BET inhibition blocks inflammation-induced cardiac dysfunction and SARS-CoV-2 infection.

Cardiac injury and dysfunction occur in COVID-19 patients and increase the risk of mortality. Causes are ill defined but could be through direct cardiac infection and/or inflammation-induced dysfunction. To identify mechanisms and cardio-protective drugs, we use a state-of-the-art pipeline combining human cardiac organoids with phosphoproteomics and single nuclei RNA sequencing. We identify an inflammatory "cytokine-storm", a cocktail of interferon gamma, interleukin 1ß, and poly(I:C), induced diastolic dysfunction. Bromodomain-containing protein 4 is activated along with a viral response that is consistent in both human cardiac organoids (hCOs) and hearts of SARS-CoV-2-infected K18-hACE2 mice. Bromodomain and extraterminal family inhibitors (BETi) recover dysfunction in hCOs and completely prevent cardiac dysfunction and death in a mouse cytokine-storm model. Additionally, BETi decreases transcription of genes in the viral response, decreases ACE2 expression, and reduces SARS-CoV-2 infection of cardiomyocytes. Together, BETi, including the Food and Drug Administration (FDA) breakthrough designated drug, apabetalone, are promising candidates to prevent COVID-19 mediated cardiac damage.

Combination Immune Checkpoint Blockade Enhances IL-2 and CD107a Production from HIV-Specific T Cells Ex Vivo in People Living with HIV on Antiretroviral Therapy.

In people with HIV (PWH) on antiretroviral therapy (ART), immune dysfunction persists, including elevated expression of immune checkpoint (IC) proteins on total and HIV-specific T cells. Reversing immune exhaustion is one strategy to enhance the elimination of HIV-infected cells that persist in PWH on ART. We aimed to evaluate whether blocking CTL-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), T cell Ig domain and mucin domain 3 (TIM-3), T cell Ig and ITIM domain (TIGIT) and lymphocyte activation gene-3 (LAG-3) alone or in combination would enhance HIV-specific CD4+ and CD8+ T cell function ex vivo. Intracellular cytokine staining was performed using human PBMCs from PWH on ART (n = 11) and expression of CD107a, IFN-γ, TNF-α, and IL-2 was quantified with HIV peptides and Abs to IC. We found the following: 1) IC blockade enhanced the induction of CD107a and IL-2 but not IFN-γ and TNF-α in response to Gag and Nef peptides; 2) the induction of CD107a and IL-2 was greatest with multiple combinations of two Abs; and 3) Abs to LAG-3, CTLA-4, and TIGIT in combinations showed synergistic induction of IL-2 in HIV-specific CD8+ and CD107a and IL-2 production in HIV-specific CD4+ and CD8+ T cells. These results demonstrate that the combination of Abs to LAG-3, CTLA-4, or TIGIT can increase the frequency of cells expressing CD107a and IL-2 that associated with cytotoxicity and survival of HIV-specific CD4+ and CD8+ T cells in PWH on ART. These combinations should be further explored for an HIV cure.

Cutting Edge: SARS-CoV-2 Infection Induces Robust Germinal Center Activity in the Human Tonsil.

Understanding the generation of immunity to SARS-CoV-2 in lymphoid tissues draining the site of infection has implications for immunity to SARS-CoV-2. We performed tonsil biopsies under local anesthesia in 19 subjects who had recovered from SARS-CoV-2 infection 24-225 d previously. The biopsies yielded >3 million cells for flow cytometric analysis in 17 subjects. Total and SARS-CoV-2 spike-specific germinal center B cells, and T follicular helper cells, were readily detectable in human tonsils early after SARS-CoV-2 infection, as assessed by flow cytometry. Responses were higher in samples within 2 mo of infection but still detectable in some subjects out to 7 mo following infection. We conclude the tonsils are a secondary lymphoid organ that develop germinal center responses to SARS-CoV-2 infection and could play a role in the long-term development of immunity.

