Reclassifying variations of unknown significance in diseases affecting Saudi Arabia’s population reveal new associations

Introduction: Physicians face diagnostic dilemmas upon reports indicating disease variants of unknown significance (VUS). The most puzzling cases are patients with rare diseases, where finding another matched genotype and phenotype to associate their results is challenging. This study aims to prove the value of updating patient files with new classifications, potentially leading to better assessment and prevention.Methodology: We recruited retrospective phenotypic and genotypic data from King Saud Medical City, Riyadh, Kingdom of Saudi Arabia. Between September 2020 and December 2021, 1,080 patients’ genetic profiles were tested in a College of American Pathologists accredited laboratory. We excluded all confirmed pathogenic variants, likely pathogenic variants and copy number variations. Finally, we further reclassified 194 VUS using different local and global databases, employing in silico prediction to justify the phenotype–genotype association.Results: Of the 194 VUS, 90 remained VUS, and the other 104 were reclassified as follows: 16 pathogenic, 49 likely pathogenic, nine benign, and 30 likely benign. Moreover, most of these variants had never been observed in other local or international databases.Conclusion: Reclassifying the VUS adds value to understanding the causality of the phenotype if it has been reported in another family or population. The healthcare system should establish guidelines for re-evaluating VUS, and upgrading VUS should reflect on individual/family risks and management strategies

Prospect of genetic disorders in Saudi Arabia

Introduction: Rare diseases (RDs) create a massive burden for governments and families because sufferers of these diseases are required to undergo long-term treatment or rehabilitation to maintain a normal life. In Saudi Arabia (SA), the prevalence of RDs is high as a result of cultural and socio-economic factors. This study, however, aims to shed light on the genetic component of the prevalence of RDs in SA.Methodology: A retrospective study was conducted between September 2020 and December 2021 at King Saud Medical City, a tertiary hospital of the Ministry of Health (MOH), SA. A total of 1080 individuals with 544 potentially relevant variants were included. The index was 738, and the samples were tested in a commercialized laboratory using different molecular techniques, including next-generation sequencing.Result: A total of 867 molecular genetics tests were conducted on 738 probands. These tests included 610 exome sequencing (ES) tests, four genome sequencing (GS) tests, 82 molecular panels, 106 single nucleotide polymorphism (SNP) array, four methylation studies, 58 single-gene studies and three mitochondrial genome sequencing tests. The diagnostic yield among molecular genetics studies was 41.8% in ES, 24% in panels, 12% in SNP array and 24% in single gene studies. The majority of the identified potential variants (68%) were single nucleotide variants (SNV). Other ascertained variants included frameshift (11%), deletion (10%), duplication (5%), splicing (9%), in-frame deletion (3%) and indels (1%). The rate of positive consanguinity was 56%, and the autosomal recessive accounted for 54%. We found a significant correlation between the ES detection rate and positive consanguinity. We illustrated the presence of rare treatable conditions in DNAJC12, SLC19A3, and ALDH7A1, and the presence of the founder effect variant in SKIC2. Neurodevelopmental disorders were the main phenotype for which genetics studies were required (35.7%).Conclusion: This is the sixth-largest local study reporting next-generation sequencing. The results indicate the influence of consanguineous marriages on genetic disease and the burden it causes for the Kingdom of SA. This study highlights the need to enrich our society’s knowledge of genetic disorders. We recommend utilising ES as a first-tier test to establish genetic diagnosis in a highly consanguineous population

A Study of Ta2O5 Nanopillars with Ni Tips Prepared by Porous Anodic Alumina Through-Mask Anodization

