Improved Homology Model of the Human all-trans Retinoic Acid Metabolizing Enzyme CYP26A1.

A new CYP26A1 homology model was built based on the crystal structure of cyanobacterial CYP120A1. The model quality was examined for stereochemical accuracy, folding reliability, and absolute quality using a variety of different bioinformatics tools. Furthermore, the docking capabilities of the model were assessed by docking of the natural substrate all-trans-retinoic acid (atRA), and a group of known azole- and tetralone-based CYP26A1 inhibitors. The preferred binding pose of atRA suggests the (4S)-OH-atRA metabolite production, in agreement with recently available experimental data. The distances between the ligands and the heme group iron of the enzyme are in agreement with corresponding distances obtained for substrates and azole inhibitors for other cytochrome systems. The calculated theoretical binding energies agree with recently reported experimental data and show that the model is capable of discriminating between natural substrate, strong inhibitors (R116010 and R115866), and weak inhibitors (liarozole, fluconazole, tetralone derivatives).

Valproic acid as a potential inhibitor of Plasmodium falciparum histone deacetylase 1 (PfHDAC1): an in silico approach.

A new Plasmodium falciparum histone deacetylase1 (PfHDAC1) homology model was built based on the highest sequence identity available template human histone deacetylase 2 structure. The generated model was carefully evaluated for stereochemical accuracy, folding correctness and overall structure quality. All evaluations were acceptable and consistent. Docking a group of hydroxamic acid histone deacetylase inhibitors and valproic acid has shown binding poses that agree well with inhibitor-bound histone deacetylase-solved structural interactions. Docking affinity dG scores were in agreement with available experimental binding affinities. Further, enzyme-ligand complex stability and reliability were investigated by running 5-nanosecond molecular dynamics simulations. Thorough analysis of the simulation trajectories has shown that enzyme-ligand complexes were stable during the simulation period. Interestingly, the calculated theoretical binding energies of the docked hydroxamic acid inhibitors have shown that the model can discriminate between strong and weaker inhibitors and agrees well with the experimental affinities reported in the literature. The model and the docking methodology can be used in screening virtual libraries for PfHDAC1 inhibitors, since the docking scores have ranked ligands in accordance with experimental binding affinities. Valproic acid calculated theoretical binding energy suggests that it may inhibit PfHDAC1.

Knowledge, attitude, and practice of artificial intelligence applications in medicine among physicians in Sudan: a national cross-sectional survey.

Background and aims: Artificial intelligence (AI) has emerged as a rapidly developing tool within the medical landscape, globally aiding in diagnosis and healthcare management. However, its integration within healthcare systems remains varied across different regions. In Sudan, there exists a burgeoning interest in AI potential applications within medicine. This study aims to evaluate the knowledge, attitudes, and practices of AI applications in medicine among physicians in Sudan. Methods: The authors conducted a web-based survey cross-sectional analytical study using an online questionnaire-based survey regarding demographic details, knowledge, attitudes, and practice of AI distributing through various e-mail listings and social media platforms. A sample of 825 Physicians including doctors in Sudan with different ranks and specialties were selected using the convenient non-probability sampling technique. Result: Out of 825 Physicians, 666 (80.7%) of Physicians have previous knowledge about AI. However, only a small number 123 (14.9%) were taught about AI during their time in medical school, even fewer, just 120 (14.5%) had AI-related lessons in their training program. Regarding attitude, 675 (81.8%) agree that AI is very important in medicine, almost the same number, 681 (82.6%) support the idea of teaching AI in medical schools. Practically, 535 (64.8%) of doctors, think that should get special training in using AI tools in healthcare. Excitingly 651 (78.9%) of physicians are interested in working with AI in future. Based on different ranks of doctors toward AI; Medical Officers exhibited the highest proportion at (32.7%) of knowledge and understanding of AI concepts, followed by House Officers at (16.7%) (p=0.076); regarding attitude, Medical Officers demonstrated the highest (31.6%) favorable attitude, followed by House Officers at (17.5%) (p=0.229); In practice also, Medical Officer showed the highest portion (28.0%) among participants (p=0.129). Conclusion: While there is a positive attitude and some level of AI practice, there remains a considerable gap in knowledge that needs addressing.

