Study protocol: How does cognitive flexibility relate to other executive functions and learning in healthy young adults?

BACKGROUND: Cognitive flexibility (CF) enables individuals to readily shift from one concept or mode of practice/thoughts to another in response to changes in the environment and feedback, making CF vital to optimise success in obtaining goals. However, how CF relates to other executive functions (e.g., working memory, response inhibition), mental abilities (e.g., creativity, literacy, numeracy, intelligence, structure learning), and social factors (e.g., multilingualism, tolerance of uncertainty, perceived social support, social decision-making) is less well understood. The current study aims to (1) establish the construct validity of CF in relation to other executive function skills and intelligence, and (2) elucidate specific relationships between CF, structure learning, creativity, career decision making and planning, and other life skills. METHODS: This study will recruit up to 400 healthy Singaporean young adults (age 18-30) to complete a wide range of cognitive tasks and social questionnaires/tasks. The richness of the task/questionnaire battery and within-participant administration enables us to use computational modelling and structural equation modelling to examine connections between the latent constructs of interest. SIGNIFICANCE AND IMPACT: The current study is the first systematic investigation into the construct validity of CF and its interrelationship with other important cognitive skills such as learning and creativity, within an Asian context. The study will further explore the concept of CF as a non-unitary construct, a novel theoretical proposition in the field. The inclusion of a structure learning paradigm is intended to inform future development of a novel intervention paradigm to enhance CF. Finally, the results of the study will be useful for informing classroom pedagogy and the design of lifelong learning policies and curricula, as part of the wider remit of the Cambridge-NTU Centre for Lifelong Learning and Individualised Cognition (CLIC).

Evaluation of Fine Needle Aspiration Cytopathology in Salivary Gland Tumors under Milan System: Challenges, Misdiagnosis Rates, and Clinical Recommendations.

(1) Background: Salivary gland tumors are rare in the head and neck. To determine the need and extent of surgical intervention, fine needle aspiration (FNA) is a widely accepted tool to approach salivary gland lesions. However, the FNA cytology varies between entities, while the lack of uniform terminology makes diagnosis more challenging. Since establishing the Milan system for reporting salivary gland cytopathology (MSRSGC) has become an increasingly accepted reporting standard, further examination and detailed recommendations were needed. (2) Methods: Between April 2013 and October 2021, 375 cases with FNA and salivary gland resection were retrospectively collected. All FNA specimens were reclassified according to the criteria of MSRSGC. After surgical excision, the FNA data were compared with the histological diagnosis to estimate the risk of malignancy (ROM), the risk of neoplasm (RON), and the diagnostic accuracy for each diagnostic category. (3) Results: Our cohort's distribution of ROM and RON was similar to the MSRSGC's recommendation. Carcinoma ex pleomorphic adenoma (CXPA) has the highest rate (66.7%) of misdiagnosed as a nonneoplastic lesion or benign salivary gland tumor. Pleomorphic adenoma (PA) and Warthin's tumor were the most common benign salivary gland tumors, while the cytology diagnosis of Warthin's tumor seems more challenging than PAs. (4) Conclusions: Despite the convenience and effectiveness of MSRSGC, we suggest close follow-up, re-biopsy, or surgical removal for salivary lesions even in Milan IVA-Benign for possibly missing FNA of malignancy, mixed lesions, or prevention of malignant transformation.

Relationship Between Pharyngeal Residues Assessed by Bolus Residue Scale or Normalized Residue Ratio SCALE and Risk of Aspiration in Head and Neck Cancer Who Underwent Videofluoroscopy.

