Faculty Bibliography

As they age, people living with HIV (PLWH) experience greater rates of inflammation-related health conditions compared to their HIV-negative peers. Because early life adversity can exaggerate proinflammatory effects of later physiological challenges, inflammation may be higher among PLWH with these combined risks, which could inform intervention approaches to mitigate multimorbidity. In this cross-sectional analysis, we investigated individual and combined effects of childhood sexual abuse (CSA) history and physiological burden (Veterans Aging Cohort Study Index scores) on serum cytokine and C-reactive protein (CRP) levels among PLWH. Participants (n ​= ​131; age 54 and older) were patients at an outpatient HIV clinic who completed a psychosocial survey and biomedical research visit as part of a larger study. 93% were virally suppressed, and 40% reported experiencing sexual abuse in childhood. Composite cytokine levels (summarizing IL-6, TNF-α, IFN-γ), CRP, and disease burden did not differ significantly between those who had a history of CSA and those who did not. Participants with greater disease burden had higher composite cytokine levels (r ​= ​0.29, p ​= ​0.001). The disease burden by CSA interaction effect was a significant predictor of composite cytokine levels (but not CRP), and remained significant after controlling for age, sex, race, BMI, anti-inflammatory medication use, selective serotonin reuptake inhibitor use, depressive symptoms, and smoking status (F(1, 114) ​= ​5.68, p ​= ​0.02). In follow-up simple slopes analysis, greater disease burden was associated with higher cytokine levels among those with CSA history (b ​= ​0.03, SE ​= ​0.008, p<0.001), but not among those without CSA history. Further, in the context of greater disease burden, individuals with a CSA history tended to have higher cytokine levels than those without a CSA history (b ​= ​0.38, SE ​= ​0.21, p ​= ​0.07). These data suggest that the physiological sequelae of childhood trauma may persist into older age among those with HIV. Specifically, links between physiological burden and inflammation were stronger among survivors of CSA in this study. The combined presence of CSA history and higher disease burden may signal a greater need for and potential benefit from interventions to reduce inflammation, an area for future work.

PURPOSE/OBJECTIVE:Telehealth's uptake has increased substantially in recent years, with an especially large jump in 2020 due to the emergence of COVID-19. This article provides background on and explores "telepresence" in healthcare literature. Telepresence strongly impacts the patient experience, but it is poorly defined in current research. The aim was to conceptually define telepresence using qualitative methods. DESIGN/METHODS:Dimensional analysis was used to analyze telepresence in clinical literature and create a clearer definition of telepresence as a concept. Multiple databases were searched for articles related to telepresence. Thirteen international articles related to telepresence were selected for analysis. METHODS:Dimensional analysis allowed for multiple viewpoints to be explored within each distinct context and perspective. FINDINGS/RESULTS:Twenty-five dimensions were discovered within the articles, which were synthesized to seven core dimensions of telepresence: connection, technological mediation, experienced realism, trust, being supportive, collaboration, and emotional consequence. CONCLUSIONS:Telepresence is highly impactful on the patient's experience of telehealth care visits. The conceptual map produced by this dimensional analysis provides direction for clinicians to improve their ability to be present with patients during telehealth care. Potential implications include a starting point for future qualitative research, and the use of this dimensional analysis to inform clinical guidelines, improve clinician training, and assist in the development of new care models. CLINICAL RELEVANCE/CONCLUSIONS:A telepresence definition brings clarity to an ill-defined concept. COVID-19 magnifies the need for a better understanding of telepresence, which allows clinicians to improve telehealth encounters.

