Publications by authors named "Robert Kalayjian"

55 Publications

Naïve CD4+ T Cell Lymphopenia and Apoptosis in Chronic Hepatitis C Virus Infection Is Driven by the CD31+ Subset and Is Partially Normalized in Direct-Acting Antiviral Treated Persons.

Front Immunol 2021 12;12:641230. Epub 2021 Apr 12.

Department of Pathology, Case Western Reserve University, Cleveland, OH, United States.

Background: The mechanisms underlying naïve CD4+ lymphopenia during chronic Hepatitis C Virus (HCV) infection are unclear. Whether direct-acting antiviral (DAA) therapy restores peripheral naïve CD4+ T cell numbers and function is unknown.

Methods: We enumerated frequencies and counts of peripheral naïve CD4+, CD4+CD31+ and CD4+CD31- T cells by flow cytometry in a cross sectional analysis comparing chronic HCV infected (n=34), DAA-treated(n=29), and age-range matched controls (n=25), as well as in a longitudinal cohort of HCV DAA treated persons (n=16). The cross-sectional cohort was stratified by cirrhosis state. Cell apoptosis/survival (AnnexinV+7AAD+/BCL-2 labeling) and cell cycle entry (Ki67 expression) of CD31+ and CD31- naïve CD4+ T cells was analyzed directly and following 3 and 5 days of culture with media, interleukin (IL) -7 or CD3/CD28 activator.

Results: In the cross-sectional cohort, naïve CD4+ proportions were lower in chronic HCV infected persons compared to controls and DAA-treated persons, an effect in part attributed to cirrhosis. Age was associated with naïve cell counts and proportions in HCV infected and treated persons as well. Naïve CD4+ cell proportions negatively correlated with plasma levels of soluble CD14 following therapy in DAA-treated persons. Naïve CD4+ cells from HCV infected persons exhibited greater direct apoptosis and cell-cycling compared to cells from DAA-treated persons and controls, and this was localized to the CD4+CD31+ subset. On the other hand, no remarkable differences in expression of BCL-2 or IL-7 Receptor (CD127) at baseline or following media or IL7 containing culture were observed. In the longitudinal cohort, naïve CD4+CD31+/CD31- ratio tended to increase 24 weeks after DAA therapy initiation.

Conclusions: Activation and apoptosis of peripheral naïve CD4+CD31+ T cells appear to contribute to naïve CD4+ lymphopenia in chronic HCV infection, and this defect is partially reversible with HCV DAA therapy. Age and cirrhosis -associated naïve CD4+ lymphopenia is present both before and after HCV DAA therapy. These findings have implications for restoration of host immune function after DAA therapy.
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http://dx.doi.org/10.3389/fimmu.2021.641230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075159PMC
April 2021

T-cell Activation Is Correlated With Monocyte Activation in HCV/HIV Coinfection and Declines During HCV Direct-Acting Antiviral Therapy.

Open Forum Infect Dis 2021 Apr 18;8(4):ofab079. Epub 2021 Feb 18.

Department of Pathology, VA Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.

Background: Immune activation markers associate with morbidity and mortality in HIV and hepatitis C virus (HCV) infection. We investigated how T-cell and monocyte activation are related over the course of HCV direct-acting antiviral (DAA) therapy during HCV/HIV coinfection.

Methods: Peripheral blood mononuclear cells from AIDS Clinical Trials Group (ACTG) A5329 participants and a single-site separate cohort treated with DAAs were analyzed for central memory (CM)/effector memory (EM) T-cell subsets, monocyte subsets, and cell activation (CD38 and HLA-DR expression) before, during, and after therapy.

Results: Before therapy, classical and inflammatory monocyte subset HLA-DR expression positively correlated with absolute counts and frequencies of CD38HLA-DR-expressing CD4 and CD8 T cells and corresponding CM and EM subsets. After therapy initiation, CD38HLA-DR co-expression on CD4 and CD8 memory T cells decreased by 12 weeks and 36 weeks, and plasma sCD14 positively correlated with CD38HLA-DR CD4 and CD4CM T-cell frequencies. Monocyte subset activation remained similar over time.

Conclusions: During HCV/HIV coinfection, memory T-cell activation is associated with monocyte subset activation, consistent with related underlying mechanisms. Following therapy initiation, memory T-cell, but not monocyte, activation decreased. Residual CD4 T-cell activation after therapy completion is associated with sCD14, potentially linking the remaining CD4 T-cell activation to residual factors driving activation in antiretroviral therapy-controlled HIV.
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http://dx.doi.org/10.1093/ofid/ofab079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043262PMC
April 2021

Plasma Citrate and Succinate Are Associated with Neurocognitive Impairment in Older People with HIV.

Clin Infect Dis 2021 Feb 10. Epub 2021 Feb 10.

Department of Internal Medicine, Division of Infectious Disease, MetroHealth Medical Center, Cleveland, OH, USA.

Background: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH.

Methods: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed.

Results: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (p=0.03), 0.07 SD lower time-updated NPZ-4 score (p=0.01), and 0.02 m/s slower time-updated gait speed (p<0.0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (p≤0.01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline.

Conclusions: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.
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http://dx.doi.org/10.1093/cid/ciab107DOI Listing
February 2021

Bisphosphonates in Perinatally Infected Children and Adolescents With Human Immunodeficiency Virus: Targeting Puberty.

Clin Infect Dis 2020 08;71(5):1289-1291

Department of Pediatrics and Medicine, University Hospitals Cleveland Medical Center and Case Western Reserve University, Cleveland, Ohio, USA.

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http://dx.doi.org/10.1093/cid/ciz962DOI Listing
August 2020

The Pitt Bacteremia Score Predicts Mortality in Nonbacteremic Infections.

Clin Infect Dis 2020 04;70(9):1826-1833

Division of Infectious Diseases, University of North Carolina, Chapel Hill.

Background: Predicting mortality risk in patients is important in research settings. The Pitt bacteremia score (PBS) is commonly used as a predictor of early mortality risk in patients with bloodstream infections (BSIs). We determined whether the PBS predicts 14-day inpatient mortality in nonbacteremia carbapenem-resistant Enterobacteriaceae (CRE) infections.

