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1.  A Description of the Methods of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) 
American journal of obstetrics and gynecology  2015;212(4):539.e1-539.e24.
The primary aim of The Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-be (nuMoM2b) is to determine maternal characteristics, including genetic, physiological response to pregnancy, and environmental factors that predict adverse pregnancy outcomes (APOs).
Nulliparous women in the first trimester of pregnancy were recruited into an observational cohort study. Participants were seen at three study visits during pregnancy and again at delivery. We collected data from in-clinic interviews, take-home surveys, clinical measurements, ultrasound studies, and chart abstractions. Maternal biospecimens (serum, plasma, urine and cervico-vaginal fluid) at antepartum study visits and delivery specimens (placenta, umbilical cord, cord blood) were collected, processed, and stored. The primary outcome of the study was defined as pregnancy ending prior to 37+0 weeks gestation. Key study hypotheses involve APOs of spontaneous preterm birth, preeclampsia, and fetal growth restriction.
10,037 women were recruited to the study. Basic characteristics of the cohort at screening are reported in this Methods paper.
The nuMoM2b cohort study methods and procedures presented can help investigators when planning future projects.
PMCID: PMC4387083  PMID: 25648779
Pregnancy; nulliparous; adverse pregnancy outcomes prediction; methods; cohort study; psychosocial
2.  Submandibular parasympathetic gangliogenesis requires Sprouty-dependent Wnt signals from epithelial progenitors 
Developmental cell  2015;32(6):667-677.
Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance.
PMCID: PMC4374127  PMID: 25805134
Gangliogenesis; Wnt; Wnt4; Wnt7b; Wnt10a; FGF; Fgf10; Fgf7; parasympathetic; ganglion; submandibular gland; progenitor
3.  Phosphorylation of the Scc2 cohesin deposition complex subunit regulates chromosome condensation through cohesin integrity 
Molecular Biology of the Cell  2015;26(21):3754-3767.
Cohesin deposition requires the Scc2/Scc4 complex. Scc2 is phosphorylated, and mutations that mimic constitutive phosphorylation lead to inviability and chromosome condensation defects, likely due to reduced Mcd1 levels resulting from compromised cohesin integrity. Thus phosphoregulation of Scc2 has important consequences for chromosome integrity.
The cohesion of replicated sister chromatids promotes chromosome biorientation, gene regulation, DNA repair, and chromosome condensation. Cohesion is mediated by cohesin, which is deposited on chromosomes by a separate conserved loading complex composed of Scc2 and Scc4 in Saccharomyces cerevisiae. Although it is known to be required, the role of Scc2/Scc4 in cohesin deposition remains enigmatic. Scc2 is a phosphoprotein, although the functions of phosphorylation in deposition are unknown. We identified 11 phosphorylated residues in Scc2 by mass spectrometry. Mutants of SCC2 with substitutions that mimic constitutive phosphorylation retain normal Scc2–Scc4 interactions and chromatin association but exhibit decreased viability, sensitivity to genotoxic agents, and decreased stability of the Mcd1 cohesin subunit in mitotic cells. Cohesin association on chromosome arms, but not pericentromeric regions, is reduced in the phosphomimetic mutants but remains above a key threshold, as cohesion is only modestly perturbed. However, these scc2 phosphomimetic mutants exhibit dramatic chromosome condensation defects that are likely responsible for their high inviability. From these data, we conclude that normal Scc2 function requires modulation of its phosphorylation state and suggest that scc2 phosphomimetic mutants cause an increased incidence of abortive cohesin deposition events that result in compromised cohesin complex integrity and Mcd1 turnover.
PMCID: PMC4626061  PMID: 26354421
4.  Refined Mapping of a Hypertension Susceptibility Locus on Rat Chromosome 12 
Hypertension  2014;64(4):883-890.
Previously, we found that transferring 6.1 Mb of SS chromosome 12 (13.4-19.5 Mb) onto the consomic SS-12BN background significantly elevated mean arterial pressure in response to an 8% NaCl diet (178±7 vs. 144±2 mmHg; P<0.001). Using congenic mapping, we have now narrowed the blood pressure locus by 86% from a 6.1 Mb region containing 133 genes to an 830 kb region (chr12:14.36-15.19 Mb) with 14 genes. Compared with the SS-12BN consomic, the 830 kb blood pressure locus was associated with a Δ+15 mmHg (P<0.01) increase in blood pressure, which coincided with elevated albuminuria (Δ+32 mg/day; P<0.001), proteinuria (Δ+48 mg/day; P<0.01), protein casting (Δ+154%; P<0.05), and renal fibrosis (Δ+79%; P<0.05). Of the 14 genes residing in the 830 kb locus, 8 were differentially expressed and among these, Chst12 (carbohydrate chondroitin 4 sulfotransferase 12) was the most consistently down-regulated by 2.6 to 4.5-fold (P<0.05) in both the renal medulla and cortex under normotensive and hypertensive conditions. Moreover, whole genome sequence analysis of overlapping blood pressure loci revealed an ∼86 kb region (chr12:14,541,567-14,627,442 bp) containing single nucleotide variants near Chst12 that are unique to the hypertensive SS strain when compared to the normotensive BN, SR, and WKY strains. Finally, the 830 kb interval is syntenic to a region on human chromosome 7 that has been genetically linked to blood pressure, suggesting that insight gained from our SS-12BN congenic strain may be translated to a better understanding of human hypertension.
