Risk and predictors of penile cancer in US Veterans with HIV.

OBJECTIVES: People living with HIV (PWH) may have an increased burden of penile cancer. We aimed to evaluate the risk of penile cancer in PWH compared to that of the general population. DESIGN: We conducted a nationwide retrospective matched cohort study of penile cancer incidence among veterans living with HIV (VWH) compared to veterans without HIV. METHODS: We compared penile cancer incidence rates in 44,173 VWH to those of veterans without Human Immunodeficiency virus (HIV) (N = 159,443; 4:1 matched in age. We used Cox regression models to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with HIV infection and for penile cancer risk factors. RESULTS: HIV positivity was associated with an increased risk of penile cancer, with adjusted hazard ratios (HR) of 2.63 (95% CI: 1.64-4.23) when adjusting for age, race/ethnicity, baseline BMI, smoking and alcohol use, economic means test, and history of condyloma. The risk increased to HR = 4.25 (95% CI: 2.75-6.57) when adjusting for all factors except history of condyloma. Risk factors for penile cancer in VWH included lower nadir CD4 count, <50% of follow-up time with undetectable HIV viral load, and history of condyloma. CONCLUSIONS: VWH--particularly those with low CD4 counts, detectable HIV viral loads, or history of condyloma--are at increased risk of penile cancer, suggesting the penile cancer prevention activities are needed in this population.

Area deprivation index and segregation on the risk of HIV: a U.S. Veteran case-control study.

Background: Preventing HIV infection remains a critically important tool in the continuing fight against HIV/AIDS. The primary aim is to evaluate the effect and interactions between a composite area-level social determinants of health measure and an area-level measure of residential segregation on the risk of HIV/AIDS in U.S. Veterans. Methods: Using the individual-level patient data from the U.S. Department of Veterans Affairs, we constructed a case-control study of veterans living with HIV/AIDS (VLWH) and age-, sex assigned at birth- and index date-matched controls. We geocoded patient's residential address to ascertain their neighborhood and linked their information to two measures of neighborhood-level disadvantage: area deprivation index (ADI) and isolation index (ISOL). We used logistic regression to estimate the odds ratio (OR) and 95% confidence interval (CI) for comparing VLWH with matched controls. We performed analyses for the entire U.S. and separately for each U.S. Census division. Findings: Overall, living in minority-segregated neighborhoods was associated with a higher risk of HIV (OR: 1.88 (95% CI: 1.79-1.97) while living in higher ADI neighborhoods was associated with a lower risk of HIV (OR: 0.88; 95% CI: 0.84-0.92). The association between living in a higher ADI neighborhood and HIV was inconsistent across divisions, while living in minority-segregated neighborhoods was consistently associated with increased risk across all divisions. In the interaction model, individuals from low ADI and high ISOL neighborhoods had a higher risk of HIV in three divisions: East South Central; West South Central, and Pacific. Interpretation: Our results suggest that residential segregation may prevent people in disadvantaged neighborhoods from protecting themselves from HIV independent from access to health care. There is the need to advance knowledge about the neighborhood-level social-structural factors that influence HIV vulnerability toward developing interventions needed to achieve the goal of ending the HIV epidemic. Funding: US National Cancer Institute.

Effect of HIV and antiretroviral therapy use on body weight changes in a cohort of U.S. veterans living with and without HIV.

