Harlen Hays

Associations between Anticholinergic Burden and Adverse Health Outcomes in Parkinson Disease

Background Elderly adults should avoid medications with anticholinergic effects since they may increase the risk of adverse events, including falls, delirium, and cognitive impairment. However, data on anticholinergic burden are limited in subpopulations, such as individuals with Parkinson disease (PD). The objective of this study was to determine whether anticholinergic burden was associated with adverse outcomes in a PD inpatient population. Methods Using the Cerner Health Facts® database, we retrospectively examined anticholinergic medication use, diagnoses, and hospital revisits within a cohort of 16,302 PD inpatients admitted to a Cerner hospital between 2000 and 2011. Anticholinergic burden was computed using the Anticholinergic Risk Scale (ARS). Primary outcomes were associations between ARS score and diagnosis of fracture and delirium. Secondary outcomes included associations between ARS score and 30-day hospital revisits. Results Many individuals (57.8%) were prescribed non-PD medications with moderate to very strong anticholinergic potential. Individuals with the greatest ARS score (≥4) were more likely to be diagnosed with fractures (adjusted odds ratio (AOR): 1.56, 95% CI: 1.29–1.88) and delirium (AOR: 1.61, 95% CI: 1.08–2.40) relative to those with no anticholinergic burden. Similarly, inpatients with the greatest ARS score were more likely to visit the emergency department (adjusted hazard ratio (AHR): 1.32, 95% CI: 1.10–1.58) and be readmitted (AHR: 1.16, 95% CI: 1.01–1.33) within 30-days of discharge. Conclusions We found a positive association between increased anticholinergic burden and adverse outcomes among individuals with PD. Additional pharmacovigilance studies are needed to better understand risks associated with anticholinergic medication use in PD.

Disparities in achieving and sustaining viral suppression among a large cohort of HIV-infected persons in care – Washington, DC*

ABSTRACT One goal of the HIV care continuum is achieving viral suppression (VS), yet disparities in suppression exist among subpopulations of HIV-infected persons. We sought to identify disparities in both the ability to achieve and sustain VS among an urban cohort of HIV-infected persons in care. Data from HIV-infected persons enrolled at the 13 DC Cohort study clinical sites between January 2011 and June 2014 were analyzed. Univariate and multivariate logistic regression were conducted to identify factors associated with achieving VS (viral load < 200 copies/ml) at least once, and Kaplan–Meier (KM) curves and Cox proportional hazards models were used to identify factors associated with sustaining VS and time to virologic failure (VL ≥ 200 copies/ml after achievement of VS). Among the 4311 participants, 95.4% were either virally suppressed at study enrollment or able to achieve VS during the follow-up period. In multivariate analyses, achieving VS was significantly associated with age (aOR: 1.04; 95%CI: 1.03–1.06 per five-year increase) and having a higher CD4 (aOR: 1.05, 95% CI 1.04–1.06 per 100 cells/mm3). Patients infected through perinatal transmission were less likely to achieve VS compared to MSM patients (aOR: 0.63, 95% CI 0.51–0.79). Once achieved, most participants (74.4%) sustained VS during follow-up. Blacks and perinatally infected persons were less likely to have sustained VS in KM survival analysis (log rank chi-square p ≤ .001 for both) compared to other races and risk groups. Earlier time to failure was observed among females, Blacks, publically insured, perinatally infected, those with longer standing HIV infection, and those with diagnoses of mental health issues or depression. Among this HIV-infected cohort, most people achieved and maintained VS; however, disparities exist with regard to patient age, race, HIV transmission risk, and co-morbid conditions. Identifying populations with disparate outcomes allows for appropriate targeting of resources to improve outcomes along the care continuum.

