5-Flucytosine Longitudinal Antifungal Susceptibility Testing of Cryptococcus neoformans: A Substudy of the EnACT Trial Testing Oral Amphotericin.

Background: The EnACT trial was a phase 2 randomized clinical trial conducted in Uganda, which evaluated a novel orally delivered lipid nanocrystal (LNC) amphotericin B in combination with flucytosine for the treatment of cryptococcal meningitis. When flucytosine (5FC) is used as monotherapy in cryptococcosis, 5FC can induce resistant Cryptococcus mutants. Oral amphotericin B uses a novel drug delivery mechanism, and we assessed whether resistance to 5FC develops during oral LNC-amphotericin B therapy. Methods: We enrolled Ugandans with HIV diagnosed with cryptococcal meningitis and who were randomized to receive 5FC and either standard intravenous (IV) amphotericin B or oral LNC-amphotericin B. We used broth microdilution to measure the minimum inhibitory concentration (MIC) of the first and last cryptococcal isolates in each participant. Breakpoints are inferred from 5FC in Candida albicans. We measured cerebral spinal fluid (CSF) 5FC concentrations by liquid chromatography and tandem mass spectrometry. Results: Cryptococcus 5FC MIC50 was 4 µg/mL, and MIC90 was 8 µg/mL. After 2 weeks of therapy, there was no evidence of 5FC resistance developing, defined as a >4-fold change in susceptibility in any Cryptococcus isolate tested. The median CSF 5FC concentration to MIC ratio (interquartile range) was 3.0 (1.7-5.5) µg/mL. There was no association between 5FC/MIC ratio and early fungicidal activity of the quantitative rate of CSF yeast clearance (R2 = 0.004; P = .63). Conclusions: There is no evidence of baseline resistance to 5FC or incident resistance during combination therapy with oral or IV amphotericin B in Uganda. Oral amphotericin B can safely be used in combination with 5FC.

Oral Lipid Nanocrystal Amphotericin B for Cryptococcal Meningitis: A Randomized Clinical Trial.

BACKGROUND: Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. METHODS: In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA). RESULTS: We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10  Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04). CONCLUSIONS: This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin. CLINICAL TRIALS REGISTRATION: NCT04031833.

Prevalence of Histoplasma Antigenuria among Outpatient Cohort with Advanced HIV in Kampala, Uganda.

In sub-Saharan Africa, an estimated 25% of people with HIV present with advanced HIV and are at high risk of opportunistic infections. Whereas histoplasmosis has occasionally been seen in Uganda, the understanding of the local risk of acute infection is limited. We sought to determine the prevalence of Histoplasma antigenuria using an enzyme immunoassay (EIA, clarus Histoplasma GM EIA, IMMY; Norman, OK, USA) in a cohort of outpatients with advanced HIV disease in Kampala, Uganda. Among the persons with positive urine Histoplasma antigen tests, we assessed their clinical presentation and outcomes. The EIA was run on stored urine samples as per the manufacturer's instructions. Specimens ≥1 EIA units were considered positive. Among the 388 tested urine samples, 4 (1.2%) were positive for Histoplasma antigen. The histoplasmosis prevalence among participants with a CD4 < 100 cells/mcL was 2.5% (4/158). Three of the four participants with a positive Histoplasma antigen test reported systemic symptoms consistent with histoplasmosis. All four participants had a positive urine lipoarabinomannan test and were treated for tuberculosis. By the four-week follow-up visit, all participants were clinically improved, alive, and in care without antifungal therapy. In advanced HIV, the clinical presentations of tuberculosis and histoplasmosis overlap. The value of histoplasmosis screening and pre-emptive treatment is an area of future research.

Association of Hyponatremia on Mortality in Cryptococcal Meningitis: A Prospective Cohort.

