± 13.8, Group X: 29.8 ± 8.2; P < .01) were significantly longer for horses in group D compared with group X. MAIN LIMITATIONS: Multiple surgeons and multiple blinded observers. CONCLUSIONS: Detomidine as compared with xylazine as premedication results in good quality sedation and surgical conditions and prolonged surgical plane of anaesthesia, without significant differences in induction or recovery quality.