The natural history and genotype-phenotype correlations of TMPRSS3 hearing loss: an international, multi-center, cohort analysis.

TMPRSS3-related hearing loss presents challenges in correlating genotypic variants with clinical phenotypes due to the small sample sizes of previous studies. We conducted a cross-sectional genomics study coupled with retrospective clinical phenotype analysis on 127 individuals. These individuals were from 16 academic medical centers across 6 countries. Key findings revealed 47 unique TMPRSS3 variants with significant differences in hearing thresholds between those with missense variants versus those with loss-of-function genotypes. The hearing loss progression rate for the DFNB8 subtype was 0.3 dB/year. Post-cochlear implantation, an average word recognition score of 76% was observed. Of the 51 individuals with two missense variants, 10 had DFNB10 with profound hearing loss. These 10 all had at least one of 4 TMPRSS3 variants predicted by computational modeling to be damaging to TMPRSS3 structure and function. To our knowledge, this is the largest study of TMPRSS3 genotype-phenotype correlations. We find significant differences in hearing thresholds, hearing loss progression, and age of presentation, by TMPRSS3 genotype and protein domain affected. Most individuals with TMPRSS3 variants perform well on speech recognition tests after cochlear implant, however increased age at implant is associated with worse outcomes. These findings provide insight for genetic counseling and the on-going design of novel therapeutic approaches.

Frontoparietal beta event characteristics are associated with early life stress and psychiatric symptoms in adults.

Recent work has found that the presence of transient, oscillatory burst-like events, particularly within the beta band (15-29 Hz), is more closely tied to disease state and behavior across species than traditional electroencephalography (EEG) power metrics. This study sought to examine whether features of beta events over frontoparietal electrodes were associated with early life stress (ELS) and the related clinical presentation. Eighteen adults with documented ELS (n = 18; ELS + ) and eighteen adults without documented ELS (n = 18; ELS-) completed eyes-closed resting state EEG as part of their participation in a larger childhood stress study. The rate, power, duration, and frequency span of transient oscillatory events were calculated within the beta band at five frontoparietal electrodes. ELS variables were positively associated with beta event rate at Fp2 and beta event duration at Pz, in that greater ELS was associated with higher resting rates and longer durations. These beta event characteristics were used to successfully distinguish between ELS + and ELS- groups. In an independent clinical dataset (n = 25), beta event power at Pz was positively correlated with ELS. Beta events deserve ongoing investigation as a potential disease marker of ELS and subsequent psychiatric treatment outcomes.

Topical Prescription Management.

With recent advances in topical therapies for atopic dermatitis (AD), steroid-sparing options like calcineurin inhibitors, Janus kinase (JAK) inhibitors, and phosphodiesterase-4 (PDE-4) inhibitors are becoming mainstays in therapy, underscoring the importance of careful selection and usage of topical corticosteroids (TCSs) to minimize side effects. Alongside the necessity of emollient use, these steroid-sparing alternatives offer rapid itch relief and efficacy in improving disease severity. While TCSs still hold a prominent role in AD management, promising novel topical treatments like tapinarof and live biotherapeutics to modulate the skin microbiome are also discussed. Overall, the recent addition of novel topical therapies offers diverse options for AD management and underscores the importance of topical treatments in the management of AD.

Age-related differences in transient gamma band activity during working memory maintenance through adolescence.

