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Abdullah Alhuzaimi,1 Alwaleed Aljohar,2 Ahmad N. Alhadi,3,4 Abdulqudous Aljenedil,2 Ahmad S Hersi1 1Department of Cardiac Sciences, King Fahad Cardiac Center, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; 2College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; 3Department of Psychiatry, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia; 4SABIC Psychological Health Research & Applications Chair (SPHRAC), College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia Purpose: Syncope is a common condition affecting almost one-third of the general population. The present study measures the prevalence of psychiatric traits in patients presenting with syncope (unexplained and vasovagal) and whether recurrent attacks have an impact on psychiatric profiles.Patients and methods: This is a case–control study in a tertiary hospital enrolling all patients aged ≥12 years with single or recurrent syncopal attacks. A self-reporting psychometric questionnaire (The Symptoms Checklist-90-Revised) was used to screen for depression, anxiety, somatization disorder, and phobia. Crude comparisons of average scores were done. Further, multiple logistic regression analyses were carried out to measure the impact of syncope on each psychiatric domain. The control group were matched for age, gender, and chronic illnesses with a ratio of 1:3.Results: There were 43 cases and 129 control subjects, with predominance of females (67.4%) and an average age of 33.8 years (standard deviation = 16). There were no significant differences in average scores of depression (13 vs 14.53, P = 0.31), anxiety (11.3 vs 10.4, P = 0.51), or phobia (5.4 vs 5.2, P = 0.88). However, the syncope group had a higher average score for somatization disorder (18.53 vs 13.66, P = 0.002). Binary logistic regression model showed that the association between syncope and somatization disorder was independent of competing confounders (odds ratio = 3.75, 95% confidence interval: 1.72, 8.15, P = 0.001). A sub-analysis of the case group showed that patients with multiple syncopal attacks (six or more) had higher average scores of depression, anxiety, phobia, and somatization disorder compared to those who had less than six attacks.Conclusion: Syncope was independently associated with somatization disorder traits. Further, recurrent syncope resulted in greater deterioration of patients’ psychiatric profiles. Thus, taking into account the psychiatric status in the management of such patients is crucial. Keywords: syncope, psychiatric disorders, anxiety, somatization disorder, phobia, depression

Casing wear is a persistent issue in oil and gas drilling facilities that call for innovative more wear-resistant materials to mitigate casing failures. The present work examines the tribological performance of a novel composite lining comprised of Kevlar honeycomb in a matrix of epoxy reinforced with Zirconia particles against hardband drillpipe tooljoint (DP-TJ). Three side loads (1000, 1200, and 1400 N) and three DP-TJ speeds (0.43, 0.76, and 1.02 m/s) were considered under dry sliding conditions. The results showed that the specific wear rate (K) increased with speed at all side loads. However, K value was found to reach a maximum, reaching 20.3*10−8 MPa−1 at 1200 N before dropping to about 8.5*10−8 MPa−1 when the load is increased to 1400 N. This decline in specific wear rate at the load of 1400 N was attributed to the growth of a double transfer layer through the alignment of zirconia particles in the lining. The scanning electron microscope (SEM) images of worn surfaces revealed that higher K values are associated with more adhesion, delamination, and fiber breakage. Energy dispersive spectroscopy (EDS) and X-ray diffraction (XRD) analysis of the worn surface and the debris collected after the wear test reveals minimal wear of DP-TJ. The epoxy/Kevlar-honeycomb composite lining demonstrated appreciable wear resistance even under dry sliding conditions.

