Building an Infectious Disease Diversity, Equity, and Antiracism (ID2EA) Curriculum: A Single Center's Experience and Reflections.

In response to longstanding healthcare inequities unmasked by the Coronavirus Disease 2019 pandemic, the infectious diseases (ID) section at the Yale School of Medicine designed and implemented a pilot curriculum integrating Infectious Disease Diversity, Equity, and Antiracism (ID2EA) into ID educational training and measured program outcomes. We herein describe a mixed-methods assessment of section members on whether the ID2EA curriculum affected their beliefs and behaviors regarding racism and healthcare inequities. Participants rated the curriculum as useful (92% averaging across sessions) and effective in achieving stated learning objectives (89% averaging across sessions), including fostering understanding of how inequities and racism are linked to health disparities and identifying strategies to effectively deal with racism and inequities. Despite limitations in response rates and assessment of longer-term behavioral change, this work demonstrates that training in diversity, equity, and antiracism can be successfully integrated into ID physicians' educational activities and affect physicians' perspectives on these topics.

Efficacy of Extended-Release Naltrexone on HIV-Related and Drinking Outcomes Among HIV-Positive Patients: A Randomized-Controlled Trial.

We sought to test the efficacy of extended-release naltrexone (XR-NTX) on HIV-related and drinking outcomes. From April 2011-February 2015, we conducted a 4-site randomized double-blind placebo controlled clinical trial involving 51 HIV-positive patients with heavy drinking and < 95% antiretroviral (ART) adherence. All participants received counseling. The primary outcome was proportion with ≥ 95% ART adherence. Secondary outcomes included HIV biomarkers, VACS Index score, and past 30-day heavy drinking days. Based on receipt of ≥ 5 injections, 23 participants were retained at 24 weeks. We did not detect an effect of XR-NTX on ART adherence (p = 0.38); undetectable HIV viral load (p = 0.26); CD4 cell count (p = 0.75) or VACS Index score (p = 0.70). XR-NTX was associated with fewer heavy drinking days (p = 0.03). While XR-NTX decreases heavy drinking days, we did not detect improvements in ART adherence or HIV outcomes. Strategies to improve retention in alcohol treatment and HIV-related outcomes among heavy drinking HIV-positive patients are needed.

Prevalence of Metabolic Syndrome in Patients with HIV in the Era of Highly Active Antiretroviral Therapy.

OBJECTIVES: Since the introduction of combination antiretroviral therapy (cART) as the standard of care for HIV disease, there has been a precipitous decline in the death rate due to HIV/ AIDS. The purpose of this study was to report the prevalence of metabolic syndrome in HIV infected patients. METHODS: Retrospective, cross-sectional, observational study of 259 patients with HIV infection treated with cART from an urban community hospital. Metabolic syndrome prevalence was defined using the International Diabetes Federation (IDF) and the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Study patients were included regardless of the duration of cART. RESULTS: The prevalence of metabolic syndrome was 27% using IDF criteria and 26% using ATP III criteria. Logistic regression analysis found an association between treatment with the protease inhibitor darunavir and metabolic syndrome. (OR 3.32 with 95% confidence interval between 1.54 and 7.15). CONCLUSION: There is a high prevalence of metabolic syndrome and obesity in HIV patients treated with cART, especially those taking the protease inhibitor darunavir.

Perspectives on unhealthy alcohol use among men who have sex with men prescribed HIV pre-exposure prophylaxis: A qualitative study.

Unhealthy alcohol use is a common, often unaddressed behavior associated with increased risk for acquisition of HIV and may also be associated with decreased adherence to oral pre-exposure prophylaxis (PrEP) among gay, bisexual, and other men who have sex with men (MSM) living in the United States. To inform future alcohol-reduction interventions among individuals engaging in PrEP care, we sought to explore perspectives on alcohol use, PrEP adherence, and the acceptability of alcohol use treatment options for MSM prescribed oral formulations of PrEP in the Northeastern United States. Between February 2019 and July 2020, we conducted semi-structured interviews with 15 MSM without HIV who were prescribed PrEP and screened positive for unhealthy alcohol use with AUDIT-C ≥ 4 and were receiving care in Providence, Rhode Island or New Haven, Connecticut. Interviews were coded and analyzed using thematic analysis. Three themes emerged: 1) Consequences of fluctuations in drinking 2) Alcohol use negatively impacts health and relationships; and 3) Desire for a multimodal approach to treatment of unhealthy alcohol use. Our findings support the need to raise awareness of potential alcohol-related harms, address the spectrum of unhealthy alcohol use among MSM prescribed PrEP, and the acceptability and preferences for alcohol reduction interventions within PrEP programs.