PMCID: PMC4162822  PMID: 25001272
Dahl salt-sensitive; Brown Norway; hypertension; genetic; congenic
5.  Measurement of Phonation Threshold Power in Normal and Disordered Voice Production 
Phonation threshold pressure (PTP) and phonation threshold flow (PTF) are useful aerodynamic parameters, but each is sensitive to different disorders. A single comprehensive aerodynamic parameter sensitive to a variety of disorders might be beneficial in quantitative voice assessment. We performed the first study of phonation threshold power (PTW) in human subjects.
PTP and PTF were measured in 100 normal subjects, 19 subjects with vocal fold immobility, and 94 subjects with a benign mass lesion. PTW was calculated from these two parameters. In 41 subjects with a polyp, measurements were obtained before and after excision. Receiver operating characteristic (ROC) analysis was used to determine the ability of the three parameters to distinguish between controls and disordered groups.
The PTW (p < 0.001), PTP (p < 0.001), and PTF (p < 0.001) were different among the three groups. All parameters decreased after polyp excision. PTW had the highest area under the ROC curve for all analyses.
PTW is sensitive to the presence of mass lesions and vocal fold mobility disorders. Additionally, changes in PTW can be observed after excision of mass lesions. PTW could be a useful parameter to describe the aerodynamic inputs to voice production.
PMCID: PMC4583103  PMID: 24224398
aerodynamic parameters; artificial neural network; mass lesion; phonation threshold power; vocal fold paralysis; voice analysis
6.  Parasympathetic innervation regulates tubulogenesis in the developing salivary gland 
Developmental cell  2014;30(4):449-462.
A fundamental question in development is how cells assemble to form a tubular network during organ formation. In glandular organs tubulogenesis is a multistep process requiring coordinated proliferation, polarization and reorganization of epithelial cells to from a lumen, and lumen expansion. Although it is clear that epithelial cells possess an intrinsic ability to organize into polarized structures, the mechanisms coordinating morphogenetic processes during tubulogenesis are poorly understood. Here, we demonstrate that parasympathetic nerves regulate ductal tubulogenesis in the developing salivary gland. We show that the neurotransmitter vasoactive intestinal peptide (VIP) secreted by the innervating ganglia promotes ductal growth, leads to the formation of a contiguous lumen, and facilitates lumen expansion through a cAMP/PKA-dependent pathway. Furthermore, we provide evidence that lumen expansion is independent of apoptosis and involves the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated Cl(−) channel. Thus, parasympathetic innervation coordinates multiple steps in tubulogenesis during organ formation.
PMCID: PMC4155578  PMID: 25158854
7.  Neonatal and Maternal Outcomes With Prolonged Second Stage of Labor 
Obstetrics and gynecology  2014;124(1):57-67.
To assess neonatal and maternal outcomes when when the second stage of labor was prolonged according to American College of Obstetricians and Gynecologists guidelines.
Electronic medical record data from a retrospective cohort (2002–2008) from 12 U.S. clinical centers (19 hospitals), including 43,810 nulliparous and 59,605 multiparous singleton deliveries ≥ 36 weeks, vertex presentation, who reached 10 cm cervical dilation were analyzed. Prolonged second stage was defined as: nulliparous women with epidural > 3 hours, without > 2 hours; multiparous women with epidural > 2 hours, without > 1 hour. Maternal and neonatal outcomes were compared and adjusted odds ratios calculated controlling for maternal race, BMI, insurance, and region.
Prolonged second stage occurred in 9.9% and 13.9% of nulliparous and 3.1% and 5.9% of multiparous women, with and without an epidural, respectively. Vaginal delivery rates with prolonged second stage compared to within guidelines were 79.9% versus 97.9% and 87.0% versus 99.4% for nulliparous women with and without epidural, respectively, and 88.7% versus 99.7% and 96.2% versus 99.9% for multiparous women with and without epidural, respectively (P<.001 for all comparisons). Prolonged second stage was associated with increased chorioamnionitis and third-degree or fourth-degree perineal lacerations. Neonatal morbidity with prolonged second stage included sepsis in nulliparous women [with epidural: 2.6% versus 1.2% (AOR 2.08; 95%CI 1.60–2.70); without epidural: 1.8% versus 1.1% (AOR 2.34; 95%CI 1.28–4.27)]; asphyxia in nulliparous women with epidural [0.3% versus 0.1%, AOR 2.39; 95% CI 1.22–4.66]; and perinatal mortality without epidural [0.18% versus 0.04% for nulliparous women (AOR 5.92; 95% CI 1.43–24.51)], and 0.21% versus 0.03% for multiparous women (AOR 6.34; 95%CI 1.32–30.34)]. However, among the offspring of women with epidurals whose second stage was prolonged (3,533 nulliparous and 1,348 multiparous women), there were no cases of hypoxic ischemic encephalopathy or perinatal death.
