Faculty Bibliography

Background: Cystic fibrosis (CF) may predispose patients to urinary stone disease (USD) via several proposed mechanisms including antibiotic exposure and intestinal malabsorption. Prevalence of USD in patients with CF was estimated at 2-6% in studies with mean age 16-27 years. These data are limited by small sample sizes and single-center settings. The CF Foundation Patient Registry (CFFPR) began collecting prevalence data on USD in 2006.
Method(s): We studied 29,396 patients in the CFFPR living in 2016 to calculate age-stratified prevalence of USD.USD was assessed by trained CF clinic staff at each encounter. For 15,531 patients age 18 or older we examined associations between age, BMI, demographics, CFTR mutation class, other clinical parameters, and prevalent USD using multivariate logistic regression.
Result(s): Overall prevalence of USD was 3.1% (95% CI 2.9-3.3%). Prevalence under age 18 years was 0.4% (0.3-0.5%), 18 to 24 years, 3.1% (2.7-3.6%), 25 to 34 years, 6.4% (5.8-7.1%), 35 to 44 years, 7.5% (6.5-8.5%), and 45 years and older, 6.7% (5.8-7.8%). Mean age of all patients was 21.3 years. We also calculated prevalence for age ranges 20-29, and 30-39 years to compare with published NHANES data for the general population. Stone prevalence was 4.8% and 7.1% in in CF patients within these two age cohorts, respectively, compared to 3.4 and 6.4% in NHANES. Multivariate adjusted odds ratios for stone prevalence were significant for female sex, OR 1.4 (95% CI 1.2-1.7), severe CFTR mutations, OR 1.8 (1.2-2.5), diabetes, OR 1.2 (1.0-1.5), hypertension, OR 1.4 (1.0-1.9), and chronic macrolide therapy, OR 1.3 (1.1-1.6). BMI was not associated with USD.
Conclusion(s): USD prevalence in CFFPR may be higher than in the general population and increased with age. Some risk factors for stone disease in the general population appear significant for adult patients with CF, including hypertension and diabetes. However, BMI did not show the same relationship. Several novel associations with USD in CF patients also were identified, including a greater prevalence in women. This study is limited by the method of USD assessment; it is possible patients with more severe CF had higher rates of reported asymptomatic stones incidentally diagnosed due to more frequent imaging. As life expectancy of people with CF increases, the prevalence of USD may also increase

OBJECTIVE: To assess impact of a 52-week elosulfase alfa enzyme replacement therapy (ERT) on exercise capacity in Morquio A patients and analyze cardiorespiratory and metabolic function during exercise to uncover exercise limitations beyond skeletal abnormalities. METHODS: Morquio A patients aged >/=7 years, able to walk >200 m in the 6-minute walk test (6MWT), received elosulfase alfa 2.0 mg/kg/week (N = 15) or 4.0 mg/kg/week (N = 10) for 52 weeks in the randomized, double-blind MOR-008 study ( ClinicalTrials.gov NCT01609062) and its extension. Exercise capacity was assessed by 6MWT, 3-minute stair climb test (3MSCT), and cardiopulmonary exercise test (CPET; N = 15 dosage groups combined). RESULTS: Changes over 52 weeks in 6MWT and 3MSCT were minimal. Baseline CPET results showed impaired weight-adjusted peak oxygen uptake (VO2), partly attributable to inability to increase tidal volume during exercise. CPET measures of exercise function showed significant improvement at 25 and/or 52 weeks in exercise duration, peak workload, O2 pulse, and peak tidal volume (% increases in duration, 16.9 (P = 0.0045) and 9.4 (P = 0.0807); peak workload, 26.5 (P = 0.0026) and 21.2 (P = 0.0132); O2 pulse, 10.7 (P = 0.0187) and 2.3 (P = 0.643); peak tidal volume, 11.7 (P = 0.1117) and 29.1 (P = 0.0142)). In addition, decreased VO2/work ratio was noted (% decrease -7.6 [-11.9, 1.3] and -9.2 [-25.7, 5.1]), indicating performance of work at reduced oxygen cost. CONCLUSIONS: CPET uncovers limitation in exercise capacity in Morquio A related to reduced lung function. ERT improves exercise capacity and efficiency of oxygen utilization, not attributable to changes in cardiac or pulmonary function. Further study of the long-term impact of ERT on exercise capacity and the clinical relevance of the observed changes is warranted.

