Mitigating psychological distress in healthcare workers as COVID-19 waves ensue: a repeated cross-sectional study from Jordan.

BACKGROUND: Jordan has experienced several COVID-19 waves in the past 2 years. Cross-sectional studies have been conducted to evaluate distress in healthcare practitioners (HCPs), but there is limited evidence with regards to the impact of continuing pandemic waves on levels of distress in HCPs. We previously studied psychological distress in HCPs during the start of the pandemic (period 1, when cases were infrequent and the country was in lockdown), and demonstrated that HCPs were experiencing considerable stress, despite the country reporting low caseloads at the time. In this study, we sought to utilize the same methodology to reexamine levels of distress as COVID-19 peaked in the country and HCPs began managing large numbers of COVID-19 cases (period 2). METHODS: A cross-sectional online survey utilizing a tool previously used during period 1 was completed by HCPs working in various settings. Demographic, professional and psychological factors such as distress, anxiety, depression, burnout, sleep issues, exhaustion, and fear were assessed; and coping strategies also were measured. Items in the tool were assessed for reliability and validity. A multivariable regression was used to identify factors that continued to impact distress during period 2. RESULTS: Samples in both periods (n = 937, n = 876, respectively) were relatively comparable in demographic characteristics, but in period 2, a greater proportion of nurses and healthcare practitioners reported working in general hospitals. During the pandemic peak (period 2), 49.0% of HCPs reported high levels of distress (compared to 32% in period 1); anxiety and depression scores were approximately 21% higher in period 2; and 50.6% reported fatigue (compared to 34.3% in period 1). Variables significantly associated with greater distress in period 2 included experiencing burnout, experiencing sleep disturbances, being fatigued, having fatalistic fears, and having fears related to workload. Conversely, being male, reporting satisfaction at work, and using positive coping practices were associated with a significantly lower odds of being in distress. CONCLUSIONS: Between the two periods (early pandemic and first wave), COVID-19-related mental health continued to deteriorate among HCPs, highlighting the need to do more to support HCP front-liners facing COVID-19 surges.

Identification of LGR4 as a prognostic biomarker in KRAS-mutant lung adenocarcinoma: Evidence from integrated bioinformatics analysis.

Globally, lung cancer is the leading cause of cancer-related deaths, primarily non-small cell lung cancer. Kirsten Rat Sarcoma Oncogene Homolog (KRAS) mutations are common in non-small cell lung cancer and linked to a poor prognosis. Covalent inhibitors targeting KRAS-G12C mutation have improved treatment for some patients, but most KRAS-mutant lung adenocarcinoma (KRAS-MT LUAD) cases lack targeted therapies. This gap in treatment options underscores a significant challenge in the field. Our study aimed to identify hub/key genes specifically associated with KRAS-MT LUAD. These hub genes hold the potential to serve as therapeutic targets or biomarkers, providing insights into the pathogenesis and prognosis of lung cancer. We performed a comprehensive analysis on KRAS-MT LUAD samples using diverse data sources. This included TCGA project data for RNA-seq, clinical information, and somatic mutations, along with RNA-seq data for adjacent normal tissues. DESeq2 identified differentially expressed genes (DEGs), while weighted gene co-expression network analysis revealed co-expression modules. Overlapping genes between DEGs and co-expression module with the highest significance were analyzed using gene set enrichment analysis and protein-protein interaction network analysis. Hub genes were identified with the Maximal Clique Centrality algorithm in Cytoscape. Prognostic significance was assessed through survival analysis and validated using the GSE72094 dataset from Gene Expression Omnibus (GEO) database. In KRAS-MT LUAD, 3122 DEGs were found (2131 up-regulated, 985 down-regulated). The blue module, among 25 co-expression modules from weighted gene co-expression network analysis, had the strongest correlation. 804 genes overlapped between DEGs and the blue module. Among 20 hub genes in the blue module, leucine-rich repeats containing G protein-coupled receptor 4 (LGR4) overexpression correlated with worse overall survival. The prognostic significance of LGR4 was confirmed using GSE72094, but surprisingly, the direction of the association was opposite to what was expected. LGR4 stands as a promising biomarker in KRAS-MT LUAD prognosis. Contrasting associations in TCGA and GSE72094 datasets reveal the intricate nature of KRAS-MT LUAD. Additional explorations are imperative to grasp the precise involvement of LGR4 in lung adenocarcinoma prognosis, particularly concerning KRAS mutations. These insights could potentially pave the way for targeted therapeutic interventions, addressing the existing unmet demands in this specific subgroup.

Safety, Tolerability, and Pharmacokinetics of Nebulized Hydroxychloroquine: A Pilot Study in Healthy Volunteers.