Methods: Patients were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and Other Enterobacteriaceae, a prospective, multicenter, observational study. We estimated risk ratios to analyze the predictive ability of the PBS overall and each of its components individually. We analyzed each component of the PBS in the prediction of mortality, assessed the appropriate cutoff value for the dichotomized score, and compared the predictive ability of the qPitt score to that of the PBS.

Results: In a cohort of 475 patients with CRE infections, a PBS ≥4 was associated with mortality in patients with nonbacteremia infections (risk ratio [RR], 21.9; 95% confidence interval [CI], 7.0, 68.8) and with BSIs (RR, 6.0; 95% CI, 2.5, 14.4). In multivariable analysis, the hypotension, mechanical ventilation, mental status, and cardiac arrest parameters of the PBS were independent risk factors for 14-day all-cause inpatient mortality. The temperature parameter as originally calculated for the PBS was not independently associated with mortality. However, a temperature <36.0°C vs ≥36°C was independently associated with mortality. A qPitt score ≥2 had similar discrimination as a PBS ≥4 in nonbacteremia infections.

Conclusions: Here, we validated that the PBS and qPitt score can be used as reliable predictors of mortality in nonbacteremia CRE infections.
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http://dx.doi.org/10.1093/cid/ciz528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7156778PMC
April 2020

Plasma Cystatin C Associates With HIV-Associated Neurocognitive Disorder but Is a Poor Diagnostic Marker in Antiretroviral Therapy-Treated Individuals.

J Acquir Immune Defic Syndr 2019 06;81(2):e49-e54

Division of Infectious Diseases, Department of Medicine, Northwestern University School of Medicine, Chicago, IL.

Objective: To examine associations between plasma cystatin C and neurocognitive impairment (NCI) and its performance as a diagnostic marker before and during initial antiretroviral therapy (ART).

Methods: Multivariable logistic regression and generalized estimating equations examined associations with NCI, determined by neuropsychological measurements, in participants of a 48-week randomized clinical trial of initial ART. Receiver operator characteristic curves examined diagnostic models of NCI.

Results: Cystatin C was associated with NCI before ART [odds ratio (OR) 3.4 (95% CI: 1.2 to 9.4) for each 2-fold increase in baseline levels] and during 48 weeks of ART, in models that excluded baseline measurements [OR 3.0 (1.2 to 7.8) for each 2-fold increase in time-updated levels]. The strength of association increased with more severe impairment using HIV-associated neurocognitive disorder criteria [OR 2.2 (0.8 to 6.0) with asymptomatic NCI and OR 4.0 (1.5 to 11.0) with mild neurocognitive disorder or HIV-associated dementia vs. no impairment, for each 2-fold increase in time-updated levels] or by global development score [OR 2.6 (1.1 to 6.3) with mild impairment and OR 4.6 (1.1 to 18.9) with moderate or severe impairment vs. no impairment]. Cystatin C performed poorly as a diagnostic marker for NCI, however, with an area under the receiver operator characteristic curve of 0.58 at baseline and 0.54 at week 48.

Conclusions: Higher plasma cystatin C levels were significantly associated with NCI, but these levels did not seem to be useful as a diagnostic marker for this condition.
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http://dx.doi.org/10.1097/QAI.0000000000002016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6546291PMC
June 2019

The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant .

Open Forum Infect Dis 2019 Jan 14;6(1):ofy351. Epub 2018 Dec 14.

Institute for Global Health and Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina.

In the Consortium on Resistance Against Carbapenems in and other (CRACKLE), trimethoprim-sulfamethoxazole (TMP-SMX) had a limited role in the treatment of less severe carbapenem-resistant (CRE) infections, especially urinary tract infections. Of tested CRE, only 29% were susceptible to TMP-SMX. Development of resistance further limits the use of TMP-SMX in CRE infections.
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http://dx.doi.org/10.1093/ofid/ofy351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324543PMC
January 2019

Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial.

Lancet HIV 2018 Dec 13. Epub 2018 Dec 13.

Department of HIV Clinical Research, Gilead Sciences, Foster City, CA, USA. Electronic address:

Background: Current treatment for HIV-infected individuals with renal failure on haemodialysis frequently requires complex regimens with multiple pills. A daily single-tablet regimen of coformulated elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is approved in Europe, the USA, and in other regions for use in HIV-1-infected individuals with mild-to-moderate chronic kidney disease (creatinine clearance 30-69 mL/min). We aimed to assess the safety, efficacy, and pharmacokinetics of this regimen in HIV-infected adults with end-stage renal disease on chronic haemodialysis.

Methods: We did an open-label, single-arm, multicentre, phase 3b trial at 26 outpatient clinics in Austria, France, Germany, and the USA. Participants were HIV-1-infected adults with end-stage renal disease (creatinine clearance <15 mL/min), on chronic haemodialysis for at least 6 months before screening. Virological suppression (ie, plasma HIV-1 RNA <50 copies per mL) on a stable antiretroviral regimen was required for at least 6 months before screening with a CD4 count of at least 200 cells per μL. We switched all participants to coformulated elvitegravir 150 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg once daily, taken after haemodialysis for up to 96 weeks. We did assessments at study visits at weeks 2, 4, 8, 12, 24, 36, and 48, and every 12 weeks thereafter up to 96 weeks. The primary endpoint was the incidence of treatment-emergent adverse events of grade 3 or higher up to week 48. All participants who received at least one dose of study drug were included in the primary analysis. This study is registered with ClinicalTrials.gov (NCT02600819) and is closed to new participants.

Findings: Between Feb 1, and Nov 3, 2016, 55 participants were enrolled and received at least one dose of study drug. Through week 48, 18 of 55 participants (33%, 95% CI 20-45) had an adverse event of grade 3 or higher on study treatment. Treatment-emergent grade 3 or higher adverse events that occurred in more than one participant included anaemia, osteomyelitis, prolonged electrocardiogram QT, fluid overload, hyperkalaemia, hypertension, and hypotension (all n=2). No adverse event of grade 3 or higher was considered by the site investigators to be treatment related. Three participants (5%, 95% CI 0-11) discontinued treatment because of adverse events; one of these (grade 1 allergic pruritus) was considered treatment related. Treatment-related adverse events were reported for six individuals (11%, 95% CI 3-19), the most common of which was nausea (in four individuals [7%]); all treatment-related adverse events were grade 1 or 2 in severity.

