The Prevalence of Weight Gain After Obtaining Employment: A Cross-Sectional Survey of Employees at the Ministry of National Guard Health Affairs, Eastern Region, Saudi Arabia.

Background and objective Even though obesity is a major global health concern, few studies in the literature have discussed obesity in the workplace. In light of this, we aimed to explore obesity in the workplace and its contributing factors. Methodology An online survey was distributed via official work emails. The survey assessed demographic variables and work environment-related factors, such as physical and mental well-being, lack of time, and social and personal habits. The total sample included 380 full-time employees, of which 16.67% were excluded for not meeting the inclusion criteria. Data were analyzed by using descriptive and inferential statistics. Results Of note, 79.87% of the participants reported an increase in weight after getting employed. The average weight gain was 10.4 kg for 8.2 years of experience. The physical and mental items and time-related items had the highest average scores of 3.24 and 3.44, respectively. The multivariable logistic regression showed a significant association between work experience (p = 0.0259) and time (p = 0.0363), as well as physical and mental domains (p = 0.0007). Conclusions Based on our findings, greater work experience, a lack of time, and negative mental and physical well-being are risk factors for weight gain among employees.

Clonidine safety and effectiveness in the management of suspected paroxysmal sympathetic hyperactivity post-traumatic brain injury: A retrospective cohort study.

INTRODUCTION: Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide. In addition, TBI may cause paroxysmal sympathetic hyperactivity (PSH), which is associated with poor clinical outcomes. This study aimed to evaluate the safety and effectiveness of clonidine in patients with TBI and suspected PSH. METHODS: A retrospective cohort study for critically ill patients with TBI with suspected PSH admitted to intensive care units (ICUs) from 1 May 2016 to 31 January 2020 at a tertiary academic medical center. Eligible patients were categorized based on clonidine use during their ICU stay (Clonidine group vs. Control group). The primary outcome was the improvement in functional outcomes during ICU stay, defined by a delta Glasgow Coma Score (GCS). Secondary outcomes included ICU and hospital length of stay, heart rate variation, and 90-day mortality. RESULTS: A total of 2915 patients were screened, of which 169 were included. Based on multiple regression analysis, patients who received clonidine showed better improvement in functional outcomes by a higher mean delta GCS than patients who did not (Beta Coeff. 0.41; CI: 0.07 - 0.74; P = 0.02). In addition, the patient's GCS upon ICU discharge and IV opioids requirement on day three were higher in the clonidine group than control (beta coefficient (95% CI): 0.18 (0.03, 0.32); p = 0.02 and beta coefficient (95% CI): 1.38 (0.24, 2.52); p = 0.02, respectively). No statistical differences were observed in any of the other secondary outcomes after adjusting for confounders. CONCLUSION: This study found that patients who received clonidine had better functional outcomes during their ICU stay, as shown by their delta GCS than those who did not. Other outcomes were similar between the groups. More data are needed to explore the role of clonidine in patients with TBI with suspected PSH.

Assessment of Risk Perception of COVID-19 Post Vaccination amongst the General Population of Riyadh Region.

COVID-19 is a highly contagious disease caused by SARS-CoV-2. Vaccination against the virus was first approved in Saudi Arabia in December 2020. Vaccinated individuals are still at risk of getting infected with the virus and can transmit the disease. Therefore, the perception of vaccinated individuals regarding the disease can help limit the spread of the virus. OBJECTIVES: To measure the risk perception of COVID-19 following vaccination and factors that have an effect on risk perception; to identify the health protective behaviours of the vaccinated individuals. METHODOLOGY: This is a quantitative analytical cross-sectional, questionnaire-based study. The target population includes individuals aged 18 and above who live in the Riyadh region and have been vaccinated, during the period of June 2021 to December 2021. RESULTS: The perception of 30.2% of participants did not change after vaccination, with many participants continuing to "always" take precautions even after vaccination. Numerous factors, such as age, gender, marital status, occupational status, employment status, and total household income, have shown significant effects towards risk perception. CONCLUSION: Many vaccinated individuals have continued to take precautionary steps and their risk perception has not changed.