Development and validation of a bedside risk score for MRSA among patients hospitalized with complicated skin and skin structure infections

BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of complicated skin and skin structure infections (cSSSI). Patients with MRSA require different empiric treatment than those with non-MRSA infections, yet no accurate tools exist to aid in stratifying the risk for a MRSA cSSSI. We sought to develop a simple bedside decision rule to tailor empiric coverage more accurately.MethodsWe conducted a large multicenter (N=62 hospitals) retrospective cohort study in a US-based database between April 2005 and March 2009. All adult initial admissions with ICD-9-CM codes specific to cSSSI were included. Patients admitted with MRSA vs. non-MRSA were compared with regard to baseline demographic, clinical and hospital characteristics. We developed and validated a model to predict the risk of MRSA, and compared its performance via sensitivity, specificity and other classification statistics to the healthcare-associated (HCA) infection risk factors.ResultsOf the 7,183 patients with cSSSI, 2,387 (33.2%) had MRSA. Factors discriminating MRSA from non-MRSA were age, African-American race, no evidence of diabetes mellitus, cancer or renal dysfunction, and prior history of cardiac dysrhythmia. The score ranging from 0 to 8 points exhibited a consistent dose–response relationship. A MRSA score of 5 or higher was superior to the HCA classification in all characteristics, while that of 4 or higher was superior on all metrics except specificity.ConclusionsMRSA is present in 1/3 of all hospitalized cSSSI. A simple bedside risk score can help discriminate the risk for MRSA vs. other pathogens with improved accuracy compared to the HCA definition.

A One Health overview, facilitating advances in comparative medicine and translational research.

Table of contentsA1 One health advances and successes in comparative medicine and translational researchCheryl StroudA2 Dendritic cell-targeted gorilla adenoviral vector for cancer vaccination for canine melanomaIgor Dmitriev, Elena Kashentseva, Jeffrey N. Bryan, David T. CurielA3 Viroimmunotherapy for malignant melanoma in the companion dog modelJeffrey N. Bryan, David Curiel, Igor Dmitriev, Elena Kashentseva, Hans Rindt, Carol Reinero, Carolyn J. HenryA4 Of mice and men (and dogs!): development of a commercially licensed xenogeneic DNA vaccine for companion animals with malignant melanomaPhilip J. BergmanA5 Successful immunotherapy with a recombinant HER2-expressing Listeria monocytogenes in dogs with spontaneous osteosarcoma paves the way for advances in pediatric osteosarcomaNicola J. Mason, Josephine S. Gnanandarajah, Julie B. Engiles, Falon Gray, Danielle Laughlin, Anita Gaurnier-Hausser, Anu Wallecha, Margie Huebner, Yvonne PatersonA6 Human clinical development of ADXS-HER2Daniel O’ConnorA7 Leveraging use of data for both human and veterinary benefitLaura S. TremlA8 Biologic replacement of the knee: innovations and early clinical resultsJames P. StannardA9 Mizzou BioJoint Center: a translational success storyJames L. CookA10 University and industry translational partnership: from the lab to commercializationMarc JacobsA11 Beyond docking: an evolutionarily guided OneHealth approach to drug discoveryGerald J. Wyckoff, Lee Likins, Ubadah Sabbagh, Andrew SkaffA12 Challenges and opportunities for data applications in animal health: from precision medicine to precision husbandryAmado S. GuloyA13 A cloud-based programmable platform for healthHarlen D. HaysA14 Comparative oncology: One Health in actionAmy K. LeBlancA15 Companion animal diseases bridge the translational gap for human neurodegenerative diseaseJoan R. Coates, Martin L. Katz, Leslie A. Lyons, Gayle C. Johnson, Gary S. Johnson, Dennis P. O’BrienA16 Duchenne muscular dystrophy gene therapyDongsheng DuanA17 Polycystic kidney disease: cellular mechanisms to emerging therapiesJames P. CalvetA18 The domestic cat as a large animal model for polycystic kidney diseaseLeslie A. Lyons, Barbara GandolfiA19 The support of basic and clinical research by the Polycystic Kidney Disease FoundationDavid A. BaronA20 Using naturally occurring large animal models of human disease to enable clinical translation: treatment of arthritis using autologous stromal vascular fraction in dogsMark L. WeissA21 Regulatory requirements regarding clinical use of human cells, tissues, and tissue-based productsDebra A. WebsterA22 Regenerative medicine approaches to Type 1 diabetes treatmentFrancis N. KaranuA23 The zoobiquity of canine diabetes mellitus, man’s best friend is a friend indeed-islet transplantationEdward J. RobbA24 One Medicine: a development model for cellular therapy of diabetesRobert J. Harman