Digital education about delirium for health care professional students: a mixed methods systematic review.

BACKGROUND: Competence in delirium care begins with pre-registration education for health care professionals. Although a common complication for hospitalised patients, delirium is avoidable and reversible. Delirium requires early recognition in person-centred care. Students need to learn how to identify and effectively care for 'at risk' patients. AIM: To identify and examine literature on how pre-registration health care professional students are prepared to recognise, assess, and deliver interventions to prevent delirium in practice, using digital/web based educational interventions. METHOD: Mixed methods systematic review with narrative synthesis. A protocol was registered with PROSPERO. The review questions and search strategy were guided by the Population, Phenomena of Interest, Context (PICo) framework. The PRISMA framework guided the screening, data extraction and analysis. Database searches (MEDLINE, Web of Science, Embase, CINAHL, Cochrane Central Register of Controlled Trials, PsycINFO & Scopus) were undertaken in April 2023 for publications from 2012 to 2023. Covidence software [30] was used to extract and manage the data. Quality appraisal was guided by the Crowe Critical Appraisal Tool (CCAT) [31]. FINDINGS: Ten papers were included: mixed methods (2), qualitative (1) and quantitative (7). Medical students were the most studied group (n = 5), followed by student nurses (n = 4) and mixed nursing and medical students (n = 1). Length of learning experience varied from 12 min virtual reality (VR) to a two-week 'geriatrics' elective. Learning was enhanced by player autonomy, engagement, safety, applicability, choices, multiple perspectives and moral reasoning opportunities. DISCUSSION: Digital programmes should be visually appealing, interactive with opportunities for practice and timely appropriate feedback.

Co-design and mixed methods evaluation of an interdisciplinary digital resource for undergraduate health profession students to improve the prevention, recognition, and management of delirium in Ireland: a study protocol.

BACKGROUND: Delirium is a common symptom of acute illness which is potentially avoidable with early recognition and intervention. Despite being a growing concern globally, delirium remains underdiagnosed and poorly reported, with limited understanding of effective delirium education for undergraduate health profession students. Digital resources could be an effective approach to improving professional knowledge of delirium, but studies utilising these with more than one profession are limited, and no evidence-based, interdisciplinary, digital delirium education resources are reported. This study aims to co-design and evaluate a digital resource for undergraduate health profession students across the island of Ireland to improve their ability to prevent, recognise, and manage delirium alongside interdisciplinary colleagues. METHODS: Utilising a logic model, three workstreams have been identified. Workstream 1 will comprise three phases: (1) a systematic review identifying the format, methods, and content of existing digital delirium education interventions for health profession students, and their effect on knowledge, self-efficacy, and behavioural change; (2) focus groups with health profession students to determine awareness and experiences of delirium care; and (3) a Delphi survey informed by findings from the systematic review, focus groups, and input from the research team and expert reference group to identify resource priorities. Workstream 2 will involve the co-design of the digital resource through workshops (n = 4) with key stakeholders, including health profession students, professionals, and individuals with lived experience of delirium. Lastly, Workstream 3 will involve a mixed methods evaluation of the digital resource. Outcomes include changes to delirium knowledge and self-efficacy towards delirium care, and health profession students experience of using the resource. DISCUSSION: Given the dearth of interdisciplinary educational resources on delirium for health profession students, a co-designed, interprofessional, digital education resource will be well-positioned to shape undergraduate delirium education. This research may enhance delirium education and the self-efficacy of future health professionals in providing delirium care, thereby improving practice and patients' experiences and outcomes. TRIAL REGISTRATION: Not applicable.

Serological assays to measure dimeric IgA antibodies in SARS-CoV-2 infections.