Background: Healthcare-Associated Infections (HAI) outbreaks remain a huge challenge to the healthcare sectors worldwide. Their impact on morbidity and mortality, economic and healthcare burden remains a public health problem and a challenge to the HAI surveillance system, infection control, and HAI management strategies. Aim: This study aimed to investigate the epidemiological patterns, distribution, causative agents of HAI outbreaks and the influence of age, COVID-19 co-infection, medical invasive procedures, and hospital units on mortality among HAI outbreaks cases. Methods: This chart review study involved HAI outbreak cases recorded in Ministry of Health hospitals during 2020–2021 in Saudi Arabia. HAI outbreak notification and investigation forms were used for data collection. A binary logistic regression model was performed to determine the significant predictors of mortality. Univariate analyses were performed to determine the association between hospital units, organisms, and COVID-19 co-infection to the site of infection. Results: A total of 217 HAI outbreaks with 1003 cases were recorded in 2020–2021. Gram-negative bacteria were isolated from 73.8% of the cases. The overall specific case fatality rate was 47.5%. The significant predictors of mortality were age, invasive medical procedures, COVID-19 co-infection, and intensive care units’ admission. Moreover, ventilator-associated events were more associated with cases co-infected with COVID-19. Conclusion: HAI outbreaks were most prevalent in the Western and Central region and in intensive care units. Gram negative bacteria were responsible for most of cases while ventilator-associated events and central line-associated bloodstream infections were the most common infection sites. Implementing targeted and effective prevention and control strategies is recommended.

Objective: To evaluate the relationship between different environmental risk factors and the severity of cleft lip with/without palate (CL ± P) and cleft palate (CP) in Saudi Arabia. Methods: This was a cross-sectional national study, of government hospitals in 10 cities distributed across major regions of Saudi Arabia, from June 2020 to June 2021. All newborns with CL ± P or CP were clinically examined and evaluated for cleft phenotype severity using the LAHSHAL classification system. Various environmental factors were evaluated by interviewing parents using a validated questionnaire. The severity of CL ± P and CP was evaluated in relation to environmental factors. Results: We recruited 174 patients with non-syndromic orofacial cleft (NSOFC); 122 (70.1 %) had CL ± P and 52 (29.9 %) had CP. After adjusting the odds ratios by ordinal regression for CL ± P and logistic regression analysis for CP, environmental factors that significantly increased the severity of CL ± P were family history of NSOFC, maternal illnesses, and maternal medication use (P = 0.02, adjusted odds ratio [AOR]:2.70; P = 0.002, AOR:3.70; and P = 0.03, AOR:2.14, respectively). Folic acid supplementation in the first trimester significantly reduced the severity of CL ± P and CP (P = 0.001, AOR:0.18 and P = 0.001, AOR:0.012, respectively). Conclusion: The severity of CL ± P was affected by some maternal exposures during the 3-month pre-gestation period. Therefore, our results suggest the possibility of controlling the severity of NSOFC.

BackgroundObesity is reaching epidemic proportions with 51% of the population expected to be obese by 2030. Recently, polyphenols have been highlighted as an effective approach to managing obesity and associated risks. Polyphenols are a large class of bioactive plant compounds classified into two major categories: flavonoids which are distinguished by the fundamental C6-C3-C6 skeleton and non-flavonoids.ObjectiveThis systematic review evaluated the effect of different polyphenol sources in overweight and obese people with and without type 2 diabetes. The primary outcome was lipid profile and the secondary outcomes were blood glucose, HbA1c (%), HOMA-IR, weight, and body mass index.MethodA search was undertaken in PubMed, Web of Science, Medline, and Wiley for randomized control trials that assessed different sources of polyphenols in overweight and obese people with or without type 2 diabetes. The quality of the included studies was assessed using the National Heart, Lung, and Blood Institute Quality Assessment Tool.ResultThe search yielded 935 studies, of which six randomized control trials met the inclusion criteria. Five studies found no significant difference in lipid profile between the control and intervention groups in triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol. However, one study showed significant differences in triglycerides (p = 0.04) and HDL cholesterol (p = 0.05) between the two groups with no significant difference in total cholesterol and LDL cholesterol. There were no significant changes in blood glucose observed in the included studies, with only two studies reporting a significant difference in A1c between the groups. Four studies found no difference in HOMA-IR, while one study showed a significant decrease in HOMA-IR in the intervention group compared to the control group. Three studies reported no difference in BMI or weight between the two groups.ConclusionThe data associated with the specific health benefits of polyphenols and their sources in people with overweight, obese, and type 2 diabetes are still limited, so further research is required to support their use and prove their benefits.