Benefits of increased vaginal delivery should be weighed against potential small increases in maternal and neonatal risks with prolonged second stage.
PMCID: PMC4065200  PMID: 24901265
8.  Hs3st3-modified heparan sulfate controls KIT+ progenitor expansion by regulating 3-O-sulfotransferases 
Developmental cell  2014;29(6):662-673.
The exquisite control of growth factor function by heparan sulfate (HS) is dictated by the tremendous structural heterogeneity of sulfated modifications. It is not known how specific HS structures control growth factor-dependent progenitor expansion during organogenesis. We isolated KIT+ progenitors from fetal salivary glands during a stage of rapid progenitor expansion and profiled HS biosynthetic enzyme expression. Enzymes generating a specific type of 3-O-sulfated-HS (3-O-HS) are enriched, and FGF10/FGFR2b signaling directly regulates their expression. Bioengineered 3-O-HS binds FGFR2b and stabilizes FGF10/FGFR2b complexes in a receptor- and growth factor-specific manner. Rapid autocrine feedback increases 3-O-HS, KIT and progenitor expansion. Knockdown of multiple Hs3st isoforms limits fetal progenitor expansion, but is rescued with bioengineered 3-O-HS, which also increases adult progenitor expansion. Rapidly altering a specific 3-O-sulfated epitope provides a cellular mechanism to modulate the response to FGFR2b signaling and control progenitor expansion. 3-O-HS may expand KIT+ progenitors in vitro for regenerative therapy.
PMCID: PMC4105206  PMID: 24960693
Heparan sulfate 3-O-sulfotransferase; FGF10; heparan sulfate; KIT; FGFR2b; salivary gland development; SMG; progenitor proliferation; progenitor expansion
9.  Combined type IIIB with bilateral type I thyroplasty for pitch lowering with maintenance of vocal fold tension 
To evaluate type IIIB thyroplasty using the excised larynx bench apparatus and determine how altering vocal fold contour by performing bilateral medialization of the inferior vocal fold affects phonation. This procedure could be performed in patients for whom pitch lowering is desirable, such as female-to-male transsexuals or male patients with mutational falsetto in whom intensive voice therapy was insufficient.
Aerodynamic, acoustic, and high-speed videokymographic data were collected for nine larynges at three subglottal pressure inputs for each of three conditions: normal; type IIIB thyroplasty; and combined type IIIB with modified bilateral type I thyroplasty intended to create a more rectangular glottal configuration. Each larynx served as its own control.
Phonation threshold flow (p=0.005), phonation threshold power (p=0.031), and airflow varied across conditions with highest values for type IIIB thyroplasty and lowest for the combined procedure. Fundamental frequency was significantly different (p<0.001), decreasing by approximately 100 Hz from control to type IIIB trials, and then by approximately 15 Hz from IIIB to combined procedure trials. Vibratory amplitudes and intrafold phase difference were highest for type IIIB trials.
Addition of bilateral inferior medialization to type IIIB thyroplasty provided some further decrease in frequency, but mostly served to increase tension, reduce airflow, and produce a vibratory pattern which more closely mirrored control trials. Exploration of this combined procedure in patients may be warranted if not completely satisfied with the results from type IIIB thyroplasty alone.
PMCID: PMC4013228  PMID: 24241252
type IIIB thyroplasty; type I thyroplasty; pitch lowering; mutational falsetto; transgender phonosurgery
10.  Anatomy, biogenesis, and regeneration of salivary glands 
An overview of the anatomy and biogenesis of salivary glands is important in order to understand the physiology, functions and disorders associated with saliva. A major disorder of salivary glands is salivary hypofunction and resulting xerostomia, or dry mouth, which affects hundreds of thousands of patients per year who suffer from salivary gland diseases or undergo head and neck cancer treatment. There is currently no curative therapy for these patients. To improve these patients’ quality of life, new therapies are being developed based on findings in salivary gland cell and developmental biology. Here we discuss the anatomy and biogenesis of the major human salivary glands and the rodent submandibular gland (SMG), which has been used extensively as a research model. We also include a review of recent research on the identification and function of stem cells in salivary glands, and the emerging field of research suggesting nerves play an instructive role during development and may be essential for adult gland repair and regeneration. Understanding the molecular mechanisms involved in gland biogenesis provides a template for regenerating, repairing or reengineering diseased or damaged adult human salivary glands. We provide an overview of three general approaches currently being developed to regenerate damaged salivary tissue, including gene therapy, stem cell-based therapy, and tissue engineering. In the future, it may be that a combination of all three will be used to repair, regenerate and reengineer functional salivary glands in patients to increase the secretion of their saliva, the focus of this monograph.
PMCID: PMC4048853  PMID: 24862590
11.  Detection of chronic laryngitis due to laryngopharyngeal reflux using color and texture analysis of laryngoscopic images 
To determine if pattern recognition of hue and textural parameters can be used to identify laryngopharyngeal reflux (LPR).
