Multidomain Intervention for the Reversal of Cognitive Frailty Using a Personalized Approach (AGELESS Trial): Recruitment and Baseline Characteristics of Participants.

BACKGROUND: Reversal of cognitive frailty through a multidomain intervention is desirable to prevent dementia. AGELESS Trial was conducted to determine the effectiveness of a comprehensive, multidomain intervention on older adults with cognitive frailty in Malaysia. However, conducting a clinical trial, particularly during and after Covid-19, posed unique challenges. OBJECTIVE: We aimed to investigate the recruitment process and baseline characteristics of the AGELESS Trial participants to better understand an at-risk population and those who agree to participate in an intervention. DESIGN/SETTING: 24-month, randomized controlled trial. PARTICIPANTS: Community-dwelling older adults with independent mobility, aged ≥ 60 years, with a mini mental state examination score of 19-25, a clinical dementia rating of 0.5 ≥ 1 Fried's physical frailty criteria, and < 22 Beck depression inventory. INTERVENTION: Participants were randomized 1:1 to a structured multidomain intervention consisting of vascular management, diet, exercise, cognitive and psychosocial stimulation, or to the arm, including routine care and general health consultation. MEASUREMENT: We analyzed the group differences between (1) cognitive frailty and non- cognitive frailty screened subjects, (2) recruited and non-recruited participants, (3) baseline characteristics of participants by arm, (4) adherence to AGELESS intervention at 12 months, and (5) preliminary findings on the effectiveness of the intervention at 12 months. RESULTS: A total of 957 older adults from two locations, i.e., urban (n = 764) and rural (n = 193) areas, were screened, of whom 38.9% had cognitive frailty and were eligible to participate. Those with cognitive frailty had fewer years of education (B = -0.08; 95%CI = 0.88-0.97; p = 0.002), and lower functioning cognition (B = -0.24; 95%CI = 0.74-0.84; p < 0.001). Among those from urban areas, only 33.1% (n = 106) agreed to participate, particularly those with multimorbidity (B = 0.86; 95%CI = 1.31-4.30; p = 0.01), higher physical activity (B = -1.02; 95%CI = 0.19-0.69; p = 0.002), slower walking speed (B = 1.26; 95%CI = 1.62-7.61; p = 0.001), and higher systolic blood pressure (B = 0.02; 95%CI = 1.00-1.03; p = 0.03). At baseline, participants' mean age was 68.1±5.6, years of education was 8.3±3.9, body mass index was 27.5±5.3 kg/m2, and mini mental state examination score was 22.7±4.0. Generally, there were no significant differences between the intervention and control groups for the main outcomes, except those in the intervention group had higher body mass index, mid-upper-arm circumference, and waist circumference (p < 0.05 for all parameters). Overall intervention adherence at 12 months was 52.8%, ranging from 52.8%-90.6% for each of the modules. Preliminary analysis of the effectiveness of the intervention at 12 months was positive on most of the cognitive domains, some of the nutrient intake and food groups, physical function, and vascular outcomes (p < 0.05 for all parameters). CONCLUSION: Despite the challenges posed by the pandemic, screening, recruitment, and 12-month intervention delivery were achieved in a Malaysian multidomain preventive randomized controlled trial in older adults at risk of dementia, with a satisfactory adherence rate and cognitive benefits at 12 months.

Factors Influencing Medical Students' Choice of Anesthesiology as a Future Specialty in Saudi Arabia.

Background According to the American Society of Anesthesiologists (ASA), anesthesiologists are experts in administering anesthesia, pain management, and critical care medicine. In addition, they provide general perioperative care. Personal interests, career stability, reputation, income, and clinical rotation experience influence medical students' career choices. Studies show that anesthesiology remains one of the least popular specialties among Saudi medical students. Our study aims to determine the preference for anesthesiology among Saudi medical students and the factors influencing their career choice options. Methodology This cross-sectional study was implemented by distributing a self-administered verified survey. Results Our study included 532 medical students, predominantly female (n=344, 64.7%), aged 18-24 years (n=424, 79.7%), and Saudi nationals (n=508, 95.5%). Most were single (n=500, 94%) without children (n=522, 98.1%). A majority were not interested in anesthesiology as a future specialty (n=297, 55.8%), with some uncertainty (n=148, 27.8%) and a smaller interested group (n=87, 16.4%). Controllable lifestyle (n=294, 55.3%) and financial income (n=213, 40%) were critical factors for choosing anesthesiology as a specialty. Interest in another specialty (n=342, 64.3%) and stress (n=286, 53.8%) were significant opposing factors. Academic year significantly affected consideration (p<0.001), with second-year students showing the highest interest (61.8%) and sixth-year the lowest (24.8%). Other factors showed no significant association. Conclusion Our study reveals low interest in anesthesiology among Saudi medical students. A controllable lifestyle and financial income are key attractions. Interest declines significantly by the sixth year due to their interest in other specialties, lifestyle concerns, and stress.