Importance: Understanding the pathophysiology of the macula in amblyopic eyes is an active research area. Objective: To correlate macular retinal vascular density changes with best-corrected visual acuity changes following occlusion therapy for amblyopia in children. Design: A prospective cohort study of children visiting the Pediatric Ophthalmology Division of our institution between January 2020 and January 2022 was conducted. Setting: A specialist eye hospital in Saudi Arabia. Participants: Thirty children with unilateral amblyopia. Exposure: Occlusion therapy for amblyopia.Main Outcome and Measures: Best corrected visual acuity (logMAR) before and at each of the four optical coherence tomographic angiographies was compared in amblyopic and fellow eyes. The effect of pretreatment determinants on the correlation between best-corrected visual acuity and retinal vascular density changes was reviewed. Results: In this cohort of 30 amblyopic and 30 fellow eyes from 30 children (mean age 8.7 ± 1.4 years; male: female 18:12. The best-corrected visual acuity improved from a median of 0.6 (interquartile range 0.5; 1.1) pretreatment to a median of 0.4 (interquartile range 0.2; 0.6) posttreatment in amblyopic eyes, and from a median of 0.1 to 0.05 in the fellow eyes. The total percentage change in retinal vascular density in the amblyopic eye was significantly higher than that in the fellow eye (Z = −1.92, P = 0.05). The change in best-corrected visual acuity in the amblyopic eye after a median of 98 months (interquartile range, 69–126 months) of intervention was significantly correlated with the refraction-adjusted change in retinal vascular density (B = −0.03, 95 % confidence interval −0.04, −0.02, P

Abstract Objectives This is the first national study to investigate the incidence of non-syndromic oro-facial clefts (NSOFC) and Pierre-Robin-Sequence in Saudi Arabia over the Covid-19 pandemic period. Methods All maternity hospitals (30-hospitals) in the major regions and cities of Saudi from November 2020-to-2021 were included in the study. Patients were evaluated for cleft phenotype using the LASHAL-classification system. The incidence of NSOFC in Saudi Arabia was calculated by comparing the number of NSOFCs cases born out of all live births during the study period at the included hospitals. Clinical examination was performed and information was gathered using a validated data collection form. Results In one year, 140,380 live-infants were born at the selected hospitals. Of these, 177 were diagnosed with NSOFC giving an incidence of 1.26/1,000 live-births in Saudi Arabia and the highest incidence in Medina city (2.46/1000 live-births). The incidence of cleft lip-and-palate (0.67/1000 live-births) was higher than that of cleft-palate (0.37/1000 live-births) and cleft-lip (0.22/1000 live-births). Pierre-Robin Sequence incidence was (0.04/1000 live-births). There were 21(12.1) or 23(13.2%) of NSOFC’s mothers exposed or vaccinated with Covid-19, respectively. Conclusion The national incidence of NSOFC in Saudi Arabia was 1.26/1000 live births with variation between phenotypes and regions in the country. In addition, to reporting Covid-19 infection prevalence and vaccine exposure among NSOFC's mothers, this study represents the first of its type to evaluate NSOFC prevalence in Saudi Arabia on a national level.