Dysphagia affects 60-75% of patients treated for head and neck cancer (HNC). We aimed to evaluate the association between residue severity and airway invasion severity using a videofluoroscopic swallowing study and identify risk factors for poor penetration-aspiration outcomes in patients with dysphagia treated for HNC. Penetration-Aspiration Scale (PAS) was used to assess airway invasion severity, while residue severity was assessed using both the Bolus Residue Scale (BRS) for residue location and the Normalized Residue Ratio Scale (NRRS) for residue amount. Relevant covariates were adjusted in the logistic regression models to account for potential confounding. Significantly higher abnormal PAS was reported for increased piriform sinus NRRS (NRRSp) [odds ratio (OR), 4.81; p = 0.042] with liquid swallowing and increased BRS value (OR, 1.52; p = 0.014) for semi-liquid swallowing in multivariate analysis. Tumor location, older age, and poorer Functional Oral Intake Scale (FOIS) were significant factors for abnormal PAS in both texture swallowings. After adjusting for confounding factors (sex, age, and FOIS score), NRRS model in liquid swallowing (area under the curve [AUC], 0.83; standard error = 0.04, 95% confidence interval [CI]: 0.75, 0.91) and BRS in semi-liquid swallowing (AUC, 0.83; SE = 0.04; 95% CI: 0.76, 0.91) predicted abnormal PAS. The results indicate that while assessing residue and swallowing aspiration in patients with HNC, it is important to consider age, tumor location, and functional swallowing status. The good predictability of abnormal PAS with BRS and NRRS indicated that residue location and amount were both related to the aspiration event in patients with HNC.

The Additive Effectiveness of Inspiratory Muscle Training on Glottic Closure and Subjective Voice Outcomes of Patients With Benign Lesion After Hyaluronic Acid Laryngoplasty.

OBJECTIVES: For patients with glottic insufficiency disease, injection laryngoplasty is a rapid and efficient management option that complements voice therapy. Some studies have indicated that respiratory muscle training may also show promise in patients with voice disorders. However, the effect of respiratory muscle training in patients with glottic insufficiency was reported to be limited, and whether it provides additional benefit after standard management requires further evaluation. We aimed to investigate the effectiveness of inspiratory muscle training on glottis closure and patient-reported voice quality in glottic insufficiency patients who had been treated with hyaluronic acid injection. STUDY DESIGN: Retrospective observational study. METHODS: We included 46 patients with glottic insufficiency who had undergone hyaluronic acid injection. Twenty of them had undergone inspiratory muscle training during three months. We measured patients' changes in glottic status according to the normalized glottal gap area and bowing index, as well as voice quality of life according to the voice handicap index 10 and the voice outcome survey, before and after training. RESULTS: Patients who underwent inspiratory muscle training had higher odds of experiencing better improvement in all scores. The range of odds ratios ranged from 2.5 to 6.3 for changes in scores, and from 3.8 to 22.2 for changes in score percentages. Of note, the effect of training on percentage changes in the normalized glottal gap area score was significant (P= 0.0127) after adjustment for the duration of vocal disease, body mass index and BMI, and history of gastroesophageal reflux disease. CONCLUSIONS: Inspiratory muscle training can improve the glottal gap after injection laryngoplasty, and may be applied in clinical practice.

Effectiveness of Positioning in Unconscious Adults During Nasogastric Intubation on Correct Placement and Intubation Time: A Systematic Review and Meta-analysis.

Nasogastric intubation is a common procedure in hospitals that causes adverse outcomes if performed incorrectly. There is currently insufficient guidance for patient positioning, which increases the success of nasogastric intubation at the bedside. Therefore, a systematic review with a meta-analysis was performed to determine the effectiveness of changing an unconscious adults' positions compared with the supine position to improve the correct placement of a nasogastric tube, intubation time, and complications. The Cochrane Library, MEDLINE, Embase, PubMed, and CINAHL databases were searched from inception to April 2019 for randomized controlled trials. The Cochrane Collaboration Risk of Bias tool was used to assess the quality of eligible studies. Cochrane Review Manager 5.3 software was used to analyze the data. A total of 288 articles were obtained in the literature search, 10 of which were included in the analysis. Most of the included trials were at low risk of bias. All postures were significantly effective, though neck flexion had the highest success rate (odds ratio = 4.87, 95% confidence interval [2.48, 9.57], Z = 4.6, p < .00001, I2 = 0%) for nasogastric intubation. In terms of the time required for the procedure, compared with the usual posture, although the total effects were significant ( MD =-10.33, 95% confidence interval [-15.38, -5.29], Z = 4.02, p < .00001, I2 = 98%), only neck flexion and lifting of the larynx reduced the time. The meta-analysis suggests that patient positioning improves the success rate of nasogastric intubation and increases safety. Finally, the authors developed a procedural instruction sheet to aid practitioners with nasogastric intubation.

Evaluation of Objective and Subjective Swallowing Outcomes in Patients with Dysphagia Treated for Head and Neck Cancer.