Interpretation: At 48 weeks, switching to the single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide was well tolerated. This regimen might provide a tolerable and convenient option for ongoing treatment of HIV-1 infection in adults with end-stage renal disease on chronic haemodialysis.

Funding: Gilead Sciences.
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http://dx.doi.org/10.1016/S2352-3018(18)30296-0DOI Listing
December 2018

Women have enhanced bone loss associated with phosphaturia and CD4+ cell restoration during initial antiretroviral therapy.

AIDS 2018 11;32(17):2517-2524

Division of Infectious Diseases, Northwestern University, Chicago, Illinois, USA.

Objective: We compared bone mineral density (BMD) changes and their correlates, between men and women participating in two randomized trials of initial [antiretroviral therapy (ART)] regimens, with or without tenofovir disoproxil fumarate (TDF).

Methods: Covariates in linear regression models of 48-week hip and spine %BMD changes, by dual energy X-ray absorptiometry, included baseline and 48-week changes in plasma viral load, CD4 cells, plasma C-terminal telopeptide, procollagen 1 N-terminal propeptide and glomerular filtration rates, and the 48-week area under the curve of fractional excretion of phosphate.

Results: Despite overall hip and spine BMD declines of 2.8 and 2.9%, respectively, plasma viral load suppression to less than 50 vs. at least 50 copies/ml was associated 1.0% (P = 0.02) and 0.8% (P = 0.01) less BMD decline. Women had lower baseline spine (P = 0.04; n = 59 women, 418 men) and hip BMD (P = 0.01) in adjusted models, with 1.7% more hip decline on ART than men (P = 0.001). Serum phosphate was positively associated with baseline spine BMD in women (P = 0.03) but not men, and area under the curve of fractional excretion of phosphate was negatively associated with spine BMD changes, particularly in women randomized to TDF regimens (P = 0.03 and 0.054 for interactions by sex, and randomization to TDF vs. non-TDF regimens, respectively; n = 44 women, 326 men). Women also had 0.6% (P = 0.004) more hip BMD decline than men associated with each 100 CD4 cells/μl increase on ART (P = 0.02; n = 49 women, 379 men).

Conclusion: Women randomized to TDF-containing ART had accentuated spine loss associated with phosphaturia, and accentuated hip loss associated with CD4 restoration, regardless of TDF exposure. Viral load suppression reduced bone loss.
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http://dx.doi.org/10.1097/QAD.0000000000001995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230267PMC
November 2018

Frailty, Neurocognitive Impairment, or Both in Predicting Poor Health Outcomes Among Adults Living With Human Immunodeficiency Virus.

Clin Infect Dis 2019 01;68(1):131-138

Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

Background: Neurocognitive impairment (NCI) is strongly associated with frailty in people living with human immunodeficiency virus (PLWH); the overlap of frailty and NCI and the impact on health outcomes in PLWH are unknown.

Methods: PLWH in a longitudinal, observational study of aging completed entry evaluations for frailty and NCI. Outcomes of falls (recurrent) increased limitations in independent activities of daily living (IADL), or mortality were combined. Poisson regression models estimated prevalence ratios (PR) for ≥1 outcome over 2 years.

Results: Among 987 participants, the median age at entry was 51 years; 19% were female; the median CD4 count was 616 cells/µL; and HIV-1 RNA was <200 copies/mL in 94%. Most (79%) participants had neither frailty nor NCI; 2% had both; 4% frailty only; and 15% NCI only. Over 2 years of observation, 100 (10%) participants experienced recurrent falls; 175 (18%) had worsening IADL limitations; 17 (2%) died; and 254 (26%) experienced ≥1 poor health outcome. In adjusted models, frailty with NCI was associated with more than double the risk of a poor health outcome (PR 2.65; 95% CI 1.98, 3.54); a significant association was also seen with frailty alone (PR 2.26; 95%CI 1.71, 2.99) and NCI alone (PR 1.73; 95% CI 1.36, 2.20).

Conclusions: The presence of frailty with NCI was associated with a greater risk of falls, disability, or death in PLWH than NCI alone. Interventions that target prevention or reversal of both frailty and NCI (such as increased physical activity) may significantly limit poor health outcomes among PLWH.
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http://dx.doi.org/10.1093/cid/ciy430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293002PMC
January 2019

Pre-vaccine plasma levels of soluble inflammatory indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and HIV infection.

Vaccine 2018 01 16;36(4):453-460. Epub 2017 Dec 16.

The Louis Stokes VA Medical Center, Cleveland, OH, USA; Department of Medicine, University Hospitals Medical Center, and the Center for AIDS Research, Case Western Reserve University, Cleveland, OH, USA. Electronic address:

Background: Chronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear.

Methods: ACTG 5232 and CFAR0910 were clinical trials where pre-vaccine levels of plasma IP10, IL-6, sCD163 and sCD14 were measured in viremic HCV- (n = 15) or HIV-infected participants (n = 24) and uninfected controls (n = 10). Accelerated dosing HAV/HBV vaccine and tetanus booster were administered and antibody response was measured at 0, 1, 3, 8, and 24 weeks.

Results: Pre-vaccine plasma IP10, IL-6, and sCD14 levels were elevated in both HCV and HIV-infected participants, while sCD163 was also elevated in HCV-infected participants. Pre-immunization tetanus antibody levels were lower in HIV-infected than in uninfected participants, while vaccine induced antibody responses were intact in HCV and HIV-infected participants. After HAV/HBV vaccination, HCV and HIV-infected participants had lower and less durable HAV and HBV antibody responses than uninfected controls. Among HCV-infected participants, pre-vaccine plasma IP10, IL-6, sCD14, and sCD163 levels inversely correlated with HAV, HBV and tetanus antibody responses after vaccine. Low HAV/HBV vaccine responses in HIV-infected participants prohibited assessment of immune correlates.

Conclusions: During HCV and HIV infection markers of systemic inflammation reflect immune dysfunction as demonstrated by poor response to HAV/HBV neo-antigen vaccine.
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http://dx.doi.org/10.1016/j.vaccine.2017.12.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767517PMC
January 2018

Carbapenem-Resistant Enterobacteriaceae Infections in Patients on Renal Replacement Therapy.

