Feasibility Analysis of ECG-Based pH Estimation for Asphyxia Detection in Neonates.

Birth asphyxia is a potential cause of death that is also associated with acute and chronic morbidities. The traditional and immediate approach for monitoring birth asphyxia (i.e., arterial blood gas analysis) is highly invasive and intermittent. Additionally, alternative noninvasive approaches such as pulse oximeters can be problematic, due to the possibility of false and erroneous measurements. Therefore, further research is needed to explore alternative noninvasive and accurate monitoring methods for asphyxiated neonates. This study aims to investigate the prominent ECG features based on pH estimation that could potentially be used to explore the noninvasive, accurate, and continuous monitoring of asphyxiated neonates. The dataset used contained 274 segments of ECG and pH values recorded simultaneously. After preprocessing the data, principal component analysis and the Pan-Tompkins algorithm were used for each segment to determine the most significant ECG cycle and to compute the ECG features. Descriptive statistics were performed to describe the main properties of the processed dataset. A Kruskal-Wallis nonparametric test was then used to analyze differences between the asphyxiated and non-asphyxiated groups. Finally, a Dunn-Sidák post hoc test was used for individual comparison among the mean ranks of all groups. The findings of this study showed that ECG features (T/QRS, T Amplitude, Tslope, Tslope/T, Tslope/|T|, HR, QT, and QTc) based on pH estimation differed significantly (p < 0.05) in asphyxiated neonates. All these key ECG features were also found to be significantly different between the two groups.

Corrigendum to "A narrative review of approved and emerging anti-obesity medications" [Saudi Pharm. J. 31(10) (2023) 101757].

[This corrects the article DOI: 10.1016/j.jsps.2023.101757.].

Identification of Potent Inhibitors Targeting EGFR and HER3 for Effective Treatment of Chemoresistance in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Despite the existence of various therapeutic options, NSCLC is still a major health concern due to its aggressive nature and high mutation rate. Consequently, HER3 has been selected as a target protein along with EGFR because of its limited tyrosine kinase activity and ability to activate PI3/AKT pathway responsible for therapy failure. We herein used a BioSolveIT suite to identify potent inhibitors of EGFR and HER3. The schematic process involves screening of databases for constructing compound library comprising of 903 synthetic compounds (602 for EGFR and 301 for HER3) followed by pharmacophore modeling. The best docked poses of compounds with the druggable binding site of respective proteins were selected according to pharmacophore designed by SeeSAR version 12.1.0. Subsequently, preclinical analysis was performed via an online server SwissADME and potent inhibitors were selected. Compound 4k and 4m were the most potent inhibitors of EGFR while 7x effectively inhibited the binding site of HER3. The binding energies of 4k, 4m, and 7x were -7.7, -6.3 and -5.7 kcal/mol, respectively. Collectively, 4k, 4m and 7x showed favorable interactions with the most druggable binding sites of their respective proteins. Finally, in silico pre-clinical testing by SwissADME validated the non-toxic nature of compounds 4k, 4m and 7x providing a promising treatment option for chemoresistant NSCLC.

Identification of Potential Inhibitors for the Treatment of Alkaptonuria Using an Integrated In Silico Computational Strategy.

Alkaptonuria (AKU) is a rare genetic autosomal recessive disorder characterized by elevated serum levels of homogentisic acid (HGA). In this disease, tyrosine metabolism is interrupted because of the alterations in homogentisate dioxygenase (HGD) gene. The patient suffers from ochronosis, fractures, and tendon ruptures. To date, no medicine has been approved for the treatment of AKU. However, physiotherapy and strong painkillers are administered to help mitigate the condition. Recently, nitisinone, an FDA-approved drug for type 1 tyrosinemia, has been given to AKU patients in some countries and has shown encouraging results in reducing the disease progression. However, this drug is not the targeted treatment for AKU, and causes keratopathy. Therefore, the foremost aim of this study is the identification of potent and druggable inhibitors of AKU with no or minimal side effects by targeting 4-hydroxyphenylpyruvate dioxygenase. To achieve our goal, we have performed computational modelling using BioSolveIT suit. The library of ligands for molecular docking was acquired by fragment replacement of reference molecules by ReCore. Subsequently, the hits were screened on the basis of estimated affinities, and their pharmacokinetic properties were evaluated using SwissADME. Afterward, the interactions between target and ligands were investigated using Discovery Studio. Ultimately, compounds c and f were identified as potent inhibitors of 4-hydroxyphenylpyruvate dioxygenase.

Ultrasound-Assisted Synthesis of Piperidinyl-Quinoline Acylhydrazones as New Anti-Alzheimer's Agents: Assessment of Cholinesterase Inhibitory Profile, Molecular Docking Analysis, and Drug-like Properties.

Alzheimer's disease (AD) is one of the progressive neurological disorders and the main cause of dementia all over the world. The multifactorial nature of Alzheimer's disease is a reason for the lack of effective drugs as well as a basis for the development of new structural leads. In addition, the appalling side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with the marketed treatment modalities and many failed clinical trials significantly limit the use of drugs and alarm for a detailed understanding of disease heterogeneity and the development of preventive and multifaceted remedial approach desperately. With this motivation, we herein report a diverse series of piperidinyl-quinoline acylhydrazone therapeutics as selective as well as potent inhibitors of cholinesterase enzymes. Ultrasound-assisted conjugation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes (4a,b) and (un)substituted aromatic acid hydrazides (7a-m) provided facile access to target compounds (8a-m and 9a-j) in 4-6 min in excellent yields. The structures were fully established using spectroscopic techniques such as FTIR, 1H- and 13C NMR, and purity was estimated using elemental analysis. The synthesized compounds were investigated for their cholinesterase inhibitory potential. In vitro enzymatic studies revealed potent and selective inhibitors of AChE and BuChE. Compound 8c showed remarkable results and emerged as a lead candidate for the inhibition of AChE with an IC50 value of 5.3 ± 0.51 µM. The inhibitory strength of the optimal compound was 3-fold higher compared to neostigmine (IC50 = 16.3 ± 1.12 µM). Compound 8g exhibited the highest potency and inhibited the BuChE selectively with an IC50 value of 1.31 ± 0.05 µM. Several compounds, such as 8a-c, also displayed dual inhibitory strength, and acquired data were superior to the standard drugs. In vitro results were further supported by molecular docking analysis, where potent compounds revealed various important interactions with the key amino acid residues in the active site of both enzymes. Molecular dynamics simulation data, as well as physicochemical properties of the lead compounds, supported the identified class of hybrid compounds as a promising avenue for the discovery and development of new molecules for multifactorial diseases, such as Alzheimer's disease (AD).

A narrative review of approved and emerging anti-obesity medications.

Background: Recently, many drugs have been approved for halting overweight and obesity-few types of research shifted to using Anti-obesity medications (AOM) solely for well-being and shape-keeping. Objective: This narrative review's objective was to explore the use of AOM in relation to their medical indications, efficacy, and cardiovascular safety. Methods and materials: We have conducted a narrative review of the literature on approved/non-approved AOM used for obesity and overweight. We have shed light on the emerging trials of therapies and evolving remedies. Results: Recently, there has been an enormous change in the use of AOM with high consumption that deserves extensive surveillance for the long-term consequences and impact on social, mental, and physical health. Nearly six AOMs and combined therapy are approved by the Food and Drug Administration. The recent guidelines for obesity management have shifted the focus from weight loss to goals that the patient considers essential and toward targeting the root cause of obesity. Conclusion: The use of AOM increased enormously despite its sometimes-dubious safety and ineffectiveness. The public and medical professionals should be vigilant to the real-world benefits of anti-obesity drugs and their achieved effectiveness with an improved safety profile.

Accessing Artificial Intelligence for Fetus Health Status Using Hybrid Deep Learning Algorithm (AlexNet-SVM) on Cardiotocographic Data.

Artificial intelligence is serving as an impetus in digital health, clinical support, and health informatics for an informed patient's outcome. Previous studies only consider classification accuracies of cardiotocographic (CTG) datasets and disregard computational time, which is a relevant parameter in a clinical environment. This paper proposes a modified deep neural algorithm to classify untapped pathological and suspicious CTG recordings with the desired time complexity. In our newly developed classification algorithm, AlexNet architecture is merged with support vector machines (SVMs) at the fully connected layers to reduce time complexity. We used an open-source UCI (Machine Learning Repository) dataset of cardiotocographic (CTG) recordings. We divided 2126 CTG recordings into 3 classes (Normal, Pathological, and Suspected), including 23 attributes that were dynamically programmed and fed to our algorithm. We employed a deep transfer learning (TL) mechanism to transfer prelearned features to our model. To reduce time complexity, we implemented a strategy wherein layers in the convolutional base were partially trained to leave others in the frozen states. We used an ADAM optimizer for the optimization of hyperparameters. The presented algorithm also outperforms the leading architectures (RCNNs, ResNet, DenseNet, and GoogleNet) with respect to real-time accuracies, sensitivities, and specificities of 99.72%, 96.67%, and 99.6%, respectively, making it a viable candidate for clinical settings after real-time validation.

Cardioprotective Effect of Rumex vesicarius Linn. Leaf Extract against Catecholamine-Induced Cardiotoxicity.

Rumex vesicarius (L.) is a folklore medicinal herb that has been used for centuries to cure cardiovascular diseases. The present work was carefully designed to ascertain the pharmacological basis for R. vesicarius's therapeutic efficacy in cardiovascular diseases, as well as the underlying mechanism. In the ex vivo investigation, the aqueous-methanolic leaf extract of R. vesicarius was shown to have endothelium-dependent vasorelaxant effects in rabbit aorta tissue preparations, and its hypotensive responses were quantified by pressure and force transducers coupled to the Power Lab Data Acquisition System. Furthermore, when rabbits were subjected to adrenaline-induced myocardial infarction, R. vesicarius demonstrated cardioprotective characteristics. In contrast to the intoxicated group, the myocardial infarction model showed lower ALP, CK-MB, CRP, LDH, ALT, troponin, and AST levels (p > 0.005−0.000), as well as edema, necrosis, apoptosis, inflammatory cell enrolment, and necrosis. R. vesicarius exhibited significant antioxidant activity and delayed noradrenaline-induced platelet aggregation. Its cardioprotective, anticoagulant, and vasorelaxant properties in both investigations (in vivo and ex vivo) are mediated through partial endothelium-dependent, NO and calcium channel blockade mediated vasorelaxation. The minimizing of adrenaline, oxidative stress, and tissue damage demonstrate its therapeutic efficacy in cardiovascular diseases.

Pharmacological Validation for the Folklore Use of Ipomoea nil against Asthma: In Vivo and In Vitro Evaluation.

Oxidative stress is the key factor that strengthens free radical generation which stimulates lung inflammation. The aim was to explore antioxidant, bronchodilatory along with anti-asthmatic potential of folkloric plants and the aqueous methanolic crude extract of Ipomoea nil (In.Cr) seeds which may demonstrate as more potent, economically affordable, having an improved antioxidant profile and providing evidence as exclusive therapeutic agents in respiratory pharmacology. In vitro antioxidant temperament was executed by DPPH, TFC, TPC and HPLC in addition to enzyme inhibition (cholinesterase) analysis; a bronchodilator assay on rabbit's trachea as well as in vivo OVA-induced allergic asthmatic activity was performed on mice. In vitro analysis of 1,1-Diphenyl-2-picrylhydrazyl radical (DPPH) expressed as % inhibition 86.28 ± 0.25 with IC50 17.22 ± 0.56 mol/L, TPC 115.5 ± 1.02 mg GAE/g of dry sample, TFC 50.44 ± 1.06 mg QE/g dry weight of sample, inhibition in cholinesterase levels for acetyl and butyryl with IC50 (0.60 ± 0.67 and 1.5 ± 0.04 mol/L) in comparison with standard 0.06 ± 0.002 and 0.30 ± 0.003, respectively, while HPLC characterization of In.Cr confirmed the existence with identification as well as quantification of various polyphenolics and flavonoids i.e., gallic acid, vanillic acid, chlorogenic acid, quercetin, kaempferol and others. However, oral gavage of In.Cr at different doses in rabbits showed a better brochodilation profile as compared to carbachol and K+-induced bronchospasm. More significant (p < 0.01) reduction in OVA-induced allergic hyper-responses i.e., inflammatory cells grade, antibody IgE as well as altered IFN-α in airways were observed at three different doses of In.Cr. It can be concluded that sound mechanistic basis i.e., the existence of antioxidants: various phenolic and flavonoids, calcium antagonist(s) as well as enzymes' inhibition profile, validates folkloric consumptions of this traditionally used plant to treat ailments of respiration.

Antioxidant and Gastroprotective Activity of Suaeda fruticosa Forssk. Ex J.F.Gmel.

Suaeda fruticosa Forssk. Ex J.F.Gmel is traditionally used for inflammatory and digestive disorders, as a carminative, and for diarrhea. This plant is widely distributed in Asia, Africa, and the Mediterranean region. Aqueous methanolic extract of S. fruticosa (Sf.Cr) was prepared and screened for phytoconstituents through qualitative and GC-MS analysis. Quantification of total phenolic and flavonoid contents was performed, while antioxidant capacity was determined by DPPH, CUPRAC, FRAP, and ABTS assays. The gastroprotective activity was assessed in an ethanol-induced ulcer model. Gastric secretory parameters and macroscopic ulcerated lesions were analyzed and scored for ulcer severity. After scoring, histopathology was performed, and gastric mucus contents were determined. Oral pre-treatment of Sf.Cr demonstrated significant gastroprotection. The gastric ulcer severity score and ulcer index were reduced while the %-inhibition of ulcer was increased dose-dependently. The Sf.Cr significantly elevated the pH of gastric juice, while a decrease in total acidity and gastric juice volume was observed. Histopathology demonstrated less oedema and neutrophil infiltration in gastric mucosa of rats pre-treated with the Sf.Cr in comparison to ethanol-intoxicated animals. Furthermore, the gastric mucus contents were increased as determined by alcian blue binding. Sf.Cr showed marked gastroprotective activity, which can be attributed to antioxidant, antisecretory, and cytoprotective effects.

Influence of Health Literacy on Medication Adherence Among Elderly Females With Type 2 Diabetes in Pakistan.

Health literacy is how well the patients are able to attain, deal with, and understand basic health information. This is particularly important when it comes to comprehending prescribed medication instructions. To improve the communication strategies for health-care professionals during patient counseling, our study aimed to assess the influence of health literacy and medication adherence in older patients. The objectives of the study were to evaluate associations that occur between the level of health literacy and medication adherence. This study used a convenience sampling method of females (older than 60 years) attending the diabetic clinic in two hospital settings (N = 524). All study participants filled three validated questionnaires: these were the Literacy Assessment for Diabetes, the Diabetes Numeracy Test, and a modified Brief Adherence Rating Scale. To assess the spectrum of health literacy differences, we used χ2 analysis and linear regression analysis. Individuals with adequate health literacy were more likely to remember to take their medications compared with those with inadequate health literacy, χ2(4) = 11.6, p = .04. Adequate literacy level study participants were more likely to not change the dose of their medications without medical advice (12.3%) compared with those individuals with inadequate health literacy (2.8%), χ2(4) = 11.13, p = .03. The results in our study suggest that health-care professionals should focus on appropriate communication attuned to the assessment of health literacy levels particularly in older female patients when discussing medication instructions.

Adverse Drug Reaction Reporting Practices Among United Arab Emirates Pharmacists and Prescribers.

Background: Underreporting of adverse drug reactions (ADRs) has placed a heavy financial burden on health care resources worldwide. Realizing the importance of proper ADR reporting is paramount for implementing better patient care. Objective: This study was designed to assess knowledge, attitude, and practice (KAP) of ADR reporting among United Arab Emirates (UAE) health care professionals to clarify their present strategies and identify steps to avoid underreporting. Methods: A self-administered cross-sectional questionnaire was designed and randomly distributed to different health care personnel (n = 150). All participants were briefly informed about the aim of the study and given sufficient time to respond. The responses were collected over 6 months. The data were statistically analyzed for each reporter category (community pharmacist, hospital pharmacist, and doctors) using the chi-square test. Results: We found that 81%, 83%, and 83.3% of doctors, community pharmacists, and hospital pharmacists, respectively, were not aware of the existence of a reporting center and 56%, 60%, and 72% were not aware of a reporting procedure. Poor ADR reporting practices were shown by responders; only 19%, 14%, and 12.1% of doctors, community pharmacists, and hospital pharmacists reported ADRs. Conclusion: This study showed poor KAP results among health care professionals. Proper educational intervention strategies should be established in different health care settings for better patient care. With proper guidance, objectives in all health care settings should be targeted to positively change the concept of health care to consider ADR reporting as a common accepted daily routine practice.

In-silico characterization of GABAT protein found in gut-brain axis associated bacteria of healthy individuals and multiple sclerosis patients.

Background: Multiple sclerosis (MS) is a neurodegenerative disease characterized by inflammation and demyelination of neurons. There is evidence to suggest that level of a neurotransmitter gamma-aminobutyric acid (GABA), due to the degradation by γ-aminobutyric acid transaminase (GABAT), is reduced in certain areas of the brain in MS patients. MS is always accompanied by gut bacteria dysbiosis. In healthy individuals, Faecalibacterium sp. while in MS patients A. calcoaceticus, Clostridium sp. and S. typhimurium are found abundantly. Although all these microbes produce GABAT but only in MS patients this enzyme significantly degrades GABA. Objective: Present study is an attempt to characterize the GABAT protein sequences of these bacteria. Methodology: Sequences of GABAT protein were retrieved from Uniprot database. Sequences were analyzed by Protparam, Gneg-mPLoc, SOSUI, PFP-FunDSeqE, Pepwheel program, PROTEUS and Alphafold and SAVES servers, MEME suite and HDOCK server. Results: In healthy individuals gastrointestinal tract (GIT) bacteria, GABAT protein was present in inner-membrane with α helix content (61 and 62%) and ß sheet content (5%), 4-helical cytokines functional domains. It has greater number of B-cell epitopes and more complex 3D configuration as compared to MS patients GIT bacterial enzymes. Conclusion: Present study might enable us to modify the GABAT encoding gene and enzyme through site-directed mutagenesis in pathogenic bacteria thus reducing their potential of causing MS.

Fetal monitoring technologies for the detection of intrapartum hypoxia - challenges and opportunities.

Intrapartum fetal hypoxia is related to long-term morbidity and mortality of the fetus and the mother. Fetal surveillance is extremely important to minimize the adverse outcomes arising from fetal hypoxia during labour. Several methods have been used in current clinical practice to monitor fetal well-being. For instance, biophysical technologies including cardiotocography, ST-analysis adjunct to cardiotocography, and Doppler ultrasound are used for intrapartum fetal monitoring. However, these technologies result in a high false-positive rate and increased obstetric interventions during labour. Alternatively, biochemical-based technologies including fetal scalp blood sampling and fetal pulse oximetry are used to identify metabolic acidosis and oxygen deprivation resulting from fetal hypoxia. These technologies neither improve clinical outcomes nor reduce unnecessary interventions during labour. Also, there is a need to link the physiological changes during fetal hypoxia to fetal monitoring technologies. The objective of this article is to assess the clinical background of fetal hypoxia and to review existing monitoring technologies for the detection and monitoring of fetal hypoxia. A comprehensive review has been made to predict fetal hypoxia using computational and machine-learning algorithms. The detection of more specific biomarkers or new sensing technologies is also reviewed which may help in the enhancement of the reliability of continuous fetal monitoring and may result in the accurate detection of intrapartum fetal hypoxia.

Molecular and metabolic characterization of petroleum hydrocarbons degrading Bacillus cereus.

Hydrocarbon constituents of petroleum are persistent, bioaccumulated, and bio-magnified in living tissues, transported to longer distances, and exert hazardous effects on human health and the ecosystem. Bioaugmentation with microorganisms like bacteria is an emerging approach that can mitigate the toxins from environmental sources. The present study was initiated to target the petroleum-contaminated soil of gasoline stations situated in Lahore. Petroleum degrading bacteria were isolated by serial dilution method followed by growth analysis, biochemical and molecular characterization, removal efficiency estimation, metabolites extraction, and GC-MS of the metabolites. Molecular analysis identified the bacterium as Bacillus cereus, which exhibited maximum growth at 72 hours and removed 75% petroleum. Biochemical characterization via the Remel RapID™ ONE panel system showed positive results for arginine dehydrolase (ADH), ornithine decarboxylase (ODC), lysine decarboxylase (LDC), o-nitrophenyl-ß-D-galactosidase (ONPG), p-nitrophenyl-ß-D-glucosidase (ßGLU), p-nitrophenyl-N-acetyl-ß-D-glucosaminidase (NAG), malonate (MAL), adonitol fermentation (ADON), and tryptophane utilization (IND). GC-MS-based metabolic profiling identified alcohols (methyl alcohol, o-, p- and m-cresols, catechol, and 3-methyl catechol), aldehydes (methanone, acetaldehyde, and m-tolualdehyde), carboxylic acid (methanoic acid, cis,cis-muconic acid, cyclohexane carboxylic acid and benzoic acid), conjugate bases of carboxylic acids (benzoate, cis,cis-muconate, 4-hydroxybenzoate, and pyruvate) and cycloalkane (cyclohexene). It suggested the presence of methane, methylcyclohexane, toluene, xylene, and benzene degradation pathways in B. cereus.

Exploring the association of ESR1 and ESR2 gene SNPs with polycystic ovary syndrome in human females: a comprehensive association study.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) affects a significant proportion of human females worldwide and is characterized by hormonal, metabolic, and reproductive dysfunctions, including infertility, irregular menstrual cycles, acanthosis nigricans, and hirsutism. Mutations in the estrogen receptor genes ESR1 and ESR2, involved in normal follicular development and ovulation, can contribute to development of the PCOS. The present study focuses on investigating the potential correlation between single nucleotide polymorphisms (SNPs) of ESR1 and ESR2 genes and the incidence of this syndrome. METHODS: For this study, SNPs in ESR1 and ESR2 genes were retrieved from the ENSEMBL database and analyzed for their effect on mutated proteins using different bioinformatics tools including SIFT, PolyPhen, CADD, REVEL, MetaLR, I-Mutant, CELLO2GO, ProtParam, SOPMA, SWISS-MODEL and HDDOCK. RESULTS: All the SNPs documented in the present study were deleterious. All the SNPs except rs1583384537, rs1450198518, and rs78255744 decreased protein stability. Two variants rs1463893698 and rs766843910 in the ESR2 gene altered the localization of mutated proteins i.e. in addition to the nucleus, proteins were also found in mitochondria and extracellular, respectively. SNPs rs104893956 in ESR1 and rs140630557, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene significantly changed the secondary structure of proteins (2D). SNPs that markedly changed 3D configuration included rs1554259481, rs188957694 and rs755667747 in ESR1 gene and rs1463893698, rs140630557, rs1596423459, rs766843910, rs1596405923, rs762454979 and rs1384121511 in ESR2 gene. Variants rs1467954450 (ESR1) and rs140630557 (ESR2) were identified to reduce the binding tendency of ESRα and ß receptors with estradiol as reflected by the docking scores i.e. -164.97 and -173.23, respectively. CONCLUSION: Due to the significant impact on the encoded proteins, these variants might be proposed as biomarkers to predict the likelihood of developing PCOS in the future and for diagnostic purposes.

Advancements and Challenges in Antiamyloid Therapy for Alzheimer's Disease: A Comprehensive Review.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder caused by the accumulation of amyloid-beta (Aß) proteins and neurofibrillary tangles in the brain. There have been recent advancements in antiamyloid therapy for AD. This narrative review explores the recent advancements and challenges in antiamyloid therapy. In addition, a summary of evidence from antiamyloid therapy trials is presented with a focus on lecanemab. Lecanemab is the most recently approved monoclonal antibody that targets Aß protofibrils for the treatment of patients with early AD and mild cognitive impairment (MCI). Lecanemab was the first drug shown to slow cognitive decline in patients with MCI or early onset AD dementia when administered as an infusion once every two weeks. In the Clarity AD trial, lecanemab was associated with infusion-site reactions (26.4%) and amyloid-related imaging abnormalities (12.6%). The clinical relevance and long-term side effects of lecanemab require further longitudinal observation. However, several challenges must be addressed before the drug can be routinely used in clinical practice. The drug's route of administration, need for imaging and genetic testing, affordability, accessibility, infrastructure, and potential for serious side effects are some of these challenges. Lecanemab's approval has fueled interest in the potential of other antiamyloid therapies, such as donanemab. Future research must focus on developing strategies to prevent AD; identify easy-to-use validated plasma-based assays; and discover newer user-friendly, and cost-effective drugs that target multiple pathways in AD pathology.

Development and Characterization of Interstitial-Fluid-Mimicking Solutions for Pre-Clinical Assessment of Hypoxia.

Asphyxia, a leading cause of illness and death in newborns, can be improved by early detection and management. Arterial blood gas (ABG) analysis is commonly used to diagnose and manage asphyxia, but it is invasive and carries risks. Dermal interstitial fluid (ISF) is an alternative physiological fluid that can provide valuable information about a person's health. ISF is more sensitive to severe hypoxia and metabolic disorders compared to blood, making it an attractive option for minimally invasive asphyxia detection using biosensors. However, obtaining ISF samples from humans is challenging due to ethical concerns and sampling difficulties. To address this, researchers are developing ISF-mimicking solutions as substitutes for early testing and evaluation of biosensors. This paper focuses on the development of these solutions for bench-based testing and validation of continuous asphyxia-monitoring biosensors. With an understanding of the factors influencing system quality and performance, these solutions can aid in the design of biosensors for in vivo monitoring of dermal ISF. Monitoring interstitial fluid pH levels can provide valuable insights into the severity and progression of asphyxia, aiding in accurate diagnosis and informed treatment decisions. In this study, buffer solutions were prepared to mimic the pH of ISF, and their electrical properties were analyzed. The results suggest that certain buffers can effectively mimic metabolic acidosis associated with asphyxia (pH < 7.30), while others can mimic metabolic alkalosis (pH > 7.45). Overall, this research contributes to the development of ISF-mimicking solutions and lays the groundwork for biosensor systems that monitor dermal ISF in real time.

Designing multi-epitope monkeypox virus-specific vaccine using immunoinformatics approach.

BACKGROUND: Monkeypox virus is an enveloped DNA virus that belongs to Poxviridae family. The virus is transmitted from rodents to primates via infected body fluids, skin lesions, and respiratory droplets. After being infected with virus, the patients experience fever, myalgia, maculopapular rash, and fluid-filled blisters. It is necessary to differentiate monkeypox virus from other poxviruses during diagnosis which can be appropriately envisioned via DNA analysis from swab samples. During small outbreaks, the virus is treated with therapies administered in other orthopoxviruses infections and does not have its own specific therapy and vaccine. Consequently, in this article, two potential peptides have been designed. METHODS: For the purpose of designing a vaccine, protein sequences were retrieved followed by the prediction of B- and T-cell epitopes. Afterward, vaccine structures were predicted which were docked with toll-like receptors. The docked complexes were analyzed with iMODS. Moreover, vaccine constructs nucleotide sequences were optimized and expressed in silico. RESULTS: COP-B7R vaccine construct (V1) has antigenicity score of 0.5400, instability index of 29.33, z-score of - 2.11-, and 42.11% GC content whereas COP-A44L vaccine construct (V2) has an antigenicity score of 0.7784, instability index of 23.33, z-score of - 0.61, and 48.63% GC content. It was also observed that COP-A44L can be expressed as a soluble protein in Escherichia coli as compared to COP-B7R which requires a different expression system. CONCLUSION: The obtained results revealed that both vaccine constructs show satisfactory outcomes after in silico investigation and have significant potential to prevent the monkeypox virus. However, COP-A44L gave better results.

Discovery of druggable potent inhibitors of serine proteases and farnesoid X receptor by ligand-based virtual screening to obstruct SARS-CoV-2.

The coronavirus, a subfamily of the coronavirinae family, is an RNA virus with over 40 variations that can infect humans, non-human mammals and birds. There are seven types of human coronaviruses, including SARS-CoV-2, is responsible for the recent COVID-19 pandemic. The current study is focused on the identification of drug molecules for the treatment of COVID-19 by targeting human proteases like transmembrane serine protease 2 (TMPRSS2), furin, cathepsin B, and a nuclear receptor named farnesoid X receptor (FXR). TMPRSS2 and furin help in cleaving the spike protein of the SARS-CoV-2 virus, while cathepsin B plays a critical role in the entry and pathogenesis. FXR, on the other hand, regulates the expression of ACE2, and its inhibition can reduce SARS-CoV-2 infection. By inhibiting these four protein targets with non-toxic inhibitors, the entry of the infectious agent into host cells and its pathogenesis can be obstructed. We have used the BioSolveIT suite for pharmacophore-based computational drug designing. A total of 1611 ligands from the ligand library were docked with the target proteins to obtain potent inhibitors on the basis of pharmacophore. Following the ADMET analysis and protein ligand interactions, potent and druggable inhibitors of the target proteins were obtained. Additionally, toxic substructures and the less toxic route of administration of the most potent inhibitors in rodents were also determined computationally. Compounds namely N-(diaminomethylene)-2-((3-((1R,3R)-3-(2-(methoxy(methyl)amino)-2-oxoethyl)cyclopentyl)propyl)amino)-2-oxoethan-1-aminium (26), (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((4-propyl-1H-imidazol-2-yl)methyl)piperidin-1-ium (29) and (1R,3R)-3-(((2-ammonioethyl)ammonio)methyl)-1-((1-propyl-1H-pyrazol-4-yl)methyl)piperidin-1-ium (30) were found as the potent inhibitors of TMPRSS2, whereas, 1-(1-(1-(1H-tetrazol-1-yl)cyclopropane-1­carbonyl)piperidin-4-yl)azepan-2-one (6), (2R)-4-methyl-1-oxo-1-((7R,11S)-4-oxo-6,7,8,9,10,11-hexahydro-4H-7,11-methanopyrido[1,2-a]azocin-9-yl)pentan-2-aminium (12), 4-((1-(3-(3,5-dimethylisoxazol-4-yl)propanoyl)piperidin-4-yl)methyl)morpholin-4-ium (13), 1-(4,6-dimethylpyrimidin-2-yl)-N-(3-oxocyclohex-1-en-1-yl)piperidine-4-carboxamide (14), 1-(4-(1,5-dimethyl-1H-1,2,4-triazol-3-yl)piperidin-1-yl)-3-(3,5-dimethylisoxazol-4-yl)propan-1-one (25) and N,N-dimethyl-4-oxo-4-((1S,5R)-8-oxo-5,6-dihydro-1H-1,5-methanopyrido[1,2-a][1,5]diazocin-3(2H,4H,8H)-yl)butanamide (31) inhibited the FXR preferentially. In case of cathepsin B, N-((5-benzoylthiophen-2-yl)methyl)-2-hydrazineyl-2-oxoacetamide (2) and N-([2,2'-bifuran]-5-ylmethyl)-2-hydrazineyl-2-oxoacetamide (7) were identified as the most druggable inhibitors whereas 1-amino-2,7-diethyl-3,8-dioxo-6-(p-tolyl)-2,3,7,8-tetrahydro-2,7-naphthyridine-4­carbonitrile (5) and (R)-6-amino-2-(2,3-dihydroxypropyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (20) were active against furin.