Adolescence is a stage of development characterized by neurodevelopmental specialization of cognitive processes. In particular, working memory continues to improve through adolescence, with increases in response accuracy and decreases in response latency continuing well into the twenties. Human electroencephalogram (EEG) studies indicate that gamma oscillations (35-65 Hz) during the working memory delay period support the maintenance of mnemonic information guiding subsequent goal-driven behavior, which decrease in power with development. Importantly, recent electrophysiological studies have shown that gamma events, more so than sustained activity, may underlie working memory maintenance during the delay period. However, developmental differences in gamma events during working memory have not been studied. Here, we used EEG in conjunction with a novel spectral event processing approach to investigate age-related differences in transient gamma band activity during a memory guided saccade (MGS) task in 164 10- to 30-year-olds. Total gamma power was found to significantly decrease through adolescence, replicating prior findings. Results from the spectral event pipeline showed age-related decreases in the mean power of gamma events and trial-by-trial power variability across both the delay period and fixation epochs of the MGS task. In addition, we found that while event number decreased with age during the fixation period, the developmental decrease during the delay period was more dramatic, resulting in an increase in event spiking from fixation to delay in adolescence but not adulthood. While average power of the transient gamma events was found to mediate age-related differences in total gamma power in the fixation and delay periods, the number of gamma events was related to total power in only the delay period, suggesting that the power of gamma events may underlie the sustained gamma activity seen in EEG literature while the number of events may directly support age-related improvements in working memory maintenance. Our findings provide compelling new evidence for mechanistic changes in neural processing characterized by refinements in neural function as behavior becomes optimized in adulthood.

AudioGene: refining the natural history of KCNQ4, GSDME, WFS1, and COCH-associated hearing loss.

Autosomal dominant non-syndromic hearing loss (ADNSHL) displays gene-specific progression of hearing loss, which is amenable to sequential audioprofiling. We sought to refine the natural history of ADNSHL by examining audiometric data in 5-year increments. 2175 audiograms were included from four genetic causes of ADNSHL-KCNQ4 (DFNA2), GSDME (DFNA5), WFS1 (DFNA6/14/38), and COCH (DFNA9). Annual threshold deterioration (ATD) was calculated for each gene: for the speech-frequency pure tone average, the ATD, respectively, was 0.72 dB/year, 0.94 dB/year, 0.53 dB/year, and 1.41 dB/year, with the largest drops occurring from ages 45-50 (0.89 dB/year; KCNQ4), 5-10 (1.42 dB/year; GSDME), 40-45 (0.83 dB/year; WFS1), and 50-55 (2.09 dB/year; COCH). 5-year interval analysis of audiograms reveals the gene specific natural history of KCNQ4, GSDME, WFS1 and COCH-related progressive hearing loss. Identifying ages at which hearing loss is most rapid informs clinical care and patient expectations. Natural history data are also essential to define outcomes of clinical trials that test novel therapies designed to correct or ameliorate these genetic forms of hearing loss.

The natural history of OTOF-related auditory neuropathy spectrum disorders: a multicenter study.

Pathogenic variations in the OTOF gene are a common cause of hearing loss. To refine the natural history and genotype-phenotype correlations of OTOF-related auditory neuropathy spectrum disorders (ANSD), audiograms and distortion product otoacoustic emissions (DPOAEs) were collected from a diverse cohort of individuals diagnosed with OTOF-related ANSD by comprehensive genetic testing and also reported in the literature. Comparative analysis was undertaken to define genotype-phenotype relationships using a Monte Carlo algorithm. 67 audiograms and 25 DPOAEs from 49 unique individuals positive for OTOF-related ANSD were collected. 51 unique OTOF pathogenic variants were identified of which 21 were missense and 30 were loss of function (LoF; nonsense, splice-site, copy number variants, and indels). There was a statistically significant difference in low, middle, and high frequency hearing thresholds between missense/missense and LoF/missense genotypes as compared to LoF/LoF genotypes (average hearing threshold for low, middle and high frequencies 70.9, 76.0, and 73.4 dB vs 88.5, 95.6, and 94.7 dB) via Tukey's test with age as a co-variate (P = 0.0180, 0.0327, and 0.0347, respectively). Hearing declined during adolescence with missense/missense and LoF/missense genotypes, with an annual mid-frequency threshold deterioration of 0.87 dB/year and 1.87 dB/year, respectively. 8.5% of frequencies measured via DPOAE were lost per year in individuals with serial tests. Audioprofiling of OTOF-related ANSD suggests significantly worse hearing with LoF/LoF genotypes. The unique pattern of variably progressive OTOF-related autosomal recessive ANSD may be amenable to gene therapy in selected clinical scenarios.

