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Abstract The degradation half-life (DegT50) of a substance in soil plays an important role in the approval process of a plant protection product and is a sensitive input parameter for regulatory models. It is usually derived through least squares optimizations of mathematical models to measured degradation data according to EU FOCUS degradation kinetics guidance. A strong consensus on degradation parameters provides a solid foundation for parts of the environmental risk assessment. The DegT50 of a substance for regulatory modeling is preferably derived from a single first-order (SFO) model as this is currently the only kinetic model implemented in EU regulatory models of the environmental fate of pesticides. However, kinetic optimisation tools do not always provide a regulatory acceptable SFO fit even though a visual inspection of the data suggests it may be possible. It was therefore hypothesized that more acceptable SFO fits might be achieved by adapting the objective function that is minimized during the optimization. Eight objective functions with varying weightings were tested on 29 laboratory soil degradation datasets. A web-based app was developed to allow experts in environmental safety of plant protection products to visually assess the goodness of fits resulting from different objective functions. The visual assessments and a quantitative metric, newly introduced in the proposed update of the FOCUS guidance, show that the acceptability of SFO fits can be increased, but no single objective function exclusively improves all fits. The assessment reveals that expert judgment is very subjective. Participants tended to change their mind when judging the acceptance of a fit, assumingly caused by a learning curve or a period of calibration. It is concluded that different objective functions could be considered in the kinetic assessment as it can improve the acceptability of SFO fits and hence endpoints for regulatory modeling. This study reveals that various qualitative factors influence the visual judgment of experts when performing a kinetic modeling assessment. The proposed quantitative metric seems to be in alignment with the visual assessment of fits to derive modeling endpoints and a promising step toward less subjective kinetic modeling assessments.

Introduction: Urban Health Centre is a key place for implementing Routine Immunization program and vaccine storage. The present study evaluated Cold Chain Point (CCP) and logistics related to routine immunization at selected Urban Health Centers (UHCs) in Ahmedabad. Objective: 1. To evaluate the cold chain infrastructure and logistics supporting routine immunization programs at UHC with a focus on assessing the quality and reliability of vaccine storage and handling practices. 2. To assess the knowledge about cold chain among the Vaccine Cold Chain Handlers (VCCHS). Method: In this cross-sectional study, one UHC from each of the seven zones of Ahmedabad city was randomly selected for assessment of Cold Chain management. Knowledge of VCCHs at each UHCs was assessed using semi-structured questionnaire. Analysis was done using Microsoft excel 2019. Results: It was observed that all UHCs were having session plans and logistics estimation. Around 28.5% UHCs were having lack of essential tools, such as Drop Out charts and maps of their catchment areas. Open vials were found without dates and times labelled in 43% of UHCs, and in one UHC, a vaccine vial was found beyond its usable Vaccine vial Monitor (VVM) stage. All the medical officers utilize various strategies to create awareness, with the majority (86%) using interpersonal communication. All Health Care Providers stated Socio-cultural beliefs and fear of side effects as reason for non-utilization of services. Only 42% of Vaccine Cold Chain Handlers (VCCHs) demonstrated complete knowledge about live vaccines. Conclusion: The study highlights certain issues at UHC like maintenance of drop out chart, map of catchment area, training of medical officers on module of immunization, ice-packs arrangement in Deep Freeze, no knowledge of VCCHs about shake test, which indicates lack of efficiency of VCCHs and need of their training.

Irrespective of medical technology improvements, cancer ranks among the leading causes of mortality worldwide. Although numerous cures and treatments exist, creating alternative cancer therapies with fewer adverse side effects is vital. Since ancient times, plant bioactive compounds have already been used as a remedy to heal cancer. These plant bioactive compounds and their anticancer activity can also deregulate the microRNAs (miRNAs) in the cancerous cells. Therefore, the deregulation of miRNAs in cancer cells by plant bioactive compounds and the usage of the related miRNA could be a promising approach for cancer cure, mainly to prevent cancer and overcome chemotherapeutic side effect problems. Hence, this review highlights the function of plant bioactive compounds as an anticancer agent through the underlying mechanism that alters the miRNA expression in cancer cells, ultimately leading to apoptosis. Moreover, this review provides insight into using plant bioactive compounds -driven miRNAs as an anticancer agent to develop miRNA-based cancer gene therapy. They can be the potential resource for gene therapy and novel strategies targeting cancer therapeutics.