Evaluation of somatic copy number variation detection by NGS technologies and bioinformatics tools on a hyper-diploid cancer genome.

BACKGROUND: Copy number variation (CNV) is a key genetic characteristic for cancer diagnostics and can be used as a biomarker for the selection of therapeutic treatments. Using data sets established in our previous study, we benchmark the performance of cancer CNV calling by six most recent and commonly used software tools on their detection accuracy, sensitivity, and reproducibility. In comparison to other orthogonal methods, such as microarray and Bionano, we also explore the consistency of CNV calling across different technologies on a challenging genome. RESULTS: While consistent results are observed for copy gain, loss, and loss of heterozygosity (LOH) calls across sequencing centers, CNV callers, and different technologies, variation of CNV calls are mostly affected by the determination of genome ploidy. Using consensus results from six CNV callers and confirmation from three orthogonal methods, we establish a high confident CNV call set for the reference cancer cell line (HCC1395). CONCLUSIONS: NGS technologies and current bioinformatics tools can offer reliable results for detection of copy gain, loss, and LOH. However, when working with a hyper-diploid genome, some software tools can call excessive copy gain or loss due to inaccurate assessment of genome ploidy. With performance matrices on various experimental conditions, this study raises awareness within the cancer research community for the selection of sequencing platforms, sample preparation, sequencing coverage, and the choice of CNV detection tools.

Willingness to Be Vaccinated Against COVID-19 Among People With HIV in the United States: Results From a National Survey.

Background: Approximately 215 million Americans have been fully vaccinated for COVID-19, representing over 65% of the total population. People with HIV (PWH) may be more susceptible to COVID-19 infection or severe disease, elevating the importance of COVID-19 vaccination uptake in the population. We report results from a national survey of PWH to evaluate the likelihood of receiving a COVID-19 vaccine. Methods: We conducted an online survey of 1,030 PWH living in the United States between December 6, 2020 and January 8, 2021 to evaluate likelihood of receiving a COVID-19 vaccine. Results: Overall, participants were highly willing to be vaccinated, with 83.8% stating they "strongly agree" (65.7%) or "somewhat agree" (18.1%). Participants' top vaccine-related concerns were side-effects (39.3%), safety (14.7%), and fair/equitable distribution of the vaccine to affected communities (13.6%). Participants were more willing to be vaccinated if they reported receiving an annual influenza vaccination (p < 0.001), had previously tested positive for (p = 0.043) COVID-19, had been hospitalized for (p = 0.027) COVID-19 infection, or had an undetectable HIV viral load (p = 0.002). Black (p < 0.001), politically conservative (p < 0.001), and participants with an annual income of ≤ $19,999 (p = 0.005) were significantly less willing to be vaccinated for COVID-19. Conclusions: The vast majority of PWH were willing to be vaccinated, though predominantly those who were already engaged in HIV care or directly affected by COVID-19. Findings from this large survey of PWH suggest intensive outreach efforts are needed to support engagement in vaccination programs, particularly among Black and politically conservative PWH.

COVID-19 Vaccine Hesitancy and Associated Factors among People with HIV in the United States: Findings from a National Survey.

