Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Evolutionary and functional studies suggested that the emergence of the Omicron variants can be determined by multiple fitness trade-offs including the immune escape, binding affinity for ACE2, conformational plasticity, protein stability and allosteric modulation. In this study, we systematically characterize conformational dynamics, structural stability and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 for BA.2, BA.2.75, XBB.1 and XBB.1.5 variants. We combined multiscale molecular simulations and dynamic analysis of allosteric interactions together with the ensemble-based mutational scanning of the protein residues and network modeling of epistatic interactions. This multifaceted computational study characterized molecular mechanisms and identified energetic hotspots that can mediate the predicted increased stability and the enhanced binding affinity of the BA.2.75 and XBB.1.5 complexes. The results suggested a mechanism driven by the stability hotspots and a spatially localized group of the Omicron binding affinity centers, while allowing for functionally beneficial neutral Omicron mutations in other binding interface positions. A network-based community model for the analysis of epistatic contributions in the Omicron complexes is proposed revealing the key role of the binding hotspots R498 and Y501 in mediating community-based epistatic couplings with other Omicron sites and allowing for compensatory dynamics and binding energetic changes. The results also showed that mutations in the convergent evolutionary hotspot F486 can modulate not only local interactions but also rewire the global network of local communities in this region allowing the F486P mutation to restore both the stability and binding affinity of the XBB.1.5 variant which may explain the growth advantages over the XBB.1 variant. The results of this study are consistent with a broad range of functional studies rationalizing functional roles of the Omicron mutation sites that form a coordinated network of hotspots enabling a balance of multiple fitness tradeoffs and shaping up a complex functional landscape of virus transmissibility

Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

A significant body of experimental structures of SARS-CoV-2 spike trimers for the BA.1 and BA.2 variants revealed a considerable plasticity of the spike protein and the emergence of druggable binding pockets. Understanding the interplay of conformational dynamics changes induced by the Omicron variants and the identification of cryptic dynamic binding pockets in the S protein is of paramount importance as exploring broad-spectrum antiviral agents to combat the emerging variants is imperative. In the current study, we explore conformational landscapes and characterize the universe of binding pockets in multiple open and closed functional spike states of the BA.1 and BA.2 Omicron variants. By using a combination of atomistic simulations, a dynamics network analysis, and an allostery-guided network screening of binding pockets in the conformational ensembles of the BA.1 and BA.2 spike conformations, we identified all experimentally known allosteric sites and discovered significant variant-specific differences in the distribution of binding sites in the BA.1 and BA.2 trimers. This study provided a structural characterization of the predicted cryptic pockets and captured the experimentally known allosteric sites, revealing the critical role of conformational plasticity in modulating the distribution and cross-talk between functional binding sites. We found that mutational and dynamic changes in the BA.1 variant can induce the remodeling and stabilization of a known druggable pocket in the N-terminal domain, while this pocket is drastically altered and may no longer be available for ligand binding in the BA.2 variant. Our results predicted the experimentally known allosteric site in the receptor-binding domain that remains stable and ranks as the most favorable site in the conformational ensembles of the BA.2 variant but could become fragmented and less probable in BA.1 conformations. We also uncovered several cryptic pockets formed at the inter-domain and inter-protomer interface, including functional regions of the S2 subunit and stem helix region, which are consistent with the known role of pocket residues in modulating conformational transitions and antibody recognition. The results of this study are particularly significant for understanding the dynamic and network features of the universe of available binding pockets in spike proteins, as well as the effects of the Omicron-variant-specific modulation of preferential druggable pockets. The exploration of predicted druggable sites can present a new and previously underappreciated opportunity for therapeutic interventions for Omicron variants through the conformation-selective and variant-specific targeting of functional sites involved in allosteric changes

Executing Quality Management Tools to Enhance Customer’s Journey at a Clothes Laundry Firm

Purpose: This project aims to assess and enhance the customer’s journey at a laundry company in Saudi Arabia from when the customer arrives at the parking lot of the laundry store until receiving the services and payment. Design, methodology, approach: A mixed-method approach was employed, in which qualitative data were gathered from focus group interviews and solo interviews, and quantitative data were gathered through the survey. Moreover, Quality Management Tools were used to build the action plan and offer conclusions and recommendations that would enhance the customer’s journey and improve satisfaction. Findings: Services quality issues are categorized into five categories: promotions, human resources; services; detergent products, and facilities. House of Quality represents the highest 15 prioritized solutions. These recommended solutions' relative weights range between 9% to 4%. The use of these tools highlights areas for improvement and the root causes of each issue. The seven quality tools are trustworthy tools to conquer challenges faced by the company and may be effective in improving service quality to positively strengthen organizational performance, customer satisfaction, and success. Originality, value: There are limited studies practically employing the seven Quality Management Tools to enhance customer satisfaction and improve their journey. The Saudi laundry market specifically has a dearth of this type of study. Furthermore, this market has seen rapid growth since it is known as a part of the SME sector in recent few years