Background: Sodium abnormalities are frequent in central nervous system infections and may be caused by cerebral salt wasting, syndrome of inappropriate antidiuretic hormone secretion, or medication adverse events. In cryptococcal meningitis (CM), the prevalence of baseline hyponatremia and whether hyponatremia adversely impacts survival is unknown. Methods: We conducted a secondary analysis of data from 2 randomized trials of human immunodeficiency virus-infected adult Ugandans with CM. We grouped serum sodium into 3 categories: <125, 125-129, and 130-145 mmol/L. We assessed whether baseline sodium abnormalities were associated with clinical characteristics and survival. Results: Of 816 participants with CM, 741 (91%) had a baseline sodium measurement available: 121 (16%) had grade 3-4 hyponatremia (<125 mmol/L), 194 (26%) had grade 2 hyponatremia (125-129 mmol/L), and 426 (57%) had a baseline sodium of 130-145 mmol/L. Hyponatremia (<125 mmol/L) was associated with higher initial cerebrospinal fluid (CSF) quantitative culture burden (P < .001), higher initial CSF opening pressure (P < .01), lower baseline Glasgow Coma Scale score (P < .01), and a higher percentage of baseline seizures (P = .03). Serum sodium <125 mmol/L was associated with increased 2-week mortality in unadjusted and adjusted survival analyses (adjusted hazard ratio, 1.87 [95% confidence interval, 1.26-2.79]; P < .01) compared to those with sodium 130-145 mmol/L. Conclusions: Hyponatremia is common in CM and is associated with excess mortality. A standardized management approach to correctly diagnose and correct hyponatremia in CM needs to be developed and tested.

Risk Prediction for Delayed Allograft Function: Analysis of the Deterioration of Kidney Allograft Function (DeKAF) Study Data.

BACKGROUND: Delayed graft function (DGF) of a kidney transplant results in increased cost and complexity of management. For clinical care or a DGF trial, it would be ideal to accurately predict individual DGF risk and provide preemptive treatment. A calculator developed by Irish et al has been useful for predicting population but not individual risk. METHODS: We analyzed the Irish calculator (IC) in the DeKAF prospective cohort (incidence of DGF = 20.4%) and investigated potential improvements. RESULTS: We found that the predictive performance of the calculator in those meeting Irish inclusion criteria was comparable with that reported by Irish et al. For cohorts excluded by Irish: (a) in pump-perfused kidneys, the IC overestimated DGF risk; (b) in simultaneous pancreas kidney transplants, the DGF risk was exceptionally low. For all 3 cohorts, there was considerable overlap in IC scores between those with and those without DGF. Using a modified definition of DGF-excluding those with single dialysis in the first 24 h posttransplant-we found that the calculator had similar performance as with the traditional DGF definition. Studying whether DGF prediction could be improved, we found that recipient cardiovascular disease was strongly associated with DGF even after accounting for IC-predicted risk. CONCLUSIONS: The IC can be a useful population guide for predicting DGF in the population for which it was intended but has limited scope in expanded populations (SPK, pump) and for individual risk prediction. DGF risk prediction can be improved by inclusion of recipient cardiovascular disease.

Chlorhexidine oral rinses for symptomatic COPD: a randomised, blind, placebo-controlled preliminary study.

OBJECTIVES: Determine the effect of twice-daily chlorhexidine oral rinses on oral and lung microbiota biomass and respiratory symptoms. SETTING: Single centre. PARTICIPANTS: Participants were aged 40-85 with chronic obstructive pulmonary disease (COPD) and chronic productive cough or COPD exacerbation within the last year. Exclusions included antibiotics in the previous 2 months and/or those with less than four teeth. Forty-four participants were recruited and 40 completed the study. INTERVENTION: Participants were randomised 1:1 to twice-daily 0.12% chlorhexidine oral rinses versus placebo for 2 months along with daily diaries. St. George's Respiratory Questionnaire (SGRQ), blood tests, oral rinse and induced sputum were collected at randomisation and the final visit. PRIMARY AND SECONDARY OUTCOMES: Primary outcome was a change in oral and sputum microbiota biomass. Secondary outcomes included: sputum and oral microbiota Shannon and Simpson diversity and taxonomy; inflammatory markers; Breathlessness, Cough and Sputum Scale and SGRQ scores. RESULTS: Neither the oral microbiota nor the sputum microbiota biomass decreased significantly in those using chlorhexidine compared with placebo (oral microbiota mean log10 difference (SE)=-0.103 (0.23), 95% CI -0.59 to 0.38, p=0.665; sputum microbiota 0.80 (0.46), 95% CI -0.15 to 1.75, p=0.096). Chlorhexidine decreased both oral and sputum microbiota alpha (Shannon) diversity (linear regression estimate (SE) oral: -0.349 (0.091), p=0.001; sputum -0.622 (0.169), p=0.001). Chlorhexidine use did not decrease systemic inflammatory markers compared with placebo (C reactive protein (chlorhexidine 1.8±7.5 vs placebo 0.4±6.8, p=0.467), fibrinogen (22.5±77.8 vs 10.0±77.0, p=0.406) or leucocytes (0.2±1.8 vs 0.5±1.8, p=0.560)). Chlorhexidine use decreased SGRQ scores compared with placebo (chlorhexidine -4.7±8.0 vs placebo 1.7±8.9, p=0.032). CONCLUSIONS: We did not detect a significant difference in microbiota biomass due to chlorhexidine use. Chlorhexidine decreased oral and sputum microbiota alpha diversity and improved respiratory health-related quality of life compared with placebo. TRIAL REGISTRATION: NCT02252588.