Introduction: Scaling up vaccination against COVID-19 is central to controlling the COVID-19 epidemic in the United States. Several vaccines are now approved for the prevention of COVID-19, but public concerns over safety and efficacy have heightened distrust and vaccine hesitancy. This is particularly concerning among people with HIV (PWH) who may be vulnerable to more severe COVID-19 disease. Here, we aimed to identify and understand COVID-19 vaccine hesitancy in a sample of PWH in the U.S. Methods: We conducted a cross-sectional online survey among PWH in the U.S. between 6 December 2020 and 8 January 2021. Measures included demographics, participants' HIV and health-related attributes, COVID-19 history and experiences, COVID-19 vaccine-related concerns, and standardized measures of attitudes towards COVID-19 vaccines. Multivariate linear regression was used to identify factors associated with vaccine hesitancy in this sample. Results: Among the 1030 respondents, most were male (89.7%), White (66.0%), and identified as gay or lesbian (84.5%). Participants' mean time living with HIV was 17.0 years (standard deviation (SD) = 11.1). The mean score for vaccine hesitancy was 1.5 (SD = 0.5; range: 1−5); 935 participants (90.8%) had a score greater than 1.0, indicating most participants had some degree of vaccine hesitancy. The final multivariate linear regression showed that greater vaccine hesitancy was associated with being Black (b = 0.149, p = 0.005), single (b = 0.070, p = 0.018), politically conservative (b = 0.157, p = 0.010), "anti-vaxxer" (b = 1.791, p < 0.001), concern about side effects (b = 0.226, p < 0.001), concern about safety (b = 0.260, p < 0.001), and being worried that the vaccine will not be effective (b = 0.169, p = 0.008) and they were being experimented on (b = 0.287, p < 0.001). Participants who were male White (b = −0.093, p = 0.008) and university graduates (b = −0.093, p < 0.001) and had a CD4 count of 200 cells/mm3 (b = −0.082, p = 0.048) and a liberal political orientation (b = −0.131, p < 0.001) were associated with lower vaccine hesitancy. Conclusions: Our findings provide important insights regarding COVID-19 vaccine hesitancy among PWH. Further efforts are required to understand how various social, political, and psychological factors contribute to COVID-19 vaccine hesitancy among key populations.

Patients' perspectives of medications for addiction treatment in HIV clinics: A qualitative study.

BACKGROUND: While substance use disorders (SUD) disproportionately impact people with HIV (PWH), HIV clinics inconsistently provide evidence-based medications for addiction treatment (MAT). Patient receptivity to MAT is critical to enhance addiction treatment in these settings. However, we know little from patients about how to best integrate MAT into HIV clinics. METHODS: This qualitative study used four focus groups informed by the Promoting Action on Research Implementation in Health Services framework to identify barriers and facilitators to receiving opioid, alcohol, and tobacco use disorder care in HIV clinics. The study population included 28 patients with HIV and SUD receiving care at one of four HIV clinics in the northeastern United States. Focus groups were recorded and transcribed for content analysis. The study also performed a brief survey assessing demographics and behaviors. RESULTS: Focus groups revealed several major themes related to MAT in HIV clinics. Barriers included stigma around MAT, knowledge deficits about available MAT options and the impact of substance use on PWH, concerns about medication side effects, substance use screening without adequate clinician follow-up, and peers who discouraged MAT. Facilitators included recognition of substance use as a threat to overall health, integrated care from HIV clinicians, and support for addiction treatment from peers with lived experience. CONCLUSIONS: Efforts to enhance MAT in HIV clinics should include patient education to help them recognize addiction as a chronic disease with available medication treatment options; clinician and staff training to promote integrated, multidisciplinary screening and treatment; and thoughtful inclusion of peers with lived experience.

Cumulative burden of non-communicable diseases predicts COVID hospitalization among people with HIV: A one-year retrospective cohort study.

There continue to be conflicting data regarding the outcomes of people with HIV (PWH) who have COVID-19 infection with most studies describing the early epidemic. We present a single site experience spanning a later timeframe from the first report on January 21, 2020 to January 20, 2021 and describe clinical outcomes and predictors of hospitalization among a cohort of PWH in an urban center in Connecticut, USA. Among 103 PWH with controlled HIV disease, hospitalization occurred in 33% and overall mortality was 1%. HIV associated factors (CD4 count, HIV viral suppression) were not associated with hospitalization. Chronic lung disease (OR: 3.35, 95% CI:1.28-8.72), and cardiovascular disease (OR: 3.4, 95% CI:1.27-9.12) were independently associated with hospitalization. An increasing number of non-communicable comorbidities increased the likelihood of hospitalization (OR: 1.61, 95% CI:1.22-2.13).