Background: Early in the coronavirus disease 2019 (COVID-19) pandemic, hydroxychloroquine (HCQ) drew substantial attention as a potential COVID-19 treatment based on its antiviral and immunomodulatory effects in vitro. However, HCQ showed a lack of efficacy in vivo, and different groups of researchers attributed this failure to the insufficient drug concentration in the lung following oral administration (HCQ is only available in the market in the tablet form). Delivering HCQ by inhalation represents a more efficient route of administration to increase HCQ exposure in the lungs while minimizing systemic toxicity. In this pilot study, the safety, tolerability, and pharmacokinetics of HCQ nebulizer solution were evaluated in healthy volunteers. Methods: Twelve healthy participants were included in this study and were administered 2 mL of HCQ01 solution (equivalent to 25 mg of HCQ sulfate) through Aerogen® Solo, a vibrating mesh nebulizer. Local tolerability and systemic safety were assessed by forced expiratory volume in the first and second electrocardiograms, clinical laboratory results (e.g., hematology, biochemistry, and urinalysis), vital signs, and physical examinations. Thirteen blood samples were collected to determine HCQ01 systemic exposure before and until 6 hours after inhalation. Results: The inhalation of HCQ01 was well tolerated in all participants. The mean value of Cmax for the 12 participants was 9.66 ng/mL. Tmax occurred at around 4.8 minutes after inhalation and rapidly decreased thereafter. The reported systemic exposure was very low with a mean value of 5.28 (0.6-15.6) ng·h/mL. Conclusion: The low systemic concentrations of HCQ01 of 9.66 ng/mL reported by our study compared with 1 µg/mL previously predicted after 200 mg BID oral administration, and the safety and tolerability of HCQ01 administered as a single dose through nebulization, support the assessment of its efficacy, safety, and tolerability in further studies for the treatment of COVID-19.

Cessation experiences and quitting perspectives of Jordanian cancer patients who smoke.

OBJECTIVES: To describe quitting experiences of cancer patients in a Cancer Center in Jordan; to study patients' perceptions regarding the process of smoking cessation; and to provide insights about patients in this difficult setting in order to inform oncology practitioners with regards to how improve perceptions and skills related to quitting. METHODS: An Arabic cross-sectional questionnaire was developed to evaluate smoking and quitting behaviors in the context of cancer. The tool used as its framework the Theoretical Domains Framework to capture quitting perceptions of cancer patients who smoke, as well as social, environmental, and system-level factors that influence quitting. Eligible patients who were treated at the Center (both in-patient and out-patient settings) and who were current smokers or who smoked up to the time of cancer diagnosis were eligible. Patients were interviewed between July, 2018 and January 2020 using two versions of the questionnaire: an 'ex-smokers' version, and a 'current smokers' version. RESULTS: Only a third of subjects (104/350) had been smoke-free for at least 30 days. Both smokers and ex-smokers generally felt that quitting was important, but mean importance and confidence scores (out of 10) were significantly lower in current smokers (8.2 versus 9.1, p-value=0.002; 6.4 versus 8.7, p-value=0.000). Roughly 31% of subjects believed smoking harms were exaggerated and that smoking was not an addiction. About 62% of subjects agreed quitting required skills, and 78.5% felt the steps to quit were clear, but across several listed strategies for quitting, use of these was limited (even in ex-smokers). Among current smokers, roughly a third exhibited forms of cessation fatigue. CONCLUSION: Jordanian cancer patients who smoke present with limited knowledge about the quitting process. Even when some success is observed, low rates of utilization of specific quitting strategies were observed, highlighting the need for better counseling about quitting.

Supporting Smokers in Difficult Settings: Suggestions for Better Education and Counseling in Cancer Centers in Jordan.

Continued smoking in cancer patients is commonly observed in Jordan. In a country that exhibits some of the highest smoking rates globally, enhancing patient education regarding the value of smoking cessation for cancer care is vital. The objectives of our study were to describe sociodemographic and clinical factors associated with continued smoking in Jordanian smokers after a cancer diagnosis; to identify reasons for smoking and knowledge regarding smoking's impact on care; to examine in a multivariable manner the factors associated with continued smoking, and to accordingly generate patient counseling recommendations. An interviewer-administered survey using the Theoretical Domains Framework was employed. Among 350 subjects (mean age 51.0, median 52.7), approximately 38% of patients had quit or were in the process of quitting; 61.7% remained smokers. Substantial knowledge gaps with regard to the impact of continued smoking on cancer care were observed. Remaining a smoker after diagnosis was associated with being employed, not receiving chemotherapy or surgery, having lower confidence in quitting, and having a lower number of identified reasons for smoking. Interventions to promote cessation in Jordanian cancer patients who smoke should focus on enhancing patient awareness about the impact of smoking in cancer care and raising perceived self-efficacy to quit.

Development of a Physiologically-Based Pharmacokinetic (PBPK) Model of Nebulized Hydroxychloroquine for Pulmonary Delivery to COVID-19 Patients.