OBJECTIVE: People living with HIV have high rates of obesity and obesity-related comorbidities. Our study sought to evaluate weight trajectory in a retrospective cohort of people living with HIV and matched HIV-negative veterans (controls) and to evaluate risk factors for weight gain. METHODS: This was a retrospective database analysis of data extracted from the VA Corporate Data Warehouse that included people living with HIV (n = 22 421) and age-matched HIV-negative controls (n = 63 072). The main outcomes were baseline body weight and weight change from baseline at 1, 2, and 5 years after diagnosis (baseline visit for controls). RESULTS: Body weight at baseline was lower in people living with HIV than in controls. People living with HIV on antiretroviral therapy (ART) gained more weight than did controls. In a sub-analysis of ART-exposed people living with HIV, age >50 years, African American race, body mass index (BMI) <25, CD4 ≤200, and HIV diagnosis year after 2000 were associated with more weight gain at year 1. Nucleoside reverse transcriptase inhibitors (NRTI) plus non-NRTIs (NNRTIs) were associated with less weight gain than NRTIs plus protease inhibitors, NRTIs plus integrase inhibitors, or NRTIs plus other agents at year 1. CONCLUSIONS: Among US veterans, those living with HIV had lower rates of obesity than age-matched HIV-negative controls; however, primarily in the first 2 years after starting ART, people living with HIV gained more weight than did controls.

Risk and incidence of head and neck cancers in veterans living with HIV and matched HIV-negative veterans.

BACKGROUND: Persons living with HIV/AIDS have a higher incidence of virus-related and tobacco/alcohol-related cancers. This study is the first to estimate the effect of HIV versus HIV-negative veterans on the risk of head and neck squamous cell carcinoma incidence in a large retrospective cohort study. METHODS: The authors constructed a retrospective cohort study using patient data from 1999 to 2016 from the National Veterans Administration Corporate Data Warehouse and the VA Central Cancer Registry. This cohort study included 45,052 veterans living with HIV/AIDS and 162,486 HIV-negative patients matched by age, sex, and index visit (i.e., HIV diagnosis date or clinic visit date). The age-standardized incidence rates and estimated adjusted hazard ratios were calculated with a Cox proportional hazards regression for oropharyngeal and nonoropharyngeal head and neck cancer squamous cell carcinoma (HNSCC). The authors also abstracted human papillomavirus (HPV) status from oropharyngeal HNSCC diagnosed after 2010. RESULTS: Veterans living with HIV/AIDS (VLWH) have 1.71 (95% confidence interval [CI], 1.36, 2.14) times the risk of oropharyngeal cancer and 2.06 (95% CI, 1.76, 2.42) times the hazard of nonoropharyngeal cancer compared with HIV-negative veterans. VLWH with oropharyngeal squamous cell carcinoma (OPSCC) were more likely to be HPV-positive (N = 30 [81.1%]) than the HIV-negative veterans with OPSCC (N = 50 [67.6%]), although this difference was not significant (p = .135). For nonoropharyngeal cancer, the increased risk of oral cavity cancer among VLWH drove the increased risk. CONCLUSIONS: The study results suggest that HIV may play a role in virally mediated and nonvirally mediated HNSCC. As the HIV prevalence rises in the United States due to better survival and the incidence of HPV-positive oropharyngeal HNSCC increases, the interaction between HPV and HIV becomes increasingly relevant.

The association between protease inhibitors and anal cancer outcomes in veterans living with HIV treated with definitive chemoradiation: a retrospective study.

BACKGROUND: The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. METHODS: Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. RESULTS: A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p < 0.01). CONCLUSION: The use of protease inhibitors during chemoradiation for anal carcinoma was not associated with any clinical outcome or increase in non-hematologic toxicity. Their use was associated with increased hospitalizations for hematologic toxicities. Further prospective research is needed to evaluate the safety and efficacy of protease inhibitors for patients undergoing chemoradiation.

National trends in oropharyngeal cancer incidence and survival within the Veterans Affairs Health Care System.