Open Forum Infect Dis 2017 6;4(4):ofx216. Epub 2017 Oct 6.

Division of Infectious Diseases, University of North Carolina, Chapel Hill, North Carolina.

Background: Patients on chronic intermittent renal replacement therapy (RRT) are at risk for infection with carbapenem-resistant Enterobacteriaceae (CRE). However, the impact of RRT on outcomes after CRE infections remains to be defined. Here we perform a comparison of outcomes for CRE-infected patients with preserved renal function compared with CRE-infected patients on RRT.

Methods: Cases and controls were defined from a prospective cohort of CRE-infected patients from the Consortium on Resistance against Carbapenems in and other Enterobacteriaceae (CRACKLE). Cases were defined as CRE-infected patients on RRT at hospital admission, while controls were defined as CRE-infected patients with serum creatinine <2 mg/dL and not receiving RRT at admission. Risk factors for 28-day in-hospital mortality were assessed using multivariable logistic regression. An ordinal ranking of outcomes by desirability analysis was performed.

Results: Patients on RRT were more likely to have diabetes mellitus and cardiac disease than controls. Urinary sources of infection were less common in the RRT group. In RRT patients, 28-day in-hospital mortality was increased as compared with controls: 22/71 (31%) vs 33/295 (11%). RRT remained significantly associated with 28-day in-hospital mortality after adjustment for source of infection, prehospitalization origin, and severity of illness (adjusted odds ratio, 2.27; 95% confidence interval [CI], 1.09-4.68; = .03). Using univariable desirability of outcome ranking analysis, RRT status was associated with a 68% (95% CI, 61%-74%) chance of a worse disposition outcome.

Conclusions: Chronic RRT in CRE-infected patients is associated with increased in-hospital mortality and worse disposition outcomes at 28 days.
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http://dx.doi.org/10.1093/ofid/ofx216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695622PMC
October 2017

A Prospective Observational Study of the Epidemiology, Management, and Outcomes of Skin and Soft Tissue Infections Due to Carbapenem-Resistant .

Open Forum Infect Dis 2017 27;4(3):ofx157. Epub 2017 Jul 27.

Department of Medicine, University of Michigan, Ann Arbor; Departments of.

Background: This study was performed to characterize the epidemiology, management, and outcomes of skin and soft tissue infection (SSTI) and colonization due to carbapenem-resistant (CRE).

Methods: Patients from the Consortium on Resistance Against Carbapenem in and Other (CRACKLE-1) from December 24, 2011 to October 1, 2014 with wound cultures positive for CRE were included in the study. Predictors of surgical intervention were analyzed. Molecular typing of isolates was performed using repetitive extragenic palindromic polymerase chain reaction (PCR). Carbapenemase genes were detected using PCR.

Results: One hundred forty-two patients were included: 62 had SSTI (44%) and 56% were colonized. Mean age was 61 years, and 48% were male: median Charlson score was 3 (interquartile range, 1-5). Forty-eight percent of patients were admitted from long-term care facilities (LTCFs), and 31% were from the community. Two strain types (ST258A and ST258B) were identified (73% of 45 tested). Carbapenemase genes were detected in 40 of 45 isolates ( [47%], [42%]). Sixty-eight patients (48%) underwent surgical intervention, 63% of whom had SSTI. Patients admitted from LTCFs were less likely to undergo surgical intervention (odds ratio [OR], 0.36; 95% confidence interval [CI], 0.18-0.71). In multivariable analysis, among patients with SSTI, those admitted from LTCFs were less likely to undergo debridement (OR, 0.18; 95% CI, 0.04-0.93).

Conclusions: Patients admitted from LTCFs with CRE SSTI were less likely to undergo surgical intervention. Sixteen percent of the patients died, and approximately 50% of survivors required more intensive care upon discharge. These findings suggest a unique, impactful syndrome within the CRE infection spectrum. Further studies are needed to assess the role of surgical debridement in management of CRE-SSTI, particularly among LTCF residents.
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http://dx.doi.org/10.1093/ofid/ofx157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5629814PMC
July 2017

Colistin Versus Ceftazidime-Avibactam in the Treatment of Infections Due to Carbapenem-Resistant Enterobacteriaceae.

Clin Infect Dis 2018 01;66(2):163-171

Department of Biostatistics and the Center for Biostatistics in AIDS Research, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Background: The efficacy of ceftazidime-avibactam-a cephalosporin-β-lactamase inhibitor combination with in vitro activity against Klebsiella pneumoniae carbapenemase-producing carbapenem-resistant Enterobacteriaceae (CRE)-compared with colistin remains unknown.

Methods: Patients initially treated with either ceftazidime-avibactam or colistin for CRE infections were selected from the Consortium on Resistance Against Carbapenems in Klebsiella and other Enterobacteriaceae (CRACKLE), a prospective, multicenter, observational study. Efficacy, safety, and benefit-risk analyses were performed using intent-to-treat analyses with partial credit and the desirability of outcome ranking approaches. The ordinal efficacy outcome was based on disposition at day 30 after starting treatment (home vs not home but not observed to die in the hospital vs hospital death). All analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW).

Results: Thirty-eight patients were treated first with ceftazidime-avibactam and 99 with colistin. Most patients received additional anti-CRE agents as part of their treatment. Bloodstream (n = 63; 46%) and respiratory (n = 30; 22%) infections were most common. In patients treated with ceftazidime-avibactam versus colistin, IPTW-adjusted all-cause hospital mortality 30 days after starting treatment was 9% versus 32%, respectively (difference, 23%; 95% bootstrap confidence interval, 9%-35%; P = .001). In an analysis of disposition at 30 days, patients treated with ceftazidime-avibactam, compared with those treated within colistin, had an IPTW-adjusted probability of a better outcome of 64% (95% confidence interval, 57%-71%). Partial credit analyses indicated uniform superiority of ceftazidime-avibactam to colistin.

Conclusions: Ceftazidime-avibactam may be a reasonable alternative to colistin in the treatment of K. pneumoniae carbapenemase-producing CRE infections. These findings require confirmation in a randomized controlled trial.
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http://dx.doi.org/10.1093/cid/cix783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850032PMC
January 2018

The Impact of Statin and Angiotensin-Converting Enzyme Inhibitor/Angiotensin Receptor Blocker Therapy on Cognitive Function in Adults With Human Immunodeficiency Virus Infection.