An association between resting state EEG parameters and the severity of topiramate-related cognitive impairment.

INTRODUCTION: Many commonly prescribed drugs cause cognitive deficits. We investigated whether parameters of the resting-state electroencephalogram (rsEEG) are related to the severity of cognitive impairments associated with administration of the antiseizure drug topiramate (TPM) and the benzodiazepine lorazepam (LZP). METHODS: We conducted a double-blind, randomized, placebo-controlled crossover study. After a baseline visit, subjects completed three sessions at which they received either a single dose of TPM, LZP, or placebo. Four-hours after drug administration and at baseline, subjects completed a working memory (WM) task after their rsEEG was recorded. After quantifying drug-related behavioral (WM accuracy (ACC)/reaction time (RT)) and electrophysiological (alpha, theta, beta (1,2), gamma power) change for each subject, we constructed drug-specific mixed effects models of change for each WM and EEG measure. Regression models were constructed to characterize the relationship between baseline rsEEG measures and drug-related performance changes. RESULTS: Linear mixed effects models showed theta power increases in response to TPM administration. The results of the regression models revealed a number of robust relationships between baseline rsEEG parameters and TPM-related, but not LZP-related, WM impairment. CONCLUSIONS: We showed for the first time that parameters of the rsEEG are associated with the severity of TPM-related WM deficits; this suggests that rsEEG measures may have novel clinical applications in the future.

Impact of repeated cycles of EGF bispecific angiotoxin (eBAT) administered at a reduced interval from doxorubicin chemotherapy in dogs with splenic haemangiosarcoma.

We previously reported that eBAT, an EGF-targeted angiotoxin, was safe and it improved the overall survival for dogs with splenic haemangiosarcoma when added to the standard of care in a single cycle of three administrations in the minimal residual disease setting. Our objective for the SRCBST-2 trial was to assess whether increased dosing through multiple cycles of eBAT would be well tolerated and would further enhance the benefits of eBAT. Eligibility was expanded to dogs with stage 3 haemangiosarcoma, provided that gross lesions could be surgically excised. The interval between eBAT and the start of chemotherapy was reduced, and the experimental therapy was expanded to three cycles, each administered at the biologically active dose (50 µg/kg) on a Monday/Wednesday/Friday schedule following splenectomy, and scheduled 1 week prior to the first, second and fifth doxorubicin chemotherapy. Twenty-five dogs were enrolled; six experienced acute hypotension with two requiring hospitalization. Self-limiting elevation of ALT was observed in one dog. A statistically significant survival benefit was not seen in this study in eBAT-treated dogs compared with a Contemporary comparison group of dogs with stages 1-3 haemangiosarcoma treated with standard of care alone. Our results indicate that repeated dosing cycles of eBAT starting 1 week prior to doxorubicin chemotherapy led to greater toxicity and reduced efficacy compared with a single cycle given between surgery and a delayed start of chemotherapy. Further work is needed to understand the precise mechanisms of action of eBAT in order to optimize its clinical benefits in the treatment of canine haemangiosarcoma and other tumours. IACUC Protocols 1110A06186 and 1507-32804A.