Functionalized Morpholine-thiazole Scaffold: Synthetic Strategies and Applications.

The thiazole derivatives as important members of heterocyclic compounds have attracted much synthetic interest due to their different biological properties. In recent years, studies on the synthesis of morpholine compounds have increased because of the properties of this core. In particular, the hybrid structures in which the thiazole ring is linked to morpholine nuclei in one molecular frame have gained popularity. The presented review is an attempt to summarize a huge volume of data on morpholinothiazoles being a widely studied class of these molecules used in modern organic and medicinal chemistry. The manuscript covers the approaches to the synthesis of the morpholinothiazoles derivatives. The synthetic strategies of the target compounds depend on one-pot or multistage reactions or the transformation of other related heterocycles. Additionally, we covered the biological activities and other applications of certain morpholinothiazoles. The information on these compounds made special consideration of medicinal chemists to yield a combinatorial library and carry out thorough efforts in the search of morpholinothiazoles.

Comparative analysis of absent in melanoma 2-inflammasome activation in Francisella tularensis and Francisella novicida.

Francisella tularensis is a highly virulent Gram-negative bacterium that causes the fatal zoonotic disease tularemia. The mechanisms and signaling pathways leading to the absent in melanoma 2 (Aim2) inflammasome activation have been elegantly elucidated using Francisella novicida as a model. Although not pathogenic for humans, F. novicida can cause tularemia in mice, and the inflammatory response it triggers is the polar opposite to that observed in mice infected with F. tularensis strains. This study aimed to understand the mechanisms of Aim2 inflammasome activation in F. tularensis-infected macrophages. The results reveal that macrophages infected with the F. tularensis live vaccine strain (LVS) induce lower levels of Aim2-dependent IL-1ß than those infected with F. novicida. The suppression/weak activation of Aim2 in F. tularensis LVS-infected macrophages is due to the suppression of the cGAS-STING DNA-sensing pathway. Furthermore, the introduction of exogenous F. tularensis LVS DNA into the cytosol of the F. tularensis LVS-infected macrophages, alone or in conjunction with a priming signal, failed to restore IL-1ß levels similar to those observed for F. novicida-infected macrophages. These results indicated that, in addition to the bacterial DNA, DNA from some other sources, specifically from the damaged mitochondria, might contribute to the robust Aim2-dependent IL-1ß levels observed in F. novicida-infected macrophages. The results indicate that F. tularensis LVS induces mitophagy that may potentially prevent the leakage of mitochondrial DNA and the subsequent activation of the Aim2 inflammasome. Collectively, this study demonstrates that the mechanisms of Aim2 inflammasome activation established for F. novicida are not operative in F. tularensis.

Chronically hypertensive transgenic mice expressing human AT1R haplotype-I exhibit increased susceptibility to Francisella tularensis.