The paper discusses the formation of Ta2O5 pillars with Ni tips during thin porous anodic alumina through-mask anodization on Si/SiO2 substrates. The tantalum nanopillars were formed through porous masks in electrolytes of phosphoric and oxalic acid. The Ni tips on the Ta2O5 pillars were formed via vacuum evaporation through the porous mask. The morphology, structure, and magnetic properties at 4.2 and 300 K of the Ta2O5 nanopillars with Ni tips have been studied using scanning electron microscopy, X-ray diffraction, and vibrating sample magnetometry. The main mechanism of the formation of the Ta2O5 pillars during through-mask anodization was revealed. The superparamagnetic behavior of the magnetic hysteresis loop of the Ta2O5 nanopillars with Ni tips was observed. Such nanostructures can be used to develop novel functional nanomaterials for magnetic, electronic, biomedical, and optical nano-scale devices

Joint Coreference Resolution for Zeros and non-Zeros in Arabic

Most existing proposals about anaphoric zero pronoun (AZP) resolution regard full mention coreference and AZP resolution as two independent tasks, even though the two tasks are clearly related. The main issues that need tackling to develop a joint model for zero and non-zero mentions are the difference between the two types of arguments (zero pronouns, being null, provide no nominal information) and the lack of annotated datasets of a suitable size in which both types of arguments are annotated for languages other than Chinese and Japanese. In this paper, we introduce two architectures for jointly resolving AZPs and non-AZPs, and evaluate them on Arabic, a language for which, as far as we know, there has been no prior work on joint resolution. Doing this also required creating a new version of the Arabic subset of the standard coreference resolution dataset used for the CoNLL-2012 shared task (Pradhan et al., 2012) in which both zeros and non-zeros are included in a single dataset

Generalized Harmonically Convex Fuzzy-Number-Valued Mappings and Fuzzy Riemann–Liouville Fractional Integral Inequalities

We propose the concept of up and down harmonically convex mapping for fuzzy-number-valued mapping as our main goal in this work. With the help of up and down harmonically fuzzy-number convexity and the fuzzy fractional integral operator, we also show the results for the Hermite–Hadamard (H–H) inequality, the Fejér type inequality, and some other related versions of inequalities. Moreover, some examples are also presented to discuss the validity of the main results. The results from the new technique show how the suggested scheme is accurate, adaptable, efficient, and user-friendly

Computational Models of Anaphora

Interpreting anaphoric references is a fundamental aspect of our language competence that has long attracted the attention of computational linguists. The appearance of ever-larger anaphorically annotated data sets covering more and more anaphoric phenomena in ever-greater detail has spurred the development of increasingly more sophisticated computational models; as a result, the most recent state-of-the-art neural models are able to achieve impressive performance by leveraging linguistic, lexical, discourse, and en- cyclopedic information. This article provides a thorough survey of anaphora resolution (coreference) throughout this development, reviewing the avail- able data sets and covering both the preneural history of the field and—in more detail—current neural models, including research on less-studied as- pects of anaphoric interpretation such as bridging reference resolution and discourse deixis interpretation

Knowledge and Attitudes of Saudi Emergency Physicians toward t-PA Use in Stroke

Background and Objectives. Tissue plasminogen activator (t-PA) within 4.5 hours from onset improves outcome in patients with ischemic stroke and has been recommended by several international guidelines. Since its approval in 1996, the debate among emergency physicians continues particularly around the result interpretation of the first positive randomized controlled trial, the National Institute of Neurological Disorders and Stroke (NINDS) clinical trial. This lack of consensus might negatively affect the delivery of effective stroke care. Here we aimed to assess the knowledge and attitude of Saudi emergency physicians toward t-PA use within 4.5 hours of onset in acute ischemic stroke. Methods. A web-based, self-administered, locally designed questionnaire was sent to all emergency physicians practicing in the city of Riyadh from January to September 2017. Results. Out of 450 emergency physicians, 122 from ten hospitals in Riyadh participated in the survey, with a 27% response rate. The majority of participants were men (78%), and their mean age was 40 ± 8 years. Half of the participants were board certified, and 36% were consultants. Half of the participants consider the evidence for t-PA use in stroke within 4.5 hours of stroke onset to be controversial, and 41% recommend against its use due to lack of proven efficacy (37%), the risk of hemorrhagic complications (35%), lack of stroke expertise (21%), and medicolegal liability (9%). Nearly half were willing to administer IV t-PA for ischemic stroke in collaboration with remote stroke neurology consultation if telestroke is implemented. Conclusion. Our study detected inadequate knowledge and a negative attitude among Saudi emergency physicians toward t-PA use in acute stroke. This might negatively impact patient outcome. Therefore, we recommend developing urgent strategies to improve emergency physicians’ knowledge, attitudes, and beliefs in the management of acute stroke

