The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants.

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Novel Therapeutics for Malaria.

Malaria is a potentially fatal disease caused by protozoan parasites of the genus Plasmodium. It is responsible for significant morbidity and mortality in endemic countries of the tropical and subtropical world, particularly in Africa, Southeast Asia, and South America. It is estimated that 247 million malaria cases and 619,000 deaths occurred in 2021 alone. The World Health Organization's (WHO) global initiative aims to reduce the burden of disease but has been massively challenged by the emergence of parasitic strains resistant to traditional and emerging antimalarial therapy. Therefore, development of new antimalarial drugs with novel mechanisms of action that overcome resistance in a safe and efficacious manner is urgently needed. Based on the evolving understanding of the physiology of Plasmodium, identification of potential targets for drug intervention has been made in recent years, resulting in more than 10 unique potential anti-malaria drugs added to the pipeline for clinical development. This review article will focus on current therapies as well as novel targets and therapeutics against malaria.

Hydroxychloroquine and Risk of Long QT Syndrome in Rheumatoid Arthritis: A Veterans Cohort Study With Nineteen-Year Follow-up.

OBJECTIVE: Recent evidence suggests that hydroxychloroquine use is not associated with higher 1-year risk of long QT syndrome (LQTS) in patients with rheumatoid arthritis (RA). Less is known about its long-term risk, the examination of which was the objective of this study. METHODS: We conducted a propensity score-matched active-comparator safety study of hydroxychloroquine in 8,852 veterans (mean age 64 ± 12 years, 14% women, 28% Black) with newly diagnosed RA. A total of 4,426 patients started on hydroxychloroquine and 4,426 started on another nonbiologic disease-modifying antirheumatic drug (DMARD) and were balanced on 87 baseline characteristics. The primary outcome was LQTS during 19-year follow-up through December 31, 2019. RESULTS: Incident LQTS occurred in 4 (0.09%) and 5 (0.11%) patients in the hydroxychloroquine and other DMARD groups, respectively, during the first 2 years. Respective 5-year incidences were 17 (0.38%) and 6 (0.14%), representing 11 additional LQTS events in the hydroxychloroquine group (number needed to harm 403; [95% confidence interval (95% CI)], 217-1,740) and a 181% greater relative risk (95% CI 11%-613%; P = 0.030). Although overall 10-year risk remained significant (hazard ratio 2.17; 95% CI 1.13-4.18), only 5 extra LQTS occurred in hydroxychloroquine group over the next 5 years (years 6-10) and 1 over the next 9 years (years 11-19). There was no association with arrhythmia-related hospitalization or all-cause mortality. CONCLUSIONS: Hydroxychloroquine use had no association with LQTS during the first 2 years after initiation of therapy. There was a higher risk thereafter that became significant after 5 years of therapy. However, the 5-year absolute risk was very low, and the absolute risk difference was even lower. Both risks attenuated during longer follow-up. These findings provide evidence for long-term safety of hydroxychloroquine in patients with RA.

Short Communication: A Pilot Study of the Effects of Losartan Versus Placebo on Pneumoproteins in HIV: A Secondary Analysis of a Randomized Double Blind Study.

HIV is an independent risk factor for lung disease, including chronic obstructive pulmonary disease (COPD) and emphysema. Angiotensin receptor blockers may be beneficial in COPD and emphysema through pathways that have been implicated in HIV-related lung disease. We performed a randomized comparison of the effects of losartan versus placebo on the plasma concentrations of the pneumoproteins, surfactant protein D (SPD) and club cell secretory protein (CCSP), in people living with HIV (PLWH). A total of 108 PLWH were included (52 assigned to losartan and 56 assigned to placebo). We found no difference in the change from baseline in log2 concentrations of CCSP or SPD over 1 year of follow-up. For SPD, we found a strong interaction by CD4+ counts, where those with CD4+ counts >350 cells/mm3 treated with losartan had more reduction (improvement) in SPD concentration than those treated with placebo (p value for interaction <.001). In conclusion, we did not find a beneficial effect of losartan on pneumoprotein concentrations in PLWH, but PLWH with higher CD4+ counts may have improvement in SPD when treated with losartan.

Cardiovascular Safety of Hydroxychloroquine in US Veterans With Rheumatoid Arthritis.

