Identification of potent indolizine derivatives against Mycobacterial tuberculosis: In vitro anti-TB properties, in silico target validation, molecular docking and dynamics studies.

In the current study, two sets of compounds: (E)-1-(2-(4-substitutedphenyl)-2-oxoethyl)-4-((hydroxyimino)methyl)pyridinium derivatives (3a-3e); and (E)-3-(substitutedbenzoyl)-7-((hydroxyimino)methyl)-2-substitutedindolizine-1-carboxylate derivatives (5a-5j), were synthesized and biologically evaluated against two strains of Mycobacterial tuberculosis (ATCC 25177) and multi-drug resistant (MDR) strains. Further, they were also tested in vitro against the mycobacterial InhA enzyme. The in vitro results showed excellent inhibitory activities against both MTB strains and compounds 5a-5j were found to be more potent, and their MIC values ranged from 5 to 16 µg/mL and 16-64 µg/mL against the M. tuberculosis (ATCC 25177) and MDR-TB strains, respectively. Compound 5h with phenyl and 4-fluorobenzoyl groups attached to the 2- and 3-position of the indolizine core was found to be the most active against both strains with MIC values of 5 µg/mL and 16 µg/mL, respectively. On the other hand, the two sets of compounds showed weak to moderate inhibition of InhA enzyme activity that ranged from 5 to 17 % and 10-52 %, respectively, with compound 5f containing 4-fluoro benzoyl group attached to the 3-position of the indolizine core being the most active (52 % inhibition of InhA). Unfortunately, there was no clear correlation between the InhA inhibitory activity and MIC values of the tested compounds, indicating the probability that they might have different modes of action other than InhA inhibition. Therefore, a computational investigation was conducted by employing molecular docking to identify their putative drug target(s) and, consequently, understand their mechanism of action. A panel of 20 essential mycobacterial enzymes was investigated, of which ß-ketoacyl acyl carrier protein synthase I (KasA) and pyridoxal-5'-phosphate (PLP)-dependent aminotransferase (BioA) enzymes were revealed as putative targets for compounds 3a-3e and 5a-5j, respectively. Moreover, in silico ADMET predictions showed adequate properties for these compounds, making them promising leads worthy of further optimization.

The frequency of os acromiale in 751 shoulder MRI of Saudi population.

Background: Os acromiale (OA) is an uncommon pathology with a variable prevalence rate among different populations. Objectives: The aim of this study was to report the frequency of OA utilizing shoulder MRI of patients with shoulder pathology. Methods: It was a retrospective study. After obtaining our IRB approval, we gathered all shoulder and upper arm MRIs from the radiology department and evaluated them. Results: The prevalence of OA was found to be 3.32%. The mean age of the affected patients was 50.87 years (25-81). Conclusion: The rate of OA in patients presenting with shoulder pain is 3.32% in Saudi Arabia, which correlates with what has been previously reported in the literature.

Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches.

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation.Communicated by Ramaswamy H. Sarma.

Implementation of a Hepatocellular Carcinoma Surveillance Program in a Community-Based Integrated Health System in Patients With Hepatitis C Cirrhosis.

