A survey of South Carolina pharmacists' readiness to prescribe human immunodeficiency virus pre-exposure prophylaxis.

Introduction: HIV pre-exposure prophylaxis (PrEP) is largely underutilized in the Southern United States. Given their community presence, pharmacists are well positioned to provide PrEP within rural, Southern regions. However, pharmacists' readiness to prescribe PrEP in these communities remains unknown. Objective: To determine the perceived feasibility and acceptability of prescribing PrEP by pharmacists in South Carolina (SC). Methods: We distributed a 43-question online descriptive survey through the University of SC Kennedy Pharmacy Innovation Center's listerv of licensed SC pharmacists. We assessed pharmacists' comfort, knowledge, and readiness to provide PrEP. Results: A total of 150 pharmacists responded to the survey. The majority were White (73%, n=110), female (62%, n=93), and non-Hispanic (83%, n=125). Pharmacists practiced in retail (25%, n=37), hospital (22%, n=33), independent (17%, n=25), community (13%, n=19), specialty (6%, n=9), and academic settings (3%, n=4); 11% (n=17) practiced in rural locales. Pharmacists viewed PrEP as both effective (97%, n=122/125) and beneficial (74% n=97/131) for their clients. Many pharmacists reported being ready (60% n=79/130) and willing (86% n=111/129) to prescribe PrEP, although over half (62% n=73/118) cited lack of PrEP knowledge as a barrier. Pharmacists described pharmacies as an appropriate location to prescribe PrEP (72% n=97/134). Conclusions: Most SC pharmacists surveyed considered PrEP to be effective and beneficial for individuals who frequent their pharmacy and are willing to prescribe this therapy if statewide statutes allow. Many felt that pharmacies are an appropriate location to prescribe PrEP but lack a complete understanding of required protocols to manage these patients. Further investigation into facilitators and barriers of pharmacy-driven PrEP are needed to enhance utilization within communities.

Development of a Human Immunodeficiency Virus Risk Prediction Model Using Electronic Health Record Data From an Academic Health System in the Southern United States.

BACKGROUND: Human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is underutilized in the southern United States. Rapid identification of individuals vulnerable to diagnosis of HIV using electronic health record (EHR)-based tools may augment PrEP uptake in the region. METHODS: Using machine learning, we developed EHR-based models to predict incident HIV diagnosis as a surrogate for PrEP candidacy. We included patients from a southern medical system with encounters between October 2014 and August 2016, training the model to predict incident HIV diagnosis between September 2016 and August 2018. We obtained 74 EHR variables as potential predictors. We compared Extreme Gradient Boosting (XGBoost) versus least absolute shrinkage selection operator (LASSO) logistic regression models, and assessed performance, overall and among women, using area under the receiver operating characteristic curve (AUROC) and area under precision recall curve (AUPRC). RESULTS: Of 998 787 eligible patients, 162 had an incident HIV diagnosis, of whom 49 were women. The XGBoost model outperformed the LASSO model for the total cohort, achieving an AUROC of 0.89 and AUPRC of 0.01. The female-only cohort XGBoost model resulted in an AUROC of 0.78 and AUPRC of 0.00025. The most predictive variables for the overall cohort were race, sex, and male partner. The strongest positive predictors for the female-only cohort were history of pelvic inflammatory disease, drug use, and tobacco use. CONCLUSIONS: Our machine-learning models were able to effectively predict incident HIV diagnoses including among women. This study establishes feasibility of using these models to identify persons most suitable for PrEP in the South.

Perceptions on HIV Pre-Exposure Prophylaxis Among Urgent Care Clinicians in the Southern United States.