Late Graft Loss After Kidney Transplantation: Is "Death With Function" Really Death With a Functioning Allograft?

BACKGROUND: About half of late kidney allograft losses are attributed to death with function (DWF), a poorly characterized outcome. An ongoing question is whether DWF is a consequence of chronic allograft dysfunction. Using the prospective Long-term Deterioration of Kidney Allograft Function study database, we sought to better define the impact, phenotype, and clinical course of DWF in the current era. METHODS: Three thousand five hundred eighty-seven kidney recipients with functional grafts at 90 days post-transplant were followed prospectively for a median of 5.2 years. RESULTS: Characteristics at transplantation in those with DWF (N = 350, 9.8%) differed from those who otherwise lost their grafts (death-censored graft failure [DC-GF], N = 295, 8.2%) or maintained function (N = 2942, 82.0%); DWF patients were older, sicker, and had been on dialysis longer, with more preexisting cardiovascular disease, whereas DC-GF patients experienced more early rejection, more acute rejection after 90 days, and a clinically significant decrease in kidney function before graft failure. In contrast, the clinical course after transplantation in DWF patients did not differ before death from those who maintained function throughout. CONCLUSIONS: DWF and DC-GF in kidney transplant recipients represent differing clinical phenotypes occurring in distinct patient populations. Reducing the impact of DWF requires better definition of causes and clinical course and then trials of therapies to improve outcomes. Composite endpoints in clinical trials that group DWF and DC-GF together may obscure important clinical findings.

Exogenous progesterone for smoking cessation in men and women: a pilot double-blind, placebo-controlled randomized clinical trial.

BACKGROUND AND AIMS: In some clinical studies men and women have been found to differ in their ability to quit smoking, perhaps as a result of progesterone. The primary aim of this study was to provide a preliminary test of whether progesterone (PRO), compared with placebo (PBO), was more effective for smoking cessation in men and women. DESIGN: Pilot double-blind, placebo-controlled randomized clinical trial. SETTING: Minneapolis/St Paul metro area, Minnesota, USA. PARTICIPANTS: A total of 216 participants were randomized, including 113 men (18-60 years; PRO = 56, PBO = 57) and 103 women (18-50 years, pre-menopausal with self-reported regular menstrual cycles; PRO = 51, PBO = 52). INTERVENTION: Participants were randomized (1 : 1 within sex group) to either PRO (200 mg twice daily) or PBO. Participants were assigned a quit date approximately 7 days after starting medication (luteal phase for women) and were followed for 12 weeks to assess relapse. MEASUREMENTS: The primary outcome was self-reported 7-day point prevalence abstinence (PPA) at week 4. Secondary outcomes included 7-day PPA at weeks 8 and 12, prolonged abstinence, continuous abstinence, urine cotinine < 50 ng/ml, expired carbon monoxide ≤ 5 parts per million (p.p.m.) and days to relapse. FINDINGS: There was a significant difference in 7-day PPA at week 4 among women [PRO: 18 (35.3%) versus PBO: 9 (17.3%), odds ratio (OR) = 2.61, 95% confidence interval (CI) = 1.04, 6.54, P = 0.041], but not among men [PRO: 13 (23.2%) versus PBO: 12 (21.1%), 1.13 (0.47, 2.76), P = 0.782]. There was some evidence that PRO delayed relapse in women (days to relapse; PRO: 20.5 ± 29.6 versus PBO: 14.3 ± 26.8, P = 0.03) but not in men (PRO: 13.4 ± 25.9 versus PBO: 13.3 ± 23.8, P = 0.69). CONCLUSIONS: Oral micronized progesterone may aid smoking cessation in women.

Long-term follow-up of the DeKAF cross-sectional cohort study.