Homology models of human all-trans retinoic acid metabolizing enzymes CYP26B1 and CYP26B1 spliced variant.

Homology models of CYP26B1 (cytochrome P450RAI2) and CYP26B1 spliced variant were derived using the crystal structure of cyanobacterial CYP120A1 as template for the model building. The quality of the homology models generated were carefully evaluated, and the natural substrate all-trans-retinoic acid (atRA), several tetralone-derived retinoic acid metabolizing blocking agents (RAMBAs), and a well-known potent inhibitor of CYP26B1 (R115866) were docked into the homology model of full-length cytochrome P450 26B1. The results show that in the model of the full-length CYP26B1, the protein is capable of distinguishing between the natural substrate (atRA), R115866, and the tetralone derivatives. The spliced variant of CYP26B1 model displays a reduced affinity for atRA compared to the full-length enzyme, in accordance with recently described experimental information.

Management of Diabetic Macular Edema: Guidelines from the Emirates Society of Ophthalmology.

In the United Arab Emirates, retinopathy has been shown to be present in 19% of the diabetic population, with diabetes identified in up to 40% of individuals aged over 55 years. Despite the prevalence of diabetic retinal diseases, there are no unified national guidelines on the management of diabetic macular edema (DME). These published guidelines are based on evidence taken from the literature and published trials of therapies, and consensus opinion of a representative expert panel with an interest in this condition, convened by the Emirates Society of Ophthalmology. The aim is to provide evidence-based, clinical guidance for the best management of different aspects of DME, with a special focus on vision-threatening diabetic retinopathy. Treatment should be initiated in patients with best-corrected visual acuity 20/30 or worse, and/or features of DME as seen on optical coherence tomography (OCT) with central retinal thickness (CRT) of at least 300 µm or in symptomatic patients with vision better than 20/25, and/or CRT less than 300 µm where there are OCT features consistent with center-involving macular edema. The treatment of DME is effective irrespective of glycated hemoglobin (HbA1c) level, and treatment must not be denied or delayed in order to optimize systemic parameters. All ophthalmic treatment options should be discussed with the patient for better compliance and expectations. Non-center-involving DME can be initially observed until progression toward the center is documented. Macular laser no longer has a primary role in center-involving DME, and anti-vascular endothelial growth factor (anti-VEGF) therapy should be considered as first-line treatment for all patients, unless contraindicated. If anti-VEGF is contraindicated, a steroid dexamethasone implant can be considered for first-line treatment. Recommendations for the treatment of DME in special circumstances and in relapsing and refractory DME are also discussed.

Update on functional imaging in the evaluation of diabetic foot infection.

Diabetic foot infection is a preventable complication of diabetes mellitus. It is an essential component of diabetic foot disease, which is characterised by a triad of neuropathy, ischaemia and infection. These factors may lead to foot ulceration, sepsis and amputation resulting in increased morbidity and poor quality of life. Confirming or excluding infection can be difficult especially when routine laboratory tests and plain radiographs are inconclusive. Early diagnosis and localization of diabetic foot infection is extremely important to institute timely, appropriate therapy. Structural imaging using computed tomography and magnetic resonance imaging all have individual applications towards the diagnostic workup of this condition but have their own limitations. Scintigraphic detection is based on physiochemical changes and hence provides a functional evaluation of bone pathology. We describe the evolution of functional nuclear medicine imaging including immunoscintigraphy in diabetic foot infection and highlight current applications of physiological 18-Fluoro-deoxyglucose positron emission tomography (18-FDG-PET) and computed tomography (18-FDG-PET/CT) in such patients. 18-FDG-PET/CT is a promising modality for imaging diabetic foot infection. Future studies will allow standardisation of technological details and options of 18-FDG-PET/CT interpretation in diabetic foot infection.

