Faculty Bibliography

Background.: Observational studies have suggested a relationship between the plasma concentration of indoxyl sulfate (IS) and p -cresyl sulfate (PCS), small gut-derived 'uremic solutes', and the high incidence of uremic cardiomyopathy in patients with end-stage renal disease (ESRD). IS and PCS are derived from the metabolism of dietary components (tryptophan and tyrosine) by gut bacteria. This pilot study was designed to examine the effects of a poorly absorbable antibiotic (vancomycin) on the plasma concentration of two gut-derived 'uremic solutes', IS and PCS, and on the composition of the gut microbiome. Methods.: Plasma concentrations of IS and PCS were measured by MS-HPLC. The gut microbiome was assessed in stool specimens sequenced for the 16S rRNA gene targeting the V4 region. Results.: The pre-dialysis mean plasma concentrations of both IS and PCS were markedly elevated. Following the administration of vancomycin (Day 0), the IS and PCS concentrations decreased at Day 2 or Day 5 and returned to baseline by Day 28. Following vancomycin administration, several changes in the gut microbiome were observed. Most striking was the decrease in diversity, a finding that was evident on Day 7 and was still evident at Day 28. There was little change at the phylum level but at the genus level, broad population changes were noted. Changes in the abundance of several genera appeared to parallel the concentration of IS and PCS. Conclusions.: These findings suggest that alteration of the gut microbiome, by an antibiotic, might provide an important strategy in reducing the levels of IS and PCS in ESRD.

Background: There is growing evidence that the accumulation of protein-bound uremic retention solutes, such as indoxyl sulfate (IS), p-cresyl sulfate (PCS) and kynurenic acid (KA), play a role in the accelerated cardiovascular disease seen in patients undergoing chronic hemodialysis. Protein-binding, presumably to albumin, renders these solutes poor-dialyzable. We had previously observed that the concentration of free solute and its unbound fraction were markedly reduced at the end of hemodialysis. We hypothesized that solute binding might be pH-dependent and the changes attributable to the higher serum pH at the end of hemodialysis. In vitro, acidification of uremic plasma to pH 6 greatly increased the proportion of unbound indoxyl sulfate.
Method(s): We tested our hypothesis by reducing the dialysate bicarbonate buffer concentration to 25 mEq/L for the initial half of hemodialysis ('isohydric dialysis'). Eight stable hemodialysis patients underwent 'isohydric dialysis' and, midway, were switched to standard buffer (37 mEq/L). A second dialysis, 2 days later, employed standard buffer throughout.
Result(s): We found a clearcut separation of blood pH and bicarbonate concentrations 90 minutes following 'isohydric dialysis' (pH = 7.37, HCO3 =22.4 mEq/l) and standard dialysis (pH= 7.49, HCO3 = 29.5). Analysis of free and bound concentrations of uremic retention solutes confirmed our prediction that binding of solute is affected by pH. However, in mixed models analysis, we found that the reduction in total uremic solute concentration during dialysis accounted for a greater proportion of the variation in free concentration, presumably an effect of saturation binding to albumin, than did the relatively small change in pH produced by isohydric dialysis.
Conclusion(s): These findings suggest that modification of dialysis technique that would expose blood to a transient decrease in pH might increase the free fraction of solute and enhance the efficacy of hemodialysis in the removal of protein-bound uremic retention solutes

The neurofibromatoses (neurofibromatosis type 1, neurofibromatosis type 2 and schwannomatosis) are rare disorders having clinical manifestations that vary greatly from patient to patient. The rarity and variability of these disorders has made it challenging for investigators to identify sufficient numbers of patients with particular clinical characteristics or specific germline mutations for participation in interventional studies. Similarly, because the natural history of all types of neurofibromatosis (NF) is variable and unique for each individual, it is difficult to identify meaningful clinical outcome measures for potential therapeutic interventions. In 2012, the Children's Tumor Foundation created a web-based patient-entered database, the NF Registry, to inform patients of research opportunities for which they fit general eligibility criteria and enable patients to contact investigators who are seeking to enroll patients in approved trials. Registrants were recruited through CTF-affiliated NF clinics and conferences, through its website, and by word-of-mouth and social media. Following online consent, demographic information and details regarding manifestations of NF were solicited on the Registry website. Statistical analyses were performed on data from a cohort of 4680 registrants (the number of registrants as of October 9, 2015) who met diagnostic criteria for one of the 3 NF conditions. The analyses support our hypothesis that patient-reported symptom incidences in the NF Registry are congruent with published clinician-sourced data. Between April 26, 2013 and July 8, 2016, the registry has been useful to investigators in recruitment, particularly for observational trials, especially those for development of patient-reported outcomes.