Decreased Overall Survival in HIV-associated Non-small-cell Lung Cancer.

INTRODUCTION: This study aimed to compare demographics, disease characteristics, and outcomes of patients with HIV-infection with non-small-cell lung cancer (NSCLC) with the general NSCLC population. PATIENTS AND METHODS: A retrospective cohort study was used to compare the HIV-infected and -uninfected groups. Medical records of all patients who were HIV-positive diagnosed with NSCLC between 2000 and 2016 at Yale New Haven Hospital (New Haven, CT) were reviewed and compared with the general Yale NSCLC population regarding demographics, NSCLC characteristics, treatment, and survival. Log-rank tests and Kaplan-Meier curves were used to analyze survival differences. Unadjusted and adjusted Cox proportional hazard models were used to assess predictors of survival. RESULTS: Thirty-five patients with HIV-NSCLC and 5187 general patients with NSCLC were identified. The median age at cancer diagnosis was 54 years (interquartile range [IQR], 49-59 years) for patients with HIV-NSCLC versus 68 years (IQR, 61-76 years) for patients with NSCLC (P < .001). Both groups had high rates of tobacco use. At the time of NSCLC diagnosis, 80% of patients with HIV-NSCLC were on antiretroviral therapy, 60% had an HIV-1 RNA < 400 copies/mL, and their median CD4 was 407 cells/µL (IQR, 218-592 cells/µL). Histology, cancer stage, and first-line cancer treatment regimens were not significantly different between groups. The overall median survival was 12.4 months (95% confidence interval [CI], 7.2-20.4 months) for patients with HIV-NSCLC versus 22.8 months (95% CI, 21.2-24.1 months) for general patients with NSCLC. Patients with HIV-NSCLC had decreased survival at 2 years (P = .028) and 3 years (P = .014) compared with general patients with NSCLC. HIV status was an independent risk factor for poorer outcomes when controlling for other factors (hazard ratio, 1.8; 95% CI, 1.24-2.62). CONCLUSION: Despite similar histology, stage, and treatment between groups, patients with HIV had worse outcomes for NSCLC.

Computational identification of Ciona intestinalis microRNAs.

MicroRNAs (miRNAs) are conserved non-coding small RNAs with potent post-transcriptional gene regulatory functions. Recent computational approaches and sequencing of small RNAs had indicated the existence of about 80 Ciona intestinalis miRNAs, although it was not clear whether other miRNA genes were present in the genome. We undertook an alternative computational approach to look for Ciona miRNAs. Conserved non-coding sequences from the C. intestinalis genome were extracted and computationally folded to identify putative hairpin-like structures. After applying additional criteria, we obtained 458 miRNA candidates whose sequences were used to design a custom microarray. Over 100 of our predicted hairpins were identified in this array when probed with RNA from various Ciona stages. We also compared our predictions to recently deposited sequences of Ciona small RNAs and report that 170 of our predicted hairpins are represented in this data set. Altogether, about 250 of our 458 predicted miRNAs were represented in either our array data or the small-RNA sequence database. These results suggest that Ciona has a large number of genomically encoded miRNAs that play an important role in modulating gene activity in developing embryos and adults.

Availability and Accessibility of Live Nonreplicating Smallpox/Mpox Vaccine.

This cross-sectional study compares the availability and accessibility of mpox vaccine sites with the number of reported cases and allocated vaccines.

Efficacy of an 8-week course of sofosbuvir and ledipasvir for the treatment of HCV infection in selected HIV-infected patients.