Prevalence and Potential Determinants of COVID-19 Vaccine Hesitancy and Resistance in Qatar: Results from a Nationally Representative Survey of Qatari Nationals and Migrants between December 2020 and January 2021.

Global COVID-19 pandemic containment necessitates understanding the risk of hesitance or resistance to vaccine uptake in different populations. The Middle East and North Africa currently lack vital representative vaccine hesitancy data. We conducted the first representative national phone survey among the adult population of Qatar, between December 2020 and January 2021, to estimate the prevalence and identify potential determinants of vaccine willingness: acceptance (strongly agree), resistance (strongly disagree), and hesitance (somewhat agree, neutral, somewhat disagree). Bivariate and multinomial logistic regression models estimated associations between willingness groups and fifteen variables. In the total sample, 42.7% (95% CI: 39.5-46.1) were accepting, 45.2% (95% CI: 41.9-48.4) hesitant, and 12.1% (95% CI: 10.1-14.4) resistant. Vaccine resistant compared with hesistant and accepting groups reported no endorsement source will increase vaccine confidence (58.9% vs. 5.6% vs. 0.2%, respectively). Female gender, Arab ethnicity, migrant status/type, and vaccine side-effects concerns were associated with hesitancy and resistance. COVID-19 related bereavement, infection, and quarantine status were not significantly associated with any willingness group. Absence of or lack of concern about contracting the virus was solely associated with resistance. COVID-19 vaccine resistance, hesitance, and side-effects concerns are high in Qatar's population compared with those globally. Urgent public health engagement should focus on women, Qataris (non-migrants), and those of Arab ethnicity.

Machine Learning Models Reveal the Importance of Clinical Biomarkers for the Diagnosis of Alzheimer's Disease.

Alzheimer's Disease (AD) is a neurodegenerative disease that causes complications with thinking capability, memory and behavior. AD is a major public health problem among the elderly in developed and developing countries. With the growth of AD around the world, there is a need to further expand our understanding of the roles different clinical measurements can have in the diagnosis of AD. In this work, we propose a machine learning-based technique to distinguish control subjects with no cognitive impairments, AD subjects, and subjects with mild cognitive impairment (MCI), often seen as precursors of AD. We utilized several machine learning (ML) techniques and found that Gradient Boosting Decision Trees achieved the highest performance above 84% classification accuracy. Also, we determined the importance of the features (clinical biomarkers) contributing to the proposed multi-class classification system. Further investigation on the biomarkers will pave the way to introduce better treatment plan for AD patients.

Potential Deoxycytidine Kinase Inhibitory Activity of Amaryllidaceae Alkaloids: An In Silico Approach.

BACKGROUND: Plants of the Amaryllidaceae family have been under intense scrutiny for the presence of a couple of alkaloidal secondary metabolites with endued cytotoxic activity, such as pancratistatin (1), 7-deoxypancratistatin (2), narciclasine (3), 7-deoxynarciclasine (4), trans-dihydronarciclasine (5), and 7-deoxy-trans-dihydronarciclasine (6). Nevertheless, preclinical evaluation of these alkaloids has been put on hold because of the limited quantity of materials available from isolation. AIM: To explore the underlying cytotoxic molecular mechanisms of the Amaryllidaceae alkaloids (1-6) and to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles using chemoinformatic tools. MATERIALS AND METHODS: AutoDock 4.0 software along with different in silico chemoinformatic tools, namely PharmMapper, Molinspiration, MetaPrint2D, and admetSAR servers, were used to assess the drugability of the Amaryllidaceae alkaloids (1-6). RESULTS: Deoxycytidine kinase (dCK) (PDB: 1P60) was predicted as a potential target with fitting score of 5.574. In silico molecular docking of (1-6) into dCK revealed good interactions, where interesting hydrogen bonds were observed with the amino acid residues-Gly-28 and Ser-35-located in the highly conserved P-loop motif. This motif plays a special role in dCK function. Contrary to (1), in silico pharmacokinetic results have shown good absorption and permeation and thus good oral bioavailability for (2-6). CONCLUSION: The in silico docking data have proposed that the reported cytotoxic activity of the Amaryllidaceae alkaloids (1-6) could be mediated through dCK inhibition. In addition, the ADMET profile of these alkaloids is promising and thus (1-6) could be candidates for future drug development.