Development and validation of a nomogram incorporating gene expression profiling and clinical factors for accurate prediction of metastasis in patients with cutaneous melanoma following Mohs micrographic surgery.

BACKGROUND: There is a need to improve prognostic accuracy for patients with cutaneous melanoma. A 31-gene expression profile (31-GEP) test uses the molecular biology of primary tumors to identify individual patient metastatic risk. OBJECTIVE: Develop a nomogram incorporating 31-GEP with relevant clinical factors to improve prognostic accuracy. METHODS: In an IRB-approved study, 1124 patients from 9 Mohs micrographic surgery centers were prospectively enrolled, treated with Mohs micrographic surgery, and underwent 31-GEP testing. Data from 684 of those patients with at least 1-year follow-up or a metastatic event were included in nomogram development to predict metastatic risk. RESULTS: Logistic regression modeling of 31-GEP results and T stage provided the simplest nomogram with the lowest Bayesian information criteria score. Validation in an archival cohort (n = 901) demonstrated a significant linear correlation between observed and nomogram-predicted risk of metastasis. The resulting nomogram more accurately predicts the risk for cutaneous melanoma metastasis than T stage or 31-GEP alone. LIMITATIONS: The patient population is representative of Mohs micrographic surgery centers. Sentinel lymph node biopsy was not performed for most patients and could not be used in the nomogram. CONCLUSIONS: Integration of 31-GEP and T stage can gain clinically useful prognostic information from data obtained noninvasively.

Pain phenotypes classified by machine learning using electroencephalography features.

Pain is a multidimensional experience mediated by distributed neural networks in the brain. To study this phenomenon, EEGs were collected from 20 subjects with chronic lumbar radiculopathy, 20 age and gender matched healthy subjects, and 17 subjects with chronic lumbar pain scheduled to receive an implanted spinal cord stimulator. Analysis of power spectral density, coherence, and phase-amplitude coupling using conventional statistics showed that there were no significant differences between the radiculopathy and control groups after correcting for multiple comparisons. However, analysis of transient spectral events showed that there were differences between these two groups in terms of the number, power, and frequency-span of events in a low gamma band. Finally, we trained a binary support vector machine to classify radiculopathy versus healthy subjects, as well as a 3-way classifier for subjects in the 3 groups. Both classifiers performed significantly better than chance, indicating that EEG features contain relevant information pertaining to sensory states, and may be used to help distinguish between pain states when other clinical signs are inconclusive.

An insight into the corrosion of alkali aluminoborosilicate glasses in acidic environments.

The majority of the literature on glass corrosion focuses on understanding the dissolution kinetics and mechanisms of silicate glass chemistries in the neutral-to-alkaline aqueous regime owing to its relevance in the fields of nuclear waste immobilization and biomaterials. However, understanding the corrosion of silicate-based glass chemistries over a broad composition space in the acidic pH regime is essential for glass packaging and touch screen electronic display industries. A thorough literature review on this topic reveals only a handful of studies that discuss acid corrosion of silicate glasses and their derivatives-these include only a narrow set of silicate-based glass chemistries. Although the current literature successfully explains the dissolution kinetics of glasses based upon classically understood aqueous corrosion mechanisms, more recent advancements in atomic-scale characterization techniques, have enabled a better understanding of reactions taking place directly at the pristine glass-fluid interface which has facilitated the development of a unifying model describing corrosion behavior of silicate glasses. Based on the corrosion mechanisms described and the questions raised in preceding literature, the present study focuses on understanding the corrosion mechanisms governing metaluminous (Na/Al = 1) sodium aluminoborosilicate glasses in acidic environments across a wide composition-space (ranging from SiO2-rich to B2O3-rich compositions), with particular emphasis on understanding the reactions taking place near the glass-fluid interface. Using state-of-the-art characterization techniques including nuclear magnetic resonance (NMR) spectroscopy, Rutherford backscattering, X-ray photoelectron spectroscopy (XPS) and elastic recoil detection analysis (ERDA), it has been shown that stepwise B2O3 substitutions into nepheline (NaAlSiO4) glass, although causing non-linear changes in glass structure network structural features, leads to strikingly linear increases in the forward dissolution rate at pH = 2. While the glasses undergo congruent dissolution in the forward rate regime, the residual rate regime displays evidence of preferential extraction near the glass surface (i.e., enrichment in aluminum content upon corrosion through AlO4→ Al(OH)3 evolution) implying that dissolution-re-precipitation processes may occur at the glass-fluid interface in both B2O3-rich and SiO2-rich glass compositions-albeit with vastly dissimilar reaction kinetics.