Breast cancer remains a significant global health challenge, necessitating the exploration of novel therapeutic options. The present study employs an integrated approach encompassing network pharmacology, molecular docking, molecular dynamics simulations, and in-vitro validation to investigate the potential of Selaginella bryopteris in breast cancer treatment. Initial network pharmacology analysis revealed different potential targets and pathways associated with breast cancer that could be modulated by S. bryopteris phytochemical constituents. Molecular docking and dynamics simulations further elucidated the stability and dynamics of protein-ligand complexes (lanaroflavone–EGFR and sequoiaflavone-CTNNB1). The in-vitro assays demonstrated the ability of S. bryopteris crude extract to inhibit cancer cell growth (IC50 - 78.34 μg/mL) migration and invasion, supporting the computational predictions. The integrated approach employed in the present study offers a robust framework for the systematic exploration of S. bryopteris in drug discovery as a promising candidate for breast cancer treatment.

Biogenic synthesis of silver nanoparticles (AgNPs) has emerged as an eco-friendly and sustainable approach with diverse biological applications. This study presents synthesis of AgNPs-LS using a probiotic strain Lactobacillus salivarius (L. salivarius) and explores their multifaceted biological activities, including antibacterial, antibiofilm, anti-quorum sensing, antifungal, antioxidant, anticancer, anticoagulant and thrombolytic properties. The biosynthesis of AgNPs-LS was successfully achieved using L. salivarius cell free supernatants, resulting in well-characterized nanoparticles as confirmed by UV–Vis spectroscopy, Fourier Transform Infrared (FTIR) spectroscopy, transmission electron microscopy (TEM) and dynamic light scattering (DLS) and zeta potential analysis. The AgNPs-LS demonstrated potent antibacterial activity against different pathogenic bacteria (C. violaceum, P. aeruginosa, S. aureus, E. coli and S. marcescens), emphasizing their potential in combating bacterial infections. Moreover, these AgNPs-LS were effective in inhibiting biofilm formation (>60 % at 1/2 MIC), a key mechanism of bacterial virulence, highlighting their utility in preventing biofilm-related infections. AgNPs-LS exhibited anti-quorum sensing activity, disrupting bacterial communication systems and potentially reducing virulence factor such as, violacein production in C. violaceum, pyocyanin production in P. aeruginosa and prodigiosin production in S. marcescens. Additionally, AgNPs-LS also exhibited notable antifungal activity towards a different pathogenic fungus (F. proliferatum, P. purpurogenum, A. niger and R. stolonifer). In terms of health applications, the AgNPs-LS displayed significant antioxidant activity, effectively scavenging DPPH• (IC50 = 42.65 μg/mL) and ABTS•+ (IC50 = 53.77 μg/mL) free radicals. Furthermore, AgNPs-LS showed cytotoxicity against breast cancer cells (MCF-7) (IC50 = 52.29 μg/mL), positioning them as promising candidates for cancer therapy. Moreover, AgNPs-LS were also shown promising anticoagulant and thrombolytic activities under practical conditions. Therefore, the biogenic synthesis of AgNPs-LS using L. salivarius offers a sustainable and cost-effective route for producing AgNPs with an array of biological activities. These AgNPs-LS have the potential to address various challenges in healthcare, ranging from antimicrobial, anticancer applications to biofilm inhibition, antioxidant therapy, anticoagulant and thrombolytic agents.