Background: With the availability of direct acting antiviral treatment for hepatitis C (HCV), HIV and HCV co-infected patients show comparable treatment responses to HCV-monoinfected patients. An 8-week course of sofosbuvir/ledipasvir (SOF/LDV) is highly effective for the treatment of HCV genotype 1 infection in treatment-naïve mono-infected patients with HCV viral loads <6 million IU/ml. There is limited data on the efficacy of this 8-week HCV treatment regimen in HIV-infected individuals with similar viral loads. Methods: The study was a retrospective review of HIV-infected adults coinfected with HCV genotype 1 for whom an 8-week course of SOF/LDV was prescribed by providers at two clinics in the Yale-New Haven Health system from November 1, 2014 until April 30, 2016. Treatment efficacy was assessed as the proportion of treatment initiators who achieved a sustained virologic response 12 weeks after completion of therapy (SVR 12). Results: Nineteen patients met study eligibility criteria and included 14 men (74%); and 12 African-Americans (63%). All patients were on antiretroviral therapy with fully suppressed HIV viral loads and were HCV treatment-naïve. All patients had pre-treatment HCV viral loads <6 million IU/mL. Eighteen patients (95%) completed HCV treatment. Overall, SVR 12 was 95%, with 1 treament failure occurring due to suboptimal adherence. Conclusion: Among our HIV-infected patient cohort with HCV genotype 1 infection, 95% of those treated with an 8 week course of SOF/LDV achieved SVR 12. This is comparable to the efficacy of the same treatment regimen in patients without HIV infection. This study lends proof of concept to the use of shorter course SOF/LDV treatment for HIV-HCV genotype 1 coinfected patients with viral loads <6 million IU/ml. Larger studies are indicated to validate our findings.

Comparative Effectiveness of Vancomycin Versus Daptomycin for MRSA Bacteremia With Vancomycin MIC >1 mg/L: A Multicenter Evaluation.

PURPOSE: Clinical studies comparing vancomycin with alternative therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia are limited. The objective of this study was to compare outcomes of early daptomycin versus vancomycin treatment for MRSA bacteremia with high vancomycin MICs in a geographically diverse multicenter evaluation. METHODS: This nationwide, retrospective, multicenter (N = 11), matched, cohort study compared outcomes of early daptomycin with vancomycin for MRSA bloodstream infection (BSI) with vancomycin MICs 1.5 to 2 µg/mL. Matching variables, based on propensity regression analysis, included age, intensive care unit (ICU), and type of BSI. Outcomes were as follows: (1) composite failure (60-day all-cause mortality, 7-day clinical or microbiologic failure, 30-day BSI relapse, or end-of-treatment failure (EOT; discontinue/change daptomycin or vancomycin because of treatment failure or adverse event]); (2) nephrotoxicity; and (2) day 4 BSI clearance. FINDINGS: A total of 170 patients were included. The median (interquartile range) age was 60 years (50-74); the median (range) Acute Physiology and Chronic Health Evaluation II score was 15 (10-18); 31% were in an ICU; and 92% had an infectious disease consultation. BSI types included endocarditis/endovascular (39%), extravascular (55%), and central catheter (6%). The median daptomycin dose was 6 mg/kg, and the vancomycin trough level was 17 mg/L. Overall composite failure was 35% (59 of 170): 15% due to 60-day all-cause mortality, 14% for lack of clinical or microbiologic response by 7 days, and 17% due to failure at end of therapy (discontinue/change because of treatment failure or adverse event). Predictors of composite failure according to multivariate analysis were age >60 years (odds ratio, 3.7; P < 0.01) and ICU stay (odds ratio, 2.64; P = 0.03). Notable differences between treatment groups were seen with: (1) end of therapy failure rates (11% vs 24% for daptomycin vs vancomycin; P = 0.025); (2) acute kidney injury rates (9% vs 23% for daptomycin vs vancomycin; P = 0.043); and (3) day 4 bacteremia clearance rates for immunocompromised patients (n = 26) (94% vs 56% for daptomycin vs vancomycin; P = 0.035). IMPLICATIONS: Results from this multicenter study provide, for the first time, a geographically diverse evaluation of daptomycin versus vancomycin for patients with vancomycin-susceptible MRSA bacteremia with vancomycin MIC values >1 µg/mL. Although the overall composite failure rates did not differ between the vancomycin and daptomycin groups when intensively matched according to risks for failure, the rates of acute kidney injury were significantly lower in the daptomycin group. These findings suggest that daptomycin is a useful therapy for clinicians treating patients who have MRSA bacteremia. Prospective, randomized trials should be conducted to better assess the potential significance of elevated vancomycin MIC.