Laryngoscopic images from 20 subjects with LPR and 42 control subjects without LPR were obtained. LPR status was determined using the Reflux Finding Score. Color and texture features were quantified using hue calculation and 2D Gabor filtering. Five regions were analyzed: true vocal folds, false vocal folds, epiglottis, interarytenoid space, and arytenoid mucosae. A multilayer perceptron artificial neural network with varying numbers of hidden nodes was used to classify images according to pattern recognition. Receiver operating characteristic (ROC) analysis was used to evaluate diagnostic utility and intraclass correlation coefficient analysis was performed to determine to gauge interrater reliability.
Classification accuracy when including all parameters was 80.5 ± 1.2% with an area under the ROC curve of 0.887. Classification accuracy decreased when including only hue (73.1±3.5%; area under the curve = 0.834) or texture (74.9±3.6%; area under the curve = 0.852) parameters. Interrater reliability was 0.97±0.03 for hue parameters and 0.85±0.11 for texture parameters.
This preliminary study suggests that a combination of hue and texture features can be used to detect chronic laryngitis due to LPR. A simple, minimally invasive assessment would be a valuable addition to the currently invasive and somewhat unreliable methods currently used for diagnosis. Including more data will likely improve classification accuracy. Additional investigations will be performed to determine if results are in accordance with those provided by pH probe monitoring.
PMCID: PMC3910322  PMID: 24314831
laryngopharyngeal reflux; hue; Gabor filter; artificial neural network; laryngitis
12.  Effect of Variations to a Simulated System of Straw Phonation Therapy on Aerodynamic Parameters Using Excised Canine Larynges 
Summary: Objectives/Hypothesis
Resonance tubes are commonly used in voice therapy. These devices modify supraglottal impedance, potentially decreasing the aerodynamic power necessary for phonation. We modeled phonation with resonance tubes in excised larynges and evaluated the effects of varying tube width, tube length, and flow input on phonation threshold pressure (PTP) and phonation threshold flow (PTF). We hypothesized that the increased vocal economy observed in human subjects and several other models would be observed in excised larynges.
Study Design
Repeated measures excised canine larynx bench experiment with each larynx serving as own control.
Nine conditions were evaluated, namely control, two tube diameters (17.5 and 6.5 mm), three tube lengths (7.8, 15.0, and 30.0 cm), and three levels of flow input (80, 114, and 200 mL/s). Aerodynamic data were collected for 11 excised canine larynges attached to an artificial vocal tract, and results from each experimental configuration were compared with control.
A significant decrease in average PTP occurred compared with control for the 114- and 200-mL/s flow inputs, 30-cm extension, and 17.5- and 6.5-mm constrictions. Average PTF decreased compared with control for every configuration, although statistically significant changes were only observed for 200-mL/s flow and 6.5-mm constriction.
Knowledge regarding the effect of vocal tract alterations could be clinically useful in determining the optimal “straw” configuration for voice therapy. Further exploration of the relationships among width, length, and flow input could provide theoretical support for the development of new therapies and resonance tube devices.
PMCID: PMC3951877  PMID: 24286626
Resonance tube; Straw phonation therapy; Phonation threshold flow; Phonation threshold pressure; Excised larynx
13.  Salivary Gland Development: A Template for Regeneration 
The mammalian salivary gland develops as a highly branched structure designed to produce and secrete saliva. This review will focus on research on mouse submandibular gland development and the translation of this basic research towards therapy for patients suffering from salivary hypofunction. Here we review the most recent literature that has enabled a better understanding of the mechanisms of salivary gland development. Additionally, we discuss approaches proposed to restore salivary function using gene and cell-based therapy. Increasing our understanding of the developmental mechanisms involved during development is critical to design effective therapies for regeneration and repair of damaged glands.
PMCID: PMC3988231  PMID: 24333774
Salivary gland development; submandibular gland; branching morphogenesis; stem cells; progenitor cells; regeneration; parasympathetic innervation
14.  Excised Larynx Evaluation of Wedge-Shaped Adjustable Balloon Implant for Minimally Invasive Type I Thyroplasty 
The Laryngoscope  2013;124(4):942-949.
To describe the method of inserting a wedge-shaped adjustable balloon implant (wABI) via a minithyrotomy for medialization thyroplasty and evaluate its effect on a range of phonatory parameters using the excised larynx bench apparatus.
Study Design
Repeated measures with each larynx serving as its own control.
A prototype wABI was deployed in six excised canine larynges of various sizes through a minithyrotomy and then filled with saline. Mucosal wave, aerodynamic, and acoustic parameters were measured for three conditions: normal, vocal fold paralysis, and paralysis with the wABI.
Phonation threshold pressure (P <.001), flow (P <.001), and power (P =.002) were significantly lower for wABI compared to paralysis trials; values did not differ significantly from normal trials. Percent jitter (P =.002) and percent shimmer (P =.007) were also significantly decreased compared to the paralysis condition, and values were not significantly different compared to normal. The mucosal wave was preserved after insertion of the wABI.