INTRODUCTION: Underutilization of hepatocellular cancer (HCC) surveillance has been reported, although data evaluating interventions to improve surveillance are sparse. We assessed the effect of a population-based HCC surveillance program on HCC surveillance utilization and outcomes. METHODS: In this retrospective cohort study, we assessed preinclusion and postinclusion HCC surveillance patterns among 597 patients with hepatitis C virus cirrhosis enrolled in a program at an integrated health system between 2013 and 2020. Adequate surveillance was defined as at least 5 surveillance studies within 36 months pre-enrollment and postenrollment; a secondary outcome was proportion of time covered by surveillance over 36 months. Tumor size, stage, and receipt of curative therapy were compared between HCC detected on the first imaging examination (prevalent HCC) and surveillance-detected HCC (incident HCC). We performed Kaplan-Meier analysis and multivariable competing risk analysis to characterize the association between surveillance and mortality. RESULTS: The surveillance program significantly improved surveillance completion (77.6% vs 5.0%, P < 0.001) and proportion time covered (80.9% vs 15.8%, P < 0.001). Compared with prevalent HCC, surveillance-detected cases were more likely unifocal (77.8% vs 44.8%, P < 0.001), early-stage (85.2% vs 44.8%, P < 0.001), with smaller maximum diameter (median 2.3 vs 3.2 cm), and more likely to undergo curative therapy (92.5% vs 72.4% P = 0.010). Survival was improved compared with prevalent cases hazard ratio (HR) 0.23 (0.11-0.51) after adjusting for age and Model for End Stage Liver Disease score. DISCUSSION: Implementation of a population-based program resulted in significant improvement in HCC surveillance use and clinical outcomes among patients with hepatitis C virus cirrhosis. These findings may inform similar interventions by other healthcare systems.

The design of TOPK inhibitors using similarity search, molecular docking, and MD simulations.

Cancer is still a major cause of death worldwide. Unfortunately, the majority of current anticancer treatments suffer many limitations, mainly emergence of resistance and lack of selectivity which necessitate the search for new therapeutics. The TOPK enzyme emerges as a promising target due to its overexpression in many cancer types while being rarely detected in normal tissues. Therefore, targeting TOPK would affect the malignant activity of cancerous cells while sparing normal ones. Further, its vital role in cell division, particularly in cytokinesis, adds to its safety to normal non-multiplying cells. In this study, a combined ligand and structure-based approach was utilized to identify potential TOPK inhibitors. Previously, we identified TOPK inhibitors using a structure-based approach following the construction of a 3D homology model of the TOPK enzyme. Herein, the most active identified inhibitor (lead) was used as a search query to conduct similarity search against PubChem and ChemBridge databases. Retrieved hits were filtered using drug-like filters, docked into the ATP binding site of the enzyme, and finally, the binding free energies of all docked poses were calculated. Based on the computational scores, eight hits were selected as potential TOPK inhibitors. The predicted ADMET descriptors of the eight selected hits were generally favorable. Further, MD simulations of the top scoring hit were conducted to investigate its binding dynamics compared to the lead compound and OTS964 which agreed with the docking results and propose the selected hits as potential TOPK inhibitors. Yet, biochemical testing is still needed to validate these results.Communicated by Ramaswamy H. Sarma.

Exploration of comprehensive marine natural products database against dengue viral non-structural protein 1 using high-throughput computational studies.

Dengue virus (DENV) non-structural protein 1 (NS1) is a versatile quasi-protein essential for the multiplication of the virus. This study applied high-throughput virtual screening (HTVS) and molecular dynamics (MD) simulation to detect the potential marine natural compounds against the NS1 of DENV. The structure of the NS1 protein was retrieved from Protein Data Bank with (PDB ID: 4O6B). Missing residues were added using modeler software. Molecular operating environment (MOE) programme was used to prepare the protein before docking. Virtual screening was performed on PyRx software to identify natural compounds retrieved from Comprehensive Marine Natural Products Database (CMNPD) against the NS1 protein, and best-docked compounds were examined by molecular docking and molecular dynamic (MD) simulation. Out of 31,561 marine compounds, the top 10 compounds showed docking scores lesser than -8.0 kcal/mol. One of the best hit compounds, CMNPD6802, was further analyzed using MD simulation study at 100 nanoseconds and Molecular Mechanics with Generalized Born and Surface Area Solvation (MM/GBSA). Based on its total binding energy, determined using the MM/GBSA approach, CMNPD6802 was ranked first. Its pharmacokinetic properties concerning the target protein NS1 were also evaluated. The results of the MD simulation showed that CMNPD6802 remained in close contact with the protein throughout the activation period, mapped using principal component analysis. These findings suggest that CMNPD6802 could serve as an NS1 inhibitor and may be a potential candidate for treating DENV infections.Communicated by Ramaswamy H. Sarma.

Campesterol and dithymoquinone as a potent inhibitors of SARS cov-2 main proteases-promising drug candidates for targeting its novel variants.

The sudden outbreak of the COVID-19 pandemic has currently taken approximately 2.4 million lives, with no specific medication and fast-tracked tested vaccines for prevention. These vaccines have their own adverse effects, which have severely affected the global healthcare system. The discovery of the main protease structure of coronavirus (Mpro/Clpro) has resulted in the identification of compounds having antiviral potential, especially from the herbal system. In this study, the computer-associated drug design tools were utilised to analyze the reported phytoconstituents of Nigella sativa for their antiviral activity against the main protease. Fifty-eight compounds were subjected to pharmacological parameter analysis to determine their lead likeness in comparison to the standard drugs (chloroquine and nirmatrelvir) used in the treatment of SARS-CoV-2. Nearly 31 compounds were docked against five different SARS-CoV-2 main proteases, and all compounds showed better binding affinity and inhibition constant against the proteases. However, dithymoquinone and campesterol displayed the best binding scores and hence were further subjected to dynamics and MMPBSA study for 100 ns. The stability analysis shows that dithymoquinone and campesterol show less variation in fluctuation in residues compared to standard complexes. Moreover, dithymoquinone exhibited higher binding affinity and favorable interaction followed by campesterol as compared to the standard drug. The in silico computational analysis provides a promising hit for regulating the main proteases activity.Communicated by Ramaswamy H. Sarma.

HDAC inhibition by Nigella sativa L. sprouts extract in hepatocellular carcinoma: an approach to study anti-cancer potential.

A wide variety of natural products have been widely used in chemoprevention therapy because they have antioxidant, anti-inflammatory, and anticancer activity. In the present study, we shed light on the 5th day germinated sprouts of N. sativa seeds and evaluated them against HDAC inhibition and antioxidant activity. The extract from the seed and sprout was extracted and characterised by LC-MS/MS, FTIR, and NMR to reveal its chemical composition, especially thymol (THY) and thymoquinone (TQ). Hepatocellular carcinoma (HCC) is a global health concern as it is a major lifestyle disease. Hence, incorporating herbal-based therapeutic compounds into everyday routines has become an attractive alternative for preventing hepatic diseases. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy for managing various carcinomas including HCC. Therefore, the 5th day of N. sativa can be used as a potential anticancer agent by inhibiting HDAC activity, as it is reported to have an important role in the management of oxidative stress. The bioactive compound of N. sativa, i.e. thymoquinone, also showed a good binding affinity with the HDAC protein (3MAX) with a stable interaction in an in silico study as compared to the standard drug (Trichostatin A) and thymol.Communicated by Ramaswamy H. Sarma.

The Use of Pain Severity and Its Impact as a Predictor for MRI Findings: A Cross-Sectional Study in Ta'if, Saudi Arabia.

Background Low back pain (LBP) is common and considerably impacts daily lives across all age groups. MRI is not frequently used as a first-line investigation for patients presenting with LBP, except in the presence of red-flag symptoms. This study aimed to use pain severity and its impact as a predictor for MRI findings to help physicians decide whether a patient needs an MRI. Methods This cross-sectional study was conducted at the outpatient clinic of the neurosurgery department. The questionnaire included demographic data of the patients, red-flag symptoms, and the Dallas Pain Questionnaire (DPQ). The primary physician then determines whether the patient should have an MRI appointment. Results The study included 100 patients with LBP, of which 71 had chronic LBP (CLBP). Out of these 71, an MRI was requested for 62, but only 26 had findings related to LBP. Regarding the impact of CLBP on daily activities as measured by the DPQ, there was a significant association between those whose CLBP affected their daily activities and the decision to request an MRI. However, no significant statistical association was found between the three other parameters of the DPQ and the primary physician's decision to request an MRI. Conclusion Concerning the use of the DPQ questionnaire to predict MRI findings in patients with CLBP, the study indicates that significant pain impact on the DPQ does not necessarily correlate with MRI findings related to LBP. This suggests that the DPQ evaluation tool has no advantage over a physician's clinical judgment.