Clin Infect Dis 2017 Nov;65(12):2042-2049

Harvard T. H. Chan School of Public Health, Boston, Massachusetts.

Background: Although statins, angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are generally well tolerated, the impact of these therapies individually or in combination on the change in neurocognitive function in persons with human immunodeficiency virus infection is unknown.

Methods: The study included participants in the AIDS Clinical Trials Group Longitudinal Linked Randomized Trials cohort participants not receiving a statin or ACEI/ARB within 30 days of first neurologic assessment (baseline), with assessments by NPZ-3 (z score of averaged Trailmaking A and B tests and digit symbol test [DST]) from ≥2 measurements. Marginal structural models estimated the causal effect of statin or ACEI/ARB initiation on neurocognitive function; initial constant slope was assumed during the first year of treatment and a second constant slope thereafter.

Results: Of 3949 eligible participants, 16% started therapy with a statin, 11% with an ACEI/ARB, and 5% with both. Statin therapy had no significant effect on the composite NPZ-3 (primary outcome), Trailmaking B test, or DST. A small, nonsignificant positive effect on the Trailmaking A test was seen during year 1 (estimate, 0.088; 95% confidence interval, -.010 to .187; P = .08) and a small but significant negative effect (-0.033; -.058 to -.009; P = .007) in each subsequent year. ACEI/ARB therapy had a significant negative effect on the DST (-0.117; 95% confidence interval, -.217 to .016; P = .02) during year 1 but minimal effect in subsequent years or on other neurocognitive domains.

Conclusions: In summary, although modest declines in neurocognitive performance were seen in single domains with statin or ACEI/ARB therapy, we did not find consistent evidence that statins or ACEI/ARB have an effect on global neurocognitive function. Future studies should focus on long-term neurocognitive effects.
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http://dx.doi.org/10.1093/cid/cix645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850423PMC
November 2017

Frailty is strongly associated with increased risk of recurrent falls among older HIV-infected adults.

AIDS 2017 10;31(16):2287-2294

aHarvard T.H. Chan School of Public Health, Department of Epidemiology bHarvard T.H. Chan School of Public Health, Center for Biostatistics in AIDS Research, Boston, Massachusetts cOhio State University, Department of Internal Medicine; Columbus, Ohio dNorthwestern University Feinberg School of Medicine, Department of Medicine; Chicago, Illinois eMetroHealth and Louis Stokes Cleveland Veterans Administration Medical Center, Department of Medicine; Cleveland, Ohio fUniversity of Colorado-Anschutz Medical Campus, Department of Medicine, Aurora, Colorado, USA.

Objective: Both frailty and falls occur at earlier-than-expected ages among HIV-infected individuals, but the contribution of frailty-to-fall risk in this population is not well understood. We examined this association among participants enrolled in AIDS Clinical Trials Group (ACTG) A5322.

Design: A prospective, multicenter cohort study of HIV-infected men and women aged at least 40 years.

Methods: Frailty assessment included a 4-m walk, grip strength, and self-reported weight loss, exhaustion, and low physical activity. Multinomial logistic regression assessed the association between baseline frailty, grip, and 4-m walk, and single and recurrent (2+) falls over the next 12 months; logistic regression assessed effect modification by several factors on association between frailty and any (1+) falls.

Results: Of 967 individuals, 6% were frail, 39% prefrail, and 55% nonfrail. Eighteen percent had at least one fall, and 7% had recurrent falls. In multivariable models, recurrent falls were more likely among frail (odds ratio 17.3, 95% confidence interval 7.03-42.6) and prefrail (odds ratio 3.80, 95% CI 1.87-7.72) than nonfrail individuals. Significant associations were also seen with recurrent falls and slow walk and weak grip. The association between frailty and any falls was substantially stronger among individuals with peripheral neuropathy.

Conclusion: Aging HIV-infected prefrail and frail individuals are at significantly increased risk of falls. Incorporation of frailty assessments or simple evaluations of walk speed or grip strength in clinical care may help identify individuals at greatest risk for falls. Peripheral neuropathy further increases fall risk among frail persons, defining a potential target population for closer fall surveillance, prevention, and treatment.
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http://dx.doi.org/10.1097/QAD.0000000000001613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654616PMC
October 2017

Human Immunodeficiency Virus and Aging in the Era of Effective Antiretroviral Therapy.

Infect Dis Clin North Am 2017 12 13;31(4):791-810. Epub 2017 Sep 13.

Division of Infectious Diseases, Geriatric Research, Education, and Clinical Center, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Case Western Reserve University School of Medicine, 10701 East Boulevard, Cleveland, OH 44106, USA; Division of Infectious Diseases, MetroHealth Medical Center, Case Western Reserve University School of Medicine, 2500 MetroHealth Drive, Cleveland, OH 44109, USA.

Persons living with HIV (PLWH) have accentuated risks for age-associated comorbidities. Compared to the general population, PLWH have a 2-fold higher risk of cardiovascular disease, a 3-fold increased risk of fracture, and a risk of kidney disease that is comparable to that in diabetes. Some comorbidities may present at younger ages than among the general population, suggesting the possibility of accelerated aging with HIV infection.
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http://dx.doi.org/10.1016/j.idc.2017.07.007DOI Listing
December 2017

Association Between Frailty and Components of the Frailty Phenotype With Modifiable Risk Factors and Antiretroviral Therapy.

J Infect Dis 2017 03;215(6):933-937

Department of Epidemiology, Harvard T. H. Chan, School of Public Health, Boston, Massachusetts, USA.

The impact of antiretroviral therapy (ART) on frailty among human immunodeficiency virus (HIV)-infected adults has not been well described. HIV-infected participants aged ≥40 years with initial ART receipt through a randomized, controlled AIDS Clinical Trials Group trial completed a frailty assessment. Ordinal logistic regression models examined factors associated with frailty. Of 1016 participants, 6% were frail, and 38% were prefrail. Frailty was associated with lower education, older age, Medicare/Medicaid, initial efavirenz, smoking, obesity, and neurocognitive impairment; physical activity and alcohol use were protective. The associations with ART require further investigation, and associations between frailty and modifiable factors provide targets for future interventions.
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http://dx.doi.org/10.1093/infdis/jix063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5407051PMC
March 2017

Disability Among Middle-Aged and Older Persons With Human Immunodeficiency Virus Infection.