Background: Severe asthma pathology encompasses a wide range of pulmonary and extrapulmonary treatable traits with a high prevalence of comorbidities. Although asthma-specific health-related quality-of-life measures are most sensitive to changes in asthma control, generic measures, such as EQ-5D-5L (EuroQol 5-Dimension 5-Level questionnaire), are potentially better for capturing the impact of comorbidities. Objective: We sought to examine the impact of pulmonary and extrapulmonary treatable traits on quality of life at initial severe asthma assessment, and to compare the characteristics of those patients whose quality of life does and does not improve during follow-up at severe asthma centers. Methods: Patients’ characteristics at baseline assessment within the UK Severe Asthma Registry were compared by EQ-5D-5L utility index quartile. Patients with follow-up review data were stratified by change in EQ-5D-5L utility index from baseline to follow-up, and characteristics similarly examined. Results: Patients in the quartiles with worst dysutility at baseline were observed to exhibit more treatable traits and in particular extrapulmonary traits associated with cumulative systemic corticosteroids, including obesity, anxiety/depression, and osteoporosis. In those patients whose quality of life improved over follow-up, a reduction in exacerbations, uncontrolled symptoms, and requirement for maintenance oral corticosteroids were observed. Conclusions: Both pulmonary and extrapulmonary treatable traits are important determinants of quality of life in severe asthma. Comorbidities associated with cumulative systemic corticosteroid exposure are particularly associated with worse quality of life, emphasizing the importance of early identification and management of severe asthma before comorbidities develop.

Abstract Enzymatic degradation of synthetic dyes holds an immense promise for addressing the environmental concerns associated with the textile and dye industries. This study aimed to isolate bacteria capable of producing laccase enzymes from an anthropogenic environment. Subsequently, viability of utilizing cost-effective agricultural residues as substrates for laccase production was assessed. Response Surface Methodology (RSM) and the One Variable at a Time (OVAT) approach was pursued for the optimization of laccase production, followed by pH and temperature stability, dye degradation and decolorization experiments, toxicological studies on the degraded dye metabolites. In results, laccase-producing bacterial strain was identified as Stenotrophomonas maltophilia strain E1 (S. maltophilia). Among variety of substrates, coconut husk exhibited optimal efficacy. In a statistical optimization study, it was found that S. maltophilia was capable of producing laccase 51.38 IU/mL, i.e., three times higher than the amount of laccase produced by unoptimized medium (16.7 IU/mL), and the enzyme activity was found to be steady at an acidic pH, and a mesophilic temperature range. The laccase obtained from S. maltophilia E1 demonstrated proficient dye decolorization capabilities, achieving a notable 92.1% reduction in Malachite green dye coloration at a concentration of 500 ppm. Gas chromatography–mass spectrometry (GC–MS) analysis of the decolorized derivatives of Malachite green revealed a conversion into a distinct compounds. Moreover, after undergoing laccase treatment, Malachite green exhibited decreased phytotoxic effects on Oryza sativa, pointing to enzymatic detoxification. Collectively, insights gained from the present study will contribute to the development of efficient enzymatic approaches for addressing the environmental pollution caused by synthetic dyes. Graphical Abstract

Antimicrobial resistance by pathogenic bacteria has become a global risk to human health in recent years. The most promising approach to combating antimicrobial resistance is to target virulent traits of bacteria. In the present study, a biosurfactant derived from the probiotic strain Lactobacillus acidophilus was tested against three Gram-negative bacteria to evaluate its inhibitory potential on their biofilms, and whether it affected the virulence factors controlled by quorum sensing (QS). A reduction in the virulence factors of Chromobacterium violaceum (violacein production), Serratia marcescens (prodigiosin production) and Pseudomonas aeruginosa (pyocyanin, total protease, LasB elastase and LasA protease production) was observed at different sub-MIC concentrations in a dose-dependent manner. Biofilm development was reduced by 65.76%, 70.64% and 58.12% at the highest sub-MIC levels for C. violaceum, P. aeruginosa and S. marcescens, respectively. Biofilm formation on glass surfaces exhibited significant reduction, with less bacterial aggregation and reduced formation of extracellular polymeric materials. Additionally, swimming motility and exopolysaccharides (EPS) production were shown to be reduced in the presence of the L. acidophilus-derived biosurfactant. Furthermore, molecular docking analysis performed on compounds identified through gas chromatography–mass spectrometry (GC-MS) analysis of QS and biofilm proteins yielded further insights into the mechanism underlying the anti-QS activity. Therefore, the present study has clearly demonstrated that a biosurfactant derived from L. acidophilus can significantly inhibit virulence factors of Gram-negative pathogenic bacteria. This could provide an effective method to inhibit the formation of biofilms and QS in Gram-negative bacteria.