BACKGROUND: Oropharyngeal squamous cell carcinoma (OPSCC) epidemiology has not been examined previously in the nationwide Veterans Affairs (VA) population. METHODS: Joinpoint regression analysis was applied to OPSCC cases identified from VA administrative data from 2000 to 2012. RESULTS: We identified 12 125 OPSCC cases (incidence: 12.2 of 100 000 persons). OPSCC incidence declined between 2000 and 2006 (annual percent change [APC] = -4.27, P < .05), then increased between 2006 and 2012 (APC = 7.02, P < .05). Significant incidence increases occurred among white (APC = 7.19, P < .05) and African American (APC = 4.87, P < .05) Veterans and across all age cohorts. The percentage of never-smokers increased from 8% in 2000 to 15.7% in 2012 (P < .001), and 2-year overall survival improved from 31.2% (95% confidence interval (CI) [30-33.4]) to 55.7% (95% CI [54.4-57.1]). CONCLUSIONS: OPSCC incidence is increasing across all racial and age cohorts in the VA population. Smoking rates remain high among Veterans with OPSCC and gains in survival lag those reported in the general population.

Effect of Body Weight and Other Metabolic Factors on Risk of Non-Small Cell Lung Cancer among Veterans with HIV and a History of Smoking.

Among people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, including dyslipidemia, which can modulate NSCLC risk. In this article, we evaluate which metabolic risk factors are associated with incident risk among PWH who smoke. This is done through a retrospective cohort study, using data of HIV+ veterans who smoke from the nationwide Veterans Affairs (VA) healthcare system. Data on diagnostic codes, medication, and laboratory values of 33,351 veterans were obtained using the VA's Corporate Data Warehouse and Central Cancer Registry. We calculated NSCLC incidence and utilized Cox regression to determine metabolic factors associated with NSCLC risk. HIV+ cohort was 97.4% male; median age = 47 years and 20,050 (60.1%) well-controlled (≥80% follow-up time undetectable viral load). Crude incidence rates were lower in well-controlled PWH (1.46 vs. 2.06/1000 PY). Metabolic factors associated with incident NSCLC risk included lower BMI at HIV diagnosis and cachexia history in both groups, while HDL and triglycerides were significant in non-well-controlled smokers only. Our findings that lower BMI at HIV diagnosis, history of cachexia among individuals with well-controlled HIV, and cachexia presence at diagnosis are associated with increased risk of developing NSCLC in PWH with a history of smoking have important implications.

Incidence and survival for oropharynx and non-oropharynx head and neck cancers among veterans living with HIV.

BACKGROUND: People living with HIV/AIDS (PLWH) have an excess risk for head and neck squamous cell carcinoma (HNSCC) compared to the general U.S. population, but little is known about HIV-specific risk factors associated with the incidence and outcomes HNSCC. We aim to identify clinical and HIV-specific risk factors associated with oropharyngeal and non-oropharyngeal HNSCC incidence and outcomes separately. METHODS: We constructed a retrospective cohort study of 45,052 PLWH aged 18 or above from the national Veteran Affairs (VA) Corporate Data from 1999 to 2015. We extracted demographic data and risk factor information, including history of alcohol abuse, smoking, CD4 count (cells/µl), and percent of follow-up time with undetectable HIV viral load as time-updated variables. We calculated the age-standardized incidence rates of oropharyngeal and non-oropharyngeal HNSCC and estimated adjusted hazard ratios (HR). We also examined overall survival using Kaplan-Meier curves and adjusted HR. RESULTS: The standardized incidence rate of oropharyngeal and non-oropharyngeal HNSCC in this veteran cohort of PLWH is 23.0 (95% confidence intervals (CIs): 17.1-28.9) and 55.4 (95% CI: 46.5-64.3) per 100,000 person-years, respectively. Nadir CD4 count ≤200 was associated with an increased risk of non-oropharyngeal HNSCC (HR: 1.78; 95% CI: 1.31-2.30 vs >200). Five-year overall survival of OPSCC (37.0%) was significantly lower than non-oropharyngeal HNSCC (49.1%). CONCLUSIONS: PLWH who receive care in the VA had higher age-adjusted HNSCC incidence rates than reported in the general population, suggesting that HIV and immunosuppression play a role. Additional studies should be conducted to study the interaction between HPV and HIV.

Risk and Predictors of Esophageal and Stomach Cancers in HIV-Infected Veterans: A Matched Cohort Study.