Age-related illnesses, including hypertension and accompanying metabolic disorders, compromise immunity and exacerbate infection-associated fatalities. Renin-angiotensin system (RAS) is the key mechanism that controls blood pressure. Upregulation of RAS through angiotensin receptor type 1 (AT1R), a G-protein coupled receptor, contributes to the pathophysiological consequences leading to vascular remodeling, hypertension, and end-organ damage. Genetic variations that increase the expression of human AT1R may cause the above pathological outcomes associated with hypertension. Previously we have shown that our chronically hypertensive transgenic (TG) mice containing the haplotype-I variant (Hap-I, hypertensive genotype) of human AT1R (hAT1R) gene are more prone to develop the metabolic syndrome-related disorders as compared to the TG mice containing the haplotype-II variant (Hap-II, normotensive genotype). Since aging and an increased risk of hypertension can impact multiple organ systems in a complex manner, including susceptibility to various infections, the current study investigated the susceptibility and potential effect of acute bacterial infection using a Gram-negative intracellular bacterial pathogen, Francisella tularensis in our hAT1R TG mice. Our results show that compared to Hap-II, F. tularensis-infected aged Hap-I TG mice have significantly higher mortality post-infection, higher bacterial load and lung pathology, elevated inflammatory cytokines and altered gene expression profile favoring hypertension and inflammation. Consistent with worsened phenotype in aged Hap-I mice post-Francisella infection, gene expression profiles from their lungs revealed significantly altered expression of more than 1,400 genes. Furthermore, bioinformatics analysis identified genes associated with RAS and IFN-γ pathways regulating blood pressure and inflammation. These studies demonstrate that haplotype-dependent over-expression of the hAT1R gene leads to enhanced susceptibility and lethality due to F. tularensis LVS infection, which gets aggravated in aged animals. Clinically, these findings will help in exploring the role of AT1R-induced hypertension and enhanced susceptibility to infection-related respiratory diseases.

Recyclization of morpholinochromonylidene-thiazolidinone using nucleophiles: facile synthesis, cytotoxic evaluation, apoptosis, cell cycle and molecular docking studies of a novel series of azole, azine, azepine and pyran derivatives.

A convenient synthetic approach for construction of a novel series of substituted azoles, azines, azepines and pyrans clubbed with a morpholinothiazolidinone hybrid was achieved. The methodology depended on ring-opening and ring-closure (RORC) of chromone ring in 2-(morpholinoimino)-5-[(4-oxo-4H-chromen-3-yl)methylene]-3-phenylthiazolidin-4-one (3) through its reaction with a series of nitrogen and carbon nucleophiles under mild reaction conditions. The cytotoxic effects of all products were evaluated against three cancerous cell lines (MCF-7, HepG-2 and SKOV-3) by the standard SRB method. Fortunately, the products 7, 11, 12, 15, 19, 22, 26 and 28 were found to be the most active against all cancer cell lines, comparable to doxorubicin. Apoptosis was determined using flow cytometry along with cell cycle analysis and supported by molecular docking. The products 7, 11, 12, 15, 19, 22, 26 and 28 induced a significant early-and late-apoptotic effect against all tumor cells. In addition, these products preferred to arrest all cancer cells in the G1 and G2 phases. Finally, molecular docking was attempted to investigate the binding mode of products 12 and 22 with p53-MDM2 protein receptor.

Neurological Manifestations and Clinical Outcomes of Patients with COVID-19 in the Aseer Region, Saudi Arabia.

COVID-19 patients also present with rheumatological problems, cardiac problems, and even neurological manifestations. However, the data are still insufficient at present to fill the gaps in our understanding of the neurological presentations of COVID-19. Therefore, the present study was undertaken to reveal the various neurological manifestations of patients with COVID-19 and to find the association between neurological manifestations and the clinical outcome. This cross-sectional study was conducted in Abha, in the Aseer region of the Kingdom of Saudi Arabia, among COVID-19 patients aged 18 years or older who were admitted with the neurological manifestations of COVID-19 to the Aseer Central Hospital and Heart Center Hospital Abha. Non-probability convenient sampling was used. All the information was gathered by the principal investigator using a questionnaire including sociodemographic information, disease characteristics of COVID-19, neurological manifestations, and other complications. Data were analyzed using the Statistical Package for Social Sciences, version 16.0 (SPSS, Inc., Chicago, IL, USA). A total of 55 patients were included in the present study. About half of the patients were admitted to the ICU, and 18 (62.1%) patients died after 1 month of follow-up. Patients aged over 60 years had a 75% mortality rate. About 66.66% of patients with pre-existing neurological disorders died. Statistically significant associations were found between neurological symptoms such as cranial nerve symptoms and a poor outcome. A statistically significant difference was also found between laboratory parameters such as the absolute neutrophil count (ANC), activated partial thromboplastin time (aPTT), total cholesterol (TC), creatinine, urea, and lactate dehydrogenase (LDH) level and the outcome. A statistically significant difference was also found between the use of medications such as antiplatelets, anticoagulants, and statins at the baseline and after a 1-month follow-up. Neurological symptoms and complications are not uncommon among COVID-19 patients. Most of these patients had poor outcomes. Further studies are required to provide more data and knowledge about this issue, including the possible risk factors and the long-term neurological consequences of COVID-19.