OBJECTIVE: Hydroxychloroquine (HCQ) may prolong the QT interval, a risk factor for torsade de pointes, a potentially fatal ventricular arrhythmia. This study was undertaken to examine the cardiovascular safety of HCQ in patients with rheumatoid arthritis (RA). METHODS: We conducted an active comparator safety study of HCQ in a propensity score-matched cohort of 8,852 US veterans newly diagnosed as having RA between October 1, 2001 and December 31, 2017. Patients were started on HCQ (n = 4,426) or another nonbiologic disease-modifying antirheumatic drug (DMARD; n = 4,426) after RA diagnosis, up to December 31, 2018, and followed up for 12 months after therapy initiation, up to December 31, 2019. RESULTS: Patients had a mean ± SD age of 64 ± 12 years, 14% were women, and 28% were African American. The treatment groups were balanced with regard to 87 baseline characteristics. There were 3 long QT syndrome events (0.03%), 2 of which occurred in patients receiving HCQ. Of the 56 arrhythmia-related hospitalizations (0.63%), 30 occurred in patients in the HCQ group (hazard ratio [HR] associated with HCQ 1.16 [95% confidence interval (95% CI) 0.68-1.95]). All-cause mortality occurred in 144 (3.25%) and 136 (3.07%) of the patients in the HCQ and non-HCQ groups, respectively (HR associated with HCQ 1.06 [95% CI, 0.84-1.34]). During the first 30 days of follow-up, there were no long QT syndrome events, 2 arrhythmia-related hospitalizations (none in the HCQ group), and 13 deaths (6 in the HCQ group). CONCLUSION: Our findings indicate that the incidence of long QT syndrome and arrhythmia-related hospitalization is low in patients with RA during the first year after the initiation of HCQ or another nonbiologic DMARD. We found no evidence that HCQ therapy is associated with a higher risk of adverse cardiovascular events or death.

Understanding Demographic Risk Factors for Adverse Outcomes in COVID-19 Patients: Explanation of a Deep Learning Model.

This study was to understand the impacts of three key demographic variables, age, gender, and race, on the adverse outcome of all-cause hospitalization or all-cause mortality in patients with COVID-19, using a deep neural network (DNN) analysis. We created a cohort of Veterans who were tested positive for COVID-19, extracted data on age, gender, and race, and clinical characteristics from their electronic health records, and trained a DNN model for predicting the adverse outcome. Then, we analyzed the association of the demographic variables with the risks of the adverse outcome using the impact scores and interaction scores for explaining DNN models. The results showed that, on average, older age and African American race were associated with higher risks while female gender was associated with lower risks. However, individual-level impact scores of age showed that age was a more impactful risk factor in younger patients and in older patients with fewer comorbidities. The individual-level impact scores of gender and race variables had a wide span covering both positive and negative values. The interaction scores between the demographic variables showed that the interaction effects were minimal compared to the impact scores associated with them. In conclusion, the DNN model is able to capture the non-linear relationship between the risk factors and the adverse outcome, and the impact scores and interaction scores can help explain the complicated non-linear effects between the demographic variables and the risk of the outcome.

Losartan to reduce inflammation and fibrosis endpoints in HIV disease.

BACKGROUND: Persistent inflammation and incomplete immune recovery among persons with HIV (PHIV) are associated with increased disease risk. We hypothesized that the angiotensin receptor blocker (ARB) losartan would reduce inflammation by mitigating nuclear factor (NF)κB responses and promote T-cell recovery via inhibition of transforming growth factor-beta (TGFß)-mediated fibrosis. METHODS: Losartan (100 mg) versus placebo over 12 months was investigated in a randomized (1 : 1) placebo-controlled trial, among PHIV age at least 50 years, receiving antiretroviral therapy (ART), with HIV RNA less than 200 copies/ml and CD4+ cell count 600 cells/µl or less. Inflammation, fibrosis and myocardial biomarkers were measured in blood using ELISA, electrochemiluminescence and immunoturbidimetric methods, and T-cell and monocyte phenotypes were assessed with flow cytometry among a subset of participants. Changes over follow-up in (log-2 transformed) biomarkers and cell phenotypes (untransformed) were compared between losartan and placebo arms using linear mixed models. RESULTS: Among 108 PHIV (n = 52 to losartan; n = 56 to placebo), 97% had a month 12 visit. Median age was 57 years and baseline CD4+ cell count was 408 cells/µl. Losartan treatment was not associated with an improvement in interleukin-6 levels, or other blood measures of inflammation, immune activation, fibrosis activity or myocardial function. CD4+ and CD8+ T cells also did not differ by treatment group. Losartan reduced SBP and DBP by 6 and 5 mmHg, respectively. CONCLUSION: Among older PHIV with viral suppression, losartan did not improve blood measures of inflammation nor T-cell immune recovery. Losartan treatment is unlikely to reduce inflammation associated comorbidities to a clinically meaningful degree, beyond the benefits from lowering blood pressure. CLINICALTRIALSGOV: NCT02049307.