We evaluated objective and subjective swallowing function outcomes in patients with dysphagia treated for head and neck cancer (HNC) and identified risk factors for poor swallowing outcomes. Patients undergoing videofluoroscopic swallowing studies (VFSS) between January 2016 and March 2021 were divided into four groups according to primary tumor sites; post-treatment dysphagia was assessed. The penetration-aspiration scale (PAS) and bolus residue scale (BRS) were used to objectively assess swallowing function through VFSS. The Functional Oral Intake Scale (FOIS) was used for subjective analyses of swallowing statuses. To account for potential confounding, important covariates were adjusted for in logistic regression models. Oropharyngeal tumors were significantly more likely to have poor PAS and BRS scores than oral cavity tumors, and the patients with nasopharyngeal tumors were significantly less likely to have poor FOIS scores. Old age, having multiple HNCs, and a history of radiotherapy were associated with an increased odds of poor PAS scores (for all types of swallows), poor BRS scores (for semiliquid and solid swallows), and poor FOIS scores, respectively. This indicates using only subjective assessments may not allow for accurate evaluations of swallowing function in patients treated for HNC. Using both objective and subjective assessments may allow for comprehensive evaluations.

A Transcanal Endoscopic Approach for Management of Pulsatile Tinnitus due to High-Riding Dehiscent Jugular Bulb.

Pulsatile tinnitus (PT) caused by a high-riding dehiscence jugular bulb (HDJB) is a rare but treatable otology disease. There are several managements include transcatheter endovascular coil embolization, transvenous stent-assisted coil embolization, or resurfacing the dehiscent bony wall of high jugular bulb under the use of microscope. Among those options, surgical resurfacing of HDJB might be an effective and safe choice with less destruction. However, previous studies approached middle ear cavity via microscope can only provide a lateral, indirect view, while resurfacing the vessel through a transcanal endoscopic ear surgery (TEES) approach may give surgeon a direct and easy way to manage HDJB. In this report, we presented a case of 40-year-old woman with HDJB and shared our clinical consideration and reasoning of the surgical management of PT via a transtympanic approach by TEES rather than a transmastoid approach.

Emergency medicine airway leads: a rapid response distributed educational model for emergency department COVID-19 airway management.

With the first case of COVID-19 confirmed in Canada in early 2020, our country joined in the fight against a novel pathogen in a global pandemic. The stress of uncertainty and practice change was most apparent in the emergency department when it came to managing known or suspected COVID-19 patients requiring airway management. Recognizing the need for a coordinated approach, a province wide rapid response distributed model of continuing professional development for airway management was developed utilizing Airway Leads to help prepare front-line medical personnel providing airway management for these patients. Airway Leads worked with local physicians to deliver consistent, high quality airway education across the province during the initial surge of cases. Education included both in person and virtual sessions along with real time ongoing support through provincial guidelines, videos, and other documents. Physician reported "stress level" pre- and post-Airway Lead support declined from a median score of 9 to 7 (on a 10-point Likert Scale).

RéSUMé: Le premier cas de COVID-19 ayant été confirmé au Canada au début de 2020, notre pays s'est joint à la lutte contre un nouveau pathogène dans une pandémie mondiale. Le stress de l'incertitude et du changement de pratique était plus évident au service d'urgence lorsqu'il s'agissait de gérer les patients connus ou soupçonnés de la COVID-19 qui avaient besoin d'une prise en charge des voies respiratoires. Reconnaissant la nécessité d'une approche coordonnée, un modèle de développement professionnel continu distribué à l'échelle de la province pour la gestion des voies aériennes a été élaboré en utilisant les Airway Leads pour aider à préparer le personnel médical de première ligne qui assure la gestion des voies aériennes de ces patients. Airway Leads a travaillé avec les médecins locaux pour dispenser un enseignement cohérent et de haute qualité sur les voies aériennes dans toute la province lors de l'augmentation initiale du nombre de cas. L'éducation comprenait à la fois des sessions en personne et virtuelles ainsi qu'un soutien continu en temps réel par le biais de directives provinciales, de vidéos et d'autres documents. Le "niveau de stress" déclaré par le médecin avant et après l'intervention de Airway Lead a diminué, passant d'un score médian de 9 à 7 (sur une échelle de Likert de 10 points).