BACKGROUND: Underutilization of HIV pre-exposure prophylaxis (PrEP) in the Southern United States (US) is well-documented. Urgent care (UC) centers are positioned as communityfacing access points to PrEP, but the feasibility of integrating PrEP services into this setting is unclear. We conducted a survey of UC clinicians in the Southern US to better understand their perceptions of the feasibility of providing PrEP in their practice setting. OBJECTIVE: The study aims to determine the feasibility and acceptability of providing PrEP services in the UC setting through a cross-sectional survey of UC clinicians. METHODS: We conducted a 48-item cross-sectional survey of UC clinicians in the Southern US, between July and September 2020. The survey was distributed through the Urgent Care Association (UCA) and American Academy of Urgent Care Medicine (AAUCM) professional listservs as well as directly to publicly listed e-mail addresses. RESULTS: Eighty-two clinicians responded to the survey. Most clinicians had familiarity with PrEP (97%). All respondents rated PrEP as an effective way to prevent HIV. However, less than half felt UC facilities were an appropriate place to prescribe PrEP. Few respondents (8%) expressed doubts that expansion of PrEP access would decrease the incidence of HIV in their community. CONCLUSION: These findings show UC clinicians are familiar with PrEP, and many believe it would benefit their patients; however, provider opinions on the appropriateness of providing PrEP in the UC setting differ. Further studies on PrEP implementation in UC centers are needed.

Feasibility, Acceptability, and Preliminary Efficacy of a Gamified Mobile Health Contingency Management Intervention for PrEP Adherence Among Black MSM.

Oral HIV pre-exposure prophylaxis (PrEP) is effective at preventing HIV. However, low adherence is common and undermines these protective effects. This is particularly relevant for groups with disproportionately higher rates of HIV, including Black men who have sex with men (MSM). The current study tested the feasibility, acceptability, and preliminary efficacy of a gamified mobile health contingency management intervention for PrEP adherence-called mSMART (Mobile App-Based Personalized Solutions for Medication Adherence of Rx Pill Tool). Fifteen Black MSM already prescribed PrEP in the community completed baseline and follow-up assessments separated by 8 weeks of using mSMART. Regarding feasibility, there was no study attrition, no mSMART functional difficulties that significantly interfered with use, and a mean rate of 82% daily mSMART use. Acceptability ratings were in the moderately to extremely satisfied range for factors such as willingness to recommend mSMART to others and user-friendliness, and in the low range for ratings on difficulty learning how to use mSMART. Scores on a system usability measure were in the acceptable range for 73% of the sample. Qualitative analysis of follow-up interviews identified individual components of mSMART that could be modified in future iterations to make it more engaging. PrEP composite adherence scores from biomarkers indicated an improvement from baseline to follow-up with a medium effect size, as well as a decrease in the number of perceived barriers to medication adherence. Findings indicate a future efficacy trial is needed to examine the effects of this gamified mobile health contingency management intervention on PrEP adherence.

Understanding Retention in Pre-Exposure Prophylaxis Care in the South: Insights from an Academic HIV Prevention Clinic.

HIV pre-exposure prophylaxis (PrEP) is poorly utilized in the southern United States. We examined PrEP retention in care and sexually transmitted infections (STIs) through a retrospective review of the Duke University PrEP Clinic from January 1, 2015 to October 15, 2019. We evaluated short-term (3 months), long-term (additional 8-12 months), and longitudinal retention in care in our clinic. Adjusted odds ratios (aOR) were generated to explore demographics associated with retention. Kaplan-Meier curves were generated to view retention longitudinally. STIs were examined at baseline (1 year before initial PrEP visit) and while retained in care. Of a total of 255 patients; 88% were men, 37% were black, and 73% were men who have sex with men (MSM). Short- and long-term retention in care were met by 130/237 (55%) and 80/217 (37%) patients, respectively. MSM were more likely to be retained in the short term (aOR = 5.22, 95% confidence interval [CI] = 1.57-17.32). Self-referred patients were more likely to be retained in the long term (aOR = 2.18, 95% CI = 1.12-4.23). Uninsured patients were less likely to be retained in the long term (aOR = 0.32, 95% CI = 0.11-0.91). STI diagnoses include 42 infections at baseline and 69 infections during follow-up. STI diagnosed while in PrEP care was associated with longer retention in care over time. Patients discontinue PrEP care over time and STIs were frequently encountered. Additional studies are needed to determine the best way to retain patients in HIV preventative care.