Manipulating the EphB4-ephrinB2 axis to reduce metastasis in HNSCC.

The EphB4-ephrinB2 signaling axis has been heavily implicated in metastasis across numerous cancer types. Our emerging understanding of the dichotomous roles that EphB4 and ephrinB2 play in head and neck squamous cell carcinoma (HNSCC) poses a significant challenge to rational drug design. We find that EphB4 knockdown in cancer cells enhances metastasis in preclinical HNSCC models by augmenting immunosuppressive cells like T regulatory cells (Tregs) within the tumor microenvironment. EphB4 inhibition in cancer cells also amplifies their ability to metastasize through increased expression of genes associated with epithelial mesenchymal transition and hallmark pathways of metastasis. In contrast, vascular ephrinB2 knockout coupled with radiation therapy (RT) enhances anti-tumor immunity, reduces Treg accumulation into the tumor, and decreases metastasis. Notably, targeting the EphB4-ephrinB2 signaling axis with the engineered EphB4 ligands EFNB2-Fc-His and Fc-TNYL-RAW-GS reduces local tumor growth and distant metastasis in a preclinical model of HNSCC. Our data suggest that targeted inhibition of vascular ephrinB2 while avoiding inhibition of EphB4 in cancer cells could be a promising strategy to mitigate HNSCC metastasis.

The pro-tumoral and anti-tumoral roles of EphA4 on T regulatory cells and tumor associated macrophages during HNSCC tumor progression.

Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly cancer with poor response to targeted therapy, largely driven by an immunosuppressive tumor microenvironment (TME). Here we examine the immune-modulatory role of the receptor tyrosine kinase EphA4 in HNSCC progression. Within the TME, EphA4 is primarily expressed on regulatory T cells (Tregs) and macrophages. In contrast ephrinB2, an activating ligand of EphA4, is expressed in tumor blood vessels. Using genetically engineered mouse models, we show that EphA4 expressed in Tregs promotes tumor growth, whereas EphA4 expressed in monocytes inhibits tumor growth. In contrast, ephrinB2 knockout in blood vessels reduces both intratumoral Tregs and macrophages. A novel specific EphA4 inhibitor, APY-d3-PEG4, reverses the accelerated tumor growth we had previously reported with EphB4 cancer cell knockout. EphA4 knockout in macrophages not only enhanced their differentiation into M2 macrophage but also increased Treg suppressive activity. APY-d3-PEG4 reversed the accelerated growth seen in the EphA4 knockout of monocytes but conferred no additional benefit when EphA4 was knocked out on Tregs. Underscoring an EphA4-mediated interplay between Tregs and macrophages, we found that knockout of EphA4 in Tregs not only decreases their activation but also reduces tumor infiltration of pro-tumoral M2 macrophages. These data identify Tregs as a primary target of APY-d3-PEG4 and suggest a role for Tregs in regulating macrophage conversion. These data also support the possible anti-cancer therapeutic value of bispecific peptides or antibodies capable of promoting EphA4 blockade in Tregs but not macrophages. Significance: EphA4 in regulatory T cells has a pro-tumoral effect while EphA4 in macrophages plays an anti-tumoral role underscoring the necessity of developing biologically rational therapeutics.

In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer.