The Use of COVID-19 Surveillance Measures in Detecting Cases of Tuberculosis (TB)

The global COVID-19 pandemic has caused countries to develop novel methods to detect and trace active cases. These methods aim to limit its spread; however, they can also be used to detect other endemic infectious diseases, such as tuberculosis (TB). The current methods used to detect COVID-19 cases, such as temperature-checking and tracing applications, led to the detection of these specific TB cases and their referral to the hospital. In this study, we present four cases of TB in which the patients come from different working backgrounds. We conclude that the current measures used for COVID-19 could also prove to be beneficial in the context of other infectious diseases, mainly TB

Development and Optimization of a Novel Lozenge Containing a Metronidazole-Peppermint Oil-Tranexamic Acid Self-Nanoemulsified Delivery System to Be Used after Dental Extraction: In Vitro Evaluation and In Vivo Appraisal

In-depth studies on essential oil–based nanoemulsions (NEs) have centered on a variety of oral health issues. NEs improve the delivery of nonpolar active agents to sites and thereby boost the dissolution and distribution of the agents. Metronidazole-peppermint oil-tranexamic acid self-nanoemulsifying drug delivery systems (MZ-PO-TX-SNEDDS) were created and loaded into novel lozenges to act as antifungal, hemostatic, antimicrobial, and analgesic dosage forms after dental extractions. The design-of-experiments approach was used in creating them. To generate the NEs, different concentrations of MZ-PO (240, 180, and 120 mg), 2% TX (600, 450, and 300 mg), and Smix1:1 (600, 400, and 200 mg) were used. The ideal formulation had serum levels of 1530 U/mL of interleukin-6, a minimal inhibitory concentration against bacteria of 1.5 µg/mL, a droplet size of 96 nm, and a blood coagulation time of 16.5 min. Moreover, the produced NE offered better MZ release. The adopted design was used to produce the ideal formulation; it contained 240 mg of MZ-PO, 600 mg of 2% TX, and 600 mg of Smix1:1. It was incorporated into lozenges with acceptable characteristics and an improved capability for drug release. These lozenges had reasonable coagulation times, IL-6 serum levels, and MIC values. All of these characteristics are desirable for managing symptoms following tooth extractions. Therefore, these lozenges loaded with MZ-PO-TX-SNEDDs might be considered a beneficial paradigm for relieving complications encountered after tooth extractions

Impact of Clinical Pilates Exercise on Pain, Cardiorespiratory Fitness, Functional Ability, and Quality of Life in Children with Polyarticular Juvenile Idiopathic Arthritis

Objective: This study intended to examine the effects of Pilates exercise on pain, cardiorespiratory fitness, functional ability, and quality of life in children with polyarticular juvenile idiopathic arthritis. Methods: Forty children with polyarticular JIA aged 10–14 years old were randomly allocated into two groups: the control group (n = 20) received conventional physical therapy (CPT), and the experimental group (n = 20) received clinical Pilates exercises combined with CPT. Patients in both groups received their program three times/week for 3 months. Pain, cardiorespiratory fitness, functional ability, and quality of life were assessed through the visual analogue scale, cardiopulmonary exercise test, 6 min walk test, and PedsQL scale, respectively, just before and after treatment. Results: Pain (p = 0.001), cardiorespiratory markers (all p < 0.05), functional ability (p = 0.002), and overall quality of life (p = 0.007) improved significantly in the experimental groups compared to the control group. Conclusion: Incorporating Pilates exercises into CPT is likely more effective for decreasing pain intensity, improving cardiorespiratory fitness, augmenting functional ability, and promoting quality of life in children with JIA than CPT alone