The DeKAF study was developed to better understand the causes of late allograft loss. Preliminary findings from the DeKAF cross-sectional cohort (with follow-up < 20 months) have been published. Herein, we present long-term outcomes in those recipients (mean follow-up ± SD, 6.6 ± 0.7 years). Eligibility included being transplanted prior to October 1, 2005; serum creatinine ≤ 2.0 mg/dL on January 1, 2006; and subsequently developing new-onset graft dysfunction leading to a biopsy. Mean time from transplant to biopsy was 7.5 ± 6.1 years. Histologic findings and DSA were studied in relation to postbiopsy outcomes. Long-term follow-up confirms and expands the preliminary results of each of 3 studies: (1) increasing inflammation in area of atrophy (irrespective of inflammation in nonscarred areas [Banff i]) was associated with increasingly worse postbiopsy death-censored graft survival; (2) hierarchical analysis based on Banff scores defined clusters (entities) that differed in long-term death-censored graft survival; and (3) C4d-/DSA- recipients had significantly better (and C4d+/DSA+ worse) death-censored graft survival than other groups. C4d+/DSA- and C4d-/DSA+ had similar intermediate death-censored graft survival. Clinical and histologic findings at the time of new-onset graft dysfunction define high- vs low-risk groups for long-term death-censored graft survival, even years posttransplant. These findings can help differentiate groups for potential intervention studies.

Individual Differences in Working Memory Capacity Predict Topiramate-Related Cognitive Deficits.

PURPOSE/BACKGROUND: Topiramate (TPM) and lorazepam (LZP) are two examples of frequently prescribed medications that are associated with a high incidence of cognitive impairment; however, the factors that underlie interindividual differences in side effect profiles have not been fully characterized. Our objective was to determine whether working memory capacity (WMC), the amount of information that can be stored and manipulated in memory over short time intervals, is one such factor. METHODS/PROCEDURES: Twenty-nine healthy volunteers completed a double-blind, randomized, placebo-controlled crossover study during which they received placebo (PBO), TPM, and LZP in random order. Four hours after drug administration, a blood draw was taken to establish drug concentrations, and subjects performed a verbal working memory task while the accuracy and reaction time of their responses were recorded. Working memory capacity was calculated based on accuracy rates during the PBO session, and the role of WMC in moderating the severity of drug-related cognitive impairment was assessed by examining drug-related performance changes from PBO as a function of WMC. FINDINGS/RESULTS: Both TPM and LZP had a negative impact on task performance, although only TPM-related deficits were modulated by WMC; high WMC was associated with more severe impairments and heightened sensitivity to increasing TPM concentrations. IMPLICATIONS/CONCLUSIONS: We have identified a potential clinical risk factor, high WMC, which is associated with drug-related adverse cognitive events. These data provide objective evidence in support of clinical observations that high-functioning patients are more likely to experience severe cognitive impairments.

Late graft failure after kidney transplantation as the consequence of late versus early events.

Beyond the first posttransplant year, 3% of kidney transplants fail annually. In a prospective, multicenter cohort study, we tested the relative impact of early versus late events on risk of long-term death-censored graft failure (DCGF). In grafts surviving at least 90 days, early events (acute rejection [AR] and delayed graft function [DGF] before day 90) were recorded; serum creatinine (Cr) at day 90 was defined as baseline. Thereafter, a 25% rise in serum Cr or new-onset proteinuria triggered graft biopsy (index biopsy, IBx), allowing comparison of risk of DCGF associated with early events (AR, DGF, baseline serum Cr >2.0 mg/dL) to that associated with later events (IBx). Among 3678 patients followed for 4.7 ± 1.9 years, 753 (20%) had IBx at a median of 15.3 months posttransplant. Early AR (HR = 1.77, P < .001) and elevated Cr at Day 90 (HR = 2.56, P < .0001) were associated with increased risk of DCGF; however, later-onset dysfunction requiring IBx had far greater impact (HR = 13.8, P < .0001). At 90 days, neither clinical characteristics nor early events distinguished those who subsequently did or did not undergo IBx or suffer DCGF. To improve long-term kidney allograft survival, management paradigms should promote prompt diagnosis and treatment of both early and later events.