Introduction: Hyperphosphorylation of tau is an important event in Alzheimer’s disease (AD) pathogenesis, leading to the generation of “neurofibrillary tangles,” a histopathological hallmark associated with the onset of AD and related tauopathies. Microtubule-affinity regulating kinase 4 (MARK4) is an evolutionarily conserved Ser-Thr (S/T) kinase that phosphorylates tau and microtubule-associated proteins, thus playing a critical role in AD pathology. The uncontrolled neuronal migration is attributed to overexpressed MARK4, leading to disruption in microtubule dynamics. Inhibiting MARK4 is an attractive strategy in AD therapeutics.Methods: Molecular docking was performed to see the interactions between MARK4 and galantamine (GLT). Furthermore, 250 ns molecular dynamic studies were performed to investigate the stability and conformational dynamics of the MARK4–GLT complex. We performed fluorescence binding and isothermal titration calorimetry studies to measure the binding affinity between GLT and MARK4. Finally, an enzyme inhibition assay was performed to measure the MARK4 activity in the presence and absence of GLT.Results: We showed that GLT, an acetylcholinesterase inhibitor, binds to the active site cavity of MARK4 with an appreciable binding affinity. Molecular dynamic simulation for 250 ns demonstrated the stability and conformational dynamics of the MARK4–GLT complex. Fluorescence binding and isothermal titration calorimetry studies suggested a strong binding affinity. We further show that GLT inhibits the kinase activity of MARK4 significantly (IC50 = 5.87 µM).Conclusion: These results suggest that GLT is a potential inhibitor of MARK4 and could be a promising therapeutic target for AD. GLT’s inhibition of MARK4 provides newer insights into the mechanism of GLT’s action, which is already used to improve cognition in AD patients.

Abstract Electronic monitoring devices (EMDs) have been trialled in interventions to improve inhaled corticosteroid adherence and clinical outcomes. This study sought to understand the perceptions and experiences of EMD end-users. Participants recruited into a six-month EMD study were invited to a semi-structured interview. Interviews were audio-recorded, transcribed verbatim and analysed using the framework approach. Twenty-eight participants (68% female, median age 47) were interviewed. Individuals described feeling responsible for their asthma control. Recent attacks motivated a desire to maintain control. Study participation led to increased awareness of asthma status and medication use. Several individuals were open to integrating digital monitoring data with other mHealth inputs, perceiving the potential to enhance communication with clinicians and empower self-management. Openness to data sharing was tied to expectations of transparent data use. Data supported integrating beliefs and habit formation to achieve behaviour change. There was a willingness for an integrated, platform-based approach to digital self-management.

Fruit of Carissa opaca Stapf ex Haines (C. opaca) is a feed additive and is commonly used against cardiac dysfunction, fever, asthma, diarrhea, gastrointestinal ailments, and skin diseases. In this study, we aimed to evaluate the metabolic profile and antioxidant potential of C. opaca fruit against carbon tetrachloride (CCl4)-induced cardiotoxicity and testicular toxicity in rats. Gas Chromatoghraphy-Mass Spectrometry (GC-MS) analysis of C. opaca fruit for the identification of potential metabolic profile, followed by methanolic extract of C. opaca and its derived fractions including n-hexane, ethyl acetate, chloroform, butanol, and aqueous were used to assess the antioxidant potential of fruits. Ten groups of rats received different treatments and got evaluated for cardiac and testicular antioxidant enzymes, histological architecture, and serum hormonal levels. GC-MS analysis of methanolic extract of C. opaca fruit showed the presence of some bioactive metabolites like cyclodecane, diethyl 2,6-pyridine dicarboxylate, tetrahydro-geraniol, S-[2-[N, N-Dimethylamino]ethyl]morpoline, 2,3-Methylenedioxyphenol, alpha-d-Glucopyranoside, 5,10-Diethoxy-2,3,7,8-tetrahydro-1H, 6H-dipyrrolo [1,2-a; 1′,2′-d] pyrazine and 1,3-Benzothiazol-2(3H)-one,3-(3,3-dimethyl-1-oxobutyl) that corresponds the medicinal properties of C. opaca fruit. Prepared fractions of C. opaca fruits mitigated the toxicity induced by CCl4 in the heart and testicular tissues of rats. Oxidative stress was caused by the inhibition of activities of glutathione and other antioxidant enzymes of the body, while on the other hand elevating the levels of nitrite and hydrogen peroxide. Treatment with C. opaca fruit extract normalized the levels of enzymes, reproductive hormones, and free radicals thus restoring the histopathological and enzymatic biomarkers towards the normal group. The study supports the indigenous use of fruits as an alternative medicine against cardiac dysfunction by providing scientific evidence of protection against CCl4-induced injuries, and it also concludes the antioxidant defensive role in testicular tissues.

