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BackgroundHearing impairment is the most frequent sensory deficit in humans, affecting more than 360 million people worldwide. In fact, hearing impairment is not merely a health problem, but it also has a great impact on the educational performance, economic income, and quality of life. Hearing impairment is therefore an important social concern. ObjectiveWe aimed to evaluate and compare the accuracy of self-perception, Hearing Handicap Inventory for the Elderly-Screening (HHIE-S) questionnaire, free-field voice test, and smartphone-based audiometry as tests for screening moderate hearing impairment in older adults in China. MethodsIn this study, 41 patients were recruited through a single otology practice. All patients were older than 65 years. Patients with otorrhea and cognitive impairment were excluded. Moderate hearing impairment was defined as mean hearing thresholds at 500, 1000, 2000, and 4000 Hz >40 dB hearing loss (pure-tone average > 40 dB hearing loss). All patients completed 5 hearing tests, namely, the self-perception test, HHIE-S questionnaire test, free-field voice test, smartphone-based audiometry test, and standard pure-tone audiometry by the same audiologist. We compared the results of these tests to the standard audiogram in the better-hearing ear. ResultsThe sensitivity and the specificity of the self-perception test were 0.58 (95% CI 0.29-0.84) and 0.34 (95% CI 0.19-0.54), respectively. The sensitivity and the specificity of the HHIE-S questionnaire test were 0.67 (95% CI 0.35-0.89) and 0.31 (95% CI 0.316-0.51), respectively. The sensitivity and the specificity of the free-field voice test were 0.83 (95% CI 0.51-0.97) and 0.41 (95% CI 0.24-0.61), respectively. The sensitivity and the specificity of the smartphone-based audiometry test were 0.92 (95% CI 0.60-0.99) and 0.76 (95% CI 0.56-0.89), respectively. Smartphone-based audiometry correctly diagnosed the presence of hearing loss with high sensitivity and high specificity. ConclusionsSmartphone-based audiometry may be a dependable screening test to rule out moderate hearing impairment in the older population.

The molecular underpinnings of acquired resistance to carboplatin are poorly understood and often inconsistent between in vitro modeling studies. After sequential treatment cycles, multiple isogenic clones reached similar levels of resistance, but significant transcriptional heterogeneity. Gene-expression based virtual synchronization of 26,772 single cells from 2 treatment steps and 4 resistant clones was used to evaluate the activity of Hallmark gene sets in proliferative (P) and quiescent (Q) phases. Two behaviors were associated with resistance: (1) broad repression in the P phase observed in all clones in early resistant steps and (2) prevalent induction in Q phase observed in the late treatment step of one clone. Furthermore, the induction of IFNα response in P phase or Wnt-signaling in Q phase were observed in distinct resistant clones. These observations suggest a model of resistance hysteresis, where functional alterations of the P and Q phase states affect the dynamics of the successive transitions between drug exposure and recovery, and prompts for a precise monitoring of single-cell states to develop more effective schedules for, or combination of, chemotherapy treatments.

As time progresses, the transmission pattern of a disease may change. To more precisely determine the spread behaviors of the disease, we develop non-autonomous topological and random spread models. In this article, we validate the survival characteristics of these spread models and elucidate their connection with mixing properties using the associated ξ -matrices or spread mean matrices. We also introduce the concept of spread rates for both periodic topological and random spread models and provide rigorous formulas for calculating these rates. Additionally, numerical examples and simulation results are provided as supporting evidence for the theory in both topological and random models. [ABSTRACT FROM AUTHOR]

APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16-fold reduced accumulation of Fe(253)3 RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167-76. ©2018 AACR.

APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0-G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time-dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177-86. ©2018 AACR.

This paper proposes an online multi-user real-time co-reading (OMURCOR) system to promote the performance of co-reading with collaborative learning. The OMURCOR system utilizes WebSocket to perform synchronization controls on co-reading to allow teachers and students to watch streaming videos together with less delay. Moreover, teachers utilize the system to synchronize control operations of videos on the student site, and the OMURCOR system can be integrated into a learning management system to strengthen students' interaction through co-reading. Unlike traditional platforms, the system supports grouping mechanisms during instruction. A survey was conducted with 104 participants. The bootstrapping square and partial least square approaches of the structural equation modeling (PLS-SEM) are employed via the SmartPLS tool to explore evidence of reliability and validity of the revised TAM. Experimental results reflected that six of the seven hypotheses were supported, and the proposed system has a significant impact on students' learning effectiveness during co-reading.