Current serological tests cannot differentiate between total immunoglobulin A (IgA) and dimeric IgA (dIgA) associated with mucosal immunity. Here, we describe two new assays, dIgA-ELISA and dIgA-multiplex bead assay (MBA), that utilize the preferential binding of dIgA to a chimeric form of secretory component, allowing the differentiation between dIgA and monomeric IgA. dIgA responses elicited through severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were measured in (i) a longitudinal panel, consisting of 74 samples (n = 20 individuals) from hospitalized cases of coronavirus disease 2019 (COVID-19); (ii) a longitudinal panel, consisting of 96 samples (n = 10 individuals) from individuals with mild COVID-19; (iii) a cross-sectional panel with PCR-confirmed SARS-CoV-2 infection with mild COVID-19 (n = 199) and (iv) pre-COVID-19 samples (n = 200). The dIgA-ELISA and dIgA-MBA demonstrated a specificity for dIgA of 99% and 98.5%, respectively. Analysis of dIgA responses in the longitudinal panels revealed that 70% (ELISA) and 50% (MBA) of patients elicited a dIgA response by day 20 after PCR diagnosis with a SARS-CoV-2 infection. Individuals with mild COVID-19 displayed increased levels of dIgA within the first 3 weeks after diagnosis but responses appeared to be short lived, compared with sustained IgA levels. However, in samples from hospitalized patients with COVID-19 we observed high and sustained levels of dIgA, up to 245 days after PCR diagnosis. Our results suggest that severe COVID-19 infections are associated with sustained levels of plasma dIgA compared with mild cases.

Psychosocial risk factors of erectile dysfunction among heterosexual men living with HIV.

ABSTRACTThe risk of erectile dysfunction (ED) is significantly higher in men living with HIV (MLWH). Despite the adverse effects of ED on quality of life for MLWH, there is a lack of research on the psychosocial factors that may influence ED, especially among heterosexual MLWH. According to a recent systematic review, findings on the psychosocial risk factors of ED in past studies have been largely conflicting or inconclusive. To bridge this gap, we analyzed psychosocial and other correlates of ED among a sample of 317 primarily Black and Latino heterosexual adult MLWH in New York City. Data collection involved quantitative surveys administered using a combination of computer-assisted personal interview and audio computer-assisted self-interview techniques. After adjusting for age and general health, the relative risk of ED among heterosexual men living with HIV was associated with higher HIV-related stigma, anxiety, depression, and negative HIV-coping; greater social support was associated with a lower risk of ED. In addition, the data were consistent with the potential effects of childhood emotional, physical, and sexual abuse and structural discrimination on the risk of ED. Overall, our research findings help provide a better understanding of the psychosocial factors associated with ED among heterosexual MLWH.

Quality of life in people living with HIV (the fourth 90) - are we there yet in Australia?

In 2014, UNAIDS outlined the 90-90-90 treatment targets. The "fourth 90" reflects the need to focus on optimising quality of life (HRQoL) in people living with HIV. Using a sample of non-heterosexual males in Melbourne, Australia, we aimed to assess HRQoL differences between HIV-positive and HIV-negative individuals, and identify factors that predict HRQoL both at baseline and after three years of follow up. Clinical information and patient-reported outcomes incorporating the Assessing Quality of Life-6D scale were collected at baseline and at three years. Sixty-two HIV-positive cases (antiretroviral therapy naïve at baseline) and 48 controls were enrolled. Results were compared between cases and controls at baseline, three-year follow-up, and between timepoints. HRQoL was significantly lower in cases compared to controls (83.5 (IQR 77.2-88.6) vs 87.3 (IQR 82.1-91.8), p = 0.022) at baseline, with increased depression and anxiety associated with reduced HRQoL in multivariate analysis. Mental health in cases improved between timepoints (75.0 (IQR 56.3-81.3) to 81.3 (IQR 62.5-81.3), p = 0.0428). No differences between the HRQoL of cases and controls were observed at three years. Increased mental health support may be required at commencement of antiretroviral therapy to enable similar levels of HRQoL between HIV-positive and HIV-negative individuals to be achieved.

Balancing Statistical Power and Risk in HIV Cure Clinical Trial Design.