A depiction of imported malaria in Connecticut.

In 2010, there were roughly 219 million cases of malaria reported worldwide resulting in an estimated 660,600 deaths [1]. In contrast, the total number of cases according to the Centers for Disease Control and Prevention (CDC) in the United States (USA) was only 1691 [2]. Of those, 1688 were cases of imported malaria [2]. This is the highest number of cases reported in U.S. since 1980 [2]. Here, we describe a case of imported malaria and conduct a retrospective case series at four Connecticut (CT) hospitals in order to describe the demographics of imported malaria and to identify potential barriers to timely diagnosis and treatment.

Vanishing bile duct syndrome in a HIV patient on HAART therapy.

Vanishing bile duct syndrome refers to a group of disorders characterised by progressive destruction of the intrahepatic bile ducts resulting in cholestasis. It is a final common pathway for many disorders. The diagnoses is mainly made by histological findings. To consider a diagnosis there should be loss of interlobular bile ducts in more than fifty per cent of small portal tracts provided that the specimen contains at least 10 portal tracts. Here the authors present a case of vanishing bile duct syndrome which developed after initiation of highly active antiretroviral treatment therapy.

Ascidians: an invertebrate chordate model to study Alzheimer's disease pathogenesis.

Here we present the ascidian Ciona intestinalis as an alternative invertebrate system to study Alzheimer's disease (AD) pathogenesis. Through the use of AD animal models, researchers often attempt to reproduce various aspects of the disease, particularly the coordinated processing of the amyloid precursor protein (APP) by alpha-, beta- and gamma-secretases to generate amyloid beta (Abeta)-containing plaques. Recently, Drosophila and C. elegans AD models have been developed, exploiting the relative simplicity of these invertebrate systems, but they lack a functional Abeta sequence and a beta-secretase ortholog, thus complicating efforts to examine APP processing in vivo. We propose that the ascidian is a more appropriate invertebrate AD model owing to their phylogenetic relationship with humans. This is supported by bioinformatic analyses, which indicate that the ascidian genome contains orthologs of all AD-relevant genes. We report that transgenic ascidian larvae can properly process human APP(695) to generate Abeta peptides. Furthermore, Abeta can rapidly aggregate to form amyloid-like plaques, and plaque deposition is significantly increased in larvae expressing a human APP(695) variant associated with familial Alzheimer's disease. We also demonstrate that nervous system-specific Abeta expression alters normal larval behavior during attachment. Importantly, plaque formation and alterations in behavior are not only observed within 24 hours post-fertilization, but anti-amyloid drug treatment improves these AD-like pathologies. This ascidian model for AD provides a powerful and rapid system to study APP processing, Abeta plaque formation and behavioral alterations, and could aid in identifying factors that modulate amyloid deposition and the associated disruption of normal cellular function and behaviors.

Predictable mosaic transgene expression in ascidian embryos produced with a simple electroporation device.

Two customized electroporators were specifically designed for creating transgenic ascidian embryos. These electroporators were simple to build, inexpensive, and produced transgenic embryos with efficiencies that equaled or rivaled commercially available machines. A key design feature of these machines resulted in the generation of consistent electroporation pulses providing repeatability between experiments. These devices were used to optimize experimental parameters allowing for the creation of transient transgenic embryos with predictable patterns of mosaic transgene expression. We used these new electroporators to examine the expression of two different fluorescent protein reporter genes with regard to embryonic cell lineage. In general, transgene expression followed the embryonic cell lineage and coelectroporated transgenes were always expressed in the same embryonic cells. Our analysis also indicated that, during development, transgenes could be lost from embryonic cells, suggesting that transgenes may be present in extrachromosomal arrays, as has been observed in other organisms. Our new electroporator designs will allow ascidian researchers to inexpensively produce transgenic ascidians and should prove useful for adapting the electroporation technique to other marine embryo systems.