Gorka Sesma,1 Tasnim Al Mairi,2 Heba Fareed Khashoggi,1 Shorog Ibrahim AlDhahi,1 Fahad Aljohar,3 Rajiv Khandekar,4 Abdulaziz Awad1 1Pediatric Ophthalmology and Strabismus Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; 2Emergency Department, Almoosa Specialist Hospital, Al Mubarraz, Saudi Arabia; 3Diagnostic and Imaging Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; 4Department of Vision Science, University of British Columbia, Vancouver, CanadaCorrespondence: Gorka Sesma, Pediatric Ophthalmology and Strabismus Division, King Khaled Eye Specialist Hospital, Al Urubah Branche Road, West Building 2nd Floor, Riyadh, 11462, Saudi Arabia, Tel +966 11 4849700, Fax +966 11 4821908, Email gsesma@kkesh.med.saPurpose: Optical coherence tomography angiography (OCTA) noninvasively images retinal microvasculature. Foveal avascular zone (FAZ) biomarkers can act as indicators of various forms of amblyopia, making them valuable tools for clinicians. The purpose of this study was to assess the effect of amblyopia therapy on the FAZ using OCTA to determine FAZ size in children with untreated amblyopia.Patients and Methods: This two-arm cohort study enrolled 23 children with untreated strabismic or anisometropic amblyopia who underwent OCTA between 2021– 2022. Each arm had 23 eyes, with one arm having amblyopic eyes and the other having normal eyes. FAZ area, perimeter, and circularity index were measured before and quarterly during 1 year of occlusion therapy. Differences in avascular zone biomarkers between amblyopic and fellow eyes were compared and linked to demographic and ocular factors.Results: Similar FAZ areas were found in the amblyopic (0.3 mm2) and nonamblyopic eyes (0.28 mm2) (P = 0.83), with no significant change in either group (P = 0.93). Amblyopic eyes showed a larger FAZ perimeter reduction (0.12 mm2) than fellow eyes (0.02 mm2), but the difference was not statistically significant (P = 0.09). The circularity index in amblyopic eyes matched with fellow eyes (0.67 mm2), P = 0.38. Initial visual acuity and strabismus correlated with changes in the follow-up FAZ area.Conclusion: Amblyopia treatment did not significantly alter FAZ area in this cohort. Perimeter variations between amblyopic and fellow eyes require further study. The conclusions were limited by the sample size and lack of randomization.Plain Language Summary: Amblyopia is a common vision problem in children in which one eye does not see the fellow eye. This can occur if the eyes are not lined up right or if their prescriptions are different. Amblyopia is treated by placing a patch over the stronger eye to help the weaker eye better see.Researchers have used a technique called optical coherence tomography angiography (OCTA) to compare the foveal avascular zone (FAZ) before and after treatment in children with amblyopia. The FAZ is a spot on the back of the eye where there are no blood vessels or light-sensitive cells. Changes in the FAZ may indicate the severity of amblyopia.The study included 23 children with untreated amblyopia. Over the course of more than a year, measurements of FAZ area, perimeter, and roundness were taken before and during occlusion therapy. The size of the FAZ was also compared between the eyes with and without amblyopia.At the start of the study and after treatment, there were no significant differences between the FAZs of amblyopic eyes and other eyes. There were some differences in the size of the FAZ between eyes. Changes in the FAZ area were linked to the initial state of vision and misalignment.Overall, this study found that occlusion therapy did not change FAZ area in children with amblyopia. More research is needed to determine why the FAZ perimeter can differ between the eyes. Larger randomized studies would provide more information about how the FAZ changes when treating amblyopia.Keywords: amblyopia, optical coherence tomography angiography, foveal avascular zone, occlusion therapy, biomarkers