Evaluation of the Knowledge of the Most Common Cancers Among Health Students at Jazan University, Saudi Arabia: A Cross-Sectional Study.

BACKGROUND: Cancer is a major public health problem worldwide, and medical students are expected to have adequate knowledge and awareness of the most common types of cancer. This study aimed to assess the cancer knowledge of medical students at Jazan University, Saudi Arabia, focusing on breast cancer (BC), prostate cancer (PC), cervical cancer (CC), and colorectal cancer (CRC). METHODS: This study employed a self-administered survey to evaluate both general and specialized knowledge of cancer types. A total of 321 medical students from different academic years participated in the study. The questionnaire used a scoring system where each correct answer was given one point, and each incorrect answer or "I don't know" response was given zero points. RESULTS: The overall knowledge scores were 18.75 ± 4.43 out of 28 (67%). The students had a good level of general knowledge about cancer (5.26 ± 1.44 out of 7, 75%) and breast cancer (5.47 ± 1.44 out of 7, 78%) and a moderate knowledge level of prostate cancer (2.83 ± 1.07 out of 4, 71%), cervical cancer (2.74 ± 1.53 out of 5, 55%), and colorectal cancer (2.55 ± 1.61 out of 5, 50%). There were significant differences in cancer knowledge by gender, academic year, and having a relative or friend with cancer. All types of cancer knowledge were positively and significantly correlated with each other. CONCLUSION: This study revealed the strengths and weaknesses of cancer knowledge among medical students at Jazan University, Saudi Arabia. The overall score for knowledge indicated a moderate level. The students had some knowledge about cancer prevention, detection, and treatment, but some gaps and misconceptions need to be addressed. More education and awareness programs are necessary to improve cancer literacy among students and promote healthy behaviors that can reduce cancer risk.

Exploring the tumor immune microenvironment in ovarian cancer: a way-out to the therapeutic roadmap.

INTRODUCTION: Despite cancer treatment strides, mortality due to ovarian cancer remains high globally. While immunotherapy has proven effective in treating cancers with low cure rates, it has limitations. Growing evidence suggests that both tumoral and non-tumoral components of the tumor immune microenvironment (TIME) play a significant role in cancer growth. Therefore, developing novel and focused therapy for ovarian cancer is critical. Studies indicate that TIME is involved in developing ovarian cancer, particularly genome-, transcriptome-, and proteome-wide studies. As a result, TIME may present a prospective therapeutic target for ovarian cancer patients. AREAS COVERED: We examined several TIME-targeting medicines and the connection between TIME and ovarian cancer. The key protagonists and events in the TIME and therapeutic strategies that explicitly target these events in ovarian cancer are discussed. EXPERT OPINION: We highlighted various targeted therapies against TIME in ovarian cancer, including anti-angiogenesis therapies and immune checkpoint inhibitors. While these therapies are in their infancy, they have shown promise in controlling ovarian cancer progression. The use of 'omics' technology is helping in better understanding of TIME in ovarian cancer and potentially identifying new therapeutic targets. TIME-targeted strategies could account for an additional treatment strategy when treating ovarian cancer.

A leaky gut contributes to postural dysfunction in patients with Alzheimer's disease.