BACKGROUND: To evaluate the risks of esophageal and stomach carcinomas in people living with HIV (PLWH) compared with the general population and risk factors for these cancers in PLWH. SETTING: Retrospective cohort study in the Veterans Health Administration. METHODS: We compared incidence rates for esophageal and stomach cancers in 44,075 HIV-infected male veterans with those in a matched HIV-uninfected cohort (N = 157,705; 4:1 matched on age and HIV-index date). We used Cox regression models to estimate Hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with HIV infection and for cancer risk factors in PLWH. RESULTS: In unadjusted models, HIV infection was associated with increased risks of esophageal squamous cell carcinoma (ESCC; HR, 2.21; 95% CI: 1.47 to 3.13) and gastric cardia cancer (HR, 1.69; 95% CI: 1.00 to 2.85) but associated with lower risk of esophageal adenocarcinoma (EAC; HR, 0.48; 95% CI: 0.31 to 0.74). After adjusting for age, race/ethnicity, smoking and alcohol use, HIV infection remained statistically significantly associated with elevated risk for ESCC [adjusted hazard ratio (aHR), 1.58; 95% CI: 1.02 to 2.47], especially among HIV-infected patients with CD4 count ≤200 (aHR, 2.20; 95% CI: 1.35 to 3.60). HIV infection was not associated with risks of EAC (aHR, 0.82; 95% CI: 0.53 to 1.26), gastric cardia (aHR, 0.80; 95% CI: 0.33 to 1.94), or noncardia (aHR, 1.06; 95% CI: 0.61 to 1.84) cancers. Risk factors for these cancers in HIV-infected patients were otherwise similar to those in general population (eg, Helicobacter pylori for gastric noncardia cancer). CONCLUSION: HIV-infected individuals with low CD4 count are at highest risk for ESCC, but HIV infection was not independently associated with EAC or gastric cancer after adjusting for confounders.

Genotoxic, Metabolic, and Oxidative Stresses Regulate the RNA Repair Operon of Salmonella enterica Serovar Typhimurium.

The σ54 regulon in Salmonella enterica serovar Typhimurium includes a predicted RNA repair operon encoding homologs of the metazoan Ro60 protein (Rsr), Y RNAs (YrlBA), RNA ligase (RtcB), and RNA 3'-phosphate cyclase (RtcA). Transcription from σ54-dependent promoters requires that a cognate bacterial enhancer binding protein (bEBP) be activated by a specific environmental or cellular signal; the cognate bEBP for the σ54-dependent promoter of the rsr-yrlBA-rtcBA operon is RtcR. To identify conditions that generate the signal for RtcR activation in S Typhimurium, transcription of the RNA repair operon was assayed under multiple stress conditions that result in nucleic acid damage. RtcR-dependent transcription was highly induced by the nucleic acid cross-linking agents mitomycin C (MMC) and cisplatin, and this activation was dependent on RecA. Deletion of rtcR or rtcB resulted in decreased cell viability relative to that of the wild type following treatment with MMC. Oxidative stress from peroxide exposure also induced RtcR-dependent transcription of the operon. Nitrogen limitation resulted in RtcR-independent increased expression of the operon; the effect of nitrogen limitation required NtrC. The adjacent toxin-antitoxin module, dinJ-yafQ, was cotranscribed with the RNA repair operon but was not required for RtcR activation, although YafQ endoribonuclease activated RtcR-dependent transcription. Stress conditions shown to induce expression the RNA repair operon of Escherichia coli (rtcBA) did not stimulate expression of the S Typhimurium RNA repair operon. Similarly, MMC did not induce expression of the E. colirtcBA operon, although when expressed in S Typhimurium, E. coli RtcR responds effectively to the unknown signal(s) generated there by MMC exposure.IMPORTANCE Homologs of the metazoan RNA repair enzymes RtcB and RtcA occur widely in eubacteria, suggesting a selective advantage. Although the enzymatic activities of the eubacterial RtcB and RtcA have been well characterized, the physiological roles remain largely unresolved. Here we report stress responses that activate expression of the σ54-dependent RNA repair operon (rsr-yrlBA-rtcBA) of S Typhimurium and demonstrate that expression of the operon impacts cell survival under MMC-induced stress. Characterization of the requirements for activation of this tightly regulated operon provides clues to the possible functions of operon components in vivo, enhancing our understanding of how this human pathogen copes with environmental stressors.