Fatigue and Cognitive Decline Associated With Depressive Symptoms Among Community-Dwelling Adults.

To investigate the prevalence of depressive symptoms in community-dwelling Saudi adults aged ≥50 years and the associated risk factors. Patient Health Questionnaire 9 (PHQ-9) was dichotomized as depressive symptoms when the participants scored ≥10. Risk factors included age, sex, body mass index, education, employment, marital status, number of chronic diseases and medications, fatigue severity scale (FSS), and Montreal Cognitive Assessment (MoCA). Among the 206 participants, the prevalence of depressive symptoms was 17.48%. The number of chronic diseases, medications, and fatigue symptoms were significantly higher in those with depressive symptoms, whereas cognitive functions were significantly lower. Fatigue symptoms and cognitive functions were significantly associated with depressive symptoms. The cut-off scores for risk factors were ≥42 (FSS) and ≤23 (MoCA scale). Fatigue and cognitive impairments were the only risk factors that distinguished participants with and without depressive symptoms.

Evaluation of Early Tocilizumab Effect on Multiorgan Dysfunction in Critically Ill Patients With COVID-19: A Propensity Score-Matched Study.

Background: Tocilizumab (TCZ) has been proposed as potential rescue therapy for severe COVID-19. No previous study has primarily assessed the role of TCZ in preventing severe COVID-19-related multiorgan dysfunction. Hence, this multicenter cohort study aimed to evaluate the effectiveness of TCZ early use versus standard of care in preventing severe COVID-19-related multiorgan dysfunction in COVID-19 critically ill patients during intensive care unit (ICU) stay. Methods: A multicenter, retrospective cohort study includes critically ill adult patients with COVID-19 admitted to the ICUs. Patients were categorized into two groups, the treatment group includes patients who received early TCZ therapy within 24 hours of ICU admission and the control group includes patients who received standard of care. The primary outcome was the multiorgan dysfunction on day three of the ICU admission. The secondary outcomes were 30-day, and in-hospital mortality, ventilator-free days, hospital length of stay (LOS), ICU LOS, and ICU-related complications. Results: After propensity score matching, 300 patients were included in the analysis based on predefined criteria with a ratio of 1:2. Patients who received TCZ had lower multiorgan dysfunction score on day three of ICU admission compared to the control group (beta coefficient: -0.13, 95% CI: -0.26, -0.01, P-value = 0.04). Moreover, respiratory failure requiring MV was statistically significantly lower in patients who received early TCZ compared to the control group (OR 0.52; 95% CI 0.31, 0.91, P-value = 0.02). The 30-day and in-hospital mortality were significantly lower in patients who received TCZ than those who did not (HR 0.56; 95% CI 0.37, 0.85, P-value = 0 .006 and HR 0.54; 95% CI 0.36, 0.82, P-value = 0.003, respectively). Conclusion: In addition to the mortality benefits associated with early TCZ use within 24 hours of ICU admission, the use of TCZ was associated with a significantly lower multiorgan dysfunction score on day three of ICU admission in critically ill patients with COVID-19.

The Five Times Sit-to-Stand Test is associated with both history of falls and fear of falling among community adults aged 50 years and older.