Background: Postural dysfunction is a common problem in patients with Alzheimer's disease (AD) and may lead to functional dependency and increasing morbidity and mortality. However, the pathophysiology of postural dysfunction in AD patients remains poorly understood. Objectives: Elevated intestinal permeability is an underlying contributor to multiple diseases, including AD. We aimed to investigate the association of elevated intestinal permeability with postural dysfunction in AD patients. Design Setting Participants Measurements: We conducted a cross-sectional, observational study on older adults, including controls and AD patients. We investigated the associations of postural balance with plasma zonulin, a marker of elevated intestinal permeability in geriatric controls (n = 74) and patients with mild (n = 71) and moderate (n = 66) AD. We used a standardized physical performance battery to measure balance in supine, tandem, and semi-tandem positions. We also measured handgrip strength (HGS), and gait speed as markers of physical capacity. Results: AD patients exhibited lower balance scores, HGS, and gait speed and higher plasma zonulin than in controls (all p < 0.05). Plasma zonulin levels demonstrated significant areas under the curves in diagnosing poor balance in AD patients (all p < 0.05). Moderate AD was associated with lower balance and physical capacity, and higher zonulin than mild AD (ALL P < 0.05). Poor scores on balance scale were associated with higher expressions of markers of inflammation, oxidative stress, and muscle damage providing a mechanistic link between increased intestinal permeability and postural dysfunction in AD patients. Conclusion: The results of our study show that plasma zonulin measurement may be used to diagnose postural dysfunction in AD patients. The study is relevant to non-ambulant and/or comatose AD patients with postural dysfunction. Our findings also highlight the therapeutic potential of repairing the intestinal leak to improve postural control and reduce the risk of falls in AD patients.

Natural and synthetic drugs and formulations for intravaginal HPV clearance.

BACKGROUND: Except for a few preventative Human Papillomavirus (HPV) vaccines, there is currently no cure for HPV infection. There are a number of cutting-edge strategies and potent medications or herbal formulations that can be applied topically for early clearance of HPV infection before HPV DNA gets integrated into host cell genome. This is facilitated due to cervical cancer having distinct and well-recognized long precancerous stages. OBJECTIVES: This review aims to outline every possible medication and formulation, both natural and synthetic, that can be applied topically as intravaginal application to help remove HPV infection at an early precancerous stage. RESULTS: Several anti-HPV/HPV clearance compounds and formulations for high-grade lesions are undergoing clinical trials. However, the majority of compounds are still in the early stages of development and require additional research to become viable HPV clearance candidates. Synthetic drugs may be more promising because they may have a more targeted effect; however, they may also have significant adverse effects. On the other hand, natural medications are safer to use. They are less specific, but have minimal to no adverse effects. CONCLUSIONS: This article may serve as a valuable resource of information for managing and preventing precancerous carcinogenic HPV infections. Research could be directed toward developing candidate drugs to make evidence-based decisions about advancing them to clinical trials and, eventually, to the market for potential use in the prevention and control of cervical cancer, which is almost always preventable or even curable if detected early.

Synthesis, biological evaluation, and computational investigation of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates as potential larvicidal agents against Anopheles arabiensis.

Malaria is one of the most known vector-borne diseases caused by female Anopheles mosquito bites. According to WHO, about 247 million cases of malaria and 619,000 deaths were estimated worldwide in 2021, of which 95% of the cases and 96% of deaths occurred in the African region. Sadly, about 80% of all malaria deaths were of children under five years old. Despite the availability of different insecticides used to control this disease, the emergence of drug-resistant mosquitoes threatens public health. This, in turn, highlighted the need for new larvicidal agents that are effective at different larval life stages. This study aimed to identify novel larvicidal agents. To this end, a series of ethyl 2,4,6-trisubstituted-1,4-dihydropyrimidine-5-carboxylates 8a-i was synthesized using a three-step chemical synthetic approach via a Biginelli reaction employed as a key step. All title compounds were screened against Anopheles arabiensis to determine their larvicidal activities. Among them, two derivatives, ethyl 2-((4-bromophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8b and ethyl 2-((4-bromo-2-cyanophenyl)amino)-4-(4-fluorophenyl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate 8f, showed the highest larvicidal activity, with mortality of 94% and 91%, respectively, and emerged as potential larvicidal agents. In addition, computational studies, including molecular docking and molecular dynamics simulations, were carried out to investigate their mechanism of action. The computational results showed that acetylcholinesterase appears to be a plausible molecular target for their larvicidal property.Communicated by Ramaswamy H. Sarma.

Immunoinformatics Strategy to Develop a Novel Universal Multiple Epitope-Based COVID-19 Vaccine.