Trends in use of genotypic resistance testing and frequency of major drug resistance among antiretroviral-naive persons in the HIV Outpatient Study, 1999–2011

BACKGROUND Monitoring antiretroviral drug resistance can inform treatment recommendations; however, there are few such data from US patients before they initiate ART. METHODS We analysed data from HIV Outpatient Study (HOPS) participants from nine US HIV clinics who were diagnosed with HIV infection during 1999-2011. Using the IAS-USA December 2010 guidelines, we assessed the frequency of major drug resistance mutations (mDRMs) related to antiretroviral agents in viral isolates from patients who underwent commercial genotypic testing (GT) for resistance before initiating ART. We employed general linear regression models to assess factors associated with having undergone GT, and then factors associated with having mDRM. RESULTS Among 1531 eligible patients, 758 (49.5%) underwent GT before first ART, increasing from 15.5% in 1999-2002 to 75.9% in 2009-11 (P < 0.001). GT was carried out a median of 1.2 months after the diagnosis of HIV. In adjusted regression analyses, patients with pre-ART CD4+ T lymphocyte counts ≥200 cells/mm(3) or with HIV RNA levels >5.0 log10 copies/mL and those with a first HOPS visit in 2006 or later were significantly (P < 0.05) more likely to have undergone GT. Of the 758 patients, 114 (15.0%) had mDRMs; mutations relating to NRTIs, NNRTIs and PIs were present in 8.0%, 7.1% and 2.6%, respectively. There was no temporal change in the frequency of mDRM, and mDRMs were associated with an HIV RNA level <4.0 log10 copies/mL. CONCLUSIONS During 1999-2011, GT use among antiretroviral-naive patients became more common, but a quarter of patients in recent years remained untested. The frequency of mDRMs remained stable over time at about 15%.

CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 >750 cells/mm3 and mortality risk

OBJECTIVES We sought to evaluate associations between CD4 at ART initiation (AI), achieving CD4 >750 cells/mm(3) (CD4 >750), long-term immunological recovery and survival. METHODS This was a prospective observational cohort study. We analysed data from ART-naive patients seen in 1996-2012 and followed ≥3 years after AI. We used Kaplan-Meier (KM) methods and log-rank tests to compare time to achieving CD4 >750 by CD4 at AI (CD4-AI); and Cox regression models and generalized estimating equations to identify factors associated with achieving CD4 >750 and mortality risk. RESULTS Of 1327 patients, followed for a median of 7.9 years, >85% received ART for ≥75% of follow-up time; 64 died. KM estimates evaluating likelihood of CD4 >750 during 5 years of follow-up, stratified by CD4-AI <50, 50-199, 200-349, 350-499 and 500-750, were 20%, 25%, 56%, 80% and 87%, respectively (log-rank P < 0.001). In adjusted models, CD4-AI ≥200 (versus CD4-AI <200) was associated with achievement of CD4 >750 [adjusted HR (aHR) = 4.77]. Blacks were less likely than whites to achieve CD4 >750 (33% versus 49%, aHR = 0.77). Mortality rates decreased with increasing CD4-AI (P = 0.004 across CD4 strata for AIDS causes and P = 0.009 for non-AIDS death causes). Among decedents with CD4-AI ≥50, 56% of deaths were due to non-AIDS causes. CONCLUSIONS Higher CD4-AI resulted in greater long-term CD4 gains, likelihood of achieving CD4 >750, longer survival and decreased mortality regardless of cause. Over 80% of persons with CD4-AI ≥350 achieved CD4 >750 by 4 years while 75% of persons with CD4-AI <200 did not. These data confirm the hazards of delayed AI and support early AI.