Sensitive and Specific Cadmium Biosensor Developed by Reconfiguring Metal Transport and Leveraging Natural Gene Repositories.

Whole-cell biosensors are useful for monitoring heavy metal toxicity in public health and ecosystems, but their development has been hindered by intrinsic trade-offs between sensitivity and specificity. Here, we demonstrated an effective engineering solution by building a sensitive, specific, and high-response biosensor for carcinogenic cadmium ions. We genetically programmed the metal transport system of Escherichia coli to enrich intracellular cadmium ions and deprive interfering metal species. We then selected 16 cadmium-sensing transcription factors from the GenBank database and tested their reactivity to 14 metal ions in the engineered E. coli using the expression of the green fluorescent protein as the readout. The resulting cadmium biosensor was highly specific and showed a detection limit of 3 nM, a linear increase in fluorescent intensities from 0 to 200 nM, and a maximal 777-fold signal change. Using this whole-cell biosensor, a smartphone, and low-tech equipment, we developed a simple assay capable of measuring cadmium ions at the same concentration range in irrigation water and human urine. This method is user-friendly and cost-effective, making it affordable to screen large amounts of samples for cadmium toxicity in agriculture and medicine. Moreover, our work highlights natural gene repositories as a treasure chest for bioengineering.

The diversity of Shine-Dalgarno sequences sheds light on the evolution of translation initiation.

Shine-Dalgarno (SD) sequences, the core element of prokaryotic ribosome-binding sites, facilitate mRNA translation by base-pair interaction with the anti-SD (aSD) sequence of 16S rRNA. In contrast to this paradigm, an inspection of thousands of prokaryotic species unravels tremendous SD sequence diversity both within and between genomes, whereas aSD sequences remain largely static. The pattern has led many to suggest unidentified mechanisms for translation initiation. Here we review known translation-initiation pathways in prokaryotes. Moreover, we seek to understand the cause and consequence of SD diversity through surveying recent advances in biochemistry, genomics, and high-throughput genetics. These findings collectively show: (1) SD:aSD base pairing is beneficial but nonessential to translation initiation. (2) The 5' untranslated region of mRNA evolves dynamically and correlates with organismal phylogeny and ecological niches. (3) Ribosomes have evolved distinct usage of translation-initiation pathways in different species. We propose a model portraying the SD diversity shaped by optimization of gene expression, adaptation to environments and growth demands, and the species-specific prerequisite of ribosomes to initiate translation. The model highlights the coevolution of ribosomes and mRNA features, leading to functional customization of the translation apparatus in each organism.

Global fitness landscapes of the Shine-Dalgarno sequence.

Shine-Dalgarno sequences (SD) in prokaryotic mRNA facilitate protein translation by pairing with rRNA in ribosomes. Although conventionally defined as AG-rich motifs, recent genomic surveys reveal great sequence diversity, questioning how SD functions. Here, we determined the molecular fitness (i.e., translation efficiency) of 49 synthetic 9-nt SD genotypes in three distinct mRNA contexts in Escherichia coli We uncovered generic principles governing the SD fitness landscapes: (1) Guanine contents, rather than canonical SD motifs, best predict the fitness of both synthetic and endogenous SD; (2) the genotype-fitness correlation of SD promotes its evolvability by steadily supplying beneficial mutations across fitness landscapes; and (3) the frequency and magnitude of deleterious mutations increase with background fitness, and adjacent nucleotides in SD show stronger epistasis. Epistasis results from disruption of the continuous base pairing between SD and rRNA. This "chain-breaking" epistasis creates sinkholes in SD fitness landscapes and may profoundly impact the evolution and function of prokaryotic translation initiation and other RNA-mediated processes. Collectively, our work yields functional insights into the SD sequence variation in prokaryotic genomes, identifies a simple design principle to guide bioengineering and bioinformatic analysis of SD, and illuminates the fundamentals of fitness landscapes and molecular evolution.

Instability evolution of the viscous elliptic liquid jet in the Rayleigh regime.

For jet flow emanating from noncircular orifices, an unbalanced surface tension force leads to capillary instability, which is independent of influence from the ambient air in the Rayleigh regime. In the present article, the dynamic behavior of incompressible elliptical jets in the Rayleigh regime is investigated. Theoretically, with the consideration of the fluid viscosity, the solution of the Cosserat equation consists of a particular solution and a complementary solution. For the complementary solution the wave number of disturbance modes has two complex conjugate roots, which are responsible for the jet breakup. To match the nonzero particular solution, a spatial wave needs to be introduced, which is independent of external perturbations. Physically, such a spatial wave is interpreted as the axis-switching phenomenon. The predicted features of the axis-switching wavelength and the damping effect from the fluid viscosity have been successfully verified by experimental results. Moreover, the dispersion relations from the present theory suggest that the growth rate of spatial instability is influenced by orifice eccentricity, the Weber number, and the Ohnesorge number.

Dual Inhibition of Bruton's Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat Non-Hodgkin's B Cell Malignancies.

Although new targeted therapies, such as ibrutinib and idelalisib, have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies, or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors, possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We discovered a single molecule, MDVN1003 (1-(5-amino-2,3-dihydro-1H-inden-2-yl)-3-(8-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine), that inhibits Bruton's tyrosine kinase and phosphatidylinositol-3-kinase δ, two proteins regulated by the B cell receptor that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2, two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together, these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients.

Novel 3-methylindoline inhibitors of EZH2: Design, synthesis and SAR.

EZH2 (enhancer of zeste homologue 2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes the methylation of lysine 27 of histone H3 (H3K27). Dysregulation of EZH2 activity is associated with several human cancers and therefore EZH2 inhibition has emerged as a promising therapeutic target. Several small molecule EZH2 inhibitors with different chemotypes have been reported in the literature, many of which use a bicyclic heteroaryl core. Herein, we report the design and synthesis of EZH2 inhibitors containing an indoline core. Partial saturation of an indole to an indoline provided lead compounds with nanomolar activity against EZH2, while also improving solubility and oxidative metabolic stability.

Problem-solving for STEM learning: navigating games as narrativized problem spaces for 21st century competencies.

Identifying educational competencies for the 21st workplace is driven by the need to mitigate disparities between classroom learning and the requirements of workplace environments. Multiple descriptors of desired 21st century skill sets have been identified through various wide-scale studies (e.g., International Commission on Education for the 21st Century) and consistently within the context of science, technology, engineering, and mathematics (STEM) learning, the ability to problem solve, particularly complex problem-solving, remains a crucial competency. In this paper, we look at how current contemporary spaces such as the immensely popular, massively multiplayer online role-playing game(MMORPG), World of Warcraft, (WoW) afford problem-solving skill acquisition in the context of Singaporean youth learners. Given that WoW exists as a contextual space with an overarching narrativized problem to be solved, our investigation focused on two important related constructs that underpin learners' problem-solving trajectory-learning and identity becoming within contemporary domains of technology learning. We present findings of an ethnographic investigation of one youth gamer within the affinity spaces of WoW. Moving away from traditional mentalistic construals of problem-solving, our findings indicate that problem-solving within WoW may be characterized by a triadic-D model of domain, disquisitional, and discursive practices within self, social, and structural dialectics. Theoretical considerations for broadening the understanding of a situated and embodied notion of problem-solving and identity becoming within STEM learning are proposed.

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ.

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

Targeting prostate cancer with compounds possessing dual activity as androgen receptor antagonists and HDAC6 inhibitors.

While enzalutamide and abiraterone are approved for treatment of metastatic castration-resistant prostate cancer (mCRPC), approximately 20-40% of patients have no response to these agents. It has been stipulated that the lack of response and the development of secondary resistance to these drugs may be due to the presence of AR splice variants. HDAC6 has a role in regulating the androgen receptor (AR) by modulating heat shock protein 90 (Hsp90) acetylation, which controls the nuclear localization and activation of the AR in androgen-dependent and independent scenarios. With dual-acting AR-HDAC6 inhibitors it should be possible to target patients who don't respond to enzalutamide. Herein, we describe the design, synthesis and biological evaluation of dual-acting compounds which target AR and are also specific towards HDAC6. Our efforts led to compound 10 which was found to have potent dual activity (HDAC6 IC50=0.0356µM and AR binding IC50=<0.03µM). Compound 10 was further evaluated for antagonist and other cell-based activities, in vitro stability and pharmacokinetics.