A developing brain shows intense reorganization and heightened neuronal plasticity allowing for environmental modulation of its development. During early life, maternal care is a key factor of this environment and defects in this care can derail adaptive brain development and may result in susceptibility to neuropsychiatric disorders. Nevertheless, the mechanisms by which those maternal interactions immediately impact the offspring's brain activity to initiate the pathway to pathology are not well understood. We do know that multiple neurotransmitter systems are involved, including the serotonergic system, a key neuromodulator involved in brain development and emotional regulation. We tested the importance of the serotonergic system and pups' immediate neural response to maternal presence using wireless electrophysiological recordings, a novel approach allowing us to record neural activity during pups' interactions with their mother. We found that maternal contact modulates the P10-P12 rat pups' anterior cingulate cortex (ACC) activity by notably increasing local-field potential (LFP) power in low-frequency bands. We demonstrated, by blocking serotonergic receptors, that this increase is mediated through 5-HT2 receptors (5-HT2Rs). Finally, we showed in isolated pups that enhancing serotonergic transmission, using a selective-serotonin-reuptake-inhibitor, is sufficient to enhance LFP power in low-frequency bands in a pattern similar to that observed when the mother is in the nest. Our results highlight a significant contribution of the serotonergic system in mediating changes of cortical activity in pups related to maternal presence.

The incidence of oral cancer in the United States is increasing, especially in young people and women. Patients with oral cancer report severe functional pain. Using a patient cohort accrued through the New York University Oral Cancer Center and immune-competent mouse models, we identify a sex difference in the prevalence and severity of oral cancer pain. A neutrophil-mediated endogenous analgesic mechanism is present in male mice with oral cancer. Local naloxone treatment potentiates cancer mediator-induced orofacial nociceptive behavior in male mice only. Tongues from male mice with oral cancer have significantly more infiltrating neutrophils compared to female mice with oral cancer. Neutrophils isolated from the cancer-induced inflammatory microenvironment express beta-endorphin and met-enkephalin. Furthermore, neutrophil depletion results in nociceptive behavior in male mice. These data suggest a role for sex-specific, immune cell-mediated endogenous analgesia in the treatment of oral cancer pain.

Background/UNASSIGNED:Neurofibromatosis 1 (NF1) is a monogenic model for syndromic autism. Statins rescue the social and cognitive phenotype in animal knockout models, but translational trials with subjects > 8 years using cognition/behaviour outcomes have shown mixed results. This trial breaks new ground by studying statin effects for the first time in younger children with NF1 and co-morbid autism and by using multiparametric imaging outcomes. Methods/UNASSIGNED:A single-site triple-blind RCT of simvastatin vs. placebo was done. Assessment (baseline and 12-week endpoint) included peripheral MAPK assay, awake magnetic resonance imaging spectroscopy (MRS; GABA and glutamate+glutamine (Glx)), arterial spin labelling (ASL), apparent diffusion coefficient (ADC), resting state functional MRI, and autism behavioural outcomes (Aberrant Behaviour Checklist and Clinical Global Impression). Results/UNASSIGNED: = 0.25) at baseline. Three of 12 (25%) simvastatin cases compared to none in placebo met 'clinical responder' criteria for behavioural outcome. Conclusions/UNASSIGNED:We show feasibility of peripheral MAPK assay and autism symptom measurement, but the study was not powered to test effectiveness. Multiparametric imaging suggests possible simvastatin effects in brain areas previously associated with NF1 pathophysiology and the social brain network. Trial registration/UNASSIGNED:EU Clinical Trial Register (EudraCT) 2012-005742-38 (www.clinicaltrialsregister.eu).