OBJECTIVES: To examine uptake of screening for all individuals born between 1945 and 1965 (referred to by the Centers for Disease Control and Prevention as the "birth cohort") and outline preliminary HCV prevalence data in the New York City jail system. METHODS: Data were extracted from electronic health records for all individuals screened for HCV between June 13, 2013, and June 13, 2014, in New York City jails. We used the Abbott EIA 2.0 HCV antibody assay for testing. RESULTS: In the year of study, 56 590 individuals were incarcerated; 15.1% were born between 1945 and 1965, and 84.6% were born after 1965. HCV screening was completed for 64.1% of the birth cohort and for 11.1% born after 1965, with 55.1% and 43.8% of cases found in these groups, respectively. The overall seropositivity rate was 20.6%. CONCLUSIONS: Birth cohort screening in a large jail system identified many HCV cases, but HCV infection was common among younger age groups. Public Health Implications. Universal screening may be warranted pending further study including cost-effectiveness analyses. (Am J Public Health. Published online ahead of print May 19, 2016: e1-e2. doi:10.2105/AJPH.2016.303163).

The current study identified bacterial factors that may improve management of methicillin-resistant Staphylococcus aureus (MRSA) nosocomial pneumonia. Isolates were obtained from 386 patients enrolled in a randomized, controlled study of antibiotic efficacy. Isolates were screened for production of virulence factors and for vancomycin susceptibility. After adjustment for host factors such as severity of illness and treatment modality, cytotoxic activity was strongly and inversely associated with mortality; however, it had no effect on clinical cure. Isolates having low cytotoxicity, which were derived largely from healthcare-associated clones, exhibited a greater prevalence of vancomycin heteroresistance, and they were recovered more often from patients who were older and frailer. Additionally, a clone with low cytotoxic activity was associated with death and poor clinical improvement. Clone specificity and attenuated virulence appear to be associated with outcome. To our knowledge, these are the first correlations between MRSA virulence and mortality in nosocomial pneumonia.

Piperacillin-tazobactam (PTZ) is frequently used as empirical and targeted therapy for Gram-negative sepsis. Time-dependent killing properties of PTZ support the use of extended-infusion (EI) dosing; however, studies have shown inconsistent benefits of EI PTZ treatment on clinical outcomes. We performed a retrospective cohort study of adult patients who received EI PTZ treatment and historical controls who received standard-infusion (SI) PTZ treatment for presumed sepsis syndromes. Data on mortality rates, clinical outcomes, length of stay (LOS), and disease severity were obtained. A total of 843 patients (662 with EI treatment and 181 with SI treatment) were available for analysis. Baseline characteristics of the two groups were similar, except for fewer female patients receiving EI treatment. No significant differences between the EI and SI groups in inpatient mortality rates (10.9% versus 13.8%; P = 0.282), overall LOS (10 versus 12 days; P = 0.171), intensive care unit (ICU) LOS (7 versus 6 days; P = 0.061), or clinical failure rates (18.4% versus 19.9%; P = 0.756) were observed. However, the duration of PTZ therapy was shorter in the EI group (5 versus 6 days; P < 0.001). Among ICU patients, no significant differences in outcomes between the EI and SI groups were observed. Patients with urinary or intra-abdominal infections had lower mortality and clinical failure rates when receiving EI PTZ treatment. We did not observe significant differences in inpatient mortality rates, overall LOS, ICU LOS, or clinical failure rates between patients receiving EI PTZ treatment and patients receiving SI PTZ treatment. Patients receiving EI PTZ treatment had a shorter duration of PTZ therapy than did patients receiving SI treatment, and EI dosing may provide cost savings to hospitals.

We assessed programmatic gaps that prevent the optimal treatment of pediatric HIV infection despite free antiretroviral care in Kenya. Of 626 HIV-infected Kenyan children, the median age was five years, 54% were male and the mortality rate was 3.2 per 100 person-years. A total of 380 (61%) children initiated antiretroviral therapy (ART) during the study period. Among the 246 children who never started ART, 129 (52%) met the criteria for ART initiation. Immunologic failure occurred in 20% of children who received ART for >24 weeks. In multivariate analysis, immunological failure was associated with having nonimmediate relative or unrelated caregivers accompanying the child to clinic (AOR = 69.16, p = 0.008). Having >/=3 types of accompanying caregivers was also associated with virologic failure in multivariate analysis (AOR = 3.84, p = 0.03). The lost to follow-up rate was 8.7/100 persons-years for the entire cohort, and significantly higher (17.7/100 persons-years) among children not on ART (p < 0.001). Among children who do initiate ART, those with the best treatment outcomes were those who had a limited number of close relatives as caregivers and good adherence to ART. Focus on early ART initiation and education of the right caregiver will likely improve retention and quality of pediatric HIV care in Kenya.

Setting: Urban, non-governmental HIV outpatient clinic in Mombasa, Kenya. Objective: To report outcomes and assess feasibility of serial clinical screening for active TB among adults enrolled in outpatient HIV care in a resource-limited setting. Design: Longitudinal analysis of screening conducted during routine clinic visits of HIV-infected Kenyan adults. The provider-initiated screen included TB symptom assessment and targeted physical exam. Participants with >1 symptom/sign were to submit sputum for microscopy and undergo chest radiography. Results: Over 33 months, 4,854 HIV-infected outpatients were serially screened for active TB at a median interval of 3 months. Treatment for active TB was started in 127 (2.6%). Of those 127, 77 (60.6%) were diagnosed based on first screen, and 50 (39.4%) were diagnosed thereafter. Among those 50 diagnosed upon subsequent screens, 28 (56%) were identified in association with positive screens, suggesting that 22% (28 of 127) of TB diagnoses could be attributed to the serial screening protocol. Conclusion: Provider-initiated serial clinical screening during routine visits of HIV-infected outpatients continued to prompt treatment of active TB beyond initial screening. Serial screening strategies may lead to earlier TB treatment in patients receiving ongoing HIV care in resource-limited settings.

OBJECTIVE: To examine genome-wide associations in HIV-infected women with a history of cervical dysplasia compared with HIV-infected women with no history of abnormal Papanicolaou (Pap) tests. DESIGN: Case-control study using data from women analyzed for the HIV Controllers Study and enrolled in HIV treatment-naive studies in the AIDS Clinical Trials Group (ACTG). METHODS: Genotyping utilized Illumina HumanHap 650 Y or 1MDuo platforms. After quality control and principal component analysis, ~610,000 significant single nucleotide polymorphisms (SNPs) were tested for association. Threshold for significance was P < 5 x 10(-8) for genome-wide associations. RESULTS: No significant genomic association was observed between women with low-grade dysplasia and controls. The genome-wide association study (GWAS) analysis between women with high-grade dysplasia or invasive cervical cancer and normal controls identified significant SNPs. In the analyses limited to African American women, 11 SNPs were significantly associated with the development of high-grade dysplasia or cancer after correcting for multiple comparisons. The model using significant SNPs alone had improved accuracy in predicting high-grade dysplasia in African American women compared to the use of clinical data (area under the receiver operating characteristic curve for genetic and clinical model = 0.9 and 0.747, respectively). CONCLUSIONS: These preliminary data serve as proof of concept that there may be a genetic predisposition to developing high-grade cervical dysplasia in African American HIV-infected women. Given the small sample size, the results need to be validated in a separate cohort.