Executing Quality Management Tools to Enhance Customer’s Journey at a Clothes Laundry Firm

Purpose: This project aims to assess and enhance the customer’s journey at a laundry company in Saudi Arabia from when the customer arrives at the parking lot of the laundry store until receiving the services and payment. Design, methodology, approach: A mixed-method approach was employed, in which qualitative data were gathered from focus group interviews and solo interviews, and quantitative data were gathered through the survey. Moreover, Quality Management Tools were used to build the action plan and offer conclusions and recommendations that would enhance the customer’s journey and improve satisfaction. Findings: Services quality issues are categorized into five categories: promotions, human resources; services; detergent products, and facilities. House of Quality represents the highest 15 prioritized solutions. These recommended solutions' relative weights range between 9% to 4%. The use of these tools highlights areas for improvement and the root causes of each issue. The seven quality tools are trustworthy tools to conquer challenges faced by the company and may be effective in improving service quality to positively strengthen organizational performance, customer satisfaction, and success. Originality, value: There are limited studies practically employing the seven Quality Management Tools to enhance customer satisfaction and improve their journey. The Saudi laundry market specifically has a dearth of this type of study. Furthermore, this market has seen rapid growth since it is known as a part of the SME sector in recent few years

Medication errors in a health care facility in southern Saudi Arabia

Purpose: To identify medication errors at Aseer Central Hospital (ACH, Abha) in the southern province of Saudi Arabia. Methods: A cross-sectional retrospective study was conducted by reviewing adult patients’ records (> 15 years old) at ACH’s inpatient and outpatients settings over an 8-week period in October and November 2015. Results: We identified 113 medication errors, including 112 prescribing errors and 1 dispensing error. Most medication errors (91.2 %) in this study were for inpatient prescriptions. The most common prescribing error was medication duplication (31.2 %) followed by missing patient identifying information (25 %). Conclusion: Medication errors, mainly in inpatient prescriptions, have been fully identified at ACH. Educational interventions such as workshops could help minimize and prevent medication errors

Comparative Analysis of Conformational Dynamics and Systematic Characterization of Cryptic Pockets in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 Spike Complexes with the ACE2 Host Receptor: Confluence of Binding and Structural Plasticity in Mediating Networks of Conserved Allosteric Sites

In the current study, we explore coarse-grained simulations and atomistic molecular dynamics together with binding energetics scanning and cryptic pocket detection in a comparative examination of conformational landscapes and systematic characterization of allosteric binding sites in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB.1 spike full-length trimer complexes with the host receptor ACE2. Microsecond simulations, Markov state models and mutational scanning of binding energies of the SARS-CoV-2 BA.2 and BA.2.75 receptor binding domain complexes revealed the increased thermodynamic stabilization of the BA.2.75 variant and significant dynamic differences between these Omicron variants. Molecular simulations of the SARS-CoV-2 Omicron spike full-length trimer complexes with the ACE2 receptor complemented atomistic studies and enabled an in-depth analysis of mutational and binding effects on conformational dynamic and functional adaptability of the Omicron variants. Despite considerable structural similarities, Omicron variants BA.2, BA.2.75 and XBB.1 can induce unique conformational dynamic signatures and specific distributions of the conformational states. Using conformational ensembles of the SARS-CoV-2 Omicron spike trimer complexes with ACE2, we conducted a comprehensive cryptic pocket screening to examine the role of Omicron mutations and ACE2 binding on the distribution and functional mechanisms of the emerging allosteric binding sites. This analysis captured all experimentally known allosteric sites and discovered networks of inter-connected and functionally relevant allosteric sites that are governed by variant-sensitive conformational adaptability of the SARS-CoV-2 spike structures. The results detailed how ACE2 binding and Omicron mutations in the BA.2, BA.2.75 and XBB.1 spike complexes modulate the distribution of conserved and druggable allosteric pockets harboring functionally important regions. The results are significant for understanding the functional roles of druggable cryptic pockets that can be used for allostery-mediated therapeutic intervention targeting conformational states of the Omicron variants

Evaluación de la prescripción y uso de medicamentos supresores de ácido en hospitales centrales en la región de Abha, Arabia Saudita