Hemodynamic-mediated endocardial signaling controls in vivo myocardial reprogramming.

Lower vertebrate and neonatal mammalian hearts exhibit the remarkable capacity to regenerate through the reprogramming of pre-existing cardiomyocytes. However, how cardiac injury initiates signaling pathways controlling this regenerative reprogramming remains to be defined. Here, we utilize in vivo biophysical and genetic fate mapping zebrafish studies to reveal that altered hemodynamic forces due to cardiac injury activate a sequential endocardial-myocardial signaling cascade to direct cardiomyocyte reprogramming and heart regeneration. Specifically, these altered forces are sensed by the endocardium through the mechanosensitive channel Trpv4 to control Klf2a transcription factor expression. Consequently, Klf2a then activates endocardial Notch signaling which results in the non-cell autonomous initiation of myocardial Erbb2 and BMP signaling to promote cardiomyocyte reprogramming and heart regeneration. Overall, these findings not only reveal how the heart senses and adaptively responds to environmental changes due to cardiac injury, but also provide insight into how flow-mediated mechanisms may regulate cardiomyocyte reprogramming and heart regeneration.

A case of cannabinoid hyperemesis syndrome with Heliobacter pylori and preeclampsia during pregnancy.

BACKGROUND: The condition termed cannabinoid hyperemesis syndrome (CHS) was characterized a decade ago by Allen et al. and includes cyclic episodes of nausea and vomiting and the learned behavior of hot bathing in individuals with chronic cannabis abuse. During pregnancy, the differential diagnosis of this syndrome is challenging, since it can be masked by typical symptoms of early pregnancy or by hyperemesis gravidarum, a complication of early pregnancy associated with excessive nausea and vomiting. CASE DESCRIPTION: The authors herein describe the case of a 21-year-old primigravida patient diagnosed with hyperemesis gravidarum at 6 weeks of gestation and with preeclampsia at 35 weeks. At 30 weeks of gestation, a drug screen was performed that was positive for cannabis; therefore, a diagnosis of CHS was made. After labor induction, the patient delivered an infant who developed normally and had a negative drug test of the umbilical cord blood. Esophagogastroduodenoscopy was performed 9 days post delivery, with biopsies taken of the duodenal, gastric, and esophageal tissues. Moderate chronic gastritis with lymphoid aggregates and slight acute inflammation were noticed, whereas no malignancy, dysplasia, or goblet cell metaplasia was detected. A number of Helicobacter-like organisms were identified by H. pylori immunostaining. CONCLUSION: Presented here is the first case reporting an association of chronic cannabis use with H. pylori colonization and preeclampsia in pregnancy, which brings to light the possible involvement of a cannabinoid-related pathway in the link between pregnancy-specific complications and bacterial colonization.

A virtual clinic improves pneumococcal vaccination coverage among patients living with HIV at a Veterans Affairs Medical Center.