BACKGROUND: Analytical treatment interruptions (ATI) are pauses of antiretroviral therapy (ART) in the context of human immunodeficiency virus (HIV) cure trials. They are the gold standard in determining if interventions being tested can achieve sustained virological control in the absence of ART. However, withholding ART comes with risks and discomforts to trial participant. We used mathematical models to explore how ATI study design can be improved to maximize statistical power, while minimizing risks to participants. METHODS: Using previously observed dynamics of time to viral rebound (TVR) post-ATI, we modelled estimates for optimal sample size, frequency, and ATI duration required to detect a significant difference in the TVR between control and intervention groups. Groups were compared using a log-rank test, and analytical and stochastic techniques. RESULTS: In placebo-controlled TVR studies, 120 participants are required in each arm to detect 30% difference in frequency of viral reactivation at 80% power. There was little statistical advantage to measuring viral load more frequently than weekly, or interrupting ART beyond 5 weeks in a TVR study. CONCLUSIONS: Current TVR HIV cure studies are underpowered to detect statistically significant changes in frequency of viral reactivation. Alternate study designs can improve the statistical power of ATI trials.

Diverse effects of interferon alpha on the establishment and reversal of HIV latency.

HIV latency is the major barrier to a cure for people living with HIV (PLWH) on antiretroviral therapy (ART) because the virus persists in long-lived non-proliferating and proliferating latently infected CD4+ T cells. Latently infected CD4+ T cells do not express viral proteins and are therefore not visible to immune mediated clearance. Therefore, identifying interventions that can reverse latency and also enhance immune mediated clearance is of high interest. Interferons (IFNs) have multiple immune enhancing effects and can inhibit HIV replication in activated CD4+ T cells. However, the effects of IFNs on the establishment and reversal of HIV latency is not understood. Using an in vitro model of latency, we demonstrated that plasmacytoid dendritic cells (pDC) inhibit the establishment of HIV latency through secretion of type I IFNα, IFNß and IFNω but not IFNε or type III IFNλ1 and IFNλ3. However, once latency was established, IFNα but no other IFNs were able to efficiently reverse latency in both an in vitro model of latency and CD4+ T cells collected from PLWH on suppressive ART. Binding of IFNα to its receptor expressed on primary CD4+ T cells did not induce activation of the canonical or non-canonical NFκB pathway but did induce phosphorylation of STAT1, 3 and 5 proteins. STAT5 has been previously demonstrated to bind to the HIV long terminal repeat and activate HIV transcription. We demonstrate diverse effects of interferons on HIV latency with type I IFNα; inhibiting the establishment of latency but also reversing HIV latency once latency is established.

Perspectives on a Couples-Based, e-Health HIV Prevention Toolkit Intervention: A Qualitative Dyadic Study with Black, Heterosexual Couples in New York State.

Web-based technology provides an unparalleled opportunity to increase access and uptake of couples-based HIV prevention interventions. e-Health HIV prevention interventions for US Black heterosexual couples have largely been understudied. To address this gap, we applied the Assessment Phase of the ADAPT-ITT Framework to investigate Black heterosexual couples' perspectives on an existing e-Health, couples-based HIV prevention intervention. Applying a qualitative descriptive approach, joint dyadic interviews were conducted with 28 Black heterosexual couples from three jurisdictions in New York State. Content dyadic analysis revealed three descriptive categories: perspectives of the toolkit intervention (sub-codes: perceived relevance, reactions to core components), recommendations to enhance intervention relevancy (sub-codes: tailoring to relationship type, adding new content), and lasting intervention considerations (sub-codes: toolkit usability and language use). Overall, couples found the toolkit intervention content and usability acceptable and reflected on its potential to build sexual and relationship health. Couples recommended to enhance toolkit adaptability for varied couple's motivation and types re-consider terms like sexual agreements, and include content to facilitate communication regarding sensitive topics (e.g., childhood sexual trauma, co-parenting, family planning) and other issues that may have more relevance to the experience of US Black persons (i.e., wealth building).