Randomized controlled trial comparing simultaneous versus optimized sequential interventricular stimulation during cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality and improves symptoms in patients with systolic heart failure (HF) and ventricular dyssynchrony. This randomized, double-blind, controlled study evaluated whether optimizing the interventricular stimulating interval (V-V) to sequentially activate the ventricles is clinically better than simultaneous V-V stimulation during CRT. METHODS: Patients with New York Heart Association (NYHA) III or IV HF, meeting both CRT and implantable cardioverter-defibrillator indications, randomly received either simultaneous CRT or CRT with optimized V-V settings for 6 months. Patients also underwent echocardiography-guided atrioventricular delay optimization to maximize left ventricular filling. The V-V optimization involved minimizing the left ventricular septal to posterior wall motion delay during CRT. The primary objective was to demonstrate noninferiority using a clinical composite end point that included mortality, HF hospitalization, NYHA functional class, and patient global assessment. Secondary end points included changes in NYHA classification, 6-minute hall walk distance, quality of life, peak VO(2), and event-free survival. RESULTS: The composite score improved in 75 (64.7%) of 116 simultaneous patients and in 92 (75.4%) of 122 optimized patients (P < .001, for noninferiority). A prespecified test of superiority showed that more optimized patients improved (P = .03). New York Heart Association functional class improved in 58.0% of simultaneous patients versus 75.0% of optimized patients (P = .01). No significant differences in exercise capacity, quality of life, peak VO(2), or HF-related event rate between the 2 groups were observed. CONCLUSIONS: These findings demonstrate modest clinical benefit with optimized sequential V-V stimulation during CRT in patients with NYHA class III and IV HF. Optimizing V-V timing may provide an additional tool for increasing the proportion of patients who respond to CRT.

Results of a 25-year longitudinal analysis of the serologic incidence of syphilis in a cohort of HIV-infected patients with unrestricted access to care.

BACKGROUND: The well-described biologic and epidemiologic associations of syphilis and HIV are particularly relevant to the military, as service members are young and at risk for sexually transmitted infections. We therefore used the results of serial serologic testing to determine the prevalence, incidence, and risk factors for incident syphilis in a cohort of HIV-infected Department of Defense beneficiaries. METHODS: Participants with a positive nontreponemal test at HIV diagnosis that was confirmed on treponemal testing were categorized as prevalent cases, and participants with an initial negative nontreponemal test who subsequently developed a confirmed positive nontreponemal test were categorized as incident cases. RESULTS: At HIV diagnosis, the prevalence of syphilis was 5.8% (n = 202). A total of 4239 participants contributed 27,192 person-years (PY) to the incidence analysis and 347 (8%) developed syphilis (rate, 1.3/100 PY; [1.1, 1.4]). Syphilis incidence was highest during the calendar years 2006 to 2009 (2.5/100 PY; [2.0, 2.9]). In multivariate analyses, younger age (per 10 year increase hazard ratio [HR], 0.8; [0.8-0.9]), male gender (HR, 5.6; [2.3-13.7]), non-European-American ethnicity (African-American HR, 3.2; [2.5-4.2]; Hispanic HR, 1.9; [1.2-3.0]), and history of hepatitis B (HR, 1.5; [1.2-1.9]) or gonorrhea (HR, 1.4; [1.1-1.8]) were associated with syphilis. CONCLUSIONS: The significant burden of disease both at and after HIV diagnosis, observed in this cohort, suggests that the cost-effectiveness of extending syphilis screening to at-risk military members should be assessed. In addition, HIV-infected persons continue to acquire syphilis, emphasizing the continued importance of prevention for positive programs.

Development of chronic hepatitis B virus infection in hepatitis B surface antigen negative HIV/HBV co-infected adults: a rare opportunistic illness.