Osteoactivin regulates head and neck squamous cell carcinoma invasion by modulating matrix metalloproteases.

Nearly 60% of patients with head and neck squamous cell carcinoma (HNSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell migration and invasion, which are in part dependent on extracellular matrix degradation by matrix metalloproteinases. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies, and has been shown to upregulate matrix metalloproteinase (MMP) expression and activity. To determine how OA modulates MMP expression and activity in HNSCC, and to investigate OA effects on cell invasion, we assessed effects of OA treatment on MMP mRNA and protein expression, as well as gelatinase and caseinolytic activity in HNSCC cell lines. We assessed the effects of OA gene silencing on MMP expression, gelatinase and caseinolytic activity, and cell invasion. OA treatment had differential effects on MMP mRNA expression. OA treatment upregulated MMP-10 expression in UMSCC14a (p = 0.0431) and SCC15 (p < 0.0001) cells, but decreased MMP-9 expression in UMSCC14a cells (p = 0.0002). OA gene silencing decreased MMP-10 expression in UMSCC12 cells (p = 0.0001), and MMP-3 (p = 0.0005) and -9 (p = 0.0036) expression in SCC25 cells. In SCC15 and SCC25 cells, OA treatment increased MMP-2 (p = 0.0408) and MMP-9 gelatinase activity (p < 0.0001), respectively. OA depletion decreased MMP-2 (p = 0.0023) and -9 (p < 0.0001) activity in SCC25 cells. OA treatment increased 70 kDa caseinolytic activity in UMSCC12 cells consistent with tissue type plasminogen activator (p = 0.0078). OA depletion decreased invasive capacity of UMSCC12 cells (p < 0.0001). OA's effects on MMP expression in HNSCC are variable, and may promote cancer cell invasion.

The V-to-Y Advancement Flap for Distal Nasal Reconstruction: Our Experience With 39 Patients.

BACKGROUND AND OBJECTIVE: The V-to-Y advancement flap, also known as the island pedicle flap, is a single-stage repair option that can be used for defects on the distal nose. We report our experience using this flap for nasal defects following Mohs micrographic surgery, as well as describe optimal patient selection and flap design. MATERIALS AND METHODS: A retrospective review was conducted of all patient charts and operative photographs of nasal V-to-Y advancement flaps performed over 6 years at the Universtiy of Texas Southwestern Medical Center. Charts were reviewed for age, sex, tumour type and location, defect size, anticoagulation, immunosuppression, postoperative complications, revisions, and outcomes. RESULTS: Thirty-nine patients with defects ranging from 0.7 to 1.7 cm in size (median of 1 cm) were included. Most defects involved the inferior, paramedian nose, and after accounting for 7 postrepair interventions on 6 (15%) patients, 38 (97%) patients were noted to have good to excellent cosmetic outcomes while 1 patient experienced a persistent trapdoor effect. CONCLUSION: The V-to-Y advancement flap is an excellent single-stage option that can reliably provide good to excellent cosmetic results when used to repair small- to medium-size sized defects on the distal half of the nose.