The ADITYA upgrade (ADITYA-U), a medium-sized $\left( {{R_0} = 75{\text{ cm}},\,\,a = 25{\text{ cm}}} \right)$ conventional tokamak facility in India, has been consistently producing experiments findings by using circular and shaped-plasmas. Recognizing the plasma parameters aligning closely with the design parameters of circular limited plasmas, ADITYA-U shifted its focus toward exploring the operational regime for experimentation on saw-tooth and MHD phenomena. Moreover, ADITYA-U has made consistent advancements toward conducting preliminary plasma shaping experiments through the activation of top and bottom divertor coils utilizing hydrogen as well as deuterium fuels. Confinement is improved by a factor of ∼1.5 in ${D_2}$ plasmas when compared to H _2 plasmas of ADITYA-U. Further, ADITYA-U operations emphasize preventing disruptions and runaway electrons (REs) to ensure safe operations for future fusion devices. Significant suppression of REs has been achieved in ADITYA-U with the application of pulsed localized vertical magnetic field (LVF) perturbation, thereby establishing the technique’s independence from the tokamak device. The successful RE mitigation requires a critical threshold of LVF pulse magnitude, which is approximately 1% of the toroidal magnetic field, and a minimum duration of ∼5 ms. Apart from this, several novel findings have been achieved in the ADITYA-U experiments, including the modification of sawtooth duration through gas-puff, the emergence of MHD-induced geodesic acoustic mode-like oscillations, the propagation of fast heat pulses induced by MHD activity, the control of RE dynamics through Gas-puffs, the propagation of pinch-driven cold-pulses, the transport and core accumulations of argon impurities, the mass dependency of plasma toroidal rotation and the detection of ‘RICE’ scaling, as well as the characterization of edge plasma using wall conditioning methods, such as glow discharge cleaning using a combination of Ar -H _2 mixture, localized wall cleaning by electron cyclotron resonant plasma, and the development of machine learning-based disruption predictions, will be discussed in this paper.

The objective of the present work was to develop and optimize an intranasal in situ gel of Pramipexole dihydrochloride for enhanced drug delivery, better patient acceptability, and possible proper treatment of Parkinson’s disease. Preliminary studies were performed to select formulation components and identify key variables affecting the formulation. The optimization of the in situ gelling system of Pramipexole dihydrochloride was achieved by applying 32 full factorial design using Design-Expert® software (Stat-Ease 9.0.6 version) and taking concentrations of Poloxamer 407 (X1) and HPMC K4M (X2) as independent variables. The gelling temperature, gel strength, and percentage of drug diffused after 8 h were taken as dependent variables. The software provided an optimized formulation, with 16.50% of X1 and 0.2% of X2 with the highest desirability. An in vivo drug retention time study was performed for the optimized formulation in Wistar rats. The results of the optimization process demonstrated that the selected gel formulation exhibited desirable characteristics, including gelation near body temperature, good gel strength, suitable viscosity, and sustained drug release. The optimized formulation displayed significantly higher drug retention, lasting about 5 h, versus the plain poloxamer gel formulation. Hence, it was concluded that the optimized formulation will remain affixed at the site of application for a significant time after intranasal administration and consequently sustain the release of the drug. The optimized formulation was found to be stable during the stability studies. The developed dosage form may improve patient compliance, enhance nasal drug residence, and offer sustained drug release. However, further clinical studies are necessary to validate these findings.