Changes in serologic status in human immunodeficiency virus (HIV)/hepatitis B virus (HBV) co-infected individuals with either isolated anti-HBc or resolved HBV infection have been reported, but the frequency of clinically meaningful long-term serologic changes is not well-defined. This study therefore, examined longitudinal serologic status for hepatitis B surface antigen (HBsAg)-negative HIV/HBV co-infected participants in a large cohort. Among 5,222 cohort participants, 347 (7%) were initially isolated anti-HBc positive, and 1,073 (21%) had resolved HBV infection (concurrently reactive for anti-HBc and anti-HBs). Thirty-three (10%) of the 347 participants with isolated anti-HBc were later positive for HBsAg at least once, compared with 3 (0.3%) of those with resolved HBV (P < 0.001). A total of 14 participants became persistently positive for HBsAg and were thus classified as having late-onset chronic HBV infection at a median of 3.7 years after initial HBV diagnosis. For those initially with HBsAg-negative HIV/HBV co-infection, the rate of late-onset chronic HBV infection was 1.39/1,000 person-years. Those with late-onset chronic HBV infection experienced significant decreases in CD4 cell counts (P = 0.002) with a mean of 132 cells/µl at the time of late-onset chronic HBV infection, but no factor distinguished those who were positive for HBsAg only once from those that developed late-onset chronic HBV infection. Over a median of 2.9 years following late-onset chronic HBV infection, 3 of 14 subsequently lost HBsAg. The occurrence of late-onset chronic HBV infection in HBsAg negative HIV/HBV co-infected adults appears to be one important, albeit rare, clinical event seen almost exclusively in those with isolated anti-HBc and low CD4 cell count.

Evidence for antibody-mediated injury as a major determinant of late kidney allograft failure.

BACKGROUND: Late graft failure (LGF) is believed to be the consequence of immunologic and nonimmunologic insults leading to progressive deterioration in kidney function. We studied recipients with new onset late kidney graft dysfunction (n=173) to determine the importance of C4d staining and circulating donor-specific antibody (DSA) in subsequent LGF. METHODS: One hundred seventy-three subjects transplanted before October 1, 2005 (mean time after transplant 7.3+/-6.0 years) had a baseline serum creatinine level of 1.4+/-0.3 mg/dL before January 1, 2006 and underwent biopsy for new onset graft dysfunction after that date (mean creatinine at biopsy 2.7+/-1.6 mg/dL). Statistical analysis was based on central DSA and blinded pathology determinations. RESULTS: Subjects were divided into four groups based on C4d and DSA: no C4d, no DSA (group A; n=74); only DSA (group B; n=31); only C4d (group C; n=28); and both C4d and DSA (group D; n=40). Among DSA+ recipients (groups B and D), group D had broader reactivity and a stronger DSA response. After 2 years, groups C and D (C4d+) were at significantly greater risk for LGF than groups A and B. Adjusting for inflammation (Banff i, t, g, and ptc scores) did not change the outcome. Local diagnosis of calcineurin inhibitor nephrotoxicity was spread across all four subgroups and did not impact risk of LGF. CONCLUSIONS: Evidence of antibody-mediated injury (DSA or C4d) is common (57%) in patients with new onset late kidney allograft dysfunction. The risk of subsequent graft failure is significantly worse in the presence of C4d+ staining.

Natural history of colonization with gram-negative multidrug-resistant organisms among hospitalized patients.

OBJECTIVE: To determine the anatomic sites and natural history of colonization with gram-negative multidrug-resistant organisms (MDROs). DESIGN: Prospective, longitudinal cohort study. SETTING: Walter Reed Army Medical Center, a 236-bed tertiary care center in Washington, DC. PATIENTS: Deployed subjects (ie, inpatients medically evacuated from Iraq or Afghanistan) or nondeployed subjects admitted to the same hospital. METHODS: Consenting patients had 6 anatomic sites cultured every 3 days for 2 weeks and then weekly. Gram-negative organisms resistant to 3 or more classes of antibiotics were considered MDROs. Isolates were genotyped using pulsed-field gel electrophoresis. Clinical data, data on antibiotic use, and clinical culture results were collected. RESULTS: Of 60 deployed subjects, 14 (23%) were colonized with an MDRO at admission, and 13 (22%) had incident colonization during hospitalization. The groin was the most sensitive anatomic site for detecting MDRO colonization, and all but one subject remained colonized for the duration of their hospitalization. Sixty percent of subjects with incident Acinetobacter colonization and 25% of subjects with incident Klebsiella colonization had strains that were related to those isolated from other subjects. Of 60 nondeployed subjects, 5 (8%) were colonized with an MDRO at admission; all had recent healthcare contact, and 1 nondeployed subject had an isolate related to a strain recovered from a deployed subject. CONCLUSIONS: Colonization with gram-negative MDROs is common among patients with war-related trauma admitted to a military hospital and also occurs among nondeployed patients with recent healthcare contact. The groin is the most sensitive anatomic site for active surveillance, and spontaneous decolonization is rare.