Nivolumab Treatment for Cancers in the HIV-infected Population.

Nivolumab is a standard treatment option in several advanced malignancies, but safety and efficacy are still unknown in patients with human immunodeficiency virus (HIV) infection. We describe a case series of people living with HIV (PLWH) receiving nivolumab in the Veterans Health Administration (VA) and report responses and toxicities. We identified all PLWH who received nivolumab at any VA facility since 2000 in the Corporate Data Warehouse (CDW), which provides nationwide research access to VA electronic medical records. We identified 16 HIV-infected nivolumab recipients. The median number of nivolumab doses received was 6 (range, 1-32). Changes in CD4 count during therapy were variable, with 70% (7/10) of patients experiencing increases. Half of PLWH were treated for non-small-cell lung cancer; 2 for Hodgkin lymphoma (HL), 2 for renal cell carcinoma, and 4 for off-label cancers. For non-small-cell lung cancer, 7 patients had evaluable responses. Although 5 of 7 patients immediately progressed, 1 had a partial response and 1 had stable disease, which were both durable. Two of 16 (14%) PLWH had complete responses; both with HL (2/2 HL, 100%). The prevalence of immune-related adverse effects was 40% overall (6/15); 27% (4/15) had pneumonitis. To our knowledge, this is the largest case series reporting outcomes with nivolumab in PLWH. Outcomes were comparable with those seen in studies of HIV-uninfected patients, and particularly interesting for HL. The reason for the high proportions of immune-related adverse effects is unclear, but needs to be confirmed in larger studies.

Are Injection Site Reactions in Monoclonal Antibody Therapies Caused by Polysorbate Excipient Degradants?

Injection site reactions (ISRs) and other adverse side effects are commonly observed during therapy with biologics. These hypersensitivity-related side effects can vary from simple rash to life-threatening anaphylactic reaction and may be linked to the immunogenicity of the drug including formation of antidrug antibodies. Reactions can also occur as a consequence of excipients in the product. We report the case of a patient who developed erythematous ISRs to both commercial PCSK9i formulations and had to go off therapy even though efficacy was not impacted. Skin testing showed that the patient was reacting to the polysorbates. Polysorbates are added to stabilize the biotherapeutic. Polysorbates can also activate complement and lead to a range of acute hypersensitivity and systemic immunostimulation reactions. Oxidative degradation products can function as haptens by reacting with proteins at the injection site. Reactive degradation products may even form adducts with the biologic itself, creating a potential neoantigen. Further research is needed to understand the fundamental causes of ISRs. It is critical that only the highest quality raw material is used, and proper storage conditions are employed to minimize degradation of polysorbates in the product. Although complete elimination of ISRs is unlikely, all efforts must be made to minimize them.

Tracheoesophageal Prosthesis Use Is Associated With Improved Overall Quality of Life in Veterans With Laryngeal Cancer.

OBJECTIVES: Veterans have an increased risk of laryngeal cancer, yet their oncologic and functional outcomes remain understudied. We sought to determine the longitudinal impact of tracheoesophageal puncture and voice prosthesis on quality-of-life measures in veterans following total laryngectomy (TL). METHODS: We performed a cross-sectional analysis of TL patients (n = 68) treated at the Michael E. DeBakey Veterans Affairs Medical Center using the Voice Handicap Index (VHI), MD Anderson Dysphagia Index (MDADI), and University of Washington Quality of Life Index (UW-QOL). RESULTS: Using tracheoesophageal (TE) speech was associated with significantly better VHI, MDADI, and UW-QOL scores compared to other forms of communication. The association between TE speech use on VHI, MDADI, and UQ-QOL persisted even when the analysis was limited to patients with >5-year follow-up and was maintained on multivariate analysis that accounted for a history of radiation and laryngectomy for recurrent laryngeal cancer. CONCLUSIONS: Using tracheoesophageal speech after total laryngectomy is associated with durable improvements in quality of life and functional outcomes in veterans. Tracheoesophageal voice restoration should be attempted whenever technically feasible in patients that meet the complex psychosocial and physical requirements to appropriately utilize TE speech.