Objective: Coronavirus disease 2019 (COVID-19) can cause intubation and ventilatory support due to respiratory failure, and extubation failure increases mortality risk. This study, therefore, aimed to explore the feasibility of using specific biochemical and ventilator parameters to predict survival status among COVID-19 patients by using machine learning. Methods: This study included COVID-19 patients from Taipei Medical University-affiliated hospitals from May 2021 to May 2022. Sequential data on specific biochemical and ventilator parameters from days 0–2, 3–5, and 6–7 were analyzed to explore differences between the surviving (successfully weaned off the ventilator) and non-surviving groups. These data were further used to establish separate survival prediction models using random forest (RF). Results: The surviving group exhibited significantly lower mean C-reactive protein (CRP) levels and mean potential of hydrogen ions levels (pH) levels on days 0–2 compared to the non-surviving group (CRP: non-surviving group: 13.16 ± 5.15 ng/mL, surviving group: 10.23 ± 5.15 ng/mL; pH: non-surviving group: 7.32 ± 0.07, survival group: 7.37 ± 0.07). Regarding the survival prediction performanace, the RF model trained solely with data from days 0–2 outperformed models trained with data from days 3–5 and 6–7. Subsequently, CRP, the partial pressure of carbon dioxide in arterial blood (PaCO2), pH, and the arterial oxygen partial pressure to fractional inspired oxygen (P/F) ratio served as primary indicators in survival prediction in the day 0–2 model. Conclusions: The present developed models confirmed that early biochemical and ventilatory parameters—specifically, CRP levels, pH, PaCO2, and P/F ratio—were key predictors of survival for COVID-19 patients. Assessed during the initial two days, these indicators effectively predicted the likelihood of successful weaning of from ventilators, emphasizing their importance in early management and improved outcomes in COVID-19-related respiratory failure. [ABSTRACT FROM AUTHOR]

We have achieved a significant breakthrough in the preparation and development of two‐dimensional nanocomposites with P‐N heterojunction interfaces as efficient cathode catalysts for electrochemical hydrogen evolution reaction (HER) and iodide oxidation reaction (IOR). P‐type acid‐doped polyaniline (PANI) and N‐type exfoliated molybdenum disulfide (MoS2) nanosheets can form structurally stable composites due to formation of P‐N heterojunction structures at their interfaces. These P‐N heterojunctions facilitate charge transfer from PANI to MoS2 structures and thus significantly enhance the catalytic efficiency of MoS2 in the HER and IOR. Herein, by combining efficient sodium‐functionalized chitosan‐assisted MoS2 exfoliation, electropolymerization of PANI on nickel foam (NF) substrate, and electrochemical activation, controllable and scalable Na‐Chitosan/MoS2/PANI/NF electrodes are successfully constructed as non‐noble metal‐based electrochemical catalysts. Compared to a commercial platinum/carbon (Pt/C) catalyst, the Na‐Chitosan/MoS2/PANI/NF electrode exhibits significantly lower resistance and overpotential, a similar Tafel slope, and excellent catalytic stability at high current densities, demonstrating excellent catalytic performance in the HER under acidic conditions. More importantly, results obtained from proton exchange membrane fuel cell devices confirm the Na‐Chitosan/MoS2/PANI/NF electrode exhibits a low turn‐on voltage, high current density, and stable operation at 2 V. Thus, this system holds potential as a replacement for Pt/C with feasibility for applications in energy‐related fields. [ABSTRACT FROM AUTHOR]

Introduction: Sensorineural hearing impairment (SNHI), a common childhood disorder with heterogeneous genetic causes, can lead to delayed language development and psychosocial problems. Next-generation sequencing (NGS) offers high-throughput screening and high-sensitivity detection of genetic etiologies of SNHI, enabling clinicians to make informed medical decisions, provide tailored treatments, and improve prognostic outcomes. Areas covered: This review covers the diverse etiologies of HHI and the utility of different NGS modalities (targeted sequencing and whole exome/genome sequencing), and includes HHI-related studies on newborn screening, genetic counseling, prognostic prediction, and personalized treatment. Challenges such as the trade-off between cost and diagnostic yield, detection of structural variants, and exploration of the non-coding genome are also highlighted. Expert opinion: In the current landscape of NGS-based diagnostics for HHI, there are both challenges (e.g. detection of structural variants and non-coding genome variants) and opportunities (e.g. the emergence of medical artificial intelligence tools). The authors advocate the use of technological advances such as long-read sequencing for structural variant detection, multi-omics analysis for non-coding variant exploration, and medical artificial intelligence for pathogenicity assessment and outcome prediction. By integrating these innovations into clinical practice, precision medicine in the diagnosis and management of HHI can be further improved. [ABSTRACT FROM AUTHOR]