The effect of human immunodeficiency virus on hepatitis B virus serologic status in co-infected adults.

BACKGROUND: Factors associated with serologic hepatitis B virus (HBV) outcomes in HIV-infected individuals remain incompletely understood, yet such knowledge may lead to improvements in the prevention and treatment of chronic HBV infection. METHODS AND FINDINGS: HBV-HIV co-infected cohort participants were retrospectively analyzed. HBV serologic outcomes were classified as chronic, resolved, and isolated-HBcAb. Chronic HBV (CHBV) was defined as the presence of HBsAg on two or more occasions at least six months apart. Risk factors for HBV serologic outcome were assessed using logistic regression. Of 2037 participants with HBV infection, 281 (14%) had CHBV. Overall the proportions of HBV infections classified as CHBV were 11%, 16%, and 19% for CD4 cell count strata of > or =500, 200-499, and <200, respectively (p<0.0001). Risk of CHBV was increased for those with HBV infection occurring after HIV diagnosis (OR 2.62; 95% CI 1.78-3.85). This included the subset with CD4 count > or =500 cells/microL where 21% of those with HBV after HIV diagnosis had CHBV compared with 9% for all other cases of HBV infection in this stratum (p = 0.0004). Prior receipt of HAART was associated with improved HBV serologic outcome overall (p = 0.012), and specifically among those with HBV after HIV (p = 0.002). In those with HBV after HIV, HAART was associated with reduced risk of CHBV overall (OR 0.18; 95% CI 0.04-0.79); including reduced risk in the subsets with CD4 > or =350 cells/microL (p<0.001) and CD4 > or =500 cells/microL (p = 0.01) where no cases of CHBV were seen in those with a recent history of HAART use. CONCLUSIONS: Clinical indicators of immunologic status in HIV-infected individuals, such as CD4 cell count, are associated with HBV serologic outcome. These data suggest that immunologic preservation through the increased use of HAART to improve functional anti-HBV immunity, whether by improved access to care or earlier initiation of therapy, would likely improve HBV infection outcomes in HIV-infected individuals.

Epidemiology of Hepatitis B virus infection in a US cohort of HIV-infected individuals during the past 20 years.

BACKGROUND: The epidemiologic trends of hepatitis B virus (HBV) infection in human immunodeficiency virus (HIV)-infected patients over the past 20 years are largely unknown. METHODS: Prevalence and risk factors for HBV infection overall, at the time of HIV infection, and after HIV infection were examined in an ongoing observational HIV cohort study. Risk factors for HBV infection at the time of diagnosis of HIV infection were evaluated using logistic regression, and risk of incident HBV infection after diagnosis of HIV infection was evaluated using Cox proportional hazards models. RESULTS: Of the 2769 evaluable participants, 1078 (39%) had HBV infection, of whom 117 (11%) had chronic HBV infection. The yearly cross-sectional prevalence of HBV infection decreased from a peak of 49% in 1995 to 36% in 2008 (P < .001). The prevalence of HBV infection at the time of diagnosis of HIV infection decreased during 1989-2008 from 34% to 9% (P < .001). The incidence of HBV infection after diagnosis of HIV infection decreased from 4.0 cases per 100 person-years during the pre-highly active antiretroviral therapy (HAART) era to 1.1 cases per 100 person-years during the HAART era (P < .001); however, this incidence remained unchanged during 2000-2008 (P = .49), with >20% of HBV infections occurring after HIV infection being chronic. Decreased risk of HBV infection after diagnosis of HIV infection was associated with higher CD4 cell count and the use of HBV-active HAART. Receipt of 1 dose of HBV vaccine was not associated with reduced risk of HBV infection after diagnosis of HIV infection. CONCLUSIONS: Although the burden of HBV infection overall is slowly decreasing among HIV-infected individuals, the persistent rate of HBV infection after diagnosis of HIV infection raises concern that more-effective prevention strategies may be needed to significantly reduce the prevalence of HBV infection in this patient population.