Currently available COVID vaccines are effective in reducing mortality and severity but do not prevent transmission of the virus or reinfection by the emerging SARS-CoV-2 variants. There is an obvious need for better and longer-lasting effective vaccines for various prevailing strains and the evolving SARS-CoV-2 virus, necessitating the development of a broad-spectrum vaccine that can be used to prevent infection by reducing both the transmission rate and re-infection. During the initial phases of SARS-CoV-2 infection, the nucleocapsid (N) protein is one of the most abundantly expressed proteins. Additionally, it has been identified as the most immunogenic protein of SARS-CoV-2. In this study, state-of-the-art bioinformatics techniques have been exploited to design novel multiple epitope vaccines using conserved regions of N proteins from prevalent strains of SARS-CoV-2 for the prediction of B- and T-cell epitopes. These epitopes were sorted based on their immunogenicity, antigenicity score, and toxicity. The most effective multi-epitope construct with possible immunogenic properties was created using epitope combinations. EAAAK, AAY, and GPGPG were used as linkers to connect epitopes. The developed vaccines have shown positive results in terms of overall population coverage and stimulation of the immune response. Potential expression of the chimeric protein construct was detected after it was cloned into the Pet28a/Cas9-cys vector for expression screening in Escherichia coli. The developed vaccine performed well in computer-based immune response simulation and covered a diverse allelic population worldwide. These computational findings are very encouraging for the further testing of our candidate vaccine, which could eventually aid in the control and prevention of SARS-CoV-2 infections globally.

Evaluation of the Knowledge, Attitudes, and Resulting Behavior Changes in Response to COVID-19 Among Students at the College of Applied Medical Sciences (CAMS), Jazan University, Saudi Arabia.

Background: The emergence of COVID-19 posed a threat to millions of lives worldwide. The pandemic impacts extended to affect people's psychological well-being, resulting in significant behavioural change. This study was designed to assess the knowledge regarding COVID-19 precautions among the College of Applied Medical Science students at Jazan University and to evaluate the general, psychosocial, and behavioral changes due to COVID-19. Methods: This is an observational study targeting 630 undergraduate students randomly selected during January 2020, using stratified random sampling. Data were collected using an online questionnaire. Linear regression models were used to evaluate the predictors of three outcome measures: knowledge, attitudes, and practice scores. Results: Knowledge of COVID-19 revealed that the students with correct answers ranged from 48.9 to 95%. Furthermore, significant gender differences are found regarding shortness of breath, fatigue, persistent chest discomfort, headache, and malaise (p < 0.05). Knowledge scores differed significantly across gender and academic level (p < 0.05) and so does attitude scores (p < 0.05). No significant difference was observed between practice scores according to socio-demographic background (p > 0.05). The linear regression model showed that females had significantly higher knowledge, attitudes, and practice scores (p < 0.05) as well as those within the 21-23 age group and above (p < 0.05). Students residing in urban and semi-urban places had significantly higher scores for knowledge, attitudes, and practice (p < 0.05). Conclusion: The results demonstrated moderate knowledge about COVID-19 among study participants, with significant differences between the responses of males and females and among the urban and rural populations. Outcomes suggest the need for interventions to bridge students' knowledge about COVID-19 and practice gaps. Students were concerned about basic life amenities and the inability to provide for their dear ones regarding behavioral changes.

Drug Overdose Patterns Among Emergency Department Patients at an Academic Hospital in Jeddah.

Background Drug overdose is a significant healthcare issue and remains a common phenomenon in the emergency department (ED). The incidents have increased over the last few years worldwide. There are a few studies about drug overdose in Saudi Arabia in general and Jeddah city specifically. We aimed to describe the pattern of drug overdoses in the emergency department at an academic hospital in Jeddah between 2015-2022. Methodology A retrospective record review study was done in 2022 at an academic hospital in Jeddah between 2015-2021, where charts were reviewed for all reported patients presenting to the ED with drug overdose, including all ages and both genders. A careful review of their medical records, data collection, and processing was done using Google Forms (Google, Mountain View, California) and Microsoft Excel (Microsoft, Redmond, Washington), respectively. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) version 26 software (IBM Inc. Armonk, New York). Results Seventy-eight patients were identified, meeting the criteria from the medical records. Most of the patients were children under 12 years of age. Most patients were clinically stable when they arrived at the emergency department. Gastrointestinal symptoms were the most common clinical presentations, followed by drowsiness, while some patients were non-symptomatic. Analgesics and nonsteroidal were the most common causes of drug overdose. Conclusion We concluded from this limited study that the most commonly used causative agent in drug overdoses was nonsteroidal and analgesics. Moreover, children younger than 12 years of age constituted the majority of drug overdose patients, and accidental overdose represented the majority of cases. Therefore, it is important to increase public awareness of proper child supervision and keep drugs out of children's reach. More research using larger and more representative data is needed to identify patterns of drug overdose in the community.

A Potential Link Between Visceral Obesity and Risk of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aß) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aß. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aß formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aß formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO.

NHS orthodontic services in Wales: orthodontic workforce distribution and primary care commissioned activity in 2021.

Objectives 1) To ascertain the volume of primary care orthodontic activity commissioned within Wales and compare this to the 12-year-old population; and 2) To ascertain the orthodontic workforce undertaking NHS orthodontic provision within Wales and their distribution.Methods Information was gathered between September and November 2021 from multiple sources within Wales, including: Freedom of Information requests; Welsh Government statistics; orthodontic professional networks; orthodontic provider websites; health boards (HBs); and directors of primary care/contracting/commissioning.Results The HBs had varying levels of orthodontic need and commissioned activity with a significant amount of cross border activity in South Wales. Overall, it indicated that Wales was only commissioning orthodontic activity to meet 76% of the annual orthodontic need. Overall, 97.9% of commissioned primary care orthodontic activity was being used to provide treatment for 9,500 patients per year. Furthermore, 112 GDC-registered clinicians provide NHS orthodontic care within Wales - 52 orthodontic specialists; 32 orthodontic therapists; 24 DwSIs; and 4 orthodontic trainees (StR 1-3). NHS orthodontic care is provided at 47 sites within Wales - 32 sites in the GDS/Specialist Practice, 6 sites within the CDS and 9 secondary care settings.Conclusions NHS commissioned primary care orthodontic activity within Wales is 76% of the potential orthodontic annual need. Primary care orthodontic services are efficient with 97.9% of commissioned activity being used to provide treatment. In total, 112 GDC-registered clinicians provide NHS orthodontic care across 47 sites within Wales, with 29.5% of clinicians working at multiple sites. The distribution of the orthodontic providers is predominately in areas of high population density, resulting in some rural communities being a significant distance from any orthodontic provider.

The impact of cycleanine in cancer research: a computational study.

Cancer is imposing a global health burden because of the steady increase in new cases. Moreover, current anticancer therapeutics are associated with many drawbacks, mainly the emergence of resistance and the severe adverse effects. Therefore, there is a continuous need for developing new anticancer agents with novel mechanisms of action and lower side effects. Natural products have been a rich source of anticancer medication. Cycleanine, a natural product, was reported to exert an antiproliferative effect on ovarian cancer cells by causing apoptosis through activation of caspases 3/7 and cleavage of poly (ADP-ribose) polymerase to form poly (ADP-ribose) polymerase-1 (PARP1). It is well-established that PARP1 is associated with carcinogenesis, and different PARP1 inhibitors are approved as anticancer drugs. In this study, the cytotoxic activity of cycleanine was computationally investigated to determine whether it is a PARP1 inhibitor or a caspase activator. Molecular docking and molecular dynamics (MD) simulations were utilized for this purpose. The results showed that cycleanine has a good binding affinity to PARP1; moreover, MD simulation showed that it forms a stable complex with the enzyme. Consequently, the results showed that cycleanine is a potential inhibitor of the PARP1 enzyme.