Functionally characterizing the genetic alterations that drive pancreatic cancer is a prerequisite for precision medicine. Here, we perform somatic CRISPR/Cas9 mutagenesis screens to assess the transforming potential of 125 recurrently mutated pancreatic cancer genes, which revealed USP15 and SCAF1 as pancreatic tumor suppressors. Mechanistically, we find that USP15 functions in a haploinsufficient manner and that loss of USP15 or SCAF1 leads to reduced inflammatory TNFα, TGF-ß and IL6 responses and increased sensitivity to PARP inhibition and Gemcitabine. Furthermore, we find that loss of SCAF1 leads to the formation of a truncated, inactive USP15 isoform at the expense of full-length USP15, functionally coupling SCAF1 and USP15. Notably, USP15 and SCAF1 alterations are observed in 31% of pancreatic cancer patients. Our results highlight the utility of in vivo CRISPR screens to integrate human cancer genomics and mouse modeling for the discovery of cancer driver genes with potential prognostic and therapeutic implications.

Evaluation of the Relationship Between Smartphone Addiction and Lower Back Pain and Neck Pain Among Medical Students at Al-Baha University.

Introduction In recent years, the increased use of smartphones has adversely affected students, leading to issues like musculoskeletal pain. Therefore, our objective was to assess the correlation between smartphone addiction and neck and lower back pain. Methodology An observational cross-sectional study was conducted at Al-Baha University, Al-Baha, Saudi Arabia. The Smartphone Addiction Scale Short Version (SAS-SV) was used to measure the level of smartphone addiction while the Nordic Musculoskeletal Questionnaire (NMQ) was utilized to evaluate musculoskeletal pain. Results Smartphone addiction was prevalent in 72% of the participants (n = 293). Significantly, lower back pain was associated with smartphone addiction (p-value = 0.004). However, none of the demographic characteristics were associated with neck or lower back pain (p-value > 0.05). Students in clinical years had a higher risk of neck pain than those in an internship (p-value = 0.048). Conclusion Almost two-thirds of the students were addicted to smartphones, with a significant association with lower back pain. Students addicted to their smartphones had a higher risk of developing lower back pain, while clinical-year students had a higher risk of developing neck pain. It's important to raise awareness about the health and safety dangers linked to smartphones and other devices.

Assessment of Arabic Web-Based Knowledge About Root Canal Treatment: An Infodemiologic Study.

BACKGROUND: Root canal treatment (RCT) is a vital dental procedure aimed at preserving tooth function and minimizing infection. Access to accurate and comprehensive information about RCT is crucial for informed decision-making. With the increasing reliance on the Internet for health-related information, it is essential to evaluate the quality and readability of web-based RCT content, particularly in Arabic-speaking regions. METHODS: This study conducted an extensive web search using three major search engines (Google, Yahoo, and Bing) to identify Arabic-language websites providing information on RCT. Inclusion criteria required websites in Arabic with comprehensive RCT content. Quality assessment employed the DISCERN instrument, JAMA benchmarks, and Health on the Net (HON) assessment tools, while readability was assessed using Flesch Kincaid Grade Level (FKGL), Simple Measure of Gobbledygook (SMOG), and Flesch Reading Ease (FRE) metrics. RESULTS: Out of 152 websites included, the majority were affiliated with university/medical centers (56.58%) and non-profit organizations (28.29%). Quality assessment revealed that the mean DISCERN score was 2.82, indicating moderate quality. Only one website achieved a high DISCERN score. JAMA benchmarks showed limited compliance, with only two websites meeting all criteria. The HON code was found on only five websites. Readability analysis indicated that most websites were reasonably easy to read by the general population. CONCLUSION: This study highlights the significant gap in the quality and reliability of web-based health information related to RCT in Arabic. While the majority of websites examined in this study did not meet established quality standards, there is a clear need for improvements in the accuracy and comprehensiveness of online resources. Patients seeking information on RCT should exercise caution and consider consulting healthcare professionals for trustworthy guidance. Further research should explore strategies to enhance the quality of web-based health information and expand the scope of evaluation to ensure that individuals have access to reliable resources for making informed decisions about their dental health.

Taxonomic discordance of immersive realities in dentistry: A systematic scoping review.