BACKGROUND: Limited evidence has examined the association between balance and mobility measures with risk of fall. AIM: To determine the prevalence and balance measures associated with falls and fear of falling among community adults aged 50 years and older. METHODS: This cross-sectional study included community-dwelling adults aged ≥ 50 years, living in Saudi Arabia. The participants were asked to report any history of falls in the past 12 months and fear of falling using the Falls Efficacy Scale (FES-I). Balance/mobility measures included the Timed Up and Go (TUG) test, Functional Reach Test (FRT), 10-m walk test (10-MWT), 6-min walk test (6-MWT), and Five Times Sit-to-Stand Test (5XSST). RESULTS: Two hundred and six participants, including 96 women, were included. The prevalence of falls was 12.6%, and the 5XSST was the only balance measure significantly associated with falls (OR 1.17, 95% CI [1.03, 1.33], p = 0.019) with a cutoff score of 13.93 s or more, a sensitivity of 0.73, and a specificity of 0.58. An increase in 5XSST time was associated with an increase in FES-I score, while a decrease in other balance measures (10-MWT, TUG, FRT, and 6-MWT) was associated with an increase in FES-I scores. CONCLUSION: Adults living in Saudi Arabia had a low prevalence of falls. The 5XSST was the only significant balance/mobility measure that distinguished fallers from non-fallers.

Cross-Cultural Adaptation and Validation of the Arabic Version of the Mini-BESTest among Community-Dwelling Older Adults in Saudi Arabia.

Backgrounds: The Mini-BESTest is a clinical assessment of balance impairment; however, the translation and psychometric properties in the Arabic-speaking population have not yet been investigated. The purpose of this study was to translate into Arabic and evaluate the psychometric properties of the Mini-BESTest in Saudi community-dwelling older adults. Methods: This is a cross-sectional transcultural adaptation and validation study. A total of 144 community-dwelling older adults were enrolled (mean age = 66.2 ± 6.2 years). The translation and cross-cultural adaptation of the Mini-BESTest from English to Arabic was performed using standardized guidelines. Test−retest reliability was examined using the intraclass correlation coefficient (ICC) with one week between test and retest. The internal consistency was assessed using Cronbach's alpha. Construct validity of the Mini-BESTest was assessed using balance such as Berg Balance Scale (BBS) and Falls Efficacy Scale International (FES-I). Results: The Arabic version of the Mini-BESTest showed good internal consistency (Cronbach's alpha = 0.93). The scale shows excellent test−retest reliability (ICC = 0.99, 95% CI, 0.98−0.99) and excellent inter-rater reliability (ICC = 0.93, 95% CI, 0.70−0.97), which is indicative of the measure's stability and repeatability. Mini-BESTest total scores showed an excellent inter-rater agreement. There was a significant correlation between total score of the Mini-BESTest and BBS (r = 0.72; p < 0.001). Mini-BESTest had a moderate association with FES-I. Conclusion: The Arabic version of the Mini-BESTest is a reliable and valid test for assessing balance in older adults. More research is needed to confirm the test's reliability and validity in a specific population, such as those with neurological problems.

ThioredoxinA1 Controls the Oxidative Stress Response of Francisella tularensis Live Vaccine Strain (LVS).

Francisella tularensis is an intracellular, Gram-negative bacterium known for causing a disease known as tularemia in the Northern Hemisphere. F. tularensis is classified as a category A select agent by the CDC based on its possible use as a bioterror agent. F. tularensis overcomes oxidative stress encountered during its growth in the environment or host macrophages by encoding antioxidant enzymes such as superoxide dismutases, catalase, and alkylhydroperoxy reductase. These antioxidant enzymes are regulated by the oxidative stress response regulator, OxyR. In addition to these antioxidant enzymes, F. tularensis also encodes two thioredoxins, TrxA1 (FTL_0611) and TrxA2 (FTL_1224); however, their role in the oxidative stress response of F. tularensis is not known. This study investigated the role of thioredoxins of F. tularensis in the oxidative stress response and intracellular survival. Our results demonstrate that TrxA1 but not TrxA2 plays a major role in the oxidative stress response of F. tularensis. Most importantly, this study elucidates a novel mechanism through which the TrxA1 of F. tularensis controls the oxidative stress response by regulating the expression of the master regulator, oxyR. Further, TrxA1 is required for the intramacrophage survival and growth of Francisella. Overall, this study describes a novel role of thioredoxin, TrxA1, in regulating the oxidative stress response of F. tularensis. IMPORTANCE The role of thioredoxins in the oxidative stress response of F. tularensis is not known. This study demonstrates that of the two thioredoxins, TrxA1 is vital to counter the oxidative stress in F. tularensis live vaccine strain (LVS). Furthermore, this study shows differences in the well-studied thioredoxins of Escherichia coli. First, the expression of TrxA1 of F. tularensis is independent of the oxidative stress response regulator, OxyR. Second and most importantly, TrxA1 regulates the expression of oxyR and, therefore, the OxyR-dependent oxidative stress response of F. tularensis. Overall, this study reports a novel regulatory role of TrxA1 of F. tularensis in the oxidative stress response.

