Clinical performance of AI-integrated risk assessment pooling reveals cost savings even at high prevalence of COVID-19.

Individual testing of samples is time- and cost-intensive, particularly during an ongoing pandemic. Better practical alternatives to individual testing can significantly decrease the burden of disease on the healthcare system. Herein, we presented the clinical validation of Segtnan™ on 3929 patients. Segtnan™ is available as a mobile application entailing an AI-integrated personalized risk assessment approach with a novel data-driven equation for pooling of biological samples. The AI was selected from a comparison between 15 machine learning classifiers (highest accuracy = 80.14%) and a feed-forward neural network with an accuracy of 81.38% in predicting the rRT-PCR test results based on a designed survey with minimal clinical questions. Furthermore, we derived a novel pool-size equation from the pooling data of 54 published original studies. The results demonstrated testing capacity increase of 750%, 60%, and 5% at prevalence rates of 0.05%, 22%, and 50%, respectively. Compared to Dorfman's method, our novel equation saved more tests significantly at high prevalence, i.e., 28% (p = 0.006), 40% (p = 0.00001), and 66% (p = 0.02). Lastly, we illustrated the feasibility of the Segtnan™ usage in clinically complex settings like emergency and psychiatric departments.

Quinazoline-chalcone hybrids as HDAC/EGFR dual inhibitors: Design, synthesis, mechanistic, and in-silico studies of potential anticancer activity against multiple myeloma.

Two new series of quinazoline-chalcone hybrids were designed, synthesized as histone deacetylase (HDAC)/epidermal growth factor receptor (EGFR) dual inhibitors, and screened in vitro against the NCI 60 human cancer cell line panel. The most potent derivative, compound 5e bearing a 3,4,5-trimethoxyphenyl chalcone moiety, showed the most effective growth inhibition value against the panel of NCI 60 human cancer cell lines. Thus, it was selected for further investigation for NCI 5 log doses. Interestingly, this trimethoxy-substituted analog inhibited the proliferation of Roswell Park Memorial Institute (RPMI)-8226 cells by 96%, at 10 µM with IC50 = 9.09 ± 0.34 µM and selectivity index = 7.19 against normal blood cells. To confirm the selectivity of this compound, it was evaluated against a panel of tyrosine kinase enzymes. Mechanistically, it successfully and selectively inhibited HDAC6, HDAC8, and EGFR with IC50 = 0.41 ± 0.015, 0.61 ± 0.027, and 0.09 ± 0.004 µM, respectively. Furthermore, the selected derivative induced apoptosis via the mitochondrial apoptotic pathway by raising the Bax/Bcl-2 ratio and activating caspases 3, 7, and 9. Also, the flow cytometry analysis of RPMI-8226 cells showed that the trimethoxy-substituted analog produced cell cycle arrest in the G1 and S phases at 55.82%. Finally, an in silico study was performed to explore the binding interaction of the most active compound within the zinc-containing binding site of HDAC6 and HDAC8.

Antioxidant and Anti-Aging Phytoconstituents from Faucaria tuberculosa: In Vitro and In Silico Studies.

Research targeting natural cosmeceuticals is now increasing due to the safety and/or limited side effects of natural products that are highly valued in cosmetology. Within a research program exploring botanical sources for valuable skincare antioxidant components, the current study investigated the phytochemical content and the biological potential of Faucaria tuberculosa. Phytochemical investigation of F. tuberculosa extract resulted in purification and characterization of six phytoconstituents, including a new one. The structure of the new constituent was elucidated as (-) catechin-(2→1',4→2')-phloroglucinol (4). The structural identity of all isolated compounds were confirmed on the basis of extensive physical and spectral (1D, 2D-NMR and HRESIMS) investigations. The ethanolic extract exhibits a rich content of total phenolics (TPC) and total flavonoids (TFC), estimated as 32 ± 0.034 mg GAE/g and 43 ± 0.004 mg RE/g, respectively. In addition, the antioxidant (ABTS and FRAP), antihyaluronidase and antityrosinase activities of all purified phytoconstituents were evaluated. The results noted (-) catechin-(2→1',4→2') phloroglucinol (4) and phloroglucinol (1) for their remarkable antioxidant activity, while isorhamnetin 3-O-rutinoside (3) and 3,5-dihydroxyphenyl ß-D-glucopyranoside (2) achieved the most potent inhibitory activity against tyrosinase (IC50 22.09 ± 0.7 µM and 29.96 ± 0.44 µM, respectively) and hyaluronidase enzymes (IC50 49.30 ± 1.57 µM and 62.58 ± 0.92, respectively) that remarkably exceeds the activity of the standard drugs kojic acid (IC50 = 65.21 ± 0.47 µM) and luteolin, (IC50 = 116.16 ± 1.69 µM), respectively. A molecular docking study of the two active compounds (3 and 2) highlighted their high potential to bind to the active sites of the two enzymes involved in the study.

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review.

Lung cancer is the second most common cause of morbidity and mortality among cancer types worldwide, with non-small cell lung cancer (NSCLC) representing the majority of most cases. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are among the most commonly used targeted therapy to treat NSCLC. Recent years have seen the evaluation of many synthetic EGFR TKIs, most of which showed therapeutic activity in pertinent models and were classified as first, second, and third-generation. The latest studies have concluded that their efficacy was also compromised by additional acquired mutations, including C797S. Because second- and third-generation EGFR TKIs are irreversible inhibitors, they are ineffective against C797S containing EGFR triple mutations (Del19/T790M/C797S and L858R/T790M/C797S). Therefore, there is an urgent unmet medical need to develop next-generation EGFR TKIs that selectively inhibit EGFR triple mutations via a non-irreversible mechanism. This review covers the fourth-generation EGFR-TKIs' most recent design with their essential binding interactions, the clinical difficulties, and the potential outcomes of treating patients with EGFR mutation C797S resistant to third-generation EGFR-TKIs was also discussed. Moreover, the utilization of various therapeutic strategies, including multi-targeting drugs and combination therapies, has also been reviewed.

Serum Cytokeratin 18 as a Potential Early Marker for Chemotherapy Response in Breast Cancer Patients: A Prospective Study.

BACKGROUND: Currently, it is well recognized that response to neoadjuvant chemotherapy is an important predictive factor for survival in breast cancer patients. However, it is still an area of research about which patient would respond to the neoadjuvant chemotherapy. METHODS: Serum CK18 levels were measured using ELISA from 52 newly diagnosed breast cancer patients, at presentation and after first cycle of neo-adjuvant chemotherapy. Pre- and post-treatment CK-18 levels were correlated with several clinical and pathological parameters. At the end of neoadjuvant treatment, changes in serum CK18 levels were correlated with tumors' response to therapy. RESULTS: Significant elevation of pre-chemotherapy CK18 level was observed in patients who had progressive disease compared to those who had complete or partial response to therapy (P=0.006 and P<0.001, respectively). Significantly higher CK18 levels were observed post-chemotherapy in complete and partial responders, in contrast to patients with stable or progressive disease (P=0.012% and P=0.001%, respectively). The percent of change was significantly higher in complete responders compared to patients who had stable or progressive disease (P=0.043% and P=0.045%, respectively). CONCLUSION: Our results suggest that patients with increasing CK18 level following chemotherapy are potential responders to their neoadjuvant protocol. Thus, the measurement of serum CK18 early in the treatment course could be a simple, noninvasive way to predict tumor response to neoadjuvant chemotherapy.

The diagnostic and prognostic utility of serum cystatin C and angiopoietin 2 in patients with liver cirrhosis complicated by acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) frequently affects patients with liver cirrhosis, diagnosed by changes in serum creatinine and urine output. This study aimed to evaluate the diagnostic and prognostic utility of serum cystatin C (Cys C) and angiopoietin 2 (Ang 2) in patients with liver cirrhosis complicated by AKI. METHODS: A total of 81 cirrhotic patients with AKI were included. AKI was diagnosed according to Kidney Disease Improving Global Outcomes criteria. All patients were assessed clinically and biochemically. Baseline serum Cys C and Ang 2 were assessed, and patients were prospectively followed-up to assess patients' and renal survival. RESULTS: Cys C significantly predicted AKI (p < 0.001). Ang 2 (≤179.7 pg/ml) was an independent predictor of mortality in multivariate analysis. Marked ascites and partial pressure of carbon dioxide ≤ 29 were significant predictors of nonrenal recovery. CONCLUSION: Cys C showed validity AKI diagnosis in cirrhotic patients while Ang 2 was an independent predictor of mortality.

Can residual kidney function affect quality of life and cognitive function in hemodialysis patients?

BACKGROUND: Residual kidney function (RKF) may provide many benefits to patients on permanent renal replacement therapy that are reflected in better control of biochemical parameters. In hemodialysis patients, quality of life (QOL) and cognitive function are often impaired. This study aimed to assess the predictors of RKF and its impact on QOL and cognitive function in chronic hemodialysis patients. PATIENTS AND METHODS: The study involved seventy-eight patients suffering from end-stage renal disease on regular hemodialysis. The patients were divided into two groups according to the presence or absence of RKF (24-hour urine volume ≥ 100 ml). Beside basic laboratory investigations, all patients were subjected to Kidney Disease Quality of Life-Short Form (KDQOL-SF) version 1.3 for assessing the quality of life and Montreal cognitive assessment (MoCA) score for assessing cognitive function. RESULTS: There was a significantly higher score for KDQOL domains and MoCA score in patients with RKF compared to patients without RKF. There was a significant positive correlation between RKF and both of MoCA score and the physical composite score (PCS) of QOL. Moreover, there were statistically significant positive correlations between the MoCA score and both PCS and mental composite score (MCS). On multivariate analysis, hemodialysis duration was the only predictor for RKF; whereas age was a significant predictor for PCS; and MoCA score could be significantly predicted by the measured RKF and patients' age. CONCLUSION: HD patients with maintained RKF had better QOL and cognitive function. The duration of HD and the age of the patients were found to be related to RKF and PCS in this study. RKF was associated with the cognitive performance of hemodialysis patients.

Characterization of Promising Cytotoxic Metabolites from Tabebuia guayacan Hemsl.: Computational Prediction and In Vitro Testing.

Genus Tabebuia is famous for its traditional uses and valuable phytoconstituents. Our previous investigation of Tabebuia species noted the promising anticancer activity of T. guayacan Hemsl. leaves extract, however, the mechanism underlying the observed anticancer activity is still unexplored. The current research was designed to explore the phytochemical content as well as to address the phytoconstituent(s) responsible for the recorded anticancer activity. Accordingly, sixteen compounds were isolated, and their structures were elucidated using different spectroscopic techniques. The drug-likeness of the isolated compounds, as well as their binding affinity with four anticancer drug target receptors: CDK-2/6, topoisomerase-1, and VEGFR-2, were evaluated. Additionally, the most promising compounds were in vitro evaluated for inhibitory activities against CDK-2/6 and VEGFR-2 enzymes using kinase assays method. Corosolic acid (3) and luteolin-7-O-ß-glucoside (16) were the most active inhibitors against CDK-2 (-13.44 kcal/mol) and topoisomerase 1 (-13.83 kcal/mol), respectively. Meanwhile, quercetin 3-O-ß-xyloside (10) scored the highest binding free energies against both CDK-6 (-16.23 kcal/mol) as well as against VEGFR-2 protein targets (-10.39 kcal/mol). Molecular dynamic simulation indicated that quercetin 3-O-ß-xyloside (10) exhibited the least fluctuations and deviations from the starting binding pose with RMSD (2.6 Å). Interestingly, in vitro testing results confirmed the potent activity of 10 (IC50 = 0.154 µg/mL) compared to IC50 = 0.159 µg/mL of the reference drug ribociclib. These findings suggest the three noted compounds (3, 10, and 16) for further in vivo anticancer studies.

Digalloyl Glycoside: A Potential Inhibitor of Trypanosomal PFK from Euphorbia abyssinica J.F. Gmel.

Human African trypanosomiasis is an endemic infectious disease caused by Trypanosoma brucei via the bite of tsetse-fly. Most of the drugs used for the treatment, e.g., Suramin, have shown several problems, including the high level of toxicity. Accordingly, the discovery of anti-trypanosomal drugs from natural sources has become an urgent requirement. In our previous study on the anti-trypanosomal potential of Euphorbia species, Euphorbia abyssinica displayed significant anti-trypanosomal activity. Therefore, a phytochemical investigation of the methanolic extract of E. abyssinica was carried out. Twelve compounds, including two triterpenes (1, 2); one sterol-glucoside (4); three ellagic acid derivatives (3, 9, 11); three gallic acid derivatives (5, 6, 10); and three flavonoids (7, 8, 12), were isolated. The structures of isolated compounds were determined through different spectroscopic techniques. Compound (10) was obtained for the first time from genus Euphorbia while all other compounds except compound (4), were firstly reported in E. abyssinica. Consequently, an in silico study was used to estimate the anti-trypanosomal activity of the isolated compounds. Several compounds displayed interesting activity where 1,6-di-O-galloyl-d-glucose (10) appeared as the most potent inhibitor of trypanosomal phosphofructokinase (PFK). Moreover, molecular dynamics (MD) simulations and ADMET calculations were performed for 1,6-di-O-galloyl-d-glucose. In conclusion, 1,6-di-O-galloyl-d-glucose revealed high binding free energy as well as desirable molecular dynamics and pharmacokinetic properties; therefore, it could be suggested for further in vitro and in vivo studies for trypanosomiasis.

The Relation of Serum Dehydroepiandrosterone Sulfate Level to Protein Energy Wasting in Hemodialysis Patients.

Protein-energy wasting (PEW) is a major risk for morbidity and mortality in hemodialysis (HD) patients. The change in the concentration of dehydroepiandrosterone sulfate (DHEA-S) may play a role in PEW. The aim of this work was to study the possible relationship between serum DHEA-S levels and various nutritional and inflammatory parameters in a cohort of HD patients. In total, 78 HD patients (47 males and 31 females) were included in this crosssectional observational study. In addition to taking their history, clinical examinations, and routine laboratory investigations, the nutritional status was assessed, and their serum DHEA-S was measured. Nutritional status was assessed by anthropometric measures, bioelectrical impedance analysis, malnutrition inflammation scores, and subjective global assessments. A diagnosis of malnutrition was made based on the recommendations of the International Society of Renal Nutrition and Metabolism. The relationship between DHEA-S and various nutritional parameters was analyzed. Eighteen patients (23.1%) suffered from PEW. Those with PEW had a longer duration of HD (P = 0.04), and lower serum levels of creatinine (P = 0.003), hemoglobin (P = 0.01), albumin (P <0.0001), cholesterol (P = 0.02), and DHEA-S (P = 0.01). Among the variables, serum DHEA-S levels were significant predictors of PEW in this cohort (odds ratio: 0.976; 95% confidence interval: 0.954-1.0; P = 0.04). PEW is frequently encountered in HD patients. Decreased serum DHEA-S levels were associated with PEW in male HD patients. Further studies are needed to assess the effect of hormone supplementation on this serious disorder in HD patients.

Adherence and Effectiveness of HBV Vaccination among Healthcare Workers in Egypt.

CONTEXT: Healthcare workers (HCWs) face a potential risk of acquiring different bloodborne pathogens, by occupational exposure to contaminated blood and body fluids. Hepatitis B vaccine is a safe, effective method of conferring long-term protection against HBV infection. AIMS: The study aimed to assess the adherence and effectiveness of HBV vaccination among HCWs at Gastrointestinal Surgical Center, Mansoura University, Egypt. SETTINGS AND DESIGN: A prospective descriptive study was carried out between June 2019 and December 2019 at Gastrointestinal Surgical Center, Mansoura University, Egypt. METHODS AND MATERIAL: All HCWs with anti-HBs levels below 10 mIU/mL were advised to receive 3 doses of recombinant HBV vaccine, at 0, 1, and 6 months. The anti-HBs levels were checked 3 months after the third dose of the HBV vaccine. STATISTICAL ANALYSIS USED: Data was analyzed using the Statistical Package of Social Science (SPSS) program for windows (version 16). RESULTS: A total of 442 healthcare providers were included. Most of them completed the 3 doses of the vaccine (81.7%), 10.2% refused the vaccine, while 0.9% and 7.2% received 1 and 2 doses, respectively. Odds of vaccination were the highest (88.1%, 273/310) among nurses (OR, 4.7; 95% CI, 2.6-5.2; P ≤ 0.001). The overall anti-HBs positivity of 97% (350/361) was observed. The main reasons for not being vaccinated included the fear of vaccine side effects 25/81 (30.9%) and lack of trust in the vaccine effectiveness 18/81 (22.2%). CONCLUSIONS: The outcome of the present study emphasizes the need to apply alternative and innovative measures to build a positive attitude toward the HBV vaccine among HCWs.

Comparison of Two Different Doses of Dexmedetomidine Added to Lignocaine in Patients Posted for Upper Limb Orthopedic Surgery Under Intravenous Regional Anaesthesia.

Background: Intravenous regional anaesthesia (IVRA) is a dependable and safe technique specific anatomical knowledge is not required. The present research aimed to evaluate the effects of dexmedetomidine in combination with lidocaine and to compare the onset of motor and sensory block and evaluate the postoperative analgesia, as well as the side effects. Methods: A prospective randomized controlled double-blinded study was conducted on 90 patients assigned randomly into three equal groups,. Group (I) received only lidocaine 2% 3mg/kg for Bier block. Group (II) received lidocaine 2% 3mg/kg with plus dexmedetomidine 0.25 µg/kg for Bier block. Group (III) received lidocaine 2% 3mg/kg plus dexmedetomidine 0.5 µg/kg for Bier block. Results: Postoperative VAS was lower in a statistically significant way in the group III patients than those in groups I and II and this followed a reduction in the analgesic requirement in group III. Conclusions: The combination of dexmedetomidine 0.5 µg/kg with lidocaine 2% (3mg/kg) when applying intravenous regional anaesthesia (IVRA) allowed improved postoperative analgesia. Furthermore, the combination reduced onset time, extended recovery time for sensory/motor blocks and did not affect the incidence of intra-operative and postoperative complications.

Quinazoline-Schiff base conjugates: in silico study and ADMET predictions as multi-target inhibitors of coronavirus (SARS-CoV-2) proteins.

The 2019 coronavirus (COVID-19) pandemic is spreading worldwide, with a dramatic increase in death without any effective therapeutic treatment available up to now. We previously reported quinazoline-trihydroxyphenyl Schiff base conjugates as phosphodiesterase 4B (PDE 4B) inhibitors (an enzyme that plays an essential role in the early stages of COVID-19 pneumonia). Additionally, the structural similarity between these conjugates and identified anti-severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2 flavonoids inspired us to in silico study their possible binding interactions with essential SARS-CoV-2 proteins. Thus, this study provides an insight into the potential bindings between quinazoline-Schiff base conjugates and SARS-CoV-2 proteins, including spike glycoprotein (SGp), main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), to offer an opportunity to find an effective therapy. Besides this, based on the role that COVID-19 plays in iron dysmetabolism, the conjugate trihydroxyphenyl moiety should be reconsidered as an iron chelator. Moreover, molecular dynamics simulations of quinazoline derivative Ic bound to the mentioned targets were carried out. Finally, ADMET calculations were performed for the studied compounds to predict their pharmacokinetic profiles.

Association between Plasma Dehydroepiandrosterone Sulfate and Carotid Intima-Media Thickness among Male and Female Patients with End-Stage Renal Disease on Hemodialysis.

BACKGROUND AND AIM: Serum dehydroepiandrosterone sulfate (DHEA-S) is known to be lower in chronic kidney disease (CKD) patients and in those with cardiac disease, and correlates with a poor cardiovascular outcome. This study aimed to assess the correlation between DHEA-S and carotid intima-media thickness (CIMT) as a predictor of cardiovascular disease in hemodialysis (HD) patients. METHODS: A total of 88 HD patients were included in this cross-sectional study. They included 53 male (group I) and 35 female patients (group II). In addition to conventional history taking, clinical examination, and routine laboratory investigations, serum DHEA-S and CIMT were measured for all patients. CIMT was measured using B-mode ultrasonography, and the mean of maximum CIMT was recorded. The 2 patient groups were further classified according to the level of DHEA-S. The correlation between serum DHEA-S and CIMT was studied. RESULTS: In male patients, CIMT and age were significantly higher in the group with low DHEA-S level (p = 0.003 and 0.001, respectively), while there was no significant difference in both parameters in females. A higher percentage of HCV-positive patients is present in the male group with low DHEA-S level (p = 0.009). Serum DHEA-S is significantly negatively correlated with CIMT in males (p = 0.003) but not in females, and has a significant negative correlation to age in both genders (p = 0.001 and 0.04, respectively). CONCLUSION: Endocrinal disturbance representing as lower serum DHEA-S is associated with increased CIMT, which is considered a predictor of cardiovascular disease in male HD patients, although it is largely explained by advancing age.