Successful expanded clinic network collaboration and patient tracing for retention in HIV care.

BACKGROUND: There are more than 7,800 people living with human immunodeficiency virus (HIV) in Victoria, Australia. Crucial in maximising the individual and population level benefits from antiretroviral therapy (ART) is understanding how to achieve patient retention in care and the factors that drive it. This study was an expansion of a 2015 assessment of HIV-care retention in Victoria, which sought out to determine whether the inclusion of a broader range of HIV-healthcare sites would yield more accurate estimates of retention in HIV-care. We aimed to improve our understanding of HIV-care retention in Victoria, Australia, identify people living with HIV (PLHIV) with unknown outcomes, and attempt to re-engage PLHIV in care. METHODS: A network of 15 HIV-care sites was established in Victoria, Australia across diverse care settings which ranged from low-caseload rural sites to high-caseload metropolitan GP clinics and hospitals. Individuals who had an HIV viral load (VL) performed in both calendar years of 2016 and 2017 were classified as retained in care. Individuals with a VL test in 2016 but not in 2017 were considered to potentially have unknown outcomes as they may have been receiving care elsewhere, have disengaged from care or died. For this group, an intervention of cross-referencing partially de-identified data between healthcare sites, and contact tracing individuals who still had unknown outcomes was performed. RESULTS: For 5223 individuals considered to be retained in care across 15 healthcare sites in the study period, 49 had unconfirmed transfers of care to an alternative provider and 79 had unknown outcomes. After the intervention, the number of unconfirmed care transfers was reduced to 17 and unknown outcomes reduced to 51. These changes were largely attributed to people being reclassified as confirmed transfers of care. Retention in care estimates that did not include the patient outcome of confirmed transfer of care ranged from 76.2 to 95.8% and did not alter with the intervention. However, retention in care estimates which considered confirmed transfers and those that re-entered care at a new site as retained in care significantly increased across five of the sites with estimates ranging from 80.9 to 98.3% pre-intervention to 83.3-100% post-intervention. Individuals whose outcomes remained unknown post-intervention were more often men who have sex with men (MSM) when compared to other categories (person who injects drugs (PWID), combined PWID/MSM, men who identify as heterosexual or unknown) (74.5% vs. 53.5%, [p = 0.06]) and receiving ART at their last HIV-care visit (84.3% vs. 67.8% [p = 0.09]). CONCLUSION: This study confirmed high retention in HIV-care and low numbers of people disengaged from HIV-care in Victoria. This was demonstrated across a larger number of sites with varying models of care than a prior assessment in 2015. These data align with national and state targets aiming for 95% of PLHIV retained in HIV-care.

Reducing complication rates for repeat craniotomies in glioma patients: a single-surgeon experience and comparison with the literature.

BACKGROUND: There is a concern that glioma patients undergoing repeat craniotomies are more prone to complications. The study's goal was to assess if the complication profiles for initial and repeat craniotomies were similar, to determine predictors of complications, and to compare results with those in the literature. METHODS: A retrospective study was conducted of glioma patients (WHO grade II-IV) who underwent either an initial or repeat craniotomy performed by the senior author from 2012 until 2019. Complications were recorded by discharge, 30 days, and 90 days postoperatively. New neurologic deficits were recorded by 90 days postoperatively. Multivariate regression was performed to identify factors associated with complications. A meta-analysis was performed to identify rates of complications based on number of prior craniotomies. RESULTS: Within the cohort of 714 patients, 400 (56%) had no prior craniotomies, 218 (30.5%) had undergone 1 prior craniotomy, and 96 (13.5%) had undergone ≥ 2 prior craniotomies. There were 27 surgical and 10 medical complications in 30 patients (4.2%) and 19 reoperations for complications in 19 patients (2.7%) with no deaths by 90 days. Complications, reoperation rates, and new neurologic deficits did not differ based on number of prior craniotomies. On multivariate analysis, older age (OR1.5, 95%CI 1.0-2.2) and significant leukocytosis due to steroid use (OR12.6, 95%CI 2.5-62.9) were predictors of complications. Complication rates in the cohort were lower than rates reported in the literature. CONCLUSION: Contrary to prior reports in the literature, repeat craniotomies can be as safe as initial operations if surgeons implement best practices.