Effective vocal fold medialization with preservation of the mucosal wave was observed with the wABI in this preliminary excised larynx experiment. The wABI offers the potential for a minimally invasive insertion in addition to postoperative adjustability. Further studies in living animals and humans are warranted to evaluate clinical utility.
PMCID: PMC4235617  PMID: 24115091
Adjustable balloon implant; medialization thyroplasty; vocal fold paralysis; glottic insufficiency
15.  Reliability of an Automated High-Resolution Manometry Analysis Program Across Expert Users, Novice Users, and Speech-Language Pathologists 
The purpose of this study was to investigate inter- and intra-rater reliability among expert users, novice users, and speech-language pathologists with a semi-automated high-resolution manometry analysis program. We hypothesized that all users would have high intra-rater reliability and high inter-rater reliability.
Three expert users, 15 novice users, and 5 speech-language pathologists participated in this study. Following a 20-minute training session, users analyzed 30 high-resolution manometry plots using an automated analysis program. Output parameters included two- and three-dimensional pressure integrals over 5 anatomical regions of interest. Intraclass correlations were used to examine inter- and intra-rater reliability. Analysis of variance was also performed to determine any differences in mean output parameter values.
Within-group inter-rater reliability ranged from 0.54-0.99 and inter-group reliability ranged from 0.92-0.99. Intra-rater reliability ranged from 0.67-1.00 across all groups. There were no significant differences of output parameters between groups.
The high reliability observed after a short training session demonstrate that individuals with little to no prior knowledge of swallowing physiology can perform at a similar level as those with expertise. Given the quickness and ease of training in the use of this program, it has the potential for research and clinical utility.
PMCID: PMC4167385  PMID: 24686522
High-resolution manometry; reproducibility of results; speech-language pathologist; swallowing; dysphagia
16.  Gestational Weight Gain and Obesity: Is 20 Pounds Too Much? 
American journal of obstetrics and gynecology  2013;209(3):214.e1-214.e11.
To compare maternal and neonatal outcomes in obese women according to weight change and obesity class.
Study design
Cohort study from the Consortium on Safe Labor of 20,950 obese women with a singleton, term, livebirth from 2002–2008. Risk for adverse outcomes was calculated by multiple logistic regression analysis for weight change categories [weight loss (<0kg), low (0−4.9kg), normal (5.0−9.0kg), high weight gain (>9.0 kg)] in each obesity class (I 30.0−34.9kg/m2, II 35.0−39.9kg/m2, and III ≥40 kg/m2) and by predicted probabilities with weight change as a continuous variable.
Weight loss was associated with decreased cesareans for class I women (nulliparas OR 0.21, 95%CI 0.11−0.42; multiparas OR 0.61, 95%CI 0.45−.83) and increased small for gestational age (SGA) infants (class I OR 1.8, 95%CI 1.3−2.5; class II OR 2.2, 95%CI 1.5−3.2; class III OR 1.7, 95%CI 1.1−2.6). High weight gain was associated with increased large for gestational age (LGA) infants (class I OR 2.4, 95%CI 1.9−2.9; class II OR 1.7, 95% CI 1.3−2.1; class III OR 1.6, 95%CI 1.3−2.1). As weight change increased, the predicted probability for cesareans and LGA infants increased. The predicted probability of low birth weight never exceeded 4% for all obesity classes, but SGA increased with decreased weight change. The lowest average predicted probability of adverse outcomes (cesarean, postpartum hemorrhage, SGA, LGA, NICU admission) occurred when women (class I,II,III) lost weight.
Optimal maternal and neonatal outcomes appear to occur when weight gain is less than current IOM recommendations for obese women. Further study of long-term outcomes is needed with respect to gestational weight changes.
PMCID: PMC3757121  PMID: 23635421
obesity; pregnancy; gestational weight gain; maternal and neonatal outcomes
17.  Differentiating arytenoid dislocation and recurrent laryngeal nerve paralysis by arytenoid movement in laryngoscopic video 
To present a new method of quantifying arytenoid movement during inspiration and determine if it can be used to distinguish arytenoid dislocation from vocal fold paralysis.
Study Design
Case series with chart review.
Retrospective study conducted in university laboratory based on university hospital data.
Subjects and Methods
Endoscopic videos from eight patients with dislocation and five patients with vocal fold paralysis diagnosed by electromyography were included. Vector analysis measured cuneiform movement, an indirect measurement of arytenoid movement, during one inspiration. Measurements normalized and not normalized to vocal fold length were evaluated. Interrater reliability (2 raters) and intrarater reliability (1 rater performing analysis twice) were evaluated using intraclass correlation coefficient (ICC) analysis. Raters were blinded to subject group during analysis.
Pixel-valued cuneiform movement was 81.16±25.62 for dislocation and 30.22±23.60 for paralysis (p=0.019). Unitless cuneiform movement was 0.58±0.17 for dislocation and 0.24±0.18 for paralysis (p=0.030). Interrater ICC was 0.942 for pixel-valued measurements and 0.962 for unitless measurements. Intrarater ICC was 0.909 for pixel-valued measurements and 0.881 for unitless measurements.
Both pixel-valued and unitless measures of arytenoid movement were significantly greater in arytenoid dislocation than vocal fold paralysis. Pixel-valued measurements were included to demonstrate the ability to make quantitative comparisons across subjects without precise knowledge of camera precision provided position is approximately stable, as each measurement is inherently normalized by vocal tract length. Future studies will apply this new method of evaluating vocal fold immobility disorders on a larger scale and incorporate a more diverse group of etiologies.
PMCID: PMC3770460  PMID: 23719396
arytenoid dislocation; vocal fold paralysis; videolaryngoscopy; endoscopy
18.  Female-specific hypertension loci on rat chromosome 13 
Hypertension  2013;62(3):10.1161/HYPERTENSIONAHA.113.01708.
A 3.7 Mb region of rat chromosome 13 (45.2–49.0 Mb) affects blood pressure (BP) in females only, indicating the presence of gender-specific BP loci in close proximity to the Renin locus. In the present study, we used a series of Dahl salt-sensitive/Mcwi (SS)-13 Brown Norway (BN) congenic rat strains to further resolve BP loci within this region. We identified 3 BP loci affecting female rats only, of which the 2 smaller loci (line9BP3 and line9BP4) were functionally characterized by sequence and expression analysis. Compared with SS, the presence of a 591 Kb region of BN chromosome 13 (line9BP3) significantly lowered BP by 21 mmHg on an 8% NaCl diet (153±7 vs 174±5 mmHg, P<0.001). Unexpectedly, the addition of 23 Kb of BN chromosome 13 (line9BP4) completely erased the female-specific BP protection on 8% NaCl diet, suggesting that BN hypertensive allele(s) reside in this region. The congenic interval of the protective line 9F strain contains 3 genes (Optc, Prelp, and Fmod) and the hypertensive line 9E contains 1 additional gene (Btg2). Sequence analysis of the 2 BP loci revealed a total of 282 intergenic variants, with no coding variants. Analysis of gene expression by RT-qPCR revealed strain- and gender-specific differences in Prelp, Fmod, and Btg2 expression, implicating these as novel candidate genes for female-specific hypertension.
PMCID: PMC3870583  PMID: 23817491
Hypertension; Genetics; Gender; Blood Pressure; Kidney
19.  Respiratory Morbidity in Late Preterm Births 
Late preterm births (LPTB, 34 0/7-36 6/7 weeks) account for a growing proportion of prematurity-associated short term morbidities, particularly respiratory, that require specialized care and prolonged neonatal hospital stays.
To assess short-term respiratory morbidity in LPTB compared to term births in a contemporary cohort of deliveries in the United States.
Design, Setting, and Participants
Retrospective collection of electronic data from 12 institutions (19 hospitals) across the United States on 233,844 deliveries between 2002 and 2008. Charts were abstracted for all neonates with respiratory compromise admitted to a neonatal intensive care unit (NICU) and LPTB were compared to term births in regard to resuscitation, respiratory support and respiratory diagnoses. A multivariate logistic regression analysis compared infants at each gestational week controlling for factors that influence respiratory outcomes.
Main outcome measures
Respiratory distress syndrome (RDS), transient tachypnea of the newborn (TTN), pneumonia, respiratory failure, standard and oscillatory ventilator support.
Of 19,334 LPTB, 7,055 were admitted to a NICU and 2,032 had respiratory compromise. Of 165,993 term infants, 11,980 were admitted to a NICU, 1,874 with respiratory morbidity.
Respiratory distress syndrome decreased from 10.5% (390/3700) at 34 weeks to 0.3% (140/41,764) at 38 weeks. Similarly, TTN decreased from 6.4% (n=236) to 0.4% (n=155), pneumonia from 1.5% (n=55) to 0.1% (n=62), and respiratory failure from 1.6% (n=61) to 0.2% (n=63). Standard and oscillatory ventilator support had similar patterns. Odds of RDS decreased with each advancing week until 38 weeks compared to 39-40 weeks (adjusted OR at 34 weeks 40.1 [95% CI 32.0-50.3] and at 38 weeks 1.1 [95% CI, 0.9-1.4]). At 37 weeks odds for RDS were greater than 39-40 weeks (3.1 [95% CI, 2.5-3.7]), but the odds at 38 weeks did not differ from 39-40 weeks. Similar patterns were noted for TTN (adjusted OR at 34 weeks 14.7 [95% CI, 11.7-18.4] and at 38 weeks 1.0 [95% CI 0.8-1.2]); pneumonia (adjusted OR at 34 weeks 7.6 [95% CI, 5.2-11.2] and at 38 weeks 0.9 [95% CI, 0.6-1.2]), and respiratory failure (adjusted OR at 34 weeks 10.5 [95% CI, 6.9-16.1] and at 38 weeks 1.4 [95% CI, 1.0-1.9]).