Comparison of goblet cell density after femtosecond laser and mechanical microkeratome in LASIK.

PURPOSE: To study the effect of the LASIK procedure performed with a femtosecond laser and a manual microkeratome on the conjunctival goblet cell and epithelial cell populations. METHODS: In this prospective, nonrandomized, masked study, 64 eyes undergoing LASIK were included: 30 with the Moria M2 (M2) microkeratome and 34 with the IntraLase femtosecond laser (IL). The preoperative spherical equivalent was -2.0 +/- 3.8 D in the M2 group and -3.1+/- 3.1 D in the IL group. The time that the suction ring was applied on the eye was registered, and goblet cell density (GCD), epithelial cell morphology, and inflammatory cells were evaluated by conjunctival impression cytology, before and after the surgery. RESULTS: All the patients in both groups showed a decrease in GCD after LASIK (P < 0.001) that recovered after 6 months. At 1 week, 1 month, and 3 months, GCD was lower with IL than with M2 (P < 0.019, P < 0.001, and P < 0.024, respectively). The mean period that the suction ring was applied was longer in the IL than in the M2 group (P < 0.001). There was a high correlation between the decrease in GCD and the suction time (R = 0.8), and the preoperative spherical equivalent (R congruent with 0.4). CONCLUSIONS: Impression cytology showed a greater reduction in goblet cell populations after IL than after M2, probably because of the length of time that the suction ring exerted pressure on the conjunctiva. These changes in the goblet cells may contribute to the development of the ocular surface syndrome after LASIK procedures.

Simultaneous Determination and Stability Studies on Diminazene Diaceturate and Phenazone Using Developed Derivative Spectrophotometric Method.

This work presents UV first derivative spectrophotometry as a precise, accurate, and feasible method for simultaneous determination of diminazene diaceturate and phenazone in bulk and dosage forms. The absorbance values of diminazene diaceturate and phenazone aqueous mixture were obtained at 398 nm and 273 nm, respectively. The developed method was proved to be linear over the concentration ranges (2-10) µg/mL and (2.496-12.48) µg/mL for diminazene diaceturate and phenazone, respectively, with good correlation coefficients (not less than 0.997). The detection and quantitation limits were found to be (LOD = 0.63 and 0.48 µg/mL; LOQ = 1.92 and 1.47 µg/mL, resp.). The developed method was employed for stability studies of both drugs under different stress conditions. Diminazene diaceturate was prone to degrade at acidic pH via first-order kinetics. The degradation process was found to be temperature dependent with an activation energy of 7.48 kcal/mole. Photo-stability was also investigated for this drug.

Posterior vitreous detachment and retinal detachment after implantation of the Visian phakic implantable collamer lens.

INTRODUCTION: To evaluate the vitreoretinal complications in myopes after Visian implantable collamer lenses (ICL) implantation. MATERIALS AND METHODS: This is a retrospective, observational, non-comparative clinical study that evaluated 617 consecutive myopes who underwent ICL implantation at the Department of Refractive Surgery, Yemen Magrabi Hospital, Sana'a, Yemen between July 2006 and May 2010. Follow up ranged from 6 months to 40 months. Preoperative and postoperative patient evaluation included manifest and cycloplegic refractions, uncorrected (UCVA) and best spectacle-corrected visual acuity (BSCVA), slit-lamp biomicroscopy, intraocular pressure and dilated retinal examination. Investigations included corneal topography, central corneal thickness, anterior chamber depth and white to white diameter. Retinal diseases and complications were recorded and analyzed preoperatively and postoperatively. RESULTS: Preoperatively, 61 (9.9%) eyes had posterior segment pathology requiring prophylactic laser photocoagulation. One eye developed spontaneous rhegmatogenous retinal detachment (RRD), one eye developed traumatic retinal detachment and two eyes required laser treatment postoperatively. The overall retinal detachment rate post-ICL was 0.32%. CONCLUSIONS: Posterior segment complications are rare after ICL implantation but dilated vitreoretinal assessment is important before and after the procedure. Patients with suspicious retinal lesions need a comprehensive vitreoretinal evaluation by a retinal specialist. If a patient develops floaters or blurry vision he/she requires further assessment by a vitreoretinal specialist.