Abstract Background The optimal revascularization strategy in patients with left main coronary artery (LMCA) disease in the emergency setting is still controversial. Thus, we aimed to compare the outcomes of percutaneous coronary interventions (PCI) vs. coronary artery bypass grafting (CABG) in patients with and without emergent LMCA disease. Methods This retrospective cohort study included 2138 patients recruited from 14 centers between 2015 and 2019. We compared patients with emergent LMCA revascularization who underwent PCI (n = 264) to patients who underwent CABG (n = 196) and patients with non-emergent LMCA revascularization with PCI (n = 958) to those who underwent CABG (n = 720). The study outcomes were in-hospital and follow-up all-cause mortality and major adverse cardiovascular and cerebrovascular events (MACCE). Results Emergency PCI patients were older and had a significantly higher prevalence of chronic kidney disease, lower ejection fraction, and higher EuroSCORE than CABG patients. CABG patients had significantly higher SYNTAX scores, multivessel disease, and ostial lesions. In patients presenting with arrest, PCI had significantly lower MACCE (P = 0.017) and in-hospital mortality (P = 0.016) than CABG. In non-emergent revascularization, PCI was associated with lower MACCE in patients with low (P = 0.015) and intermediate (P

Aluminum can potentially cause toxicity in pediatrics and neonates receiving parenteral nutrition. Some PN solutions and ingredients in Saudi Arabia do not comply with US FDA regulations regarding aluminum exposure. This study aims to determine the aluminum concentration in samples of PN solutions and ingredients used to feed infants in Saudi Arabia. The aluminum in the samples was determined using inductively coupled plasma mass spectrometry. The concentration of metal contaminants in each sample was determined in triplicate. The aluminum content of 38 samples was investigated, 15 of which originated from components included in the prepared PN solutions. Among the 15 samples, the least measurable aluminum content was detected in potassium chloride solutions (0.81 mcg/L). In contrast, the greatest amount of aluminum was detected in potassium phosphate and calcium gluconate (141,64 mcg/L and 462.7 mcg/L), respectively. The results showed that the final PN solution (PNS) product contained more aluminum levels than the content ingredients; in addition, the study found a statistically significant relationship among 18 pediatric patients at KFMC who had intestinal failure and needed long-term parenteral nutrition. Specifically, their high aluminum levels, exceeding the normal range of 0.6 ng/ml, indicate that the current use of PN solutions will likely cause toxicity due to aluminum contamination in additives. Hence, reducing aluminum in PN solutions is imperative to ensure patient safety.

Abstract Background The environmental etiology of non-syndromic orofacial clefts (NSOFCs) is still under research. The aim of this case-control study is to assess COVID-19 associated factors that may be related to the risk of NSOFC in five Arab countries. These factors include COVID-19 infection, COVID-19 symptoms, family member or friends infected with COVID-19, stress, smoking, socioeconomic status and fear of COVID-19. Methods The study took place in governmental hospitals in five Arab countries from November 2020 to November 2021. Controls are matched in the month of delivery and site of recruitment. A clinical examination was carried out using LASHAL classification. Maternal exposure to medication, illnesses, supplementation, COVID-19 infection during their pregestation and 1st trimester periods were evaluated using a validated questionnaire. Maternal exposure to stress was assessed using the Life Events scale, fear of covid-19 scale, family member or friend affected with covid-19 infection, pregnancy planning and threatened abortion. Results The study recruited 1135 infants (386 NSOFC and 749 controls). Living in urban areas, maternal exposure to medications 3-months pregestation, maternal exposure to any of the prenatal life events and maternal fear of COVID-19 significantly increased the risk of having a child with NSOFC. On the other hand, mothers exposed to supplementation 3-months pregestation, mothers suspected of having COVID-19 infection, family members or friends testing positive with COVID-19 significantly decreased the risk of having a child with NSOFC. Conclusions This study suggests that NSOFC may be associated with maternal exposure to lifetime stress and COVID-19 fear in particular, with no direct effect of the COVID-19 infection itself. This highlights the importance of providing psychological support for expecting mothers during stressful events that affect populations such as the COVID-19 pandemic, in addition to the usual antenatal care.