Disparities in Kaposi sarcoma incidence and survival in the United States: 2000-2013.

OBJECTIVE: Geographic and racial disparities may contribute to variation in the incidence and outcomes of HIV-associated cancers in the United States. METHOD: Using the Surveillance, Epidemiology, and End Results (SEER) database, we analyzed Kaposi sarcoma (KS) incidence and survival by race and geographic region during the combined antiretroviral therapy era. Reported cases of KS in men from 2000 to 2013 were obtained from 17 SEER cancer registries. Overall and age-standardized KS incidence rates were calculated and stratified by race and geographic region. We evaluated incidence trends using joinpoint analyses and calculated adjusted hazard ratios (aHR) for overall and KS-specific mortality using multivariable Cox proportional hazards models. RESULTS: Of 4,455 KS cases identified in men younger than 55 years (median age 40 years), the annual percent change (APC) for KS incidence significantly decreased for white men between 2001 and 2013 (APC -4.52, p = 0.02). The APC for AA men demonstrated a non-significant decrease from 2000-2013 (APC -1.84, p = 0.09). Among AA men in the South, however, APC has significantly increased between 2000 and 2013 (+3.0, p = 0.03). In addition, compared with white men diagnosed with KS during the same time period, AA men were also more likely to die from all causes and KS cancer-specific causes (aHR 1.52, 95% CI 1.34-1.72, aHR 1.49, 95% CI 1.30-1.72 respectively). CONCLUSION: Although overall KS incidence has decreased in the U.S., geographic and racial disparities in KS incidence and survival exist.

Risk factors for oropharynx cancer in a cohort of HIV-infected veterans.

OBJECTIVE: To evaluate HIV-related and other clinical risk factors associated with oropharynx cancer (OPSCC) in HIV-infected U.S. Veterans. METHODS: Retrospective cohort study utilizing Veterans Affairs HIV Clinical Case Registry (CCR) data from 1985 to 2010. Outcome was incident OPSCC as indicated by 1 inpatient or 2 outpatient ICD-9 codes. Cox proportional hazard models were used to determine hazard ratios (HR) and 95% confidence intervals (CI) for each risk factor on the time to OPSCC diagnosis. RESULTS: A total of 40,996 HIV-infected male veterans were included in the cohort with 97 cases of OPSCC. The age adjusted incidence rate was 23.2/100,000 [95% CI 17.8-29.2]. Age>50 (aHR=3.8, 95% CI 1.9-7.8), recent CD4<200 (aHR=3.8, 95% CI 2.0-7.3), and undetectable HIV viral loads 40-79% of the time (aHR=1.8, 95% CI 1.1-3.0) were associated with an increased risk of OPSCC. Era of HIV diagnosis, utilization of cART, nadir CD4 count, race, smoking history, and previous risk of HPV disease, including condyloma or invasive squamous cell carcinoma of the anus (SCCA) were not associated with increased risk of OPSCC. CONCLUSION: Patients who were older at beginning of follow up, had lower CD4 counts around the time of OPSCC diagnosis, and moderate HIV viral control during follow-up had an increased risk of OPSCC. Other HPV-related diseases such as SCCA and condyloma did not increase the risk for OPSCC.

Novel DNA Binding and Regulatory Activities for σ54 (RpoN) in Salmonella enterica Serovar Typhimurium 14028s.