Nlrp3 Increases the Host's Susceptibility to Tularemia.

Francisella tularensis (F. tularensis) is a Gram-negative, intracellular bacterium and the causative agent of a fatal human disease known as tularemia. The CDC has classified F. tularensis as a Tier 1 Category A select agent based on its ease of aerosolization, low infectious dose, past use as a bioweapon, and the potential to be used as a bioterror agent. Francisella has a unique replication cycle. Upon its uptake, Francisella remains in the phagosomes for a short period and then escapes into the cytosol, where the replication occurs. Francisella is recognized by cytosolic pattern recognition receptors, Absent In Melanoma 2 (Aim2) and Nacht LRR and PYD domains containing Protein 3 (Nlrp3). The recognition of Francisella ligands by Aim2 and Nlrp3 triggers the assembly and activation of the inflammasome. The mechanism of activation of Aim2 is well established; however, how Nlrp3 inflammasome is activated in response to F. tularensis infection is not known. Unlike Aim2, the protective role of Nlrp3 against Francisella infection is not fully established. This study investigated the role of Nlrp3 and the potential mechanisms through which Nlrp3 exerts its detrimental effects on the host in response to F. tularensis infection. The results from in vitro studies demonstrate that Nlrp3 dampens NF-κB and MAPK signaling, and pro-inflammatory cytokine production, which allows replication of F. tularensis in infected macrophages. In vivo, Nlrp3 deficiency results in differential expression of several genes required to induce a protective immune response against respiratory tularemia. Nlrp3-deficient mice mount a stronger innate immune response, clear bacteria efficiently with minimal organ damage, and are more resistant to Francisella infection than their wild-type counterparts. Together, these results demonstrate that Nlrp3 enhances the host's susceptibility to F. tularensis by modulating the protective innate immune responses. Collectively, this study advances our understanding of the detrimental role of Nlrp3 in tularemia pathogenesis.

Aim2 and Nlrp3 Are Dispensable for Vaccine-Induced Immunity against Francisella tularensis Live Vaccine Strain.

Francisella tularensis is a facultative, intracellular, Gram-negative bacterium that causes a fatal disease known as tularemia. Due to its extremely high virulence, ease of spread by aerosolization, and potential to be used as a bioterror agent, F. tularensis is classified by the CDC as a tier 1 category A select agent. Previous studies have demonstrated the roles of the inflammasome sensors absent in melanoma 2 (AIM2) and NLRP3 in the generation of innate immune responses to F. tularensis infection. However, contributions of both the AIM2 and NLRP3 to the development of vaccine-induced adaptive immune responses against F. tularensis are not known. This study determined the contributions of Aim2 and Nlrp3 inflammasome sensors to vaccine-induced immune responses in a mouse model of respiratory tularemia. We developed a model to vaccinate Aim2- and Nlrp3-deficient (Aim2-/- and Nlrp3-/-) mice using the emrA1 mutant of the F. tularensis live vaccine strain (LVS). The results demonstrate that the innate immune responses in Aim2-/- and Nlrp3-/- mice vaccinated with the emrA1 mutant differ from those of their wild-type counterparts. However, despite these differences in the innate immune responses, both Aim2-/- and Nlrp3-/- mice are fully protected against an intranasal lethal challenge dose of F. tularensis LVS. Moreover, the lack of both Aim2 and Nlrp3 inflammasome sensors does not affect the production of vaccination-induced antibody and cell-mediated responses. Overall, this study reports a novel finding that both Aim2 and Nlrp3 are dispensable for vaccination-induced immunity against respiratory tularemia caused by F. tularensis.