Objective: The aim of this study was to study and assess the indications of acid suppressive drugs and to find out percentage of irrational prescriptions with acid suppressive drugs. Material/Methods: It is a prospective observational study conducted in the Armed Forces Hospitals Southern Region and Abha Maternity Hospital, both in Abha in Assir region (Saudi Arabia). The sample size of study was 185 patients. The case sheets of the patients’ prescription order were reviewed for acid suppressive drugs prescription and relevant data was taken. Patients’ age above 18 were identified. The duration of study was 8 weeks, between May and June 2017. Results: Our results showed that the majority of the prescriptions of proton pump inhibitors (68.1%) were unjustifiable and that proton pump inhibitor was the most commonly prescribed acid suppressive drugs for the patients (97.8%). The frequency of prescribing for the autism spectrum disorders in our study was found to be higher in patients with an existing risk factor and was mostly recommended by physicians as concomitant medications (67.6%). The most common concomitant medications used with the proton pump inhibitors were non-steroidal anti-inflammatory drugs (29.2%) in which aspirin composed 13.5% of the non-steroidal anti-inflammatory drugs prescribed followed by antimicrobials (9.2%). Conclusion: Acid suppressive drugs are the most commonly prescribed drugs with no proper indications hence irrational. Based on the results of this study, creating awareness about reasonable use of acid suppressive drugs is a necessity.Objetivo: El objetivo de este estudio fue estudiar y evaluar las indicaciones de los medicamentos supresores de ácidos y averiguar el porcentaje de recetas irracionales con medicamentos supresores de ácidos. Material / Métodos: es un estudio observacional prospectivo realizado en los Hospitales de las Fuerzas Armadas del Sur y en el Hospital de Maternidad Abha, ambos en Abha en la región de Assir (Arabia Saudita). El tamaño muestral del estudio fue de 185 pacientes. Se revisaron las hojas de casos de orden de prescripción de los pacientes para la prescripción de medicamentos supresores de ácido y se tomaron los datos pertinentes. Se identificó la edad de los pacientes mayores de 18 años. La duración del estudio fue de 8 semanas, entre mayo y junio de 2017. Resultados: nuestros resultados mostraron que la mayoría de las prescripciones de inhibidores de la bomba de protones (68,1%) eran injustificables y que este era el fármaco supresor de ácido más comúnmente prescrito para los pacientes (97,8%). La frecuencia de prescripción para los trastornos del espectro autistas en nuestro estudio, fue mayor en pacientes con un factor de riesgo existente y fue recomendada principalmente por los médicos como medicamentos concomitantes (67,6%). Los medicamentos concomitantes más comunes que se usaron con los inhibidores de la bomba de protones fueron los antiinflamatorios no esteroideos (29.2%) en los cuales la aspirina supuso el 13,5% de los antiinflamatorios no esteroideos prescritos, seguidos por los antimicrobianos (9.2%) Conclusión: los medicamentos supresores de ácido son los medicamentos más comúnmente recetados sin indicaciones adecuadas, por lo que son irracionales. Basado en los resultados de este estudio, crear conciencia sobre el uso razonable de los medicamentos supresores del ácido es una necesidad

Robust kernel regression function with uncertain scale parameter for high dimensional ergodic data using k k -nearest neighbor estimation

In this paper, we consider a new method dealing with the problem of estimating the scoring function $\gamma_a$, with a constant $a$, in functional space and an unknown scale parameter under a nonparametric robust regression model. Based on the $k$ Nearest Neighbors ($k$NN) method, the primary objective is to prove the asymptotic normality aspect in the case of a stationary ergodic process of this estimator. We begin by establishing the almost certain convergence of a conditional distribution estimator. Then, we derive the almost certain convergence (with rate) of the conditional median (scale parameter estimator) and the asymptotic normality of the robust regression function, even when the scale parameter is unknown. Finally, the simulation and real-world data results reveal the consistency and superiority of our theoretical analysis in which the performance of the $k$NN estimator is comparable to that of the well-known kernel estimator, and it outperforms a nonparametric series (spline) estimator when there are irrelevant regressors

Type 1 and Type 2 Diabetes among Youths in Jordan: Incidence and Trends for the period (2011-2016)

This study aimed at analyzing the incidence of Type 1 and Type 2 diabetes among youths in Jordan for the period (2011-2016), the researchers adopted the survey methodology for the period of five years from the records of the medical centers (public and private) in Jordan. Also investigated the differences between Type 1 and Type 2 diabetes in diagnosis and treatments. Results showed significant upward trend in the incidence of type 1 diabetes was observed overall with considerable variation across demographic subgroups of age, sex. And also showed among youths who were 10 to 19 years of age, unadjusted models revealed significant increases in the incidence of type 2 diabetes with increases observed across all age and sex