Background As tumor genomes are shaped by their interaction with the immune system, a phenomenon known as immunoediting, it is critical to understand how immunotherapies impact this process. Checkpoint inhibitors directly influence T cells responding to neoantigens, as such, these therapies drastically affect the genomes of surviving tumor clones. Similar to the concept of immune camouflage, observed in infectious diseases, where genomes of pathogens evolve in a way to avoid immune detection, we hypothesized that tumor clones surviving checkpoint inhibition therapy harbor mutations more prone to immune avoidance. Methods We analyzed a cohort of nivolumab-treated melanoma patients (n=41) for which tumor samples were collected from the same site prior (Pre samples) and during (On samples) nivolumab therapy.1 The immunogenic and tolerance potential of mutations from the Pre and On samples were evaluated with the Ancer neoantigen screening platform,2 which includes the EpiMatrix algorithm to identify HLA-I and HLA-II neoepitopes and the JanusMatrix algorithm to evaluate neoepitopes homology with self. Prior work with JanusMatrix showed epitopes highly homologous to self can be inhibitory.3 Matching Pre and On therapy samples were compared to identify mutations deleted (unique to the Pre samples), maintained (found in both the Pre and On samples), and induced while on therapy (unique to the On samples). Results Mutations from the On therapy samples had a lower immunogenic potential than mutations found in the Pre therapy samples (figure 1A, Mann-Whitney test, p=0.0001). After further distinguishing mutations deleted, maintained, and induced while on therapy, we observed that newly induced mutations had a significantly lower immunogenic potential compared to other mutations (Kruskal-Wallis test, p<0.0001). In addition, newly induced mutations were more homologous to self than other mutations (figure 1B, Kruskal-Wallis test, p<0.0001), indicating a greater likelihood for these new mutations to be tolerated by the immune system. In summary, we showed that mutations generated after nivolumab therapy are less immunogenic and more tolerated than mutations found prior to therapy. Abstract 313 Figure 1 Immunogenicity (A) and tolerance (B) potentials of mutations found in matching melanoma tumor samples collected before (Pre) and during (On) nivolumab therapy. Conclusions Our Ancer analysis suggests that nivolumab therapy affects the immunogenicity and tolerance profiles of newly generated mutations in a manner that is consistent with the concepts of immunoediting and immune camouflaging. Mutations induced after therapy appear less immunogenic and more self-like, illustrating a potential mechanism tumors employ to avoid immune surveillance. Furthermore, our approach highlights in silico tools can distinguish effector from tolerance inducing neoepitopes, a critical feature for designing novel neoantigen-based precision immunotherapies

Mycobacterium abscessus subsp. abscessus is one of the most difficult pathogens to treat and its incidence in disease is increasing. Dual β-lactam combinations act synergistically in vitro, but are not widely employed in practice. A recent study shows that a combination of imipenem and ceftaroline significantly lowers the minimum inhibitory concentration (MIC) of clinical isolates despite both drugs targeting the same peptidoglycan synthesis enzymes. The underlying mechanism of this effect provides a basis for further investigations of dual β-lactam combinations in the treatment of M. abscessus subsp. abscessus eventually leading to a clinical trial. Furthermore, dual β-lactam strategies may be explored for other difficult mycobacterial infections.

AIMS/OBJECTIVE:Aortic valve calcification (AVC) has been shown to be associated with increased cardiovascular disease (CVD) risk; however, whether this is independent of traditional risk factors and coronary artery calcification (CAC) remains unclear. METHODS AND RESULTS/RESULTS:From the multicentre CAC Consortium database, 10 007 patients (mean 55.8±11.7 years, 64% male) with concomitant CAC and AVC scoring were included in the current analysis. AVC score was quantified using the Agatston score method and categorized as 0, 1-99, and ≥100. The endpoints were all-cause, CVD, and coronary heart disease (CHD) deaths. AVC (AVC>0) was observed in 1397 (14%) patients. During a median 7.8 (interquartile range: 4.7-10.6) years of study follow-up, 511 (5.1%) deaths occurred; 179 (35%) were CVD deaths, and 101 (19.8%) were CHD deaths. A significant interaction between CAC and AVC for mortality was observed (P<0.001). The incidence of mortality events increased with higher AVC; however, AVC ≥100 was not independently associated with all-cause, CVD, and CHD deaths after adjusting for CVD risk factors and CAC (P=0.192, 0.063, and 0.206, respectively). When further stratified by CAC<100 or ≥100, AVC ≥100 was an independent predictor of all-cause and CVD deaths only in patients with CAC <100, after adjusting for CVD risk factors and CAC [hazard ratio (HR): 1.93, 95% confidence interval (CI): 1.14-3.27; P=0.013 and HR: 2.71, 95% CI: 1.15-6.34; P=0.022, respectively]. CONCLUSION/CONCLUSIONS:Although the overall prognostic significance of AVC was attenuated after accounting for CAC, high AVC was independently associated with all-cause and CVD deaths in patients with low coronary atherosclerosis burden.