Clin Infect Dis 2017 Jul;65(1):83-91

Department of Medicine, University of Colorado-Anschutz Medical Campus, Aurora.

Background: Older human immunodeficiency virus (HIV)-infected adults may experience higher rates of frailty and disability than the general population. Improved understanding of the prevalence, risk factors, and types of impairment can better inform providers and the healthcare system.

Methods: HIV-infected participants within the AIDS Clinical Trials Group A5322 HAILO study self-reported disability by the Lawton-Brody Instrumental Activities of Daily Living (IADL) Questionnaire. Frailty was measured by 4-m walk time, grip strength, self-reported weight loss, exhaustion, and low activity. Logistic regression models identified characteristics associated with any IADL impairment. Agreement between IADL impairment and frailty was assessed using the weighted kappa statistic.

Results: Of 1015 participants, the median age was 51 years, 15% were aged ≥60 years, 19% were female, 29% black, and 20% Hispanic. At least 1 IADL impairment was reported in 18% of participants, most commonly with housekeeping (48%) and transportation (36%) and least commonly with medication management (5%). In multivariable models, greater disability was significantly associated with neurocognitive impairment, lower education, Medicare/Medicaid insurance (vs private/other coverage), smoking, and low physical activity. Although a greater proportion of frail participants had IADL impairment (52%) compared to non-frail (11%) persons, agreement was poor (weighted kappa <0.18, 95% confidence interval, 0.13, 0.23).

Conclusion: IADL disability occurs frequently among middle-aged and older HIV-infected adults on effective antiretroviral therapy. Potentially modifiable risk factors (smoking, physical activity) provide targets for interventions to maintain independent living. Systematic recognition of persons at greater risk for disability can facilitate connection to resources that may help preserve independence.
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http://dx.doi.org/10.1093/cid/cix253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5815567PMC
July 2017

Minimally Invasive Aortic Valve Replacement via Right Anterior Minithoracotomy and Central Aortic Cannulation: A 13-Year Experience.

Innovations (Phila) 2017 Mar/Apr;12(2):87-94

From the *MemorialCare Heart & Vascular Institute at Long Beach Memorial, Long Beach, CA USA; †Orange Coast Memorial, Fountain Valley, CA USA; ‡University of California San Diego, Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, CA USA; and §Division of Cardiology, University of California Irvine, CA USA.

Objective: This study reports the evolution of a minimally invasive aortic valve replacement (mini-AVR) technique that uses a right anterior minithoracotomy approach with central cannulation, for a 13-year period. This technique has become our standard approach for isolated primary AVR in nearly all patients.

Methods: This observational study evaluated perioperative clinical outcomes of patients 18 years or older who underwent mini-AVR from November 2003 to June 2015.

Results: The mini-AVR technique was used in 202 patients during two periods of 2003 to 2009 (n = 65, "early") and 2010 to 2015 (n = 137, "late"). The mean ± SD age was 72.5 ± 12.9 years and 60% were male. Demographic parameters were statistically similar between the study periods, except for increased body weight in the later period (75.3 ± 14.7 vs 80.9 ± 20.8 kg, P = 0.03). The mean cardiopulmonary bypass and aortic cross-clamp times were significantly different by each year and Bonferroni adjustment, with significant decreases in cardiopulmonary bypass and aortic cross-clamp times beginning 2006. Compared with the early study period, late study period patients were more often extubated intraoperatively (52% vs 12%, P < 0.001), had less frequent prolonged ventilator use postoperatively (6% vs 16%, P = 0.018), required fewer blood transfusions (mean, 2.0 ± 2.3 U vs 3.6 ± 3.0 U; P = 0.011), and had shorter postoperative stay (6.3 ± 4.5 days vs 8.0 ± 5.9 days, P = 0.026). Numerically, fewer postoperative strokes (1% vs 6%, P = 0.09) and fewer reoperations for bleeding (3% vs 6%, P = 0.3) occurred in the late period. In-hospital mortality did not differ (1/65 early vs 3/137 late).

Conclusions: Overall mini-AVR intraoperative and postoperative clinical outcomes improved for this 13-year experience.
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http://dx.doi.org/10.1097/IMI.0000000000000358DOI Listing
September 2017

Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality.

Clin Infect Dis 2017 03;64(6):711-718

Division of Infectious Diseases, University of North Carolina, Chapel Hill, USA.

Background: Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide.

Methods: A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling.

Results: In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp.

Conclusions: In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates.
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http://dx.doi.org/10.1093/cid/ciw805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850634PMC
March 2017

Hospital Readmissions in Patients With Carbapenem-Resistant Klebsiella pneumoniae.

Infect Control Hosp Epidemiol 2016 Mar 21;37(3):281-8. Epub 2015 Dec 21.

16Division of Infectious Diseases,University of North Carolina,Chapel Hill,North Carolina.

Background: Various transmission routes contribute to spread of carbapenem-resistant Klebsiella pneumoniae (CRKP) in hospitalized patients. Patients with readmissions during which CRKP is again isolated ("CRKP readmission") potentially contribute to transmission of CRKP.

Objective: To evaluate CRKP readmissions in the Consortium on Resistance against Carbapenems in K. pneumoniae (CRaCKLe).

Design: Cohort study from December 24, 2011, through July 1, 2013.

Setting: Multicenter consortium of acute care hospitals in the Great Lakes region.

Patients: All patients who were discharged alive during the study period were included. Each patient was included only once at the time of the first CRKP-positive culture.

Methods: All readmissions within 90 days of discharge from the index hospitalization during which CRKP was again found were analyzed. Risk factors for CRKP readmission were evaluated in multivariable models.

Results: Fifty-six (20%) of 287 patients who were discharged alive had a CRKP readmission. History of malignancy was associated with CRKP readmission (adjusted odds ratio [adjusted OR], 3.00 [95% CI, 1.32-6.65], P<.01). During the index hospitalization, 160 patients (56%) received antibiotic treatment against CRKP; the choice of regimen was associated with CRKP readmission (P=.02). Receipt of tigecycline-based therapy (adjusted OR, 5.13 [95% CI, 1.72-17.44], using aminoglycoside-based therapy as a reference in those treated with anti-CRKP antibiotics) was associated with CRKP readmission.

