Publications

BACKGROUND

Primary amoebic meningoencephalitis (PAM) is a rare, often lethal, cause of encephalitis, for which early diagnosis and prompt initiation of combination antimicrobials may improve clinical outcomes.

METHODS

In this study, we sequenced a full draft assembly of the Balamuthia mandrillaris genome (44.2 Mb in size) from a rare survivor of PAM, and recovered the mitochondrial genome from six additional Balamuthia strains. We also used unbiased metagenomic next-generation sequencing (NGS) and SURPI bioinformatics analysis to diagnose an ultimately fatal case of Balamuthia mandrillaris encephalitis in a 15-year-old girl.

RESULTS AND DISCUSSION

Comparative analysis of the mitochondrial genome and high-copy number genes from six additional Balamuthia mandrillaris strains demonstrated remarkable sequence variation, and the closest Balamuthia homologs corresponded to other amoebae, hydroids, algae, slime molds, and peat moss. Real-time NGS testing of hospital day 6 CSF and brain biopsy samples detected Balamuthia on the basis of high-quality hits to 16S and 18S ribosomal RNA sequences present in the National Center for Biotechnology Information (NCBI) nt reference database. The presumptive diagnosis of PAM by visualization of amoebae on brain biopsy histopathology and NGS analysis was subsequently confirmed at the US Centers for Disease Control and Prevention (CDC) using a Balamuthia-specific PCR assay. Retrospective analysis of a day 1 CSF sample revealed that more timely identification of Balamuthia by metagenomic NGS, potentially resulting in a better clinical outcome, would have required availability of the complete genome sequence.

CONCLUSIONS

These results underscore the diverse evolutionary origins of Balamuthia mandrillaris, provide new targets for diagnostic assay development, and will facilitate further investigations of the biology and pathogenesis of this eukaryotic pathogen. The failure to identify PAM from a day 1 sample without a fully sequenced Balamuthia genome in the database highlights the critical importance of whole-genome reference sequences for microbial detection by metagenomic NGS.

IMPORTANCE

There has been limited surveillance for acute flaccid paralysis in North America since the regional eradication of poliovirus. In 2012, the California Department of Public Health received several reports of acute flaccid paralysis cases of unknown etiology.

OBJECTIVE

To quantify disease incidence and identify potential etiologies of acute flaccid paralysis cases with evidence of spinal motor neuron injury.

DESIGN, SETTING, AND PARTICIPANTS

Case series of acute flaccid paralysis in patients with radiological or neurophysiological findings suggestive of spinal motor neuron involvement reported to the California Department of Public Health with symptom onset between June 2012 and July 2015. Patients meeting diagnostic criteria for other acute flaccid paralysis etiologies were excluded. Cerebrospinal fluid, serum samples, nasopharyngeal swab specimens, and stool specimens were submitted to the state laboratory for infectious agent testing.

MAIN OUTCOMES AND MEASURES

Case incidence and infectious agent association.

RESULTS

Fifty-nine cases were identified. Median age was 9 years (interquartile range [IQR], 4-14 years; 50 of the cases were younger than 21 years). Symptoms that preceded or were concurrent included respiratory or gastrointestinal illness (n = 54), fever (n = 47), and limb myalgia (n = 41). Fifty-six patients had T2 hyperintensity of spinal gray matter on magnetic resonance imaging and 43 patients had cerebrospinal fluid pleocytosis. During the course of the initial hospitalization, 42 patients received intravenous steroids; 43, intravenous immunoglobulin; and 13, plasma exchange; or a combination of these treatments. Among 45 patients with follow-up data, 38 had persistent weakness at a median follow-up of 9 months (IQR, 3-12 months). Two patients, both immunocompromised adults, died within 60 days of symptom onset. Enteroviruses were the most frequently detected pathogen in either nasopharynx swab specimens, stool specimens, serum samples (15 of 45 patients tested). No pathogens were isolated from the cerebrospinal fluid. The incidence of reported cases was significantly higher during a national enterovirus D68 outbreak occurring from August 2014 through January 2015 (0.16 cases per 100,000 person-years) compared with other monitoring periods (0.028 cases per 100,000 person-years; P <.001).

CONCLUSIONS AND RELEVANCE

In this series of patients identified in California from June 2012 through July 2015, clinical manifestations indicated a rare but distinct syndrome of acute flaccid paralysis with evidence of spinal motor neuron involvement. The etiology remains undetermined, most patients were children and young adults, and motor weakness was prolonged.

BACKGROUND

In the context of orthotopic liver transplantation (OLT), renal dysfunction is used as a criterion for simultaneous liver-kidney transplantation. Changes in glomerular filtration rate (GFR) the year before and after OLT have not been well defined.

METHODS

In a cohort of 416 OLT patients from 1996 to 2009, estimated GFR (eGFR) was assessed during the 12 months before OLT (period A), at time of OLT (period B), and the 12 months after OLT (period C). Outcomes included progression to end stage renal disease (ESRD), length of stay, and mortality.

RESULTS

The overall rate of progression to ESRD over 15 years of follow-up was 0.155/person-year and was strongly associated with eGFR <60 (hazard ratio [HR] = 2.7; P < 0.001), diabetes (HR = 2.6; P < 0.001), and with a combination of the 2 (HR = 5.5; P < 0.0001). Mean eGFR decreased from period A (86 mL/min per 1.73 m) to period B (77; P < 0.001) to period C (71; P < 0.001), with similar decreases in eGFR across subgroups of clinical variables. Patients with eGFR less than 60 mL/min per 1.73 m at OLT had acute and large decreases in eGFR from periods A to B, then increases to period C. Length of stay was associated with eGFR at OLT, hepatorenal syndrome, dialysis requirement, model for end-stage liver disease score, and alcoholic liver disease. Twelve-month mortality was strongly associated with time-dependent change in eGFR, hepatorenal syndrome, dialysis requirement, hepatitis C, and model for end-stage liver disease era transplantation but was not associated with eGFR at OLT.

CONCLUSIONS

Among OLT patients, renal function worsened in all subgroups from before to after OLT, but the association of progression to ESRD was particularly high among patients with both diabetes and eGFR less than 60 at the time of OLT. This suggests that diabetes could be considered as a criterion when making decisions regarding simultaneous liver-kidney transplantation.

RATIONALE

Frailty is associated with morbidity and mortality in abdominal organ transplantation but has not been examined in lung transplantation.

OBJECTIVES

To examine the construct and predictive validity of frailty phenotypes in lung transplant candidates.

METHODS

In a multicenter prospective cohort, we measured frailty with the Fried Frailty Phenotype (FFP) and Short Physical Performance Battery (SPPB). We evaluated construct validity through comparisons with conceptually related factors. In a nested case-control study of frail and nonfrail subjects, we measured serum IL-6, tumor necrosis factor receptor 1, insulin-like growth factor I, and leptin. We estimated the association between frailty and disability using the Lung Transplant Valued Life Activities disability scale. We estimated the association between frailty and risk of delisting or death before transplant using multivariate logistic and Cox models, respectively.

MEASUREMENTS AND MAIN RESULTS

Of 395 subjects, 354 completed FFP assessments and 262 completed SPPB assessments; 28% were frail by FFP (95% confidence interval [CI], 24-33%) and 10% based on the SPPB (95% CI, 7-14%). By either measure, frailty correlated more strongly with exercise capacity and grip strength than with lung function. Frail subjects tended to have higher plasma IL-6 and tumor necrosis factor receptor 1 and lower insulin-like growth factor I and leptin. Frailty by either measure was associated with greater disability. After adjusting for age, sex, diagnosis, and transplant center, both FFP and SPPB were associated with increased risk of delisting or death before lung transplant. For every 1-point worsening in score, hazard ratios were 1.30 (95% CI, 1.01-1.67) for FFP and 1.53 (95% CI, 1.19-1.59) for SPPB.

CONCLUSIONS

Frailty is prevalent among lung transplant candidates and is independently associated with greater disability and an increased risk of delisting or death.

OBJECTIVE

We examined whether nonadherence to hydroxychloroquine (HCQ) or immunosuppressive medications (ISMs) was associated with higher subsequent acute care utilization among Medicaid beneficiaries with systemic lupus erythematosus (SLE).

METHODS

We utilized US Medicaid data from 2000-2006 to identify adults ages 18-64 years with SLE who were new users of HCQ or ISMs. We defined the index date as receipt of HCQ or ISMs without use in the prior 6 months. We measured adherence using the medication possession ratio (MPR), the proportion of days covered by total days' supply dispensed, for the 1-year post-index date. Our outcomes were all-cause and SLE-related emergency department (ED) visits and hospitalizations in the subsequent year. We used multivariable Poisson regression models to examine the association between nonadherence (MPR <80%) and acute care utilization, adjusting for sociodemographics and comorbidities.

RESULTS

We identified 9,600 HCQ new users and 3,829 ISM new users with SLE. The mean ± SD MPR for HCQ was 47.8% ± 30.3% and for ISMs was 42.7% ± 30.7%. Seventy-nine percent of HCQ users and 83% of ISM users were nonadherent (MPR <80%). In multivariable models, among HCQ users, the incidence rate ratio (IRR) of ED visits was 1.55 (95% confidence interval [95% CI] 1.43-1.69) and the IRR of hospitalizations was 1.37 (95% CI 1.25-1.50), comparing nonadherers to adherers. For ISM users, the IRR of ED visits was 1.64 (95% CI 1.42-1.89) and of hospitalizations was 1.67 (95% CI 1.41-1.96) for nonadherers versus adherers.

CONCLUSION

In this cohort, nonadherence to HCQ and ISMs was common and was associated with significantly higher subsequent acute care utilization.

BACKGROUND

Antiretroviral therapy (ART) adherence interruptions have been associated with viral rebound; however, the true risk is unknown because HIV RNA has never been measured during ongoing interruptions.

METHODS

The Uganda AIDS Rural Treatment Outcomes Study is an observational longitudinal cohort of adults initiating ART. We monitored adherence with the device that wirelessly transmits records of device openings, and routinely assessed HIV RNA quarterly. When lapses of 48+ hours between device openings were detected, we made unannounced visits to participants to investigate the cause and assess HIV RNA. Generalized estimating equation logistic regressions were used to assess factors associated with viral rebound.

RESULTS

We followed 479 participants (median: 25 months per participant). Most were women (72%), median age was 36 years, median pre-ART CD4 count was 198 cells per microliter, median pre-ART HIV RNA level was 5.0 log10 copies per milliliter, and median duration of prior viral suppression was 13 months. A total of 587 adherence interruptions followed confirmed prior viral suppression, of which 13 (2%) had detectable viral rebound. Viral rebound was associated with duration of adherence interruption (odds ratio: 1.25 for each day beyond 48 hours; P = 0.007) and 30-day adherence before the interruption (odds ratio: 0.73; P = 0.02).

DISCUSSION

This article is the first demonstration of HIV RNA rebound during adherence interruptions objectively measured in real time. Odds of viral rebound increased by 25% with each day beyond 48 hours. Real-time adherence monitoring was feasible in a sub-Saharan African setting. Further research should assess the potential for real-time adherence interventions to sustain adherence to affordable first-line regimens.

INTRODUCTION

Numerous treatments are approved for metastatic castration-resistant prostate cancer (mCRPC), including sipuleucel-T, an FDA-approved immunotherapy.

MATERIALS AND METHODS

In this paper we review recent data providing insights into the mechanism of action of sipuleucel-T which suggests sipuleucel-T may be most effective when administered to mCRPC patients with a low burden of disease. Published and presented data from the sipuleucel-T clinical trials NeoACT (NCT00715104), IMPACT (NCT00065442), ProACT (NCT00715078), PROTECT (NCT00779402), OpenACT (NCT00901342), STAMP (NCT01487863) and STAND (NCT01431391), individually or across trials, were included in this review.

RESULTS

Overall, a growing body of evidence supports the concept that sipuleucel-T, like some other immunotherapies, has long term effects that result in an overall survival benefit. mCRPC patients with a low tumor burden may derive a greater therapeutic benefit, since the immune response may be more robust when the disease is less advanced and immunosuppressive effects from the tumor or traditional therapies may be less marked. In addition, treatment with sipuleucel-T in early mCRPC does not preclude subsequent treatment with other approved mCRPC therapies.

CONCLUSIONS

Collectively, clinical data to date suggest the optimal timing for sipuleucel-T treatment may be early in the mCRPC treatment paradigm.