BACKGROUND:Almost half of Veterans with localized prostate cancer receive inappropriate, wasteful staging imaging. Our team has explored the barriers and facilitators of guideline-concordant prostate cancer imaging and found that (1) patients with newly diagnosed prostate cancer have little concern for radiographic staging but rather focus on treatment and (2) physicians trust imaging guidelines but are apt to follow their own intuition, fear medico-legal consequences, and succumb to influence from imaging-avid colleagues. We used a theory-based approach to design a multi-level intervention strategy to promote guideline-concordant imaging to stage incident prostate cancer. METHODS:We designed the Prostate Cancer Imaging Stewardship (PCIS) intervention: a multi-site, stepped wedge, cluster-randomized trial to determine the effect of a physician-focused behavioral intervention on Veterans Health Administration (VHA) prostate cancer imaging use. The multi-level intervention, developed according to the Theoretical Domains Framework (TDF) and Behavior Change Wheel, combines traditional physician behavior change methods with novel methods of communication and data collection. The intervention consists of three components: (1) a system of audit and feedback to clinicians informing individual clinicians and their sites about how their behavior compares to their peers' and to published guidelines, (2) a program of academic detailing with the goal to educate providers about prostate cancer imaging, and (3) a CPRS Clinical Order Check for potentially guideline-discordant imaging orders. The intervention will be introduced to 10 participating geographically distributed study sites. DISCUSSION/CONCLUSIONS:This study is a significant contribution to implementation science, providing VHA an opportunity to ensure delivery of high-quality care at the lowest cost using a theory-based approach. The study is ongoing. Preliminary data collection and recruitment have started; analysis has yet to be performed. TRIAL REGISTRATION/BACKGROUND:CliniclTrials.gov NCT03445559. Prospectively registered on February 26, 2018.

PURPOSE OF REVIEW/OBJECTIVE:Calcium pyrophosphate deposition disease (CPPD) arises from calcium pyrophosphate deposition throughout the body, leading to different clinical syndromes that may be diagnosed using various imaging modalities. The purpose of this review is to highlight recent updates in the imaging of CPPD. RECENT FINDINGS/RESULTS:Conventional radiography remains the initial test when imaging CPPD; but musculoskeletal ultrasound and conventional computed tomography (CT) may also assist in diagnosing and characterizing CPP deposits, with increased sensitivity. Dual-energy CT is also being used to differentiate CPP crystals from other crystal deposition diseases. CPP discitis has been diagnosed with MRI, but MRI has lower sensitivity and specificity than the aforementioned imaging studies in CPPD diagnosis. Assorted imaging modalities are increasingly used to diagnose CPPD involving atypical joints, avoiding invasive procedures. Each modality has its advantages and disadvantages. Future imaging may be able to provide more utility than what is currently available.

BACKGROUND:Levofloxacin prophylaxis is recommended to prevent Gram-negative bloodstream infections (BSIs) in patients with prolonged chemotherapy-induced neutropenia. However, increasing fluoroquinolone resistance may decrease the effectiveness of this approach. METHODS:We assessed the prevalence of colonization with fluoroquinolone-resistant Enterobacterales (FQRE) among patients admitted for hematopoietic cell transplantation (HCT) from November 2016-August 2019 and compared the risk of Gram-negative BSI between FQRE-colonized and non-colonized patients. All patients received levofloxacin prophylaxis during neutropenia. Stool samples were collected upon admission for HCT and weekly thereafter until recovery from neutropenia, and underwent selective culture for FQRE. All isolates were identified and underwent antimicrobial susceptibility testing by broth microdilution. FQRE isolates also underwent whole-genome sequencing. RESULTS:Fifty-four (23%) of 234 patients were colonized with FQRE prior to HCT, including 30 (25%) of 119 allogeneic and 24 (21%) of 115 autologous HCT recipients. Recent antibacterial use was associated with FQRE colonization (P=0.048). Ninety-one percent of colonizing FQRE isolates were Escherichia coli and 29% produced extended-spectrum ß-lactamases. Seventeen (31%) FQRE-colonized patients developed Gram-negative BSI despite levofloxacin prophylaxis, compared to only two (1.1%) of 180 patients who were not colonized with FQRE on admission (P<0.001). Of the 17 Gram-negative BSIs in FQRE-colonized patients, 15 (88%) were caused by FQRE isolates that were genetically identical to the colonizing strain. CONCLUSIONS:Nearly one-third of HCT recipients with pre-transplant FQRE colonization developed Gram-negative BSI while receiving levofloxacin prophylaxis and infections were typically caused by their colonizing strains. In contrast, levofloxacin prophylaxis was highly effective in patients not initially colonized with FQRE.