Prescription Treatment Options.

Atopic dermatitis frequently requires the use of over-the-counter and prescription medications for effective management. Emollients and topical corticosteroids are effective for most patients and are the most commonly utilized agents by experienced dermatologists. Antihistamines, antibiotics, and calcineurin inhibitors may also prove helpful in the correct clinical scenarios. Severe atopic dermatitis, however, can be difficult to manage and not infrequently require substantial immunomodulatory medications. Targeted molecular therapies, such as dupilumab, are promising, emerging atopic dermatitis therapies. The medication pearls reviewed in this chapter will assist providers in managing atopic dermatitis patients.

Osteoactivin Promotes Migration of Oral Squamous Cell Carcinomas.

Nearly 50% of patients with oral squamous cell carcinoma (OSCC) die of metastases or locoregional recurrence. Metastasis is mediated by cancer cell adhesion, migration, and invasion. Osteoactivin (OA) overexpression plays a role in metastases in several malignancies. The aims were to determine how integrin interactions modulate OA-induced OSCC cell migration; and to investigate OA effects on cell survival and proliferation. We confirmed OA mRNA and protein overexpression in OSCC cell lines. We assessed OA's interactions with integrins using adhesion inhibition assays, fluorescent immunocytochemistry and co-immunoprecipitation. We investigated OA-mediated activation of mitogen-activated protein kinases (MAPKs) and cell survival. Integrin inhibition effects on OA-mediated cell migration were determined. We assessed effects of OA knock-down on cell migration and proliferation. OA is overexpressed in OSCC cell lines, and serves as a migration-promoting adhesion molecule. OA co-localized with integrin subunits, and co-immunoprecipitated with the subunits. Integrin blocking antibodies, especially those directed against the ß1 subunit, inhibited cell adhesion (P = 0.03 for SCC15 cells). Adhesion to OA activated MAPKs in UMSCC14a cells and OA treatment promoted survival of SCC15 cells. Integrin-neutralizing antibodies enhanced cell migration with OA in the extracellular matrix. OA knock-down resulted in decreased proliferation of SCC15 and SCC25 cells, but did not inhibit cell migration. OA in the extracellular matrix promotes OSCC cell adhesion and migration, and may be a novel target in the prevention of HNSCC spread. J. Cell. Physiol. 231: 1761-1770, 2016. © 2015 Wiley Periodicals, Inc.

Multiscale characterization and representation of composite materials during processing.

Given the importance of residual stresses and dimensional changes in composites manufacturing, process simulation has been the focus of many studies in recent years. Consequently, various constitutive models and simulation approaches have been developed and implemented for composites process simulation. In this paper, various constitutive models, ranging from elastic to nonlinear viscoelastic; and simulation approaches ranging from separated flow/solid phases to multiscale integrated phases are presented and their applicability for process simulation is discussed. Attention has been paid to practical aspects of the problem where the complexity of the model coupled with the complexity and size scaling of the structure increases the characterization and simulation costs. Two specific approaches and their application are presented in detail: the pseudo-viscoelastic cure hardening instantaneously linear elastic (CHILE) and linear viscoelastic (VE). It is shown that CHILE can predict the residual stress formation in simple cure cycles such as the one-hold cycle for HEXCEL AS4/8552 where the material does not devitrify during processing. It is also shown that using this simple approach, the cure cycle can be modified to lower the residual stress level and therefore increase the mechanical performance of the composite laminate. For a more complex cure cycle where the material is devitrified during a post-cure, it is shown that a more complex model such as VE is required. This article is part of the themed issue 'Multiscale modelling of the structural integrity of composite materials'.

The solid state conversion reaction of epitaxial FeF2(110) thin films with lithium studied by angle-resolved X-ray photoelectron spectroscopy.