In a contemporary cohort, late preterm birth, compared with term delivery, was associated with increased risk for respiratory distress syndrome and other respiratory morbidity.
PMCID: PMC4146396  PMID: 20664042
20.  Quantifying Contributions of the Cricopharyngeus to Upper Esophageal Sphincter Pressure Changes by Means of Intramuscular Electromyography and High-Resolution Manometry 
We sought to determine whether the association between cricopharyngeus muscle activity and upper esophageal sphincter pressure may change in a task-dependent fashion. We hypothesized that more automated tasks related to swallow or airway protection would yield a stronger association than would more volitional tasks related to tidal breathing or voice production.
Six healthy adult subjects underwent simultaneous intramuscular electromyography of the cricopharyngeus muscle and high-resolution manometry of the upper esophageal sphincter. Correlation coefficients were calculated to characterize the association between the time-linked series.
Cricopharyngeus muscle activity was most strongly associated with upper esophageal sphincter pressure during swallow and effortful exhalation tasks (r = 0.77 and 0.79, respectively; P < .01). The association was also less variable during swallow and effortful exhalation.
These findings suggest a greater coupling for the more automatic tasks, and may suggest less coupling and more flexibility for the more volitional, voice-related tasks. These findings support the important role of central patterning for respiratory- and swallow-related tasks.
PMCID: PMC4128397  PMID: 24633943
cricopharyngeus; deglutition; electromyography; high-resolution manometry; upper esophageal sphincter
21.  Three-dimensional analysis of pharyngeal high-resolution manometry data 
The Laryngoscope  2013;123(7):1746-1753.
High-resolution manometry (HRM) represents a critical advance in the quantification of swallow-related pressure events in the pharynx. Previous analyses of the pressures measured by HRM, though, have been largely two-dimensional, focusing on a single sensor in a given region. We present a method a three-dimensional approach which combines information from adjacent sensors in a region. Two- and three-dimensional approaches were compared for their ability to classify data correctly as normal or disordered.
Study Design
Case series evaluating new method of data analysis.
1,324 total swallows from 16 normal subjects and 61 subjects with dysphagia were included. Two-dimensional single sensor integrals of the area under the curves created by rises in pressure in the velopharynx, tongue base, and UES were calculated. Three-dimensional multi-sensor integrals of the volume under all curves corresponding to the same regions were also computed. The two sets of measurements were compared for their ability to classify data correctly as normal or disordered using an artificial neural network (ANN).
Three-dimensional parameters yielded a maximal classification accuracy of 86.71±1.47%, while two-dimensional parameters achieved a maximum accuracy of 83.36±1.42%. When combining two- and three-dimensional parameters with all other variables, including three-dimensional parameters yielded a classification accuracy of 96.99±0.51%, and including 2-dimensional parameters yielded a classification accuracy of 96.32±1.05%.
Three-dimensional analysis led to improved classification of swallows based on pharyngeal HRM. Artificial neural network performance with both two-dimensional and three-dimensional analyses was effective, classifying a large percentage of swallows correctly, thus demonstrating its potential clinical utility.
PMCID: PMC3774539  PMID: 23417441
high-resolution manometry; swallowing; pharynx; dysphagia
22.  Classification of high-resolution manometry data according to videofluoroscopic parameters using pattern recognition 
To determine if pattern recognition techniques applied to high-resolution manometry (HRM) spatiotemporal plots of the pharyngeal swallow can identify features of disordered swallowing reported on the Modified Barium Swallow Impairment Profile (MBSImP).
Study Design
Case series evaluating new method of data analysis.
University hospital.
Subjects and Methods
Simultaneous HRM and videofluoroscopy was performed on 30 subjects (335 swallows) with dysphagia. Videofluoroscopic studies were scored according to the MBSImP guidelines while HRM plots were analyzed using a novel program. Pattern recognition using a multilayer perceptron artificial neural network (ANN) was performed to determine if seven pharyngeal components of the MBSImP as well as penetration/aspiration status could be identified from the HRM plot alone. Receiver operating characteristic (ROC) analysis was also performed.
MBSImP parameters were identified correctly as normal or disordered at an average rate of approximately 91% (area under the ROC curve ranged from 0.902 to 0.981). Classifications incorporating two MBSImP parameters resulted in classification accuracies over 93% (area under the ROC curve ranged from 0.963 to 0.989).
Pattern recognition coupled with multiparameter quantitative analysis of HRM spatiotemporal plots can be used to identify swallowing abnormalities which are currently assessed using videofluoroscopy. The ability to provide quantitative, functional data at the bedside while avoiding radiation exposure make HRM an appealing tool to supplement and, at times, replace traditional videofluoroscopic studies.
PMCID: PMC3823556  PMID: 23728150
High-resolution manometry; pharyngeal swallow; MBSImP; videofluoroscopy
23.  Micro-patterned surfaces reduce bacterial colonization and biofilm formation in vitro: Potential for enhancing endotracheal tube designs 
Ventilator-associated pneumonia (VAP) is a leading hospital acquired infection in intensive care units despite improved patient care practices and advancements in endotracheal tube (ETT) designs. The ETT provides a conduit for bacterial access to the lower respiratory tract and a substratum for biofilm formation, both of which lead to VAP. A novel microscopic ordered surface topography, the Sharklet micro-pattern, has been shown to decrease surface attachment of numerous microorganisms, and may provide an alternative strategy for VAP prevention if included on the surface of an ETT. To evaluate the feasibility of this micro-pattern for this application, the microbial range of performance was investigated in addition to biofilm studies with and without a mucin-rich medium to simulate the tracheal environment in vitro.
The top five pathogens associated with ETT-related pneumonia, Methicillin-Resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter baumannii, and Escherichia coli, were evaluated for attachment to micro-patterned and un-patterned silicone surfaces in a short-term colonization assay. Two key pathogens, MRSA and Pseudomonas aeruginosa, were evaluated for biofilm formation in a nutrient rich broth for four days and minimal media for 24 hours, respectively, on each surface type. P. aeruginosa was further evaluated for biofilm formation on each surface type in a mucin-modified medium mimicking tracheal mucosal secretions. Results are reported as percent reductions and significance is based on t-tests and ANOVA models of log reductions. All experiments were replicated at least three times.
Micro-patterned surfaces demonstrated reductions in microbial colonization for a broad range of species, with up to 99.9% (p < 0.05) reduction compared to un-patterned controls. Biofilm formation was also reduced, with 67% (p = 0.12) and 52% (p = 0.05) reductions in MRSA and P. aeruginosa biofilm formation, respectively. Further, a 58% (p < 0.01) reduction was demonstrated on micro-patterned surfaces for P. aeruginosa biofilms under clinically-simulated conditions when compared to un-patterned controls.
This engineered micro-pattern reduces the colonization and biofilm formation of key VAP-associated pathogens in vitro. Future application of this micro-pattern on endotracheal tubes may prevent or prolong the onset of VAP without the need for antimicrobial agents.
PMCID: PMC3996152  PMID: 24739529
Micro-pattern; Sharklet; VAP; Endotracheal tube; Biofilm inhibition
24.  Congenic mapping and sequence analysis of the Renin locus 
Hypertension  2013;61(4):850-856.
Renin was the first blood pressure (BP) quantitative trait locus (QTL) mapped by linkage analysis in the rat. Subsequent BP linkage and congenic studies capturing different portions of the renin region have returned conflicting results, suggesting that multiple interdependent BP loci may be residing in the chromosome 13 BP QTL that includes Renin. We used SS-13BN congenic strains to map 2 BP loci in the Renin region (chr13:45.2–49.0 Mb). We identified a 1.1 Mb protective Brown Norway (BN) region around Renin (chr13:46.1–47.2 Mb) that significantly decreased BP by 32 mmHg. The Renin protective BP locus was offset by an adjacent hypertensive locus (chr13:47.2–49.0 Mb) that significantly increased BP by 29 mmHg. Sequence analysis of the protective and hypertensive BP loci revealed 1,433 and 2,063 variants between Dahl salt-sensitive/Mcwi (SS) and BN rats, respectively. To further reduce the list of candidate variants, we re-genotyped an overlapping SS-13SR congenic strain (S/renrr) with a previously reported BP phenotype. Sequence comparison between SS, Dahl R (SR), and BN reduced the number of candidate variants in the 2 BP loci by 42% for further study. Combined with previous studies, these data suggest that at least 4 BP loci reside within the 30 cM chromosome 13 BP QTL that includes Renin.
PMCID: PMC3770301  PMID: 23460292
hypertension; genetic; congenic; Dahl salt-sensitive rat; Brown Norway
25.  Artificial neural network classification of pharyngeal high-resolution manometry with impedance data 
The Laryngoscope  2012;123(3):713-720.
To use classification algorithms to classify swallows as safe, penetration, or aspiration based on measurements obtained from pharyngeal high-resolution manometry (HRM) with impedance.
Study design
Case series evaluating new method of data analysis.
Multilayer perceptron (MLP), an artificial neural network (ANN), was evaluated for its ability to classify swallows as safe, penetration, or aspiration. Data were collected from 25 disordered subjects swallowing 5 or 10 ml boluses. Following extraction of relevant parameters, a subset of the data was used to train the models and the remaining swallows were then independently classified by the ANN.
A classification accuracy of 89.4±2.4% was achieved when including all parameters. Including only manometry-related parameters yielded a classification accuracy of 85.0±6.0% while including only impedance-related parameters yielded a classification accuracy of 76.0±4.9%. Receiver operating characteristic (ROC) analysis yielded areas under the curve (AUC) of 0.8912 for safe, 0.8187 for aspiration, and 0.8014 for penetration.
Classification models show high accuracy in classifying swallows from dysphagic patients as safe or unsafe. HRM-impedance with ANN represents one method which could be used clinically to screen for patients at risk for penetration or aspiration.
PMCID: PMC3648989  PMID: 23070810
artificial neural network; classification model; high-resolution manometry; impedance; aspiration; dysphagia

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