Phacoviscocanalostomy in pseudoexfoliation glaucoma versus primary open-angle glaucoma.

OBJECTIVE: To compare the outcome of phacoviscocanalostomy in pseudoexfoliation glaucoma (PEXG) versus that in primary open-angle glaucoma (POAG). DESIGN: Prospective comparative study. PARTICIPANTS: Sixty eyes of 60 patients who underwent phacoviscocanalostomy for cataract and medically uncontrolled PEXG (30 eyes) or POAG (30 eyes). METHODS: Success rate was based on intraocular pressure (IOP) reduction and need for antiglaucoma medication. Visual acuity (VA) and complication rates were secondary outcomes. RESULTS: The mean follow-up was 19.7 months (range, 12-36 months). The mean IOP values in both groups were significantly less than the preoperative values at all postoperative intervals (p < 0.001). From 1 month onward, the decrease in IOP was more dramatic in PEXG eyes than in POAG eyes (p < 0.05). At last visit, the mean percentage of IOP reduction was 49.7% in the PEXG group and 30.9% in the POAG group. All study eyes required decreased antiglaucoma medications and showed improved VA postoperatively. Transient complications included Descemet's membrane microperforations, macroperforation, zonular dehiscence, and postoperative IOP spike. No eyes developed trabeculectomy-type bleb, hyphema, fibrin exudation, or bleb-related complications. CONCLUSIONS: Phacoviscocanalostomy achieved excellent IOP control and VA improvement in both PEXG and POAG groups. PEXG demonstrated greater IOP reduction and fewer postoperative medications than POAG. The complication rate was low and did not affect surgical outcome. Phacoviscocanalostomy can be an effective and safe surgical alternative to phacotrabeculectomy in both groups of patients.

Reasons for not performing keratorefractive surgery in patients seeking refractive surgery in a hospital-based cohort in "yemen".

BACKGROUND: To determine and analyze the reasons why keratorefractive surgery, laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) were not performed in patients who presented for refractive surgery consultation. MATERIALS AND METHODS: A retrospective observational study was performed between January 2006 and December 2007 in the Yemen Magrabi Hospital. The case records of 2,091 consecutive new patients who presented for refractive surgery were reviewed. Information from the pre-operative ophthalmic examination, such as refractive error, corneal topography and visual acuity, were analyzed. The reasons for not performing LASIK and PRK in the cases that were rejected were recorded and analyzed. RESULTS: In this cohort, 1,660 (79.4%) patients were advised to have LASIK or PRK from the 2,091 patients examined. LASIK and PRK were not advised in 431 (21%) patients. The most common reasons for not performing the surgery were high myopia >-11.00 Diopters (19%), keratoconus (18%), suboptimal central corneal thickness (15%), cataract (12%) and keratoconus suspect (forme fruste keratoconus) (10%). CONCLUSION: Patients who requested keratorefractive surgery have a variety of problems and warrant comprehensive attention to selection criteria on the part of the surgeon. Corneal topographies and pachymetry of refractive surgery candidates need to be read cautiously. High-refractive error, keratoconus and insufficient corneal thickness were found to be the leading reasons for not performing keratorefractive surgery in this study.

Vitreoretinal complications in Yemeni patients with keratorefractive surgery.