The variable sigma (σ) subunit of the bacterial RNA polymerase (RNAP) holoenzyme, which is responsible for promoter specificity and open complex formation, plays a strategic role in the response to environmental changes. Salmonella enterica serovar Typhimurium utilizes the housekeeping σ70 and five alternative sigma factors, including σ54 The σ54-RNAP differs from other σ-RNAP holoenzymes in that it forms a stable closed complex with the promoter and requires ATP hydrolysis by an activated cognate bacterial enhancer binding protein (bEBP) to transition to an open complex and initiate transcription. In S. Typhimurium, σ54-dependent promoters normally respond to one of 13 different bEBPs, each of which is activated under a specific growth condition. Here, we utilized a constitutively active, promiscuous bEBP to perform a genome-wide identification of σ54-RNAP DNA binding sites and the transcriptome of the σ54 regulon of S. Typhimurium. The position and context of many of the identified σ54 RNAP DNA binding sites suggest regulatory roles for σ54-RNAP that connect the σ54 regulon to regulons of other σ factors to provide a dynamic response to rapidly changing environmental conditions.IMPORTANCE The alternative sigma factor σ54 (RpoN) is required for expression of genes involved in processes with significance in agriculture, bioenergy production, bioremediation, and host-microbe interactions. The characterization of the σ54 regulon of the versatile pathogen S. Typhimurium has expanded our understanding of the scope of the σ54 regulon and how it links to other σ regulons within the complex regulatory network for gene expression in bacteria.

Feasibility of identifying out of care HIV-positive patients in a hospital setting and enrolling them in a retention intervention.

BACKGROUND: The hospital setting provides an opportunity to re-engage people living with HIV (PLWH) in HIV care. We developed and implemented a protocol to identify PLWH in a hospital setting. The aim of the current study was to report on our strategy to recruit hospitalized HIV patients into an intervention study, and to report on lessons learned for future studies. METHODS: Our protocol was developed based on experience of our research staff in recruiting HIV patients as well as clinical input from providers and administrators on delivering care in hospitalized settings. We identified hospitalized PLWH between 2010 and 2013 who were potentially eligible for an intervention study. Patients were identified by review of electronic medical records and clinician referral, followed by in-person screening to confirm eligibility. We examined factors related to identifying and enrolling hospitalized patients, and documented lessons learned. RESULTS: Key strategies included systematic medical record review followed by in-person screening, collaboration with staff, and flexibility in recruitment logistics. We identified 1801 PLWH hospitalized during the 3-year study period. Eighty-four percent (n = 1514) met the met the inclusion criteria based on medical record review. Of these, 48% (n = 733) were ineligible. Among eligible patients, 59% (n = 460) were enrolled. Only 3% (n = 23) of eligible patients declined; 84% (n = 321) were not enrolled because they were discharged before enrollment. Lessons learned included (1) needing to identify patients and deliver the intervention before hospital discharge, (2) limiting the complexity of the intervention, and (3) having research staff available on weekends and after hours. CONCLUSIONS: Targeted recruitment of hospitalized populations is a feasible and productive approach for finding and engaging PLWH who are newly diagnosed or out of routine care.

Statin drugs decrease progression to cirrhosis in HIV/hepatitis C virus coinfected individuals.