People living with the human immunodeficiency virus (HIV) should receive pneumococcal vaccinations as part of their routine health maintenance. Our goal was to create a "virtual clinic" to help increase rates of pneumococcal vaccination among people living with HIV without adding substantially to the workload of primary providers. We used administrative data from our Veterans Affairs (VA) medical center to identify a cohort of veterans living with HIV who were not current with either the 13-valent pneumococcal conjugate vaccine (PCV13), the 23-valent pneumococcal polysaccharide vaccine (PPSV23) or both. We enrolled these individuals (n = 99) into a virtual clinic, notified providers via the electronic medical record and mailed letters to the veterans recommending they receive a pneumococcal vaccine. We also wrote orders for the appropriate pneumococcal vaccine that expired after 90 days. Among the virtual clinic cohort, 38% (38/99) of patients received the recommended vaccine within 180 days. Concurrent with our intervention, the Veterans Health Administration deployed a system-wide pneumococcal vaccine clinical reminder that incorporated recent PCV13 recommendations. To discern any effect of the virtual clinic beyond that of the clinical reminder, we compared the rate of PCV13 vaccinations among all HIV-positive veterans at our institution to the equivalent population from 2 other VA medical centers in Ohio. With consideration of the VHA's system-wide clinical reminder, the proportion of HIV-positive patients who received PCV13 in the first 90 days following the virtual clinic intervention was greater at our facility compared to another Ohio VA medical center (P < 0.05). The virtual clinic improved the pneumococcal vaccine coverage among HIV-positive veterans. These outcomes suggest that even in conjunction with a system-wide clinical reminder, the virtual clinic strategy improves vaccination rates among a high-risk population.

Vaccination with Live Attenuated Simian Immunodeficiency Virus (SIV) Protects from Mucosal, but Not Necessarily Intravenous, Challenge with a Minimally Heterologous SIV.

UNLABELLED: Few studies have evaluated the impact of the viral challenge route on protection against a heterologous simian immunodeficiency virus (SIV) challenge. We vaccinated seven macaques with a live attenuated SIV that differed from SIVmac239Δnef by 24 amino acids, called m3KOΔnef. All animals were protected from an intrarectal SIVmac239 challenge, whereas only four animals were protected from subsequent intravenous SIVmac239 challenge. These data suggest that immune responses elicited by vaccination with live attenuated SIV in an individual animal can confer protection from intrarectal challenge while remaining insufficient for protection from intravenous challenge. IMPORTANCE: Our study is important because we show that vaccinated animals can be protected from a mucosal challenge with a heterologous SIV, but the same animals are not necessarily protected from intravenous challenge with the same virus. This is unique because in most studies, either vaccinated animals are challenged multiple times by the same route or only a single challenge is performed. An individually vaccinated animal is rarely challenged multiple times by different routes, so protection from different challenge routes cannot be measured in the same animal. Our data imply that vaccine-elicited responses in an individual animal may be insufficient for protection from intravenous challenge but may be suitable for protection from a mucosal challenge that better approximates human immunodeficiency virus (HIV) exposure.

A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.

HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.

Acute-phase CD8 T cell responses that select for escape variants are needed to control live attenuated simian immunodeficiency virus.

The overall CD8 T cell response to human/simian immunodeficiency virus (HIV/SIV) targets a collection of discrete epitope specificities. Some of these epitope-specific CD8 T cells emerge in the weeks and months following infection and rapidly select for sequence variants, whereas other CD8 T cell responses develop during the chronic infection phase and rarely select for sequence variants. In this study, we tested the hypothesis that acute-phase CD8 T cell responses that do not rapidly select for escape variants are unable to control viral replication in vivo as well as those that do rapidly select for escape variants. We created a derivative of live attenuated SIV (SIVmac239Δnef) in which we ablated five epitopes that elicit early CD8 T cell responses and rapidly accumulate sequence variants in SIVmac239-infected Mauritian cynomolgus macaques (MCMs) that are homozygous for the M3 major histocompatibility complex (MHC) haplotype. This live attenuated SIV variant was called m3KOΔnef. Viremia was significantly higher in M3 homozygous MCMs infected with m3KOΔnef than in either MHC-mismatched MCMs infected with m3KOΔnef or MCMs infected with SIVmac239Δnef. Three CD8 T cell responses, including two that do not rapidly select for escape variants, predominated during early m3KOΔnef infection in the M3 homozygous MCMs, but these animals were unable to control viral replication. These results provide evidence that acute-phase CD8 T cell responses that have the potential to rapidly select for escape variants in the early phase of infection are needed to establish viral control in vivo.

Experimental analysis of sources of error in evolutionary studies based on Roche/454 pyrosequencing of viral genomes.