OBJECTIVE: To evaluate vitreoretinal complications in patients undergoing laser keratorefractive surgery. METHODS: This retrospective observational non-comparative clinical study was carried out between June 2005 and March 2008, and included 4691 consecutive laser keratorefractive surgery procedures for 2480 patients performed in the Department of Refractive Surgery, Yemen Magrabi Hospital, Sana'a, Yemen. Patients were followed up for 12-36 months. The preoperative patient evaluation included manifest and cycloplegic refractions, uncorrected visual acuity, best spectacle-corrected visual acuity, slit-lamp biomicroscopy, and dilated vitreoretinal assessment. Retinal diseases were recorded and analyzed during the preoperative and postoperative care. RESULTS: Sixty-five (1.4%) of the 4691 eyes had posterior segment pathology requiring intervention. In the preoperative assessment, 57 eyes had prophylactic laser photocoagulation for retinal lesions. Seven eyes developed posterior vitreous detachment postoperatively, and 4 of these required prophylactic laser therapy for lattice degeneration and retinal breaks. Two eyes (0.04%) developed rhegmatogenous retinal detachment, which occurred spontaneously. One patient developed cystoid macular edema in both eyes. CONCLUSION: Most complications are related to the refractive outcome or to corneal and anterior segment injury. Posterior segment complications are rare, but dilated vitreoretinal assessment is important before and after laser keratorefractive procedures. Patients with suspicious retinal lesions need a comprehensive vitreoretinal evaluation by a retinal specialist.

Intraoperative and early postoperative complications of laser in situ keratomileusis in Yemen.

OBJECTIVE: To determine the intraoperative and early postoperative complications and visual outcome of laser in situ keratomileusis (LASIK) surgery for the correction of myopia. METHODS: The first 2000 consecutive myopic LASIK eyes operated at the Department of Refractive Surgery, Yemen Magrabi Hospital, Sana'a, Yemen from June 2005 to October 2006 were the study group. This is a retrospective observational noncomparative clinical study. The preoperative and postoperative spherical equivalent, best-corrected visual acuity, and corneal status was recorded. The intraoperative and early postoperative complications were reviewed. RESULTS: There were 15 (0.8%) intraoperative microkeratome-related flap complications recorded namely, buttonhole (5), incomplete cut (3), thin flap (3), epithelial defect (3) and eccentric flap (1). There were 4 (0.2%) non-keratome related surgical events of inability to obtain sufficient suction. There were 46 (2.3%) first-day postoperative complications. Nine eyes required repositioning of the flap for macro-striae (5), or displaced flap (4). Four needed washing under the flap for severe deep lamellar keratitis (2), and gauze debris under the flap (2). Laser enhancement was carried out in 28 eyes (1.4%), and uncorrected visual acuity of 20/40 or better was attained in 96.9% of treated eyes. Twenty-four eyes (1.3%) lost more than 2 lines of best-corrected vision. CONCLUSION: The LASIK is a safe and effective procedure for the correction of myopia. A small number of patients may suffer complications, most of which are not serious, and rarely lead to visual loss of more than 2 Snellen lines.

Changes in keratoconic corneas after intracorneal ring segment explantation and reimplantation.

PURPOSE: To evaluate the outcome and potential reversibility of the changes induced in keratoconic eyes after intracorneal ring segment explantation. DESIGN: Retrospective, interventional case series. PARTICIPANTS: Five eyes of 4 patients who underwent uneventful implantation of one or two intracorneal ring segment segments for the correction of clear corneal keratoconus and who required explantation of one segment due to complications. MAIN OUTCOME MEASURES: Visual acuity, refraction, keratometric readings, and corneal topography. The follow-up was up to 1 year from the primary implantation procedure in all cases. RESULTS: Explantation was performed easily in all cases without intraoperative or postoperative complications. The segments were extracted due to migration and local melting. The visual, refractive, and topographic map findings regressed to approximate the original clinical situation before segment implantation. CONCLUSIONS: Intracorneal ring segments are safely and easily explanted from keratoconic eyes. Most of the visual, refractive, and topographic findings return to near the preimplantation levels.