Background: Mucosal immunity may be critical to protection from HIV acquisition. Serum antibodies (Abs) targeted specifically to the region of the V2 loop harboring HIV's a4b7 integrin receptor binding site were associated with protection from HIV acquisition in humans. Mucosal Abs of this type may have been further associated with protection in a matched non-human primate model. Cholera toxin B (CTB) is a powerful mucosal adjuvant. We engineered CTB to display the SIVmac251 region of the V2 loop harboring the a4b7 site for testing in Rhesus macaques.
Method(s): The SIVmac251 a4b7 site was fused to CTB and the integrity of the immunogen was confirmed by X-ray crystallography. Antigenicity of the construct was confirmed with the ITS-12 monoclonal antibody. Serum immunogenicity was tested in rabbits and mucosal immunogenicity in young male Rhesus macaques. The macaque study compares 5 intramuscular (IM) and rectal topical co-administrations of CTB-V2 over 24 weeks to a matched-timeline regimen of two sequential DNA SIV gp120 immunizations followed by three ALVAC-SIV immunizations, the last two of which are coadministered with the IM and mucosal CTB-V2 protein boost.
Result(s): The engineered CTB-V2 protein binds galactose, which approximates mucosal GM1-gangliosides, binds ITS-12 potently and elicits titers >10k against the SIVmac251 a4b7 site in 5 of 5 rabbits. Rhesus macaques were successfully inoculated rectally with 200ug of this protein and tolerated the immunization well. The serum and mucosal responses were profiled.
Conclusion(s): Anti-V2, a4b7-site-targeted antibodies may be elicited by mucosal application of an engineered, validated CTB-V2 immunogen. Comparison to potent ALVAC-based regimens may provide insight into protective immune responses elicited by vaccination

Methods of functional connectivity are applied ubiquitously in studies involving non-invasive whole-brain signals, but may be not optimal for exploring the propagation of the steady-state responses, which are strong oscillatory patterns of neurodynamics evoked by periodic stimulation. In our study, we explore a functional network underlying the somatosensory steady-state response using methods of effective connectivity. Human magnetoencephalographic (MEG) data were collected in 10 young healthy adults during 23-Hz vibro-tactile stimulation of the right hand index finger. The whole-brain dynamics of MEG source activity was reconstructed with a linearly-constrained minimum variance beamformer. We applied information-theoretic tools to quantify asymmetries in information flows between primary somatosensory area SI and the rest of the brain. Our analysis identified a pattern of coupling, leading from area SI to a source in the secondary somato-sensory area SII, thalamus, and motor cortex all contralateral to stimuli as well as to a source in the cerebellum ipsilateral to the stimuli. Our results support previously reported empirical evidence collected both in in vitro and in vivo, indicating critical areas of activation of the somatosensory system at the level of systems neuroscience.

Background/UNASSIGNED:The corpus callosum is implicated in the pathophysiology of autism spectrum disorder (ASD). However, specific structural deficits and underlying mechanisms are yet to be well defined. Methods/UNASSIGNED:) diffusivities, which reflect myelination and microstructural organization of the extracellular space. The relationships between DKI metrics and processing speed, a cognitive feature known to be impaired in ASD, were also examined. Results/UNASSIGNED: > .05). Conclusion/UNASSIGNED:Decreased DKI metrics suggested that ASD may be associated with axonal deficits such as reduced axonal caliber and density in the corpus callosum, especially in the mid and posterior callosal areas. These data suggest that impaired interhemispheric connectivity may contribute to decreased processing speed in ASD participants.

Cogmed Working Memory Training (CWMT), an online cognitive training program developed for children, is an increasingly popular non-pharmacological intervention for ADHD amongst all ages, despite limited supporting evidence. The initial objective of the present work was to examine the short- and long-term impacts of CWMT on brain function in adults with ADHD. However, during the conduct of our study, we experienced multiple levels of failures in recruitment and retention that signaled potential concerns about the suitability of CWMT for adults with ADHD. This perspective piece aims to describe the difficulties we encountered in the context of studies examining the efficacy of CWMT in comparable populations. We trace these difficulties to the limited tolerability of the current CWMT structure for adults with ADHD, and review similar limitations in the literature. We suggest that efficacy of CWMT in children may be due in large part to close monitoring and scaffolding provided by clinicians and caregivers. For CWMT to have viability for widespread use in adults, greater support and structure will be needed for users to improve the likelihood of adherence. We discuss implications and considerations for future efforts in both research and clinical practice.