Electronic Health Record-Related Stress Among Nurses: Determinants and Solutions.

Background: Documentation and navigation through electronic health records (EHRs) is an essential, but stressful, task. We present the magnitude, determinants of such events, and solutions proposed by nurses to address EHR-related stress (EHR-S) at a tertiary eye hospital in Saudi Arabia. Methods: Nurses of an eye hospital were surveyed in 2019 about EHR-S. A Likert scale was used to assess the responses of 10 components of EHR-related work. The total score was graded as follows: minimum (<-10), mild (<0 to -10), moderate (1-10), and severe (>11). The score was correlated with determinants. Solutions suggested by nurses to reduce stress were reviewed. Results: This survey covered 212 nurses. Of them, 106 (50%; 95% confidence interval: 43.3-56.7) reported EHR-S. The median EHR-S score was -3.0 (interquartile range: -9.0; +8.0). Thirty-five (16%) nurses reported severe EHR-S. Senior nurses (M-W, p < 0.02) and those working in emergency and recovery units (M-W, p < 0.01) had statistically higher EHR-S. The main stressors were incomplete EHR work by other departments affecting nursing care (70.8%), difficulty in correction after entering the data (60.4%), and difficulty in data retrieval (60.4%). The main solutions to reduce EHR-S were to reduce the frequency of changes to configuration of the EHR (58%), more training (54.2%), and appreciation of good work (52.8%). Conclusions: EHR-S is experienced by half of the nurses working at an eye care hospital. Implementation of solutions such as better training and fewer changes to the EHR system could reduce stress levels of nurses.

Analysis of transcript-deleterious variants in Mendelian disorders: implications for RNA-based diagnostics.

BACKGROUND: At least 50% of patients with suspected Mendelian disorders remain undiagnosed after whole-exome sequencing (WES), and the extent to which non-coding variants that are not captured by WES contribute to this fraction is unclear. Whole transcriptome sequencing is a promising supplement to WES, although empirical data on the contribution of RNA analysis to the diagnosis of Mendelian diseases on a large scale are scarce. RESULTS: Here, we describe our experience with transcript-deleterious variants (TDVs) based on a cohort of 5647 families with suspected Mendelian diseases. We first interrogate all families for which the respective Mendelian phenotype could be mapped to a single locus to obtain an unbiased estimate of the contribution of TDVs at 18.9%. We examine the entire cohort and find that TDVs account for 15% of all "solved" cases. We compare the results of RT-PCR to in silico prediction. Definitive results from RT-PCR are obtained from blood-derived RNA for the overwhelming majority of variants (84.1%), and only a small minority (2.6%) fail analysis on all available RNA sources (blood-, skin fibroblast-, and urine renal epithelial cells-derived), which has important implications for the clinical application of RNA-seq. We also show that RNA analysis can establish the diagnosis in 13.5% of 155 patients who had received "negative" clinical WES reports. Finally, our data suggest a role for TDVs in modulating penetrance even in otherwise highly penetrant Mendelian disorders. CONCLUSIONS: Our results provide much needed empirical data for the impending implementation of diagnostic RNA-seq in conjunction with genome sequencing.

Chemotherapy-Induced Peripheral Neuropathy and its Impact on Health-Related Quality of Life among Multiple Myeloma Patients: A Single-Center Experience.