Conclusion: Hospitalized patients with CRKP-specifically those with a history of malignancy-are at high risk of readmission with recurrent CRKP infection or colonization. Treatment during the index hospitalization with a tigecycline-based regimen increases this risk.
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http://dx.doi.org/10.1017/ice.2015.298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4785868PMC
March 2016

Community-Acquired Pyelonephritis in Pregnancy Caused by KPC-Producing Klebsiella pneumoniae.

Antimicrob Agents Chemother 2015 Aug;59(8):4375-8

University of Queensland Centre for Clinical Research, Royal Brisbane and Women's Hospital, Brisbane, Australia.

Carbapenem-resistant Enterobacteriaceae (CRE) usually infect patients with significant comorbidities and health care exposures. We present a case of a pregnant woman who developed community-acquired pyelonephritis caused by KPC-producing Klebsiella pneumoniae. Despite antibiotic treatment, she experienced spontaneous prolonged rupture of membranes, with eventual delivery of a healthy infant. This report demonstrates the challenge that CRE may pose to the effective treatment of common infections in obstetric patients, with potentially harmful consequences to maternal and neonatal health.
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http://dx.doi.org/10.1128/AAC.00553-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505232PMC
August 2015

Residence in Skilled Nursing Facilities Is Associated with Tigecycline Nonsusceptibility in Carbapenem-Resistant Klebsiella pneumoniae.

Infect Control Hosp Epidemiol 2015 Aug 20;36(8):942-8. Epub 2015 May 20.

11Division of Infectious Diseases,Detroit Medical Center,Wayne State University,Detroit,Michigan.

Objective: To determine the rates of and risk factors for tigecycline nonsusceptibility among carbapenem-resistant Klebsiella pneumoniae (CRKPs) isolated from hospitalized patients.

Design: Multicenter prospective observational study.

Setting: Acute care hospitals participating in the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle).

Patients: A cohort of 287 patients who had CRKPs isolated from clinical cultures during hospitalization.

Methods: For the period from December 24, 2011 to October 1, 2013, the first hospitalization of each patient with a CRKP during which tigecycline susceptibility for the CRKP isolate was determined was included. Clinical data were entered into a centralized database, including data regarding pre-hospital origin. Breakpoints established by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) were used to interpret tigecycline susceptibility testing.

Results: Of 287 patients included in the final cohort, 155 (54%) had tigecycline-susceptible CRKPs. Of all index isolates, 81 (28%) were tigecycline-intermediate and 51 (18%) were tigecycline resistant. In multivariate modeling, independent risk factors for tigecycline nonsusceptibility were (1) admission from a skilled nursing facility (OR, 2.51; 95% CI, 1.51-4.21; P=.0004), (2) positive culture within 2 days of admission (OR, 1.82; 95% CI, 1.06-3.15; P=.03), and (3) receipt of tigecycline within 14 days (OR, 4.38, 95% CI, 1.37-17.01, P=.02).

Conclusions: In hospitalized patients with CRKPs, tigecycline nonsusceptibility was more frequently observed in those admitted from skilled nursing facilities and occurred earlier during hospitalization. Skilled nursing facilities are an important target for interventions to decrease antibacterial resistance to antibiotics of last resort for treatment of CRKPs.
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http://dx.doi.org/10.1017/ice.2015.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4642723PMC
August 2015

Impact of therapy and strain type on outcomes in urinary tract infections caused by carbapenem-resistant Klebsiella pneumoniae.

J Antimicrob Chemother 2015 Apr 9;70(4):1203-11. Epub 2014 Dec 9.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, OH, USA Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, OH, USA Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.

Objectives: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an important healthcare-associated pathogen. We evaluated the impact of CRKP strain type and treatment on outcomes of patients with CRKP bacteriuria.

Patients And Methods: Physician-diagnosed CRKP urinary tract infection (UTI)-defined as those patients who received directed treatment for CRKP bacteriuria-was studied in the multicentre, prospective Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRaCKle) cohort. Strain typing by repetitive extragenic palindromic PCR (rep-PCR) was performed. Outcomes were classified as failure, indeterminate or success. Univariate and multivariate ordinal analyses to evaluate the associations between outcome, treatment and strain type were followed by binomial analyses.

Results: One-hundred-and-fifty-seven patients with physician-diagnosed CRKP UTI were included. After adjustment for CDC/National Healthcare Safety Network (NHSN)-defined UTI, critical illness and receipt of more than one active antibiotic, patients treated with aminoglycosides were less likely to fail therapy [adjusted OR (aOR) for failure 0.34, 95% CI 0.15-0.73, P=0.0049]. In contrast, patients treated with tigecycline were more likely to fail therapy (aOR for failure 2.29, 95% CI 1.03-5.13, P=0.0425). Strain type data were analysed for 55 patients. The predominant clades were ST258A (n=18, 33%) and ST258B (n=26, 47%). After adjustment for CDC/NHSN-defined UTI and use of tigecycline and aminoglycosides, infection with strain type ST258A was associated with clinical outcome in ordinal analysis (P=0.0343). In multivariate binomial models, strain type ST258A was associated with clinical failure (aOR for failure 5.82, 95% CI 1.47-28.50, P=0.0113).

Conclusions: In this nested cohort study of physician-diagnosed CRKP UTI, both choice of treatment and CRKP strain type appeared to impact on clinical outcomes.
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http://dx.doi.org/10.1093/jac/dku495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4356203PMC
April 2015

Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America.

Clin Infect Dis 2014 Nov 17;59(9):e96-138. Epub 2014 Sep 17.

MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.
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http://dx.doi.org/10.1093/cid/ciu617DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271038PMC
November 2014

Older age is associated with peripheral blood expansion of naïve B cells in HIV-infected subjects on antiretroviral therapy.

PLoS One 2014 10;9(9):e107064. Epub 2014 Sep 10.

Geriatric Research Center Clinical Core (GRECC), Department of Infectious Diseases, Louis Stokes Cleveland VA Medical Center, Case Western Reserve University, Cleveland, Ohio, United States of America.