Monkeypox infection presenting as genital rash, Australia, May 2022.

Rapid diagnosis and whole genome sequencing confirmed a case of monkeypox in an HIV-positive individual receiving antiretroviral therapy. The patient had a normal CD4+ T-cell count and suppressed HIV viral load and presented with a genital rash in Melbourne, Australia after return from Europe in May 2022. He subsequently developed systemic illness and disseminated rash and 11 days after symptom onset, he was hospitalised to manage painful bacterial cellulitis of the genital area.

A New Method for Estimating the Incidence of Infectious Diseases.

Ambitious World Health Organization targets for disease elimination require monitoring of epidemics using routine health data in settings of decreasing and low incidence. We evaluated 2 methods commonly applied to routine testing results to estimate incidence rates that assume a uniform probability of infection between consecutive negative and positive tests based on 1) the midpoint of this interval and 2) a randomly selected point in this interval. We compared these with an approximation of the Poisson binomial distribution, which assigns partial incidence to time periods based on the uniform probability of occurrence in these intervals. We assessed bias, variance, and convergence of estimates using simulations of Weibull-distributed failure times with systematically varied baseline incidence and varying trend. We considered results for quarterly, half-yearly, and yearly incidence estimation frequencies. We applied the methods to assess human immunodeficiency virus (HIV) incidence in HIV-negative patients from the Treatment With Antiretrovirals and Their Impact on Positive and Negative Men (TAIPAN) Study, an Australian study of HIV incidence in men who have sex with men, between 2012 and 2018. The Poisson binomial method had reduced bias and variance at low levels of incidence and for increased estimation frequency, with increased consistency of estimation. Application of methods to real-world assessment of HIV incidence found decreased variance in Poisson binomial model estimates, with observed incidence declining to levels where simulation results had indicated bias in midpoint and random-point methods.

Bringing evidence from press release to the clinic in the era of COVID-19.

The urgent need to develop effective therapeutics and disseminate information from clinical studies has led to data from clinical trials being made available by alternate methods prior to peer-reviewed publication, including press releases, social media and pre-print papers. While this allows clinicians more open access to these data, a trust has to be placed with the investigators releasing these data without the availability of scientifically rigorous peer review. The examples of results from trials studying dexamethasone and hydroxychloroquine for treatment of COVID-19 have had contrasting outcomes, including the potential for significant numbers of lives saved with the early release of results from the RECOVERY trial studying dexamethasone contrasting with unsubstantiated data being presented from trials studying hydroxychloroquine. Clinicians and researchers must maintain a healthy scepticism when reviewing results prior to peer-reviewed publication, but also consider when these opportunities may allow for early implementation of potentially lifesaving interventions for people infected with COVID-19.

eHealth interventions for reducing cardiovascular disease risk in men: A systematic review and meta-analysis.

Men remain at a higher risk of developing cardiovascular disease (CVD) than women and behavioral risk factor modification is an important preventive measure. However, engaging men in behavior change interventions is challenging. Although men often indicate a preference for gender-specific information and support, this rarely occurs. eHealth interventions have the potential to address this gap, though their effectiveness for reducing CVD risk in men is unclear. Therefore, the aim of this systematic review and meta-analysis was to evaluate the effectiveness of eHealth interventions for reducing CVD risk in men. A search of published randomised controlled trials with no date restrictions up to July 2020 was conducted to identify those targeting at least two major CVD risk factors. Nine trials were identified and reviewed. Study quality ranged from low to unclear, with one trial at a high risk of bias. Compared to those in a control group or receiving printed materials, participants randomised to an eHealth intervention had statistically significant improvements in BMI (Z=-2.75, p=0.01), body weight (Z=-3.25, p=0.01), waist circumference (Z=-2.30, p=0.02) and systolic (Z=-3.57, p=0.01) and diastolic (Z=-3.56, p=0.01) blood pressure. Though less evident, there were also improvements in physical activity and diet in favour of the intervention group. This review suggests that eHealth interventions can reduce CVD risk in adult men through behavior change. However, we were unable to determine the association between intervention characteristics and outcomes. Also, overall, participant adherence to the intervention was poor. Both of these issues should be considered in future studies.

Ecological and Syndemic Predictors of Drug Use During Sex and Transactional Sex among U.S. Black Men Who Have Sex with Men: A Secondary Data Analysis from the HPTN 061 Study.

Threats to sexual health among U.S. Black men who have sex with men (MSM) may manifest in a context of social adverse experiences. Situational sex is one such context, which we characterize as sexual behaviors driven either by a desire to cultivate a specific sexual experience or attributable to social vulnerability. Two characterizations of situational sex explored in this study were drug use during sex and transactional sex. Guided by ecological and syndemic frameworks, we conducted a secondary data analysis of social conditions and sexual behaviors among a prospective cohort of Black MSM from the HIV Prevention Trial Network (HPTN) 061 study. Using structural equation modeling, this analysis examined the indirect effect of syndemic factors (substance use, depression, violence exposure) in the relationship between ecological constructs (anti-Black/homophobic stigma, childhood violence, and economic vulnerability) and situational sex (drug use during sex, transactional sex). Model fit indices, CFI (.870) and SRMR (.091), demonstrated reasonable fit. Significant indirect effects emerged via substance use for economic vulnerability (indirect effect = .181, 95% CI [.078, .294]) and anti-Black/homophobic violence and stigma (indirect effect = .061, 95% CI [.008, .121]) on drug use during sex; as well as on transactional sex (economic vulnerability indirect effect = .059, 95% CI [.018, .121] and anti-Black/homophobic stigma and violence indirect effect = .020, 95% CI [.003, .051]). Findings implicate the need for social and fiscal intervention to address upstream, ecological, and syndemic factors that influence inherent vulnerability of situational sex and overall threats to sexual health among Black MSM.

The pragmatic, rapid, and iterative dissemination and implementation (PRIDI) cycle: adapting to the dynamic nature of public health emergencies (and beyond).

BACKGROUND: Public health emergencies-such as the 2020 COVID-19 pandemic-accelerate the need for both evidence generation and rapid dissemination and implementation (D&I) of evidence where it is most needed. In this paper, we reflect on how D&I frameworks and methods can be pragmatic (i.e., relevant to real-world context) tools for rapid and iterative planning, implementation, evaluation, and dissemination of evidence to address public health emergencies. THE PRAGMATIC, RAPID, AND ITERATIVE D&I (PRIDI) CYCLE: The PRIDI cycle is based on a "double-loop" learning process that recognizes the need for responsiveness and iterative adaptation of implementation cycle (inner loop) to the moving landscapes, presented by the outer loops of emerging goals and desired outcomes, emerging interventions and D&I strategies, evolving evidence, and emerging characteristics and needs of individuals and contexts. Stakeholders iteratively evaluate these surrounding landscapes of implementation, and reconsider implementation plans and activities. CONCLUSION: Even when the health system priority is provision of the best care to the individuals in need, and scientists are focused on development of effective diagnostic and therapeutic technologies, planning for D&I is critical. Without a flexible and adaptive process of D&I, which is responsive to emerging evidence generation cycles, and closely connected to the needs and priorities of stakeholders and target users through engagement and feedback, the interventions to mitigate public health emergencies (e.g., COVID-19 pandemic), and other emerging issues, will have limited reach and impact on populations that would most benefit. The PRIDI cycle is intended to provide a pragmatic approach to support planning for D&I throughout the evidence generation and usage processes.