AIM: Chemotherapy-induced peripheral neuropathy (CIPN) is a long-term neurological health issue in patients diagnosed with multiple myeloma (MM). The aim of this study was to assess CIPN symptoms and health-related quality of life (HRQOL) among MM patients. METHODS: A cross-sectional survey was conducted among patients diagnosed with MM in a tertiary care hospital using a self-reported Arabic questionnaire, European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire for CIPN scale (QLQ-CIPN20). The HRQOL was assessed using EORTC multiple myeloma module (QLQ-MY20). Categorical variables were reported in frequency tables and percentages. Age and duration of MM diagnosis were reported as mean and standard deviation. Survey responses were presented using descriptive statistics. RESULTS: In total, 62 patients had participated. Males were 60%. The average age was 58.74 ± 11.49 years. On sensory scale, 20% reported "quite a bit"/"very much" tingling in fingers/hands, 23% in toes/feet, 39% numbness in fingers/hands, 37% in toes/feet, and 43% reported trouble standing or walking. On motor scale, 40% reported trouble walking and 60% had difficulty in climbing stairs/standing up from chair. On autonomic scale, 27% reported orthostatic hypotension and only 13/37 (46%) males reported erectile dysfunction. For HRQOL, 50% reported bone aches/pain, 42% reported back pain, 57% reported feeling ill, 33% reported lost hair, 35% had been thinking about their illness, whereas 28% were worried about future health and 22% had reported being worried about dying. CONCLUSION: MM patients encounter CIPN symptoms with impaired HRQOL. Capturing CIPN as a patient-reported outcome needs to be considered in routine clinical practice.

Stringent response governs the oxidative stress resistance and virulence of Francisella tularensis.

Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and, based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones. The relA and spoT gene products generate alarmones in several Gram-negative bacterial pathogens. RelA is a ribosome-associated ppGpp synthetase that gets activated under amino acid starvation conditions whereas, SpoT is a bifunctional enzyme with both ppGpp synthetase and ppGpp hydrolase activities. Francisella encodes a monofunctional RelA and a bifunctional SpoT enzyme. Previous studies have demonstrated that stringent response under nutritional stresses increases expression of virulence-associated genes encoded on Francisella Pathogenicity Island. This study investigated how stringent response governs the oxidative stress response of F. tularensis. We demonstrate that RelA/SpoT-mediated ppGpp production alters global gene transcriptional profile of F. tularensis in the presence of oxidative stress. The lack of stringent response in relA/spoT gene deletion mutants of F. tularensis makes bacteria more susceptible to oxidants, attenuates survival in macrophages, and virulence in mice. This work is an important step forward towards understanding the complex regulatory network underlying the oxidative stress response of F. tularensis.

A national economic and clinical model for ischemic stroke care development in Saudi Arabia: A call for change.

BACKGROUND: Stroke is a significant burden in Saudi Arabia and the Saudi Ministry of Health's stroke committee has identified an urgent need to improve care. AIM: The purpose of this study was to undertake a health-economic analysis to quantify the impact of developing stroke care in the country. METHODS: An economic model was developed to assess the costs and clinical outcomes associated with an ischemic stroke care development program compared with current stroke care. Based on Saudi epidemiological data, cohorts of ischemic stroke patients enter the model each year for the first 10 years based on increasing incidence. Four treatment options were modeled including reperfusion and non-reperfusion treatments. The development scenario estimates the impact of gradually increasing uptake of more effective treatments over 10 years. Changes in the stroke care organization are considered along with resources required to increase capacity, allowing more patients to be admitted to stroke hospitals and access effective treatments. RESULTS: The stroke care development program is associated with an increase in functionally independent patients and a decrease in disabling strokes compared with current stroke care. Additionally, the development program is associated with estimated cost savings of $602 million over 15 years ($255 million direct costs, $348 million indirect costs). CONCLUSIONS: The model predicts that the stroke care development program is associated with improved patient outcomes and lower overall costs compared with the current stroke care program.