The phase evolution and morphology of the solid state FeF2 conversion reaction with Li has been characterized using angle-resolved X-ray photoelectron spectroscopy (ARXPS). An epitaxial FeF2(110) film was grown on a MgF2(110) single crystal substrate and exposed to atomic lithium in an ultra-high vacuum chamber. A series of ARXPS spectra was taken after each Li exposure to obtain depth resolved chemical state information. The Li-FeF2 reaction initially proceeded in a layer-by-layer fashion to a depth of ∼1.2 nm. Beyond this depth, the reaction front became non-planar, and regions of unreacted FeF2 were observed in the near-surface region. This reaction progression is consistent with molecular dynamics simulations. Additionally, the composition of the reacted layer was similar to that of electrochemically reacted FeF2 electrodes. An intermediary compound FexLi2-2xF2, attributed to iron substituted in the LiF lattice, has been identified using XPS. These measurements provide insight into the atomistics and phase evolution of high purity FeF2 conversion electrodes without contamination from electrolytes and binders, and the results partially explain the capacity losses observed in cycled FeF2 electrodes.

Clinical and Pathologic Factors Predictive of Positive Radiologic Findings in High-Risk Cutaneous Squamous Cell Carcinoma.

BACKGROUND: At present, there exists considerable clinical uncertainty regarding the role of radiologic imaging in the staging and management of high-risk cutaneous squamous cell carcinoma (hrSCC). OBJECTIVE: The authors sought to investigate the clinical and pathologic features predictive of bony invasion, perineural invasion, or lymphadenopathy in patients that had undergone head and neck imaging for hrSCC. MATERIALS AND METHODS: The authors conducted a single-center retrospective chart review of patients (n = 82) that had undergone head and neck imaging for hrSCC. RESULTS: Twenty-nine percent (24/82) of patients in the study had positive findings on radiologic imaging. Immunocompromised patients were more likely to have the radiologic finding of lymphadenopathy (p = .04). Tumor size was found to correlate with the radiologic finding of bony invasion (correlation coefficient = 0.40, p = .0002). There was no relationship between either high risk location or high risk histopathology and positive radiologic findings. The low number of patients and its retrospective nature are study limitations. CONCLUSION: The clinical features of host immunosuppression and tumor size are predictive of positive imaging findings in hrSCC. The decision to perform radiologic imaging in patients with hrSCC may be influenced by these factors, but continue to be more firmly guided by physical exam and clinical suspicion.

Site-specific analysis of inflammatory markers in discoid lupus erythematosus skin.

Prior studies identified T cells, B cells, and macrophages in the inflammatory infiltrate and up-regulation of their protein products in discoid lupus erythematosus (DLE) skin; however, they lacked rigorous analyses to define their specific locations in skin. Thus, we compared expressions of selected T cell, B cell, and macrophage markers in five areas of DLE, psoriasis, and normal skin. Immunostainings for CD3, CD4, CD8, CD20, CD68, CXCR3, CXCL10, and TIA-1 were performed in biopsies of 23 DLE lesional skin, 11 psoriasis lesional skin, and 5 normal skin. Three independent observers used a graded scale to rate each marker's presence in the epidermis, dermatoepidermal junction (DEJ), perivascular area, periadnexal area, and deep dermis. DLE lesional skin contained an increased abundance of CD3(+), CD8(+), and CD68(+) cells at the DEJ, and CD20(+) and CD68(+) cells in the periadnexal area versus psoriasis and normal skin. CXCR3, CXCL10, and TIA-1 were elevated in periadnexal sites of DLE lesional skin versus psoriasis lesional skin. The aggregation of T cells, B cells, macrophages, and their protein products (CXCR3, CXCL10, and TIA-1) in the DEJ and periadnexal area of DLE lesional skin may contribute to the pathology of DLE through a coordinated, sophisticated process.

Edematous lip in a HIV patient on highly active antiretroviral therapy.

A 59-year-old HIV-positive, hepatitis C positive man on highly active antiretroviral therapy presented with a 2-year history of extreme swelling of the lower lip. Granulomatous cheilitis was diagnosed.