Factors affecting the reliability of Roche/454 pyrosequencing for analyzing sequence polymorphism in within-host viral populations were assessed by two experiments: 1) sequencing four clonal simian immunodeficiency virus (SIV) stocks and 2) sequencing mixtures in different proportions of two SIV strains with known fixed nucleotide differences. Observed nucleotide diversity and frequency of undetermined nucleotides were increased at sites in homopolymer runs of four or more identical nucleotides, particularly at AT sites. However, in the mixed-strain experiments, the effects on estimated nucleotide diversity of such errors were small in comparison to known strain differences. The results suggest that biologically meaningful variants present at a frequency of around 10% and possibly much lower are easily distinguished from artifacts of the sequencing process. Analysis of the clonal stocks revealed numerous rare variants that showed the signature of purifying selection and that elimination of variants at frequencies of less than 1% reduced estimates of nucleotide diversity by about an order of magnitude. Thus, using a 1% frequency cutoff for accepting a variant as real represents a conservative standard, which may be useful in studies that are focused on the discovery of specific mutations (such as those conferring immune escape or drug resistance). On the other hand, if the goal is to estimate nucleotide diversity, an optimal strategy might be to include all observed variants (even those at less than 1% frequency), while masking out homopolymer runs of four or more nucleotides.

Transcriptionally abundant major histocompatibility complex class I alleles are fundamental to nonhuman primate simian immunodeficiency virus-specific CD8+ T cell responses.

Simian immunodeficiency virus (SIV)-infected macaques are the preferred animal model for human immunodeficiency virus (HIV) vaccines that elicit CD8(+) T cell responses. Unlike humans, whose CD8(+) T cell responses are restricted by a maximum of six HLA class I alleles, macaques express up to 20 distinct major histocompatibility complex class I (MHC-I) sequences. Interestingly, only a subset of macaque MHC-I sequences are transcriptionally abundant in peripheral blood lymphocytes. We hypothesized that highly transcribed MHC-I sequences are principally responsible for restricting SIV-specific CD8(+) T cell responses. To examine this hypothesis, we measured SIV-specific CD8(+) T cell responses in MHC-I homozygous Mauritian cynomolgus macaques. Each of eight CD8(+) T cell responses defined by full-proteome gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay were restricted by four of the five transcripts that are transcriptionally abundant (>1% of total MHC-I transcripts in peripheral blood lymphocytes). The five transcriptionally rare transcripts shared by these animals did not restrict any detectable CD8(+) T cell responses. Further, seven CD8(+) T cell responses were defined by identifying peptide binding motifs of the three most frequent MHC-I transcripts on the M3 haplotype. Combined, these results suggest that transcriptionally abundant MHC-I transcripts are principally responsible for restricting SIV-specific CD8(+) T cell responses. Thus, only a subset of the thousands of known MHC-I alleles in macaques should be prioritized for CD8(+) T cell epitope characterization.

Changes in pain and disability secondary to shoe lift intervention in subjects with limb length inequality and chronic low back pain: a preliminary report.

STUDY DESIGN: Preassessment and postassessment of treatment intervention. OBJECTIVE: To determine the changes in pain and disability secondary to shoe lift intervention for subjects with chronic low back pain (LBP) who have a limb length inequality (LLI). BACKGROUND: Previous reports have suggested that LLI may be a cause of LBP Most prior studies of lift therapy for management of LLI in patients with LBP have lacked clear guidelines for clinicians regarding the implementation of shoe lift intervention. METHODS AND MEASURES: Twelve subjects (6 male, 6 female) between the ages of 19 and 62 years with LLI (6.4-22.2 mm) and chronic LBP (1-30 years) participated. Visual analog scale pain ratings and disability questionnaire scores were acquired before and after lift intervention. Subjects determined their lift height based on resolution of LBP symptoms. RESULTS: Subjects experienced relief of general pain symptoms (P = .0006) and pain associated with standing (P= .002) following lift intervention, with minimally clinically important (MCID) reductions in general pain for 9 of 12 subjects and MCID reductions in standing pain for 8 of 10 subjects. Subjects also had less disability on the disability questionnaire (P = .001) following the intervention, with 9 of 12 subjects experiencing MCID reductions in disability. CONCLUSION: Shoe lifts may reduce LBP and improve function for patients who have chronic LBP and an LLI. Randomized controlled trials are needed to assess the efficacy of this intervention.