Candidiasis, caused by opportunistic fungal pathogens of the Candida genus, poses a significant threat to immunocompromised individuals. Natural compounds derived from medicinal plants have gained attention as potential sources of anti-fungal agents. Ajwa dates (Phoenix dactylifera L.) have been recognized for their diverse phytochemical composition and therapeutic potential. In this study, we employed a multi-faceted approach to explore the anti-candidiasis potential of Ajwa dates’ phytochemicals. Utilizing network pharmacology, we constructed an interaction network to elucidate the intricate relationships between Ajwa dates phytoconstituents and the Candida-associated molecular targets of humans. Our analysis revealed key nodes in the network (STAT3, IL-2, PTPRC, STAT1, CASP1, ALB, TP53, TLR4, TNF and PPARG), suggesting the potential modulation of several crucial processes (the regulation of the response to a cytokine stimulus, regulation of the inflammatory response, positive regulation of cytokine production, cellular response to external stimulus, etc.) and fungal pathways (Th17 cell differentiation, the Toll-like receptor signaling pathway, the C-type lectin receptor signaling pathway and necroptosis). To validate these findings, molecular docking studies were conducted, revealing the binding affinities of the phytochemicals towards selected Candida protein targets of humans (ALB–rutin (−9.7 kJ/mol), STAT1–rutin (−9.2 kJ/mol), STAT3–isoquercetin (−8.7 kJ/mol), IL2–β-carotene (−8.5 kJ/mol), CASP1–β-carotene (−8.2 kJ/mol), TP53–isoquercetin (−8.8 kJ/mol), PPARG–luteolin (−8.3 kJ/mol), TNF–βcarotene (−7.7 kJ/mol), TLR4–rutin (−7.4 kJ/mol) and PTPRC–rutin (−7.0 kJ/mol)). Furthermore, molecular dynamics simulations of rutin–ALB and rutin-STAT1 complex were performed to gain insights into the stability and dynamics of the identified ligand–target complexes over time. Overall, the results not only contribute to the understanding of the molecular interactions underlying the anti-fungal potential of specific phytochemicals of Ajwa dates in humans but also provide a rational basis for the development of novel therapeutic strategies against candidiasis in humans. This study underscores the significance of network pharmacology, molecular docking and dynamics simulations in accelerating the discovery of natural products as effective anti-fungal agents. However, further experimental validation of the identified compounds is warranted to translate these findings into practical therapeutic applications.

The emergence of antibiotic resistance poses a serious threat to humankind, emphasizing the need for alternative antimicrobial agents. This study focuses on investigating the antibacterial, antibiofilm, and anti-quorum-sensing (anti-QS) activities of saponin-derived silver nanoparticles (AgNPs-S) obtained from Ajwa dates (Phoenix dactylifera L.). The design and synthesis of these novel nanoparticles were explored in the context of developing alternative strategies to combat bacterial infections. The Ajwa date saponin extract was used as a reducing and stabilizing agent to synthesize AgNPs-S, which was characterized using various analytical techniques, including UV–Vis spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and transmission electron microscopy (TEM). The biosynthesized AgNPs-S exhibited potent antibacterial activity against both Gram-positive and Gram-negative bacteria due to their capability to disrupt bacterial cell membranes and the leakage of nucleic acid and protein contents. The AgNPs-S effectively inhibited biofilm formation and quorum-sensing (QS) activity by interfering with QS signaling molecules, which play a pivotal role in bacterial virulence and pathogenicity. Furthermore, the AgNPs-S demonstrated significant antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radicals and cytotoxicity against small lung cancer cells (A549 cells). Overall, the findings of the present study provide valuable insights into the potential use of these nanoparticles as alternative therapeutic agents for the design and development of novel antibiotics. Further investigations are warranted to elucidate the possible mechanism involved and safety concerns when it is used in vivo, paving the way for future therapeutic applications in combating bacterial infections and overcoming antