Faculty Bibliography

OBJECTIVES/HYPOTHESIS: The primary objectives of this study were to determine the intrasubject reliability of repeated measures of maximum phonation time (MPT) duration during a single session and to examine the effects of age, sex, and total phonatory airflow on this reliability. STUDY DESIGN: This study used repeated measures. METHODS: Duration and total phonatory airflow during three consecutive MPT trials were collected from 20 participants evenly distributed between age (young/old) and sex (male/female) groups. Intraclass correlation coefficient and repeated-measures analysis of variance were used to examine the reliability of MPT across trials and to test for possible effects of age and sex. RESULTS: Intraclass correlation for MPT duration was strong across all participants (0.86), but MPT duration was not stable across trials (F2, 32 = 3.58, P = 0.04), with the second trial having the longest duration on average (P = 0.03). There was no effect of trial on total phonatory airflow (F2, 32 = 1.08, P = 0.35). The relationship between MPT duration and total phonatory airflow, however, did not remain consistent across trials (F2, 31 = 3.58, P = 0.04). There were no effects of age or sex on any variables. CONCLUSIONS: The variability in MPT duration across trials and the inconsistent relationship between MPT duration and total phonatory airflow indicate that there is variability in laryngeal efficiency across repeated MPT trials. Therefore, the results of this study corroborate previous research supporting the assertion that MPT is not a reliable measure of laryngeal aerodynamics.

BACKGROUND: Among older adults receiving long-term services and supports (LTSS), debilitating hospitalizations is a pervasive clinical and research problem. Multiple chronic conditions (MCCs) are prevalent in LTSS recipients. However, the combination of MCCs and diseases associated with hospitalizations of LTSS recipients is unclear. OBJECTIVE: The purpose of this analysis was to determine the association between classes of MCCs in newly enrolled LTSS recipients and the number of hospitalizations over a 1-year period following enrollment. METHODS: This report is based on secondary analysis of extant data from a longitudinal cohort study of 470 new recipients of LTSS, 60 years and older, receiving services in assisted living facilities, nursing homes, or through home- and community-based services. Using baseline chronic conditions reported in medical records, latent class analysis was used to identify classes of MCCs and posterior probabilities of membership in each class. Poisson regressions were used to estimate the relative ratio between posterior probabilities of class membership and number of hospitalizations during the 3-month period prior to the start of LTSS (baseline) and then every 3 months forward through 12 months. RESULTS: Three latent MCC-based classes named Cardiopulmonary, Cerebrovascular/Paralysis, and All Other Conditions were identified. The Cardiopulmonary class was associated with elevated numbers of hospitalizations compared to the All Other Conditions class (relative ratio [RR] = 1.88, 95% CI [1.33, 2.65], p < .001). CONCLUSION: Older LTSS recipients with a combination of MCCs that includes cardiopulmonary conditions have increased risk for hospitalization.

Spermatogenesis is an extraordinary complex process. The differentiation of spermatogonia into spermatozoa requires the participation of several cell types, hormones, paracrine factors, genes and epigenetic regulators. Recent researches in animals and humans have furthered our understanding of the male gamete differentiation, and led to clinical tools for the better management of male infertility. There is still much to be learned about this intricate process. In this review, the critical steps of human spermatogenesis are discussed together with its main affecting factors.

Localizing neuronal patterns that generate pathological brain signals may assist with tissue resection and intervention strategies in patients with neurological diseases. Precise localization requires high spatiotemporal recording from populations of neurons while minimizing invasiveness and adverse events. We describe a large-scale, high-density, organic material-based, conformable neural interface device ("NeuroGrid") capable of simultaneously recording local field potentials (LFPs) and action potentials from the cortical surface. We demonstrate the feasibility and safety of intraoperative recording with NeuroGrids in anesthetized and awake subjects. Highly localized and propagating physiological and pathological LFP patterns were recorded, and correlated neural firing provided evidence about their local generation. Application of NeuroGrids to brain disorders, such as epilepsy, may improve diagnostic precision and therapeutic outcomes while reducing complications associated with invasive electrodes conventionally used to acquire high-resolution and spiking data.

BACKGROUND: Reconstruction of maxillary defects following tumor extirpation is challenging because of combined aesthetic and functional roles of the maxilla. One-stage reconstruction combining osseous free flaps with immediate osseointegrated implants are becoming the standard for mandibular defects, and have similar potential for maxillary reconstruction. METHODS: A woman with maxillary Ewing sarcoma successfully treated at age 9 with neoadjuvant chemotherapy, right hemimaxillectomy, and obturator prosthetic reconstruction presented for definitive reconstruction, complaining of poor obturator fit, and hypernasality. Her reconstruction was computer-simulated by a multidisciplinary team, consisting of left hemi-Lefort I advancement and right maxillary reconstruction with a free fibula flap with immediate osseointegrated implants and dental prosthesis. RESULTS: Full dental restoration, midface projection, and oral fistula corrections were achieved in 1 operative stage using this approach. CONCLUSIONS: This patient demonstrates a successful approach for maxillary reconstruction using computer-planned orthognathic surgery with free fibula reconstruction and immediate osseointegrated implants with dental prosthesis.

Pediatric glioblastoma is one of the most common and most deadly brain tumors in childhood. Using an integrative genetic analysis of 53 pediatric glioblastomas and five in vitro model systems, we identified previously unidentified gene fusions involving the MET oncogene in ~10% of cases. These MET fusions activated mitogen-activated protein kinase (MAPK) signaling and, in cooperation with lesions compromising cell cycle regulation, induced aggressive glial tumors in vivo. MET inhibitors suppressed MET tumor growth in xenograft models. Finally, we treated a pediatric patient bearing a MET-fusion-expressing glioblastoma with the targeted inhibitor crizotinib. This therapy led to substantial tumor shrinkage and associated relief of symptoms, but new treatment-resistant lesions appeared, indicating that combination therapies are likely necessary to achieve a durable clinical response.

The detection of a sensory stimulus arises from a significant change in neural activity, but a sensory neuron's response is rarely identical to successive presentations of the same stimulus. Large trial-to-trial variability would limit the central nervous system's ability to reliably detect a stimulus, presumably affecting perceptual performance. However, if response variability were to decrease while firing rate remained constant, then neural sensitivity could improve. Here, we asked whether engagement in an auditory detection task can modulate response variability, thereby increasing neural sensitivity. We recorded telemetrically from the core auditory cortex of gerbils, both while they engaged in an amplitude-modulation detection task and while they sat quietly listening to the identical stimuli. Using a signal detection theory framework, we found that neural sensitivity was improved during task performance, and this improvement was closely associated with a decrease in response variability. Moreover, units with the greatest change in response variability had absolute neural thresholds most closely aligned with simultaneously measured perceptual thresholds. Our findings suggest that the limitations imposed by response variability diminish during task performance, thereby improving the sensitivity of neural encoding and potentially leading to better perceptual sensitivity. SIGNIFICANCE STATEMENT: The detection of a sensory stimulus arises from a significant change in neural activity. However, trial-to-trial variability of the neural response may limit perceptual performance. If the neural response to a stimulus is quite variable, then the response on a given trial could be confused with the pattern of neural activity generated when the stimulus is absent. Therefore, a neural mechanism that served to reduce response variability would allow for better stimulus detection. By recording from the cortex of freely moving animals engaged in an auditory detection task, we found that variability of the neural response becomes smaller during task performance, thereby improving neural detection thresholds.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1alpha (Hif1alpha)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.