INTRODUCTION: Chronic HIV/hepatitis C virus (HCV) coinfection carries increased risk of cirrhosis, hepatocellular carcinoma, and death. Due to anti-inflammatory properties, 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) inhibitors (statins) may be useful adjunctive therapy to reduce liver disease progression. METHODS: Clinical information was extracted from the Veterans Affairs HIV and HCV Clinical Case Registries (1999-2010). HIV-related variables included combination antiretroviral therapy era of diagnosis, CD4 cell count, and percentage time with undetectable HIV viral load. Metabolic variables included diabetes, low high-density lipoprotein (HDL), and hypertension. Statin use was measured as percentage time with active prescription (time-updated throughout the follow-up period). Cox proportional hazards analysis was used to determine risk factors for cirrhosis (International Classification of Diseases-9 or aminotransferase-to-platelet ratio index >2) overall and in groups stratified by alanine aminotransferase (ALT) level above and below 40 IU/l. RESULTS: The cohort included 5985 HIV/HCV coinfected veterans. The majority was black race, and the mean age at index date was 45 years. Statin use was significantly protective of cirrhosis for patients with ALT 40 IU/l or less; for every 30% increase in time on statin, there was a 32% decreased risk of developing cirrhosis (hazard ratio 0.68, 95% confidence interval 0.47-0.98). Diabetes and low HDL were significantly associated with cirrhosis in patients with ALT greater than 40 IU/l (hazard ratio 1.15, P < 0.04 and hazard ratio 1.3, P < 0.0001). CONCLUSION: Statin drug use is beneficial in mitigating the risk of liver disease progression for HIV/HCV coinfected patients without advanced liver disease. Low HDL and diabetes in coinfected patients with abnormal ALT have greater risk of cirrhosis development.

Modulating Salmonella Typhimurium's Response to a Changing Environment through Bacterial Enhancer-Binding Proteins and the RpoN Regulon.

Transcription sigma factors direct the selective binding of RNA polymerase holoenzyme (Eσ) to specific promoters. Two families of sigma factors determine promoter specificity, the σ(70) (RpoD) family and the σ(54) (RpoN) family. In transcription controlled by σ(54), the Eσ(54)-promoter closed complex requires ATP hydrolysis by an associated bacterial enhancer-binding protein (bEBP) for the transition to open complex and transcription initiation. Given the wide host range of Salmonella enterica serovar Typhimurium, it is an excellent model system for investigating the roles of RpoN and its bEBPs in modulating the lifestyle of bacteria. The genome of S. Typhimurium encodes 13 known or predicted bEBPs, each responding to a unique intracellular or extracellular signal. While the regulons of most alternative sigma factors respond to a specific environmental or developmental signal, the RpoN regulon is very diverse, controlling genes for response to nitrogen limitation, nitric oxide stress, availability of alternative carbon sources, phage shock/envelope stress, toxic levels of zinc, nucleic acid damage, and other stressors. This review explores how bEBPs respond to environmental changes encountered by S. Typhimurium during transmission/infection and influence adaptation through control of transcription of different components of the S. Typhimurium RpoN regulon.

A Randomized Trial to Test a Peer Mentor Intervention to Improve Outcomes in Persons Hospitalized With HIV Infection.

BACKGROUND: Few interventions have been shown to improve retention in human immunodeficiency virus (HIV) care, and none have targeted the hospitalized patient. Peer mentoring has not been rigorously tested. METHODS: We conducted a randomized, controlled clinical trial of a peer mentoring intervention. Eligible adults were hospitalized and were either newly diagnosed with HIV infection or out of care. The intervention included 2 in-person sessions with a volunteer peer mentor while hospitalized, followed by 5 phone calls in the 10 weeks after discharge. The control intervention provided didactic sessions on avoiding HIV transmission on the same schedule. The primary outcome was a composite of retention in care (completed HIV primary care visits within 30 days and between 31 and 180 days after discharge) and viral load (VL) improvement (≥1 log10 decline) 6 months after discharge. RESULTS: We enrolled 460 participants in 3 years; 417 were in the modified intent-to-treat analysis. The median age was 42 years; 74% were male; and 67% were non-Hispanic black. Baseline characteristics did not differ between the randomized groups. Twenty-eight percent of the participants in both arms met the primary outcome (P = .94). There were no differences in prespecified secondary outcomes, including retention in care and VL change. Post hoc analyses indicated interactions between the intervention and length of hospitalization and between the intervention and receipt of linkage services before discharge. CONCLUSIONS: Peer mentoring did not increase reengagement in outpatient HIV care among hospitalized, out-of-care persons. More intense and system-focused interventions warrant further study. CLINICAL TRIALS REGISTRATION: NCT01103856.