OBJECTIVES: This review aimed to map taxonomy frameworks, descriptions, and applications of immersive technologies in the dental literature. DATA: The Preferred reporting items for systematic reviews and meta-analyses extension for scoping reviews (PRISMA-ScR) guidelines was followed, and the protocol was registered at open science framework platform (https://doi.org/10.17605/OSF.IO/H6N8M). SOURCES: Systematic search was conducted in MEDLINE (via PubMed), Scopus, and Cochrane Library databases, and complemented by manual search. STUDY SELECTION: A total of 84 articles were included, with 81 % between 2019 and 2023. Most studies were experimental (62 %), including education (25 %), protocol feasibility (20 %), in vitro (11 %), and cadaver (6 %). Other study types included clinical report/technique article (24 %), clinical study (9 %), technical note/tip to reader (4 %), and randomized controlled trial (1 %). Three-quarters of the included studies were published in oral and maxillofacial surgery (38 %), dental education (26 %), and implant (12 %) disciplines. Methods of display included head mounted display device (HMD) (55 %), see through screen (32 %), 2D screen display (11 %), and projector display (2 %). Descriptions of immersive realities were fragmented and inconsistent with lack of clear taxonomy framework for the umbrella and the subset terms including virtual reality (VR), augmented reality (AR), mixed reality (MR), augmented virtuality (AV), extended reality, and X reality. CONCLUSIONS: Immersive reality applications in dentistry are gaining popularity with a notable surge in the number of publications in the last 5 years. Ambiguities are apparent in the descriptions of immersive realities. A taxonomy framework based on method of display (full or partial) and reality class (VR, AR, or MR) is proposed. CLINICAL SIGNIFICANCE: Understanding different reality classes can be perplexing due to their blurred boundaries and conceptual overlapping. Immersive technologies offer novel educational and clinical applications. This domain is fast developing. With the current fragmented and inconsistent terminologies, a comprehensive taxonomy framework is necessary.

Assessment of the Arabic patient-centered online information about orthodontic pain: A quality and readability assessment.

BACKGROUND: This study assesses the quality and readability of Arabic online information about orthodontic pain. With the increasing reliance on the internet for health information, especially among Arabic speakers, it's critical to ensure the accuracy and comprehensiveness of available content. Our methodology involved a systematic search using the Arabic term for (Orthodontic Pain) in Google, Bing, and Yahoo. This search yielded 193,856 results, from which 74 websites were selected based on predefined criteria, excluding duplicates, scientific papers, and non-Arabic content. MATERIALS AND METHODS: For quality assessment, we used the DISCERN instrument, the Journal of the American Medical Association (JAMA) benchmarks, and the Health on the Net (HON) code. Readability was evaluated using the Simplified Measure of Gobbledygook (SMOG), Flesch Reading Ease Score (FRES), and Flesch-Kincaid Grade Level (FKGL) scores. RESULTS: Results indicated that none of the websites received the HONcode seal. The DISCERN assessment showed median total scores of 14.96 (± 5.65), with low overall quality ratings. In JAMA benchmarks, currency was the most achieved aspect, observed in 45 websites (60.81%), but none met all four criteria simultaneously. Readability scores suggested that the content was generally understandable, with a median FKGL score of 6.98 and a median SMOG score of 3.98, indicating middle school-level readability. CONCLUSION: This study reveals a significant gap in the quality of Arabic online resources on orthodontic pain, highlighting the need for improved standards and reliability. Most websites failed to meet established quality criteria, underscoring the necessity for more accurate and trustworthy health information for Arabic-speaking patients.

Genome-wide CRISPR screens identify novel regulators of wild-type and mutant p53 stability.

Tumor suppressor p53 (TP53) is frequently mutated in cancer, often resulting not only in loss of its tumor-suppressive function but also acquisition of dominant-negative and even oncogenic gain-of-function traits. While wild-type p53 levels are tightly regulated, mutants are typically stabilized in tumors, which is crucial for their oncogenic properties. Here, we systematically profiled the factors that regulate protein stability of wild-type and mutant p53 using marker-based genome-wide CRISPR screens. Most regulators of wild-type p53 also regulate p53 mutants, except for p53 R337H regulators, which are largely private to this mutant. Mechanistically, FBXO42 emerged as a positive regulator for a subset of p53 mutants, working with CCDC6 to control USP28-mediated mutant p53 stabilization. Additionally, C16orf72/HAPSTR1 negatively regulates both wild-type p53 and all tested mutants. C16orf72/HAPSTR1 is commonly amplified in breast cancer, and its overexpression reduces p53 levels in mouse mammary epithelium leading to accelerated breast cancer. This study offers a network perspective on p53 stability regulation, potentially guiding strategies to reinforce wild-type p53 or target mutant p53 in cancer.