Despite inconclusive evidence, chloroquine (CQ) and hydroxychloroquine (HCQ)are commonly used for the treatment of Corona virus Disease 2019(COVID-19) in critically ill patients.It was hypothesized that HCQ as an aerosol application can reach the antiviral concentration of ~1-5 µM in the alveolar cells which has been proven effective in vitro. A physiologically-based pharmacokinetic (PBPK) model of nebulized HCQ for pulmonary delivery to COVID-19 patients using the Nasal-Pulmonary Module in GastroPlus® V9.7 simulator, in order to calculate the necessary inhalation dose regimen of HCQ, was developed. The physiological, drug disposition, and pharmacokinetic parameters were obtained from the literature and used during model building after optimization using Optimization Module, while oral data was used for validation. The 25 mg BID inhalation dosing was predicted to lead to alveolar HCQ levels of 7 µM (above EC50 of ~1-5 µM), and small plasma levels of 0.18 µM (as compared to plasma levels of 3.22 µM after 200 mg BID oral dosing). However, average contact time (>1 µM) is around 0.5 h in lung parts, suggesting indirect exposure response effect of HCQ.The developed PBPK model herein predicted HCQ levels in plasma and different lung parts of adults after multiple inhalation dosing regimens for 5 days. This in-silico work needs to be tested in vivo on healthy subjects and COVID-19 patients using 12.5 mg BID and 25 mg BID inhalation doses.

The inevitability of Covid-19 related distress among healthcare workers: Findings from a low caseload country under lockdown.

OBJECTIVES: To characterize psychological distress and factors associated with distress in healthcare practitioners working during a stringent lockdown in a country (Jordan) that had exhibited one of the lowest incidence rates of Covid-19 globally at the time of the survey. METHODS: A cross-sectional online survey sent to healthcare practitioners working in various hospitals and community pharmacies. Demographic, professional and psychological characteristics (distress using Kessler-6 questionnaire, anxiety, depression, burnout, sleep issues, exhaustion) were measured as were sources of fear. Descriptive and multivariable statistics were performed using level of distress as the outcome. RESULTS: We surveyed 937 practitioners (56.1% females). Approximately 68%, 14%, and 18% were nurses/technicians, physicians, and pharmacists (respectively). 32% suffered from high distress while 20% suffered from severe distress. Exhaustion, anxiety, depression, and sleep disturbances were reported (in past seven days) by approximately 34%, 34%, 19%, and 29% of subjects (respectively). Being older or male, a positive perception of communications with peers, and being satisfied at work, were significantly associated with lower distress. Conversely, suffering burnout; reporting sleep-related functional problems; exhaustion; being a pharmacist (relative to a physician); working in a cancer center; harboring fear about virus spreading; fear that the virus threatened life; fear of alienation from family/friends; and fear of workload increases, were significantly associated with higher distress. CONCLUSION: Despite low caseloads, Jordanian practitioners still experienced high levels of distress. Identified demographic, professional and psychological factors influencing distress should inform interventions to improve medical professionals' resilience and distress likelihood, regardless of the variable Covid-19 situation.

Population Pharmacokinetics Modeling of Lamotrigine in Jordanian Epileptic Patients Using Dried Blood Spot Sampling.

AIMS: To characterize the population pharmacokinetics of lamotrigine in Jordanian epileptic patients and to identify factors affecting therapeutic parameters. PATIENTS AND METHODS: A population pharmacokinetics model for lamotrigine was established based on a prospectively collected data of 52 steady-state concentrations from 38 adult and pediatric patients with epilepsy. Lamotrigine concentrations were determined by a dried blood spot liquid chromatography method. Data were analyzed according to a one-compartment model with first-order absorption and elimination using the nonlinear mixed effect modeling program. The covariates effect of total body weight, gender, age, and co-medication with topiramate, carbamazepine, phenytoin, phenobarbital, and valproic acid on lamotrigine clearance were investigated using a stepwise forward addition followed by a stepwise backward elimination. RESULTS: The final population pharmacokinetics model for lamotrigine clearance was as follows: CL/Fpop=θ1*exp (θ3*age)*exp (θ5*carbamazepine)*exp (θ6*valproic acid) , where θ1 is the relative clearance (L/hr) estimated, and θ3, θ5, and θ6 are the fixed parameters relating to age and co-medication with carbamazepine and valproic acid, respectively.The population mean value of lamotrigine total clearance generated in the final model (with covariates) was 2.12 L/hr. Inter-individual variability and residual unexplained variability expressed as the coefficient of variation was 37.1 and 26.1%, respectively. CONCLUSION: Lamotrigine total clearance in the Jordanian patients is comparable to that reported by others for Caucasian patients. Age and concomitant therapy with carbamazepine and valproic acid significantly affected lamotrigine clearance, and accounted for 48% of its inter-individual variability.