Background: Healthcare workers (HCWs) have been highly affected by COVID-19 due to their fundamental duties in diagnosing, caring, and treating the rapidly increasing number of infected patients. Thus, are facing the occupational risk of COVID-19 infection and mortality. Purpose: To investigate the COVID-19 disease clinical characteristic and associated factors among HCWs in Saudi Arabia. Methods: This was a nationwide, retrospective analytical study conducted from 5th of March 2020–21 st of August 2021. All deceased HCWs who were diagnosed with COVID-19 were included in this study. Results: As of August 21, 2021, a total of 305 deaths were recorded due to COVID-19 infection among HCWs in all Saudi healthcare facilities. The case fatality rate was 0.35%. Deaths were highest among physicians (40.0%). Most of deceased HCWs acquired the infection from the community (80%). 71% of deceased HCWs had at least one chronic medical condition. Most of them were admitted to ICU before they passed away (83.6%). Three significant variables predicting ICU admission were presence of one or more comorbidities, hypertension, and chronic respiratory diseases Conclusion: HCWs are at higher risk for exposure to COVID‐19 due to their occupational risk. Our study encourages future research to provide more comprehensive information regarding COVID-19 morbidity and mortality among HCWs.

Spebrutinib is a new Bruton tyrosine kinase inhibitor developed by Avila Therapeutics and Celgene. Spebrutinib (SPB) is currently in phase Ib clinical trials for the treatment of lymphoma in the United States. Preliminary in-silico studies were first performed to predict susceptible sites of metabolism, reactivity pathways and structural alerts for toxicities by StarDrop WhichP450™ module, Xenosite web predictor tool and DEREK software; respectively. SPB metabolites and adducts were characterized in vitro from rat liver microsomes (RLM) using LC-MS/MS. Formation of reactive intermediates was investigated using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles for the unstable and reactive iminium, iminoquinone and aldehyde intermediates, respectively, with the aim to produce stable adducts that can be detected and characterized using mass spectrometry. Fourteen phase I metabolites, four cyanide adducts, six GSH adducts and three methoxylamine adducts of SPB were identified and characterized. The proposed metabolic pathways involved in generation of phase I metabolites of SPB are oxidation, hydroxylation, o-dealkylation, epoxidation, defluorination and reduction. Several in vitro reactive intermediates were identified and characterized, the formation of which can aid in explaining the adverse drug reactions of SPB. Several iminium, 2-iminopyrimidin-5(2H)-one and aldehyde intermediates of SPB were revealed. Acrylamide is identified as a structural alert for toxicity by DEREK report and was found to be involved in the formation of several glycidamide and aldehyde reactive intermediates.

Introduction: The evidence about the optimal revascularization strategy in patients with left main coronary artery (LMCA) disease and impaired renal function is limited. Thus, we aimed to compare the outcomes of LMCA disease revascularization (percutaneous coronary intervention [PCI] vs. coronary artery bypass grafting [CABG]) in patients with and without impaired renal function. Methods: This retrospective cohort study included 2,138 patients recruited from 14 centers between 2015 and 2,019. We compared patients with impaired renal function who had PCI (n= 316) to those who had CABG (n = 121) and compared patients with normal renal function who had PCI (n = 906) to those who had CABG (n = 795). The study outcomes were in-hospital and follow-up major adverse cardiovascular and cerebrovascular events (MACCE). Results: Multivariable logistic regression analysis showed that the risk of in-hospital MACCE was significantly higher in CABG compared to PCI in patients with impaired renal function (odds ratio [OR]: 8.13 [95% CI: 4.19–15.76], p < 0.001) and normal renal function (OR: 2.59 [95% CI: 1.79–3.73]; p < 0.001). There were no differences in follow-up MACCE between CABG and PCI in patients with impaired renal function (HR: 1.14 [95% CI: 0.71–1.81], p = 0.585) and normal renal function (HR: 1.12 [0.90–1.39], p = 0.312). Conclusions: PCI could have an advantage over CABG in revascularization of LMCA disease in patients with impaired renal function regarding in-hospital MACCE. The follow-up MACCE was comparable between PCI and CABG in patients with impaired and normal renal function.