Preoperative antibiotics and cardiovascular implantable electronic device infection: A cohort study in veterans.

BACKGROUND: Cefazolin is used as standard preoperative prophylaxis for a variety of surgical procedures that involve the skin. In contrast, vancomycin is recommended for a minority of patients, specifically those with an IgE-mediated allergy to beta-lactams and considered in patients with known colonization with methicillin-resistant Staphylococcus aureus or at high risk for such. Vancomycin, however, has been overprescribed, has nephrotoxicity risk, and may be less effective due to its inferior coverage of methicillin-susceptible S. aureus and lack of Gram-negative coverage. This study was performed to assess whether vancomycin use was associated with an increased incidence of cardiovascular implantable electronic device infection (CIEDI) as compared to that of cefazolin or other antistaphylococcal beta-lactam antibiotics. METHODS: The VA Informatics and Computing Infrastructure database, which included all veterans who underwent CIED placement or revision between 2008 and 2015, was used. A logistic regression model was constructed to estimate the adjusted odds of CIEDI. RESULTS: Overall, 10,454 CIED procedures were included, and 98% of them were performed in men with a mean age of 71 ± 12 years. The logistic regression analysis showed that vancomycin use alone or in combination with other antibiotics was associated with an increased risk of CIEDI (odds ratio 2.99 [1.76-5.06], P-value < 0.001), after controlling for other effects. CONCLUSIONS: Our study revealed that among patients who received surgical site infection prophylaxis for CIED placement or revision, there was: (1) an unanticipated high rate of vancomycin use, and (2) a threefold increase in the incidence of subsequent CIEDI among vancomycin recipient.

Inflammation Associates With Impaired Small Arterial Elasticity Early in HIV Disease.

We estimated small arterial elasticity and used linear regression to evaluate its association with inflammatory biomarkers among antiretroviral therapy-naïve, HIV-positive patients with high CD4+ counts. After adjustment, high-sensitivity C-reactive protein and interleukin-6 were inversely associated with small arterial elasticity. These data suggest that systemic inflammation may contribute to vascular dysfunction even in very early HIV disease.

Antimicrobial Stewardship in Long-Term Care Facilities: Approaches to Creating an Antibiogram when Few Bacterial Isolates Are Cultured Annually.

Antibiograms are important clinical tools to report and track antibiotic susceptibility and help guide empiric antimicrobial therapy. Antibiograms support compliance with antimicrobial stewardship (AMS) requirements from the Centers for Medicare and Medicaid Services and are in line with recommendations from the Centers for Disease Control and Prevention Core Elements of AMS for nursing homes/long-term care facilities (LTCFs). Unlike most acute-care settings, LTCFs are challenged in creating antibiograms because of the low number of bacterial isolates collected annually. Determining the best methodology for creating clinically useful antibiograms for LTCFs needs to be explored. Possible approaches include (1) extending the isolate data beyond 1 year, (2) combining isolate data from the same geographic region, (3) using a nearby acute-care facility's antibiogram as a proxy, or (4) collapsing isolate data. This article discusses the benefits and limitations of each approach.

Statin use and the risk of cardiovascular implantable electronic device infection: A cohort study in a veteran population.

BACKGROUND: The rate of cardiovascular implantable electronic device infection (CIEDI) has increased, despite the use of perioperative antibiotics at the time of device placement or revision. This is due, in part, to the presence of multiple comorbid conditions in an elderly population, in general, who require CIED. Statins may have an antibacterial effect, although there is currently no evidence that the likelihood of CIEDI has been impacted by statin use. METHODS: A retrospective cohort study was performed to assess whether statins are associated with a reduced risk of CIEDI. The VA Informatics and Computing Infrastructure (VINCI) database, which includes all veterans who underwent CIED placement between 2008 and 2015, was used. A logistic regression model was constructed to estimate the adjusted risk of CIEDI among patients who were receiving statins after adjusting for confounding factors. RESULTS: Overall, 18,970 CIED procedures were included, and 98% of them were performed in men with a mean age of 71 ± 11 years. The rate of diabetes mellitus, heart failure, advanced chronic kidney diseases, CIEDI, positive methicillin-resistant Staphylococcus aureus nasal colonization, and statin use were 23%, 15.7%, 3.3%, 1.14%, 12.6%, and 56%, respectively. The logistic regression analysis showed that statins were significantly associated with a reduced risk of CIEDI; after controlling for other effects, the reduction was 66% (odds ratio 0.34 [0.2-0.59], P-value < 0.001). The effect of statins was confirmed by propensity score analysis. CONCLUSIONS: Our study showed that among patients receiving statins who had undergone CIED placement, there was a 66% reduction in subsequent CIEDI.

Internal Medicine Resident Perspectives Regarding Broad-Spectrum Antibiotic Usage.

Focus groups held with internal medicine residents discussed their perspectives regarding broad-spectrum antibiotic (BSA) usage. Residents knew of BSA-associated adverse events, but they did not associate such events with increased patient morbidity and mortality, and they were more likely to use BSA in situations with diagnostic uncertainty and sick patients.

Reduction of Clinical Culture Contamination in an Inpatient Medical Unit by Revisiting Microbiology Education.

Clinical culture contaminations delay the correct diagnosis, result in repeat testing, and may extend the length of a hospital stay. A simple educational session reminding providers of the ubiquitous presence of bacteria on the skin and in our environment, led to a significant decrease in contaminated cultures (16.9% versus 10.9%, p = 0.03). J Contin Educ Nurs. 2016;47(10):446-448.

Tuberculosis reactivation in hepatocellular carcinoma: association with transarterial chemoembolization.

Transarterial chemoembolization (TACE) is an important therapeutic option for patients with hepatocellular carcinoma (HCC). We discuss five patients with HCC and tuberculosis (TB) reactivation following TACE. Screening patients for latent TB infection at diagnosis of cirrhosis or HCC should be considered because of the immunosuppression inherent in both the diseases and their treatments.

Active injection drug-abuse offsets healthcare engagement in HIV-infected patients.

Active injection drug use (IDU) is a behavior with the potential to offset healthcare engagement for those with HIV. At the Washington DC Veterans Affairs Medical Center, we identified 316 patients with a history of addiction during an 11-year period while actively engaged in routine visits to our HIV-primary care clinic. Among all IDU, active-abuse was determined in 141/316 (45 %). There were 120 clinically relevant blood stream infection (BSI) episodes. HIV/HCV co-infection (95 %) and use of antiretroviral therapy (76 %) were common at the time of BSI. The majority of BSIs occurred among those with active-IDU (72/120, 60 %). Active-IDU behavior was associated with more thrombotic disease (12 vs. 2 %, P = 0.001) and more frequent hospitalization (1.1/year ± 1.2 vs. 0.8/year ± 1.1, P = 0.03). When compared to drug-users with no active injection practices or those with remote IDU, active-IDU was associated with an increase in all-cause mortality (43 vs. 27 %, P = 0.003) and a decrease in age-adjusted survival (HR 1.7, CI 1.16-2.51, P = 0.007). Addressing addiction has the potential to impact avoidable medical complications and contribute to the continued, overall health of patients linked to HIV-care.

Using a board game to reinforce learning.

Experiential gaming strategies offer a variation on traditional learning. A board game was used to present synthesized content of fundamental catheter care concepts and reinforce evidence-based practices relevant to nursing. Board games are innovative educational tools that can enhance active learning.

Changing Behavior among Nurses to Track Indwelling Urinary Catheters in Hospitalized Patients.

Catheter-associated urinary tract infections (CAUTIs) are preventable complications of hospitalization. An interdisciplinary team developed a curriculum to increase awareness of the presence of indwelling urinary catheters (IUCs) in hospitalized patients, addressed practical, primarily nurse-controlled inpatient risk-reduction interventions, and promoted the use of the IUC labels ("tags"). Five thirty-minute educational sessions were cycled over three daily nursing shifts on two inpatient medical floors over a 1-year period; participants were surveyed (n = 152) to elicit feedback and provide real-time insight on the learning objectives. Nurse self-reported IUC tagging was early and sustained; after the IUC tag was introduced, there was a significant increase in tagging reported by the end of the block of educational sessions (from 46.2% to 84.6%, P = 0.001). Early engagement combined with a targeted educational initiative led to increased knowledge, changes in behavior, and renewed CAUTI awareness in hospitalized patients with IUCs. The processes employed in this small-scale project can be applied to broader, hospitalwide initiatives and to large-scale initiatives for healthcare interventions. As first-line providers with responsibility for the placement and daily maintenance of IUCs, nurses are ideally positioned to implement efforts addressing CAUTIs in the hospital setting.

Candidemia outcomes not improved with statin use.

Candidemia is an important cause of morbidity and mortality. As statins interfere with yeast membrane synthesis, we assessed whether use of statins during candidemia may cause differences in clinical outcomes. A retrospective review of 124 candidemia episodes during 2003-2008 in which all-cause and attributable mortality, length of stay and level of care were compared for patients who received and those who did not receive statins. A total of 124 candidemia events were observed involving 14 patients on statins and 110 without statins. Overall mortality in candidemia cases was 46%, but only 2% was attributed to candidemia. No differences were observed in clinical outcomes for the two groups of patients. During the last 2-year period of our study, there were higher rates of candidemia caused by non-C. albicans Candida spp., particularly those due to C. glabrata and C. parapsilosis. In conclusion, statin use during candidemia did not alter mortality, length of stay, or intensive care requirement of our patients, despite higher rates of non-C. albicans Candida species isolated during the last 2 years of our study.

Inflammation predicts changes in high-density lipoprotein particles and apolipoprotein A1 following initiation of antiretroviral therapy.

BACKGROUND: The effects of HIV infection and antiretroviral therapy (ART) on usual lipid levels have been reported. The effects of initiating versus deferring ART on high-density and low-density lipoprotein particle (HDL-P and LDL-P, respectively) concentrations and apolipoprotein (Apo) levels are not well described. METHODS: In a subgroup of participants not taking ART at study entry who were randomized in the Strategies for Management of Antiretroviral Therapy (SMART) trial to immediately initiate ART ('viral suppression group') or to defer it ('drug conservation group'), lipoprotein particle concentrations and ApoA1 and ApoB levels were measured at baseline and at 2 and 6 months following randomization. RESULTS: Compared with drug conservation group (n = 126), HDL-P and ApoA1 levels increased among viral suppression participants (n = 128) after starting ART. At 6 months, viral suppression participants had 13% higher total HDL-P (P < 0.001) and 9% higher ApoA1 (P < 0.001). LDL-P, very low density lipoprotein particle, and ApoB did not differ significantly between the viral suppression and drug conservation groups. Among viral suppression participants, predictors of HDL-P and ApoA1 increases included baseline levels of high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL-6), but not HIV RNA level, CD4 cell count, or traditional cardiovascular disease risk factors. The effect of starting ART on changes in HDL-P and ApoA1 was greater for those with higher versus lower baseline levels of IL-6 (P = 0.001 and 0.08, respectively, for interaction) or hsCRP (P = 0.01 and 0.04, respectively, for interaction). CONCLUSION: HDL-P and ApoA1 increase following ART initiation, to a degree that depends on the degree of inflammation present at entry. These findings suggest that activation of inflammatory pathways contribute to HIV-associated changes in HDL.

Present and past influences on current smoking among HIV-positive male veterans.

INTRODUCTION: Cigarette smoking has become an important influence of morbidity and mortality for HIV-positive individuals in the era of highly active antiretroviral therapy. Although smoking is common among military personnel and veterans, the lasting impact of military service on smoking at a later stage of life has not been examined. The current study investigated present and past influences on current smoking among HIV-positive male veterans. METHODS: Participants were 200 HIV-positive men served by the Veterans Affairs Medical Center. A survey was administered via audio-enhanced computer-assisted self-interview, and additional information was extracted from the computerized patient record system. RESULTS: Logistic regression was performed to test hypotheses concerning the participants' current situations as well as characteristics of their past military service. Having smokers in one's environment, being more depressed, and having used alcohol or drugs were associated with having smoked in the previous 30 days, whereas stronger endorsement of attitudes stating adverse effects of smoking was linked to lower likelihood of smoking. Neither having been in a military conflict nor the length of the military service was significantly related to current smoking. CONCLUSIONS: Remote experiences in the military did not have a sustained effect on smoking behavior years later. Implications of this study for the development of smoking cessation programs targeting HIV-positive veterans include the importance of altering attitudes about tobacco, treating underlying depression, addressing social influence, decreasing substance use, and increasing awareness of the heightened vulnerability to a variety of negative consequences of smoking among infected individuals.