Older HIV infected subjects were previously found to have significant B cell expansion during initial antiretroviral therapy in a prospective age-differentiated cohort of older and younger (≥45 vs. ≤30 years) HIV-infected subjects initiating antiretroviral therapy (ART) through the AIDS Clinical Trials Group. Here to further describe this expansion, using a subset of subjects from the same cohort, we characterized B cell phenotypes at baseline and after 192 weeks of ART in both older and younger HIV-infected groups and compared them to uninfected age-matched controls. We also examined whether phenotypes at baseline associated with response to tetanus and hepatitis A vaccine at 12 weeks. Forty six subjects were analyzed in the HIV infected group (21 older, 25 younger) and 30 in the control group (15 per age group). We observed naïve B cells to normalize in younger subjects after 192 weeks of ART, while in older subjects naïve B cells increased to greater levels than those of controls (p = 0.045). Absolute resting memory (RM) cell count was significantly lower in the older HIV infected group at baseline compared to controls and numbers normalized after 192 weeks of ART (p<0.001). Baseline RM cell count positively correlated with week 12 increase in antibody to tetanus vaccine among both younger and older HIV-infected subjects combined (p = 0.01), but not in controls. The age-associated naïve B cell expansion is a novel finding and we discuss several possible explanations for this observation. Relationship between RM cells at baseline and tetanus responses may lead to insights about the effects of HIV infection on B cell memory function and vaccine responses.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107064PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4160206PMC
March 2016

Proteinuria is associated with neurocognitive impairment in antiretroviral therapy treated HIV-infected individuals.

J Acquir Immune Defic Syndr 2014 Sep;67(1):30-5

*Department of Medicine, MetroHealth Medical Center; Cleveland, OH; †Geriatric Research Education and Clinical Centers, Louis Stokes Cleveland Veterans Administration, Cleveland, OH; ‡Statistical and Data Analysis Center, Harvard School of Public Health; Boston, MA; §Department of Neurology and Neurological Surgery, Washington University of St. Louis, St. Louis, MO; ‖UCLA CARE Center, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA; and ¶Department of Epidemiology, Milken Institute School of Public Health, George Washington University, Washington, DC.

Background: Proteinuria is a marker of vascular dysfunction that predicted increased cardiovascular mortality and is associated with neurocognitive impairment (NCI) in population-based studies. We examined associations between proteinuria and HIV-associated NCI.

Methods: Multivariable logistic regression was used to examine associations between NCI at the first neurocognitive assessment (baseline) and simultaneous, clinically significant proteinuria [as random spot urine protein-to-creatinine ratios (UP/Cr) ≥200 mg/g] in a prospective multicenter observational cohort study. Generalized estimating equations were used to examine associations between baseline proteinuria and subsequent NCI among subjects without NCI at baseline. NCI was defined as a Z-score, derived from the combination of normalized scores from the Trailmaking A and B and the Wechsler Adult Intelligence Scale-Revised Digit Symbol tests.

Results: A total of 1972 subjects were included in this analysis. Baseline proteinuria was associated with increased odds of NCI [odds ratio (OR): 1.41, 95% confidence interval (CI): 1.08 to 1.85; P = 0.01] and with subsequent NCI among subjects without NCI at baseline (OR: 1.39, 95% CI: 1.01 to 1.93; P = 0.046) in multivariable models adjusted for risk factors and potential confounders. Similar associations were evident when these analyses were limited to visits at which time study subjects maintained plasma HIV RNA levels <200 copies per milliliter.

Conclusions: The association between proteinuria and NCI observed in this study adds to a growing body of evidence implicating contributions by vascular disease to NCI in antiretroviral treated individuals. Studies examining interventions that improve vascular function are warranted.
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http://dx.doi.org/10.1097/QAI.0000000000000237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4133749PMC
September 2014

Editorial commentary: Cystatin C and statins in HIV disease.

Clin Infect Dis 2014 Oct 11;59(8):1157-9. Epub 2014 Jul 11.

MetroHealth Medical Center, Cleveland, Ohio.

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http://dx.doi.org/10.1093/cid/ciu527DOI Listing
October 2014

Surveillance of carbapenem-resistant Klebsiella pneumoniae: tracking molecular epidemiology and outcomes through a regional network.

Antimicrob Agents Chemother 2014 Jul 5;58(7):4035-41. Epub 2014 May 5.

Research Service, Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Cleveland, Ohio, USA Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA

Carbapenem resistance in Gram-negative bacteria is on the rise in the United States. A regional network was established to study microbiological and genetic determinants of clinical outcomes in hospitalized patients with carbapenem-resistant (CR) Klebsiella pneumoniae in a prospective, multicenter, observational study. To this end, predefined clinical characteristics and outcomes were recorded and K. pneumoniae isolates were analyzed for strain typing and resistance mechanism determination. In a 14-month period, 251 patients were included. While most of the patients were admitted from long-term care settings, 28% of them were admitted from home. Hospitalizations were prolonged and complicated. Nonsusceptibility to colistin and tigecycline occurred in isolates from 7 and 45% of the patients, respectively. Most of the CR K. pneumoniae isolates belonged to repetitive extragenic palindromic PCR (rep-PCR) types A and B (both sequence type 258) and carried either blaKPC-2 (48%) or blaKPC-3 (51%). One isolate tested positive for blaNDM-1, a sentinel discovery in this region. Important differences between strain types were noted; rep-PCR type B strains were associated with blaKPC-3 (odds ratio [OR], 294; 95% confidence interval [CI], 58 to 2,552; P < 0.001), gentamicin nonsusceptibility (OR, 24; 95% CI, 8.39 to 79.38; P < 0.001), amikacin susceptibility (OR, 11.0; 95% CI, 3.21 to 42.42; P < 0.001), tigecycline nonsusceptibility (OR, 5.34; 95% CI, 1.30 to 36.41; P = 0.018), a shorter length of stay (OR, 0.98; 95% CI, 0.95 to 1.00; P = 0.043), and admission from a skilled-nursing facility (OR, 3.09; 95% CI, 1.26 to 8.08; P = 0.013). Our analysis shows that (i) CR K. pneumoniae is seen primarily in the elderly long-term care population and that (ii) regional monitoring of CR K. pneumoniae reveals insights into molecular characteristics. This work highlights the crucial role of ongoing surveillance of carbapenem resistance determinants.
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http://dx.doi.org/10.1128/AAC.02636-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4068524PMC
July 2014