Fenebrutinib is an orally available Bruton tyrosine kinase inhibitor. It is currently in multiple phase III clinical trials for the management of B-cell tumors and autoimmune disorders. Elementary in-silico studies were first performed to predict susceptible sites of metabolism and structural alerts for toxicities by StarDrop WhichP450™ module and DEREK software; respectively. Fenebrutinib metabolites and adducts were characterized in-vitro in rat liver microsomes (RLM) using MS3 method in Ion Trap LC-MS/MS. Formation of reactive and unstable intermediates was explored using potassium cyanide (KCN), glutathione (GSH) and methoxylamine as trapping nucleophiles to capture the transient and unstable iminium, 6-iminopyridin-3(6H)-one and aldehyde intermediates, respectively, to generate a stable adducts that can be investigated and analyzed using mass spectrometry. Ten phase I metabolites, four cyanide adducts, five GSH adducts and six methoxylamine adducts of fenebrutinib were identified. The proposed metabolic reactions involved in formation of these metabolites are hydroxylation, oxidation of primary alcohol to aldehyde, n-oxidation, and n-dealkylation. The mechanism of reactive intermediate formation of fenebrutinib can provide a justification of the cause of its adverse effects. Formation of iminium, iminoquinone and aldehyde intermediates of fenebrutinib was characterized. N-dealkylation followed by hydroxylation of the piperazine ring is proposed to cause the bioactivation to iminium intermediates captured by cyanide. Oxidation of the hydroxymethyl group on the pyridine moiety is proposed to cause the generation of reactive aldehyde intermediates captures by methoxylamine. N-dealkylation and hydroxylation of the pyridine ring is proposed to cause formation of iminoquinone reactive intermediates captured by glutathione. FBB and several phase I metabolites are bioactivated to fifteen reactive intermediates which might be the cause of adverse effects. In the future, drug discovery experiments utilizing this information could be performed, permitting the synthesis of new drugs with better safety profile. Overall, in silico software and in vitro metabolic incubation experiments were able to characterize the FBB metabolites and reactive intermediates using the multistep fragmentation capability of ion trap mass spectrometry.

Fenebrutinib (GDC-0853; FNB) is an oral small molecule that was developed by Roche Pharmaceuticals to slow multiple sclerosis progression. FNB is a reversible bruton tyrosine kinase (BTK) inhibitor, which showed the maximum potency of BTK inhibitors in phase III clinical trials for multiple sclerosis. In the current study, a fast, specific, and sensitive UPLC-MS/MS method for FNB quantification in human liver microsomes (HLMs) was established with application to the evaluation of metabolic stability. The UPLC-MS/MS methodology was verified using the stated USFDA validation guidelines for bioanalytical methodologies that involve selectivity, linearity, accuracy and precision, carryover and extraction recovery, stability, and matrix effect. The FNB calibration curve displayed a linearity in the range from 1 ng/mL to 3000 ng/mL (y = 1.731x + 2.013; R2: 0.9954; RSD < 4.37%) in the HLMs matrix. The limit of quantification was 0.88 ng/mL, which verified the UPLC-MS/MS analytical method sensitivity. The intraday and interday precision and accuracy results of the developed UPLC-MS/MS method were −3.99–14.0% and 0.52–3.83%, respectively. FNB and savolitinib (SVB) (internal standard) were chromatographically separated utilizing an isocratic mobile phase system with a ZORBAX Eclipse plus-C18 (50 mm, 2.1 mm, and 1.8 μm) column. The metabolic stability parameters for FNB, involving high intrinsic clearance (58.21 mL/min/kg) and a short in vitro half-life (13.93 min), revealed the high extraction ratio of FNB. Reviewing the literature revealed that the current UPLC-MS/MS method is the first analytical method for FNB quantification in the HLMs matrix with application to the assessment of FNB metabolic stability.

Background: Despite its importance, no study from the Middle East has assessed the neonatal pain knowledge of health-care providers in neonatal intensive care units (NICUs). Objectives: To evaluate the knowledge and attitudes of pediatricians and nurses in Saudi Arabia toward procedural pain assessment and its management in neonates. Materials and Methods: This questionnaire-based, cross-sectional study was conducted between March and June 2015 at three NICUs in the Eastern Province of Saudi Arabia, namely, King Fahd Hospital of the University, Al Khobar; Security Forces Hospital, Dammam; and King Fahd Medical Military Complex, Dhahran. All pediatricians/neonatologists and nurses in these units were included, and a previously validated questionnaire was distributed and collected by an assigned clinician. The questionnaire elicited pain-related knowledge of seven procedures using a 10-point Likert scale. Results: A total of 150 questionnaires were distributed, from which 107 complete responses were obtained (nurses: 81 [75.7%]; doctors: 26 [24.3%]). The overall knowledge scores were high (mean ± standard deviation = 77.3% ±11.6%). The mean pain rankings of doctors (7.2) were higher than those of nurses (6.5) for all procedures. Nurses reported more frequent use of analgesia than doctors (15.4% vs. 11.5%). Doctors often did not use comfort measures for any procedures, except during procedures on term to 28-day-old neonates. The use of pain tools was reported by only 12 (11%) clinicians. Conclusion: This study found that despite adequate knowledge about pain perception by neonates, the use of analgesia for procedural pain relief is low among doctors in the NICUs of the Eastern Province of Saudi Arabia. In addition, there is underutilization of pain assessment tools, thereby indicating the need to address this knowledge–practice gap.

Haitham AlRabiah,1 Adnan A Kadi,1 Haya I Aljohar,1 Mohamed W Attwa,1 Nasser S Al-Shakliah,1 Sabry M Attia,2 Gamal AE Mostafa1,3 1Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11459, Saudi Arabia; 2Department of Pharmacology Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; 3Micro-Analytical Laboratory, Applied Organic Chemistry Department, National Research Center, Dokki, Cairo, EgyptCorrespondence: Gamal AE Mostafa, Email gmostafa@ksu.edu.saBackground: Dovitinib (TKI 258) is a small-molecule multi-kinase inhibitor for the treatment of different types of cancer. There is currently no validated method for its quantitative determination; therefore, we aimed to develop a reliable method to assay dovitinib.Method and Results: An electrospray ionization tandem mass spectrometry (ESI-MS/MS) method was used to separate dovitinib using an analytical C18 column (50 × 2.1 mm, 1.8 μm) at 25°C. Bosutinib was used as the internal standard (IS). Dovitinib was extracted from mouse plasma using a precipitation procedure. The mobile phase consisted of 10 mM ammonium formate: acetonitrile (68:32, v/v, pH 4.3) run at a rate of 0.3 mL min− 1. MS detection was performed in the positive ion mode. Multiple reaction monitoring transitions were 393→ 337 and 393→ 309 for dovitinib, and 530→ 141 and 530→ 113 for bosutinib. The investigated method was validated as a bio-analytical method based on FDA guidelines. The linearity of the developed method was over the range of 5– 500 ng mL,− 1 coefficient of determination (r2= 0.9998). The average intra-day recovery and relative standard deviation (RSD) of the quality control (QC) sample were 97.24% and 1.32%, whereas the overall inter-day accuracy and precision were 97.99% and 0.54%, respectively. Dovitinib was stable during sample storage and handling conditions. Furthermore, the dilution integrity of the method was demonstrated by good recovery (97– 99%) and RSD values (0.5– 0.7%).Conclusion: This method was selectively sensitive and exhibited no matrix effect, with an acceptable accuracy and precision according to the FDA guidelines. The developed method could be efficiently used for pharmacokinetic studies of dovitinib.Keywords: HPLC, MS detection, dovitinib, mouse plasma, pharmacokinetics