sEMG-based automatic characterization of swallowed materials.

Monitoring of ingestive activities is critically important for managing the health and wellness of individuals with various health conditions, including the elderly, diabetics, and individuals seeking better weight control. Monitoring swallowing events can be an ideal surrogate for developing streamlined methods for effective monitoring and quantification of eating or drinking events. Swallowing is an essential process for maintaining life. This seemingly simple process is the result of coordinated actions of several muscles and nerves in a complex fashion. In this study, we introduce automated methods for the detection and quantification of various eating and drinking activities. Wireless surface electromyography (sEMG) was used to detect chewing and swallowing from sEMG signals obtained from the sternocleidomastoid muscle, in addition to signals obtained from a wrist-mounted IMU sensor. A total of 4675 swallows were collected from 55 participants in the study. Multiple methods were employed to estimate bolus volumes in the case of fluid intake, including regression and classification models. Among the tested models, neural networks-based regression achieved an R2 of 0.88 and a root mean squared error of 0.2 (minimum bolus volume was 10 ml). Convolutional neural networks-based classification (when considering each bolus volume as a separate class) achieved an accuracy of over 99% using random cross-validation and around 66% using cross-subject validation. Multiple classification methods were also used for solid bolus type detection, including SVM and decision trees (DT), which achieved an accuracy above 99% with random validation and above 94% in cross-subject validation. Finally, regression models with both random and cross-subject validation were used for estimating the solid bolus volume with an R2 value that approached 1 and root mean squared error values as low as 0.00037 (minimum solid bolus weight was 3 gm). These reported results lay the foundation for a cost-effective and non-invasive method for monitoring swallowing activities which can be extremely beneficial in managing various chronic health conditions, such as diabetes and obesity.

N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Novel Disperse Dyes Based on Enaminones: Synthesis, Dyeing Performance on Polyester Fabrics, and Potential Biological Activities.

1-(3-aryl)-3-(dimethylamino)prop-2-en-1-one (enaminones) derivatives and the diazonium salt of para-chloroaniline were used to synthesize several novel disperse azo dyes with high yield and the use of an environmentally friendly approach. At 100 and 130 °C, we dyed polyester fabrics using the new synthesized disperse dyes. At various temperatures, the dyed fabrics' color intensity was assessed. The results we obtained showed that dyeing utilizing a high temperature method at 130 °C was enhanced than dyeing utilizing a low temperature method at 100 °C. Reusing dye baths once or twice was a way to achieve two goals at the same time. The first was obtaining a dyed product at no cost, and the second was a way to treat the wastewater of dyeing bath effluents and reuse it again. Good results were obtained for the fastness characteristics of polyester dyed with disperse dyes. When the disperse dyes were tested against certain types of microbes and cancer cells, they demonstrated good and encouraging findings for the potential to be used as antioxidants and antimicrobial agents.

Utility of diffusion tensor imaging in differentiating benign from malignant hepatic focal lesions.

OBJECTIVES: To assess the diagnostic accuracy of diffusion tensor imaging (DTI) in the characterization of hepatic focal lesions (HFLs) and compare it to diffusion-weighted imaging (DWI). METHODS: Prospective analysis was done for 49 patients (23 male and 26 female) with 74 HFLs who underwent dynamic MRI, DWI, and DTI. Apparent diffusion coefficient (ADC) values from DWI, fractional anisotropy (FA) values, and mean diffusivity (MD) values from DTI were measured by two independent radiologists. HFLs were classified into benign and malignant HFLs; the latter were subdivided into HCC and non-HCC lesions. Binary logistic regression was performed to analyze the associations between the DTI parameters and the distinction of malignant lesions. RESULTS: The ADC, MD, and FA at cutoff values of ≤ 1.17 × 10-3 mm2/s, ≤ 1.71 × 10-3 mm2/s, and > 0.29, respectively, are excellent discriminators for differentiating malignant and benign HFLs. The mean ADC and MD values of hemangiomas were significantly higher than HCC and non-HCC malignant lesions. In contrast, the mean FA values of hemangiomas were significantly lower than those of non-HCC malignant lesions and HCCs. The ADC and MD were very good discriminators at cutoff values of > 1.03 × 10-3 mm2/s and > 1.12 × 10-3 mm2/s, respectively. The FA at a cutoff value > 0.38 is an excellent discriminator for HCC versus non-HCC malignant lesions. Only FA value > 0.38 was a statistically significant independent predictor of HCC versus non-HCC lesions among the three parameters. There was an excellent inter-observer agreement with ICC > 0.9. CONCLUSION: MD and FA of DTI are non-invasive, very good, and excellent discriminators superior to ADC measured by DWI for the differentiation of HFLs. KEY POINTS: • The ADC, MD, and FA at cutoff values of ≤ 1.17 × 10-3 mm2/s, ≤ 1.71 × 10-3 mm2/s, and > 0.29, respectively, are excellent discriminators for differentiating malignant and benign HFLs. • The mean ADC and MD values of hemangiomas were significantly higher than those of HCC and non-HCC malignant lesions. In contrast, the mean FA values of hemangiomas were significantly lower than those of non-HCC malignant lesions and HCCs, respectively. • Multivariate regression analysis revealed that only FA value > 0.38 was a statistically significant independent predictor of HCC vs. non-HCC lesions. A lesion with FA > 0.38 has 34 times higher odds of being HCC rather than non-HCC lesions.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

Triazoloquinoxalines-based DNA intercalators-Topo II inhibitors: design, synthesis, docking, ADMET and anti-proliferative evaluations.

Sixteen [1, 2, 4]triazolo[4,3-a]quinoxalines as DNA intercalators-Topo II inhibitors have been prepared and their anticancer actions evaluated towards three cancer cell lines. The new compounds affected on high percentage of MCF-7. Derivatives 7e, 7c and 7b exhibited the highest anticancer activities. Their activities were higher than that of doxorubicin. Molecular docking studies showed that the HBA present in the chromophore, the substituted distal phenyl moiety and the extended linkers enable our derivatives to act as DNA binders. Also, the pyrazoline moiety formed six H-bonds and improved affinities with DNA active site. Finally, 7e, 7c and 7b exhibited the highest DNA affinities and act as traditional intercalators of DNA. The most active derivatives 7e, 7c, 7b, 7g and 6e were subjected to evaluate their Topo II inhibition and DNA binding actions. Derivative 7e exhibited the highest binding affinity. It intercalates DNA at IC50 = 29.06 µM. Moreover, compound 7e potently intercalates DNA at an IC50 value of 31.24 µM. Finally, compound 7e demonstrated the most potent Topo II inhibitor at a value of 0.890 µM. Compound 7c exhibited an equipotent IC50 value (0.940 µM) to that of doxorubicin. Furthermore, derivatives 7b, 7c, 7e and 7g displayed a high ADMET profile.

Relationship of the pulmonary disease severity scoring with thromboembolic complications in COVID-19.

PURPOSE: To correlate thromboembolic (TE) complications secondary to COVID-19 with the extent of the pulmonary parenchymal disease using CT severity scores and other comorbidities. METHODS: In total, 185 patients with COVID-19 and suspected thromboembolic complications were classified into two groups based on the presence or absence of thromboembolic complications. Thromboembolic complications were categorized based on location. Chest CT severity scoring system was used to assess the pulmonary parenchymal disease severity in all patients. Based into severity scores, patients were categorized into three groups (mild, moderate, and sever disease). RESULTS: The final study cohort consisted of 171 patients (99 male and 72 female) after excluding 14 patients with non-diagnostic CT pulmonary angiography. The TE group included 53 patients with a mean age of 55.1 ± 7.1, while the non-TE group included 118 patients with a mean age of 52.9 ± 10.8. Patients with BMI > 30 kg/m2 or having a history of smoking and HTN were found more frequently in the TE group (p < 0.05). Patients admitted to ICU were significantly higher in the TE group (p < 0.001). There was statistically significant difference (p = 0.002) in chest CT-SS between the TE group (22.8 ± 11.4) and non-TE group (17.6 ± 10.7). The percentage of severe parenchymal disease in the TE group was significantly higher compared to the non-TE group (p < 0.05). Severe parenchymal disease, BMI > 30 kg/m2, smoking, and HTN had a higher and more significant odds ratio for developing TE complications. CONCLUSION: The present data suggest that severe pulmonary parenchymal disease secondary to COVID-19 is associated with a higher incidence of thromboembolic complications.

Diagnostic performance of chest computed tomography for COVID-19 in children: a systematic review and meta-analysis of clinical and computed tomography features in 987 patients.

Purpose: The outbreak of a new coronavirus is still spreading worldwide, affecting children and adults. However, COVID-19 in children shows distinctive characteristics in clinical and radiological presentation. We aimed to assess the diagnostic performance of chest CT and clarify the clinicoradiological CT features of COVID-19 among children with COVID-19. Material and methods: Adhering to PRISMA-DTA guidelines, we searched databases (PubMed, Google Scholar, and Web of Science) to identify relevant articles. The search keywords were: "Chest CT" AND "COVID-19" OR "coronavirus" OR "SARS-COV-2" AND "Children" OR "Pediatric". Published reports providing clinical and imaging findings of paediatric COVID-19 were included. Results: Twenty-eight studies were included, with 987 patients. Most of the patients were symptomatic (76.9%; 95% CI: 69.2-84.7%), with fever being the most frequent manifestation (64%; 95% CI: 58.0-71.2%). Only 2.3% of the cases were critical, and mortality was reported in one case. The proportion of COVID-19 detected by chest CT among children is relatively high (658/987), with ground-glass opacity (GGO) being the most prevalent feature (52.5%; 95% CI: 40.5-64.7%). The pooled sensitivity of chest CT in all patients was 67%; however, it was different between symptomatic and asymptomatic patients (71% and 33%, respectively). The pooled specificity was (67%), which was calculated after considering the symptomatic PCR-positive patients as the gold standard. Conclusions: Chest CT showed moderate pooled sensitivity and specificity among symptomatic children with COVID-19 and low sensitivity among asymptomatic children. This means that CT is not to be used as a screening tool or for confirmation of the diagnosis in children and should be reserved for specific clinical situations.

Coupled metamaterial optical resonators for infrared emissivity spectrum modulation.

We study the absorptivity of coupled metamaterial resonators in the mid-infrared range. We consider resonators supporting either a bright mode or a dark mode, introducing an additional degree of freedom for spectral modulation relative to bright modes alone. In a dark-bright coupled resonator system, we demonstrate tunable spectral splitting by changing the separation between resonators. We show via coupled mode theory that resonator separation can be mapped to coupling constant. We further introduce a dark-dark coupled resonator system, which gives rise to an emissive bright mode only in the presence of inter-resonator coupling. The dark-dark system yields a broadband emissivity that decays to zero exponentially with resonator separation, providing a design method for strong thermal emissivity control.

Design and implementation of the European-Mediterranean Postgraduate Programme on Organ Donation and Transplantation (EMPODaT) for Middle East/North Africa countries.

This prospective study reports the design and results obtained after the EMPODaT project implementation. This project was funded by the Tempus programme of the European Commission with the objective to implement a common postgraduate programme on organ donation and transplantation (ODT) in six selected universities from Middle East/North Africa (MENA) countries (Egypt, Lebanon and Morocco). The consortium, coordinated by the University of Barcelona, included universities from Spain, Germany, Sweden and France. The first phase of the project was to perform an analysis of the current situation in the beneficiary countries, including existing training programmes on ODT, Internet connection, digital facilities and competences, training needs, and ODT activity and accreditation requirements. A total of 90 healthcare postgraduate students participated in the 1-year training programme (30 ECTS academic credits). The methodology was based on e-learning modules and face-to-face courses in English and French. Training activities were evaluated through pre- and post-tests, self-assessment activities and evaluation charts. Quality was assessed through questionnaires and semi-structured interviews. The project results on a reproducible and innovative international postgraduate programme, improvement of knowledge, satisfaction of the participants and confirms the need on professionalizing the activity as the cornerstone to ensure organ transplantation self-sufficiency in MENA countries.

Design, Synthesis, biological Evaluation, and molecular docking studies of novel Pyrazolo[3,4-d]Pyrimidine derivative scaffolds as potent EGFR inhibitors and cell apoptosis inducers.

A series of novel hybrid pyrazolo[3,4-d]pyramidine derivatives was designed and chemically synthesized in useful yields. The synthesized compounds were structurally characterized by the usual techniques. All the new synthesized compounds were biologically screened in vitro for their antiproliferative activities against a panel of four cancer cell lines, namely HepG-2, MCF-7, HCT-116, and Hela. The results of cytotoxic evaluation indicated that compound 14d was appeared to be the most prominent broad-spectrum cytotoxic activity and significantly more potent than sorafenib with IC50 values of 4.28, 5.18, 3.97, and 9.85 µM against four cell lines (HePG2, Hela, HCT-116 and MCF-7). In addition, compound 15 was displayed promising antiproliferative effect against all tested cell lines with IC50 value less than 11 µM compared with sorafenib as a control drug. Besides, structurally pharmacophoric features indicated that pyrazolo[3,4-d]pyrimidine scaffold having an amide linker and substituted with phenyl moiety at the 5-position was more potent than those possessing azomethine methyl, azomethine proton and carbomethene linkers, which lead to significant decrease in antiproliferative activity. The most potent compounds were further selected and evaluated for their activities against epidermal growth factor receptor (EGFR) kinase inhibitors according to homogenous time resolved fluorescence (HTRF) assay. The most potent compound 14d exhibited the most promising inhibitory activity against EGFRWT with IC50 value of 56.02 ± 1.38 µM compared with gefitinib as control drug with IC50 value of 41.79 ± 1.07 µM. Moreover, the inhibition of cell cycle progression and induction of apoptosis in the A549 cell line at G2/M and pre-G1 phases of cell cycle might contribute to cancer treatment that evaluated by Annexin V-FITC/PI double staining detection method. Finally, molecular docking studies were conducted to investigate that probable binding conformations of these anticancer agents and ADME properties were calculated to predict pharmacokinetics and toxic properties of the target compounds.

Design, synthesis, and molecular docking studies of new [1,2,4]triazolo[4,3-a]quinoxaline derivatives as potential A2B receptor antagonists.

Many shreds of evidence have recently correlated A2B receptor antagonism with anticancer activity. Hence, the search for an efficient A2B antagonist may help in the development of a new chemotherapeutic agent. In this article, 23 new derivatives of [1,2,4]triazolo[4,3-a]quinoxaline were designed and synthesized and its structures were confirmed by different spectral data and elemental analyses. The results of cytotoxic evaluation of these compounds showed six promising active derivatives with IC50 values ranging from 1.9 to 6.4 µM on MDA-MB 231 cell line. Additionally, molecular docking for all synthesized compounds was performed to predict their binding affinity toward the homology model of A2B receptor as a proposed mode of their cytotoxic activity. Results of molecular docking were strongly correlated with those of the cytotoxic study. Finally, structure activity relationship analyses of the new compounds were explored.

Thoracic Anesthesia during the COVID-19 Pandemic: 2021 Updated Recommendations by the European Association of Cardiothoracic Anaesthesiology and Intensive Care (EACTAIC) Thoracic Subspecialty Committee.

The novel coronavirus pandemic has radically changed the landscape of normal surgical practice. Lifesaving cancer surgery, however, remains a clinical priority, and there is an increasing need to fully define the optimal oncologic management of patients with varying stages of lung cancer, allowing prioritization of which thoracic procedures should be performed in the current era. Healthcare providers and managers should not ignore the risk of a bimodal peak of mortality in patients with lung cancer; an imminent spike due to mortality from acute coronavirus disease 2019 (COVID-19) infection, and a secondary peak reflecting an excess of cancer-related mortality among patients whose treatments were deemed less urgent, delayed, or cancelled. The European Association of Cardiothoracic Anaesthesiology and Intensive Care Thoracic Anesthesia Subspecialty group has considered these challenges and developed an updated set of expert recommendations concerning the infectious period, timing of surgery, vaccination, preoperative screening and evaluation, airway management, and ventilation of thoracic surgical patients during the COVID-19 pandemic.

Pharmacophore-linked pyrazolo[3,4-d]pyrimidines as EGFR-TK inhibitors: Synthesis, anticancer evaluation, pharmacokinetics, and in silico mechanistic studies.

Targeting the epidermal growth factor receptors (EGFRs) with small inhibitor molecules has been validated as a potential therapeutic strategy in cancer therapy. Pyrazolo[3,4-d]pyrimidine is a versatile scaffold that has been exploited for developing potential anticancer agents. On the basis of fragment-based drug discovery, considering the essential pharmacophoric features of potent EGFR tyrosine kinase (TK) inhibitors, herein, we report the design and synthesis of new hybrid molecules of the pyrazolo[3,4-d]pyrimidine scaffold linked with diverse pharmacophoric fragments with reported anticancer potential. These fragments include hydrazone, indoline-2-one, phthalimide, thiourea, oxadiazole, pyrazole, and dihydropyrazole. The synthesized molecules were evaluated for their anticancer activity against the human breast cancer cell line, MCF-7. The obtained results revealed comparable antitumor activity with that of the reference drugs doxorubicin and toceranib. Docking studies were performed along with EGFR-TK and ADMET profiling studies. The results of the docking studies showed the ability of the designed compounds to interact with key residues of the EGFR-TK through a number of covalent and noncovalent interactions. The obtained activity of compound 25 (IC50 = 2.89 µM) suggested that it may serve as a lead for further optimization and drug development.

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Correlation of radiographic parameters with clinical correction in idiopathic congenital talipes equinovarus undergoing Ponseti treatment.

PURPOSE: Idiopathic congenital talipes equinovarus is the most commonly encountered congenital deformity of the foot. Ponseti technique of manipulation is the treatment of choice. The Pirani classification is a reliable scoring system for clinical evaluation of clubfeet. The role of radiographic parameters in the evaluation and treatment of clubfeet is still controversial. The aim of this study was to evaluate the correlation of radiological parameters with clinical correction in patients with idiopathic clubfeet undergoing correction using Ponseti method. METHODS: Between March 2018 and March 2019, 42 feet in 27 patients with idiopathic clubfeet were treated in our hospital. We used the Pirani scoring system for clinical evaluation. Anteroposterior and lateral views of the feet were taken before and after correction and at the last follow-up. The anteroposterior view was evaluated for the talocalcaneal angle and talo-first metatarsal angle, while the lateral view was only evaluated for the talocalcaneal angle. RESULTS: Twelve were boys (44.4%), and 15 were girls (55.6%). The deformity was bilateral in 15 patients (55.6%) and unilateral in 12 patients (44.4%). The average age was three months. According to the Pirani score, the mean Pirani Total score was 4.4 before correction and reduced to 0.4 after correction. The mean talocalcaneal angle in anteroposterior and lateral views was 15.1° and 7.8° before correction, increased to 32.7° and 31.8° after correction, respectively. The mean talocalcaneal index increased from 23.2 before correction to 64.5 after correction. The mean talo-first metatarsal angle in anteroposterior view improved from 25.7° before correction to - 1.6° after correction. The relation between the differences in Pirani scores before and after correction and the differences in measured radiographic parameters before and after correction revealed a statistically significant correlation. CONCLUSION: Radiographic parameters showed a statistically significant correlation with the clinical outcome. Thus, evaluation of clubfeet correction treated by Ponseti technique can rely mainly on clinical scores with limited utilization of radiological assessment.

Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses.

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1-CLN8, CLN10-CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

Antimicrobial screening and pharmacokinetic profiling of novel phenyl-[1,2,4]triazolo[4,3-a]quinoxaline analogues targeting DHFR and E. coli DNA gyrase B.

A novel series of [1,2,4]triazolo[4,3-a]quinoxaline derivatives of different heteroaromatization members were synthesized. The newly synthesized molecules were explored for their potential antimicrobial activities against a panel of pathogenic organisms. Among these derivatives, the chalcone compound 6e with a methoxy substituent exhibited broad potent antimicrobial activity against most of the bacterial and fungal strains. Furthermore, the analysis of the SAR disclosed that the linker and terminal aromatic fragments perform critical roles in exerting antibacterial activity. The molecular docking calculations were executed on two of the most bacterial targets, ATP-binding sites of DNA gyrase B, and the folate-binding site of DHFR enzymes. The results presented good binding data to the pockets of both enzymes showing different linkers contributions through the hydrogen-bonding and aromatic stacking interactions that stabilize the compounds in their pockets taking 6e compound as representative of most active analogs. In addition, good pharmacokinetic profiling data for the 6e compound was obtained and compared to reference drugs. Accordingly, our findings suggest that [1,2,4]triazolo[4,3-a]quinoxaline scaffold is an interesting precursor for the design of potent antimicrobial agents with multitarget inhibition.

Age and Tumor Location Predict Survival in Nonmetastatic Osteosarcoma in Upper Egypt.

AIM: The aims of this study were to assess survival outcome of pediatric patients with localized osteosarcoma of the extremities in Upper Egypt, identify factors of prognostic significance for survival, and to determine factors predictive of surgical methods used in these patients, as well as developing a clinical model for risk prediction. PATIENTS AND METHODS: A retrospective analysis of data assembled from medical records of 30 pediatric patients with a histologically verified nonmetastatic osteosarcoma of the extremities treated at South Egypt Cancer Institute with a unified chemotherapy protocol between January 2001 and December 2015 was carried out. Prognostic factors were determined using univariable and multivariable methods. A model for surgical outcomes in these patients based on the baseline clinical factors, and the parameters predictive of their tumor response to chemotherapy, was developed. RESULTS: With a median follow-up of 63 months for the study population, the estimates for event-free survival and overall survival (OS) at 3 and 5 years were 69.5% and 79% and 65.2% and 65.3%, respectively. Age 16 years or above was independently associated with both worse metastasis-free survival (hazard ratio [HR]=6.05, 95% confidence interval [CI]: 1.43-25.6, P=0.015) and OS (HR=7.9, 95% CI: 1.71-36.2, P=0.008). In the multivariable analysis, a proximal location within the limb gained a statistical significance to be independently associated with worse OS (HR=2.4, 95% CI: 1.13-22.1, P=0.003). Poor response to chemotherapy was marginally associated with worse metastasis-free survival (HR=4.9, 95% CI: 1.02-23.8, P=0.047) only in the univariable analysis. The patients found to be more likely to undergo an amputation surgery (odds ratio=14.1, 95% CI: 1.34-149.4, P=0.028) were those in whom a tumor was poorly responding to chemotherapy. CONCLUSION: In Upper Egypt, despite the reasonable survival outcomes in nonmetastatic osteosarcoma, a relatively high limb amputation rate has been encountered. The development of a clinical prediction model for future planning of possible outcome improvement in these patients, however, is still feasible.

Randomized controlled open-label study of the effect of vitamin E supplementation on fertility in clomiphene citrate-resistant polycystic ovary syndrome.

AIM: To evaluate the effect of vitamin E on ovulation and pregnancy in women with clomiphene citrate (CC)-resistant polycystic ovary syndrome (PCOS). METHODS: A prospective, randomized, controlled, open label study was conducted on women with CC-resistant PCOS. Patients were randomized, to either control group (n = 30), who received metformin 500 mg thrice daily, in addition to 150 mg/day CC for 5 days starting from day 3 of menstruation for three menstruation cycles, or vitamin E group (n = 30) who received vitamin E 1500 IU/day for the whole study period in addition to metformin and CC with the same previous regimen. The primary outcome was cumulative ovulation rate, while secondary outcomes were pregnancy rate, serum midluteal progesterone, mean follicular diameter, number of dominant follicles and endometrial thickness. RESULTS: Ovulation was reported in 57 (64.8%) of 88 cycles in the control group and 63 (73.3%) of 86 cycles in the vitamin E group (P = 0.227), while pregnancy was reported in 4 (4.5%) of 88 cycles in the control group and 6 (7%) of 86 cycles in the vitamin E group (P = 0.491).There were nonsignificant differences between groups regarding serum midluteal progesterone, number of dominant follicles and mean follicular diameter. Endometrial thickness was significantly higher in the vitamin E group compared to the control group. CONCLUSION: The findings of this trial do not support the hypothesis that vitamin E may increase the ovulation and pregnancy rates in women with clomiphene citrate-resistant PCOS.