Incidence of Hepatitis C Virus Infection in the Human Immunodeficiency Virus Outpatient Study Cohort, 2000-2013

Abstract Background. There are few recent studies of incident hepatitis C virus (HCV) infection among human immunodeficiency virus (HIV)-infected patients in the United States. Methods. We studied HIV Outpatient Study (HOPS) participants seen in 9 HIV-specialty clinics who had ≥1 clinical encounter during 2000–2013 and ≥2 HCV-related tests, the first of which was a negative HCV antibody test (Ab). Hepatitis C virus incident cases were identified by first positive HCV Ab, viral load, or genotype. We assessed rates of incident HCV overall, by calendar intervals, and by demographic and HIV risk strata, and we explored risk factors for incident HCV using Cox proportional hazards models. Results. The 1941 eligible patients (median age 40 years, 23% female, 61% men who had sex with men [MSM], and 3% persons who injected drugs [PWID]) experienced 102 (5.3%) incident HCV infections for an overall incidence of 1.07 (95% confidence interval [CI], 0.87–1.30) per 100 person-years (py). Hepatitis C virus incidence decreased from 1.83 in 2000–2003 to 0.88 in 2011–2013 (P = .024), with decreases observed (P < .05) among PWID and heterosexuals, but not among MSM. Overall, MSM comprised 59% of incident cases, and PWID were at most risk for incident HCV infection (adjusted hazard ratio [aHR] for PWID = 4.62 and 95% CI = 2.11–10.13; for MSM, aHR = 1.48 and 95% CI = 0.86–2.55 compared with heterosexuals). Conclusions. Among HIV-infected patients in care during 2000–2013, incidence of HCV infection exceeded 1 case per 100 py. Our findings support recommendations for annual HCV screenings for HIV-infected persons, including persons with only MSM risk, to enable HCV diagnosis and treatment for coinfected individuals.

Treatment of candidemia with echinocandins: data on hospital resource use from a real world setting.

Abstract Objective: Real-world data on patients treated with echinocandins for candidemia are limited. This study examined the effect of three echinocandin-based treatment regimens on resource utilization in patients with Candida infection. Research design and methods: A retrospective cohort study of patients hospitalized between 2005 and 2010 with a blood culture positive for Candida. Length of stay (LOS) following AF initiation (post-AF LOS) and total days with AF treatment were compared in patients treated with three different echinocandin regimens: patients with echinocandin only, patients who received fluconazole prior to an echinocandin (fluconazole-echinocandin), and patients who received an echinocandin prior to fluconazole (echinocandin-fluconazole). Generalized linear models were used to adjust for confounders. Results: A total of 647 patients met inclusion criteria. Patients treated with echinocandin only were more acutely ill, having more organ dysfunction and sepsis. Unadjusted post-AF LOS was significantly greater in the groups that received both echinocandin and fluconazole (mean, 13.1 days for echinocandin-only vs 25.5 and 21.2 days for fluconazole-echinocandin and echinocandin-fluconazole groups, respectively, p < 0.001). These groups also had a higher total number of days with AF orders. These differences remained after multivariate adjustment and in survivor-only analyses. Compared with echinocandin-only treatment, the average marginal effect of fluconazole-echinocandin and echinocandin-fluconazole regimens were associated with significantly longer adjusted post-AF LOS (by 7.2 days and 9.3 days, respectively, p < 0.001) and significantly more adjusted total AF days (by 5.3 days for fluconazole-echinocandin and 6.5 days for echinocandin-fluconazole patients, p < 0.001). Limitations included lack of visibility to specific reasons for therapy changes. Conclusions: Fluconazole before or after echinocandin was associated with significantly greater resource utilization than echinocandin use alone.

Sexually Transmitted Infections Among HIV-Infected Individuals in the District of Columbia and Estimated HIV Transmission Risk: Data From the DC Cohort

Abstract Background Washington, DC, has one of the highest rates of HIV infection in the United States. Sexual intercourse is the leading mode of HIV transmission, and sexually transmitted infections (STIs) are a risk factor for HIV acquisition and transmission. Methods We evaluated the incidence and demographic factors associated with chlamydia, gonorrhea, and syphilis among HIV-infected persons enrolled at 13 DC Cohort sites from 2011 to 2015. Using Poisson regression, we assessed covariates of risk for incident STIs. We also examined HIV viral loads (VLs) at the time of STI diagnosis as a proxy for HIV transmission risk. Results Six point seven percent (451/6672) developed an incident STI during a median follow-up of 32.5 months (4% chlamydia, 3% gonorrhea, 2% syphilis); 30% of participants had 2 or more STI episodes. The incidence rate of any STIs was 3.8 cases per 100 person-years (95% confidence interval [CI], 3.5–4.1); age 18–34 years, 10.8 (95% CI, 9.7–12.0); transgender women, 9.9 (95% CI, 6.9–14.0); Hispanics, 9.2 (95% CI, 7.2–11.8); and men who have sex with men (MSM), 7.7 (95% CI, 7.1–8.4). Multivariate Poisson regression showed younger age, Hispanic ethnicity, MSM risk, and higher nadir CD4 counts to be strongly associated with STIs. Among those with an STI, 41.8% had a detectable VL within 1 month of STI diagnosis, and 14.6% had a VL ≥1500 copies/mL. Conclusions STIs are highly prevalent among HIV-infected persons receiving care in DC. HIV transmission risk is considerable at the time of STI diagnosis. Interventions toward risk reduction, antiretroviral therapy adherence, and HIV virologic suppression are critical at the time of STI evaluation.

Outcomes associated with conventional versus lipid-based formulations of amphotericin B in propensity-matched groups

Background Lipid-based formulations of amphotericin B (LF-AMB) are indicated for treatment of invasive fungal infections in patients intolerant to conventional amphotericin B (CAB) or with refractory infections. Physicians still may choose to administer CAB to such patients. We described the use of CAB and LF-AMB in this population and quantified differences in post-amphotericin B length of stay (LOS) among survivors and hospital mortality in matched patients. Methods Data were extracted from Health Facts (Cerner Corporation, Kansas City, MO, USA) for a retrospective cohort analysis. Inpatients aged ≥18 years with evidence of fungal infection and with orders for LF-AMB or CAB on ≥2 days from January 2001 to June 2010 were identified. Patients were required to have renal insufficiency or other relative contraindications to use of CAB, exposure to nephrotoxic agents, or evidence of a CAB-refractory infection. Multilevel (hierarchical) mixed-effects logistic regression was used to determine factors associated with initial exposure to LF-AMB versus CAB. Multivariate adjustment of outcomes was done using propensity score matching. Results 655 patients were identified: 322 patients initiated therapy with CAB and 333 initiated treatment with LF-AMB. Compared to those initiating CAB, patients initiating LF-AMB had greater acuity and underlying disease severity. In unadjusted analyses, hospital mortality was significantly higher in the LF-AMB group (32.2% versus 23.7%; P = 0.02). After propensity score matching and covariate adjustment, mortality equalized and observed differences in LOS after amphotericin B initiation decreased. Conclusion Among patients at risk for amphotericin B toxicity, differences between CAB and LF-AMB seen in crude outcomes analyses relate to channeling of sicker patients to initiate treatment with LF-AMB. Failing to account for differences among patients that drive clinical decision-making will result in inaccurate conclusions about the real-world effectiveness of different amphotericin B formulations.