Cardiac myosin light chain-2: a novel essential component of thick-myofilament assembly and contractility of the heart.

Although it is well known that mutations in the cardiac regulatory myosin light chain-2 (mlc-2) gene cause hypertrophic cardiomyopathy, the precise in vivo structural and functional roles of MLC-2 in the heart are only poorly understood. We have isolated a mutation in zebrafish, tell tale heart (tel(m225)), which selectively perturbs contractility of the embryonic heart. By positional cloning, we identified tel to encode the zebrafish mlc-2 gene. In contrast to mammals, zebrafish have only 1 cardiac-specific mlc-2 gene, which we find to be expressed in atrial and ventricular cardiomyocytes during early embryonic development, but also in the adult heart. Accordingly, loss of zMLC-2 function cannot be compensated for by upregulation of another mlc-2 gene. Surprisingly, ultrastructural analysis of tel cardiomyocytes reveals complete absence of organized thick myofilaments. Thus, our findings provide the first in vivo evidence that cardiac MLC-2 is required for thick-filament stabilization and contractility in the vertebrate heart.

Comparison of full-field digital mammography to screen-film mammography with respect to contrast and spatial resolution in tissue equivalent breast phantoms.

To determine if the improved contrast resolution of full-field digital mammography (FFDM) with reduced spatial resolution allows for superior or equal phantom object detection compared with screen-film mammography (SFM). Tissue equivalent breast phantoms simulating an adipose to glandular ratio of 50/50,30/70, and 20/80 were imaged according to each manufacturers' recommendation with four full-field digital mammography units (Fuji, Sectra, Fischer, and General Electric) and a screen-film mammography unit (MammoMatII 2000, Siemens, Munich, Germany). A total of 20 images were obtained in both hard- and soft-copy formats. For the purpose of soft-copy display, the screen-film hard-copy images were digitized with a 50 microm micron scanner. Six radiologists, experts in breast imaging, and three physicists, experts in scoring mammography phantoms, participated in a reader study where each reader scored each phantom for visibility of line-pairs and for 24 objects (fibers, clusters of specks, and masses). The data were recorded, entered into a database, and analyzed by a mixed-effect model. The limiting spatial resolution in line-pairs per millimeter visible with the digital units was less, regardless of display modality used, than that provided by the screen-film unit. The difference was statistically significant for the General Electric (p < 0.01) and Fuji digital mammography units (p = 0.03). With respect to the number of visible objects, a statistically significant higher number could be detected with the screen-film unit as compared to the Fischer (p < 0.01) and Sectra (p < 0.01) digital mammography units, but there was no significant difference between the other digital units and screen film. Overall, there was significantly better performance on the 50/50 phantom than with the 30/70 and 20/80 phantoms (p = 0.01, p < 0.01) for object visibility. For the digital mammography units, soft-copy display performed better than hard-copy display for the Fischer and Sectra images, but worse for Fuji and General Electric. In addition, soft-copy display of digitized screen-film images was significantly better than hard-copy display (p =0.02) of the original screen films for object visibility, but worse for spatial resolution. The higher contrast resolution of the FFDM units tested did not result in improved detection of line-pair resolution or objects in the phantoms tested versus screen-film mammography. The phantom performance of a digital mammography unit seems to be influenced by the type of detection task (line-pair resolution versus object visibility), the display modality (soft-copy versus hard-copy) chosen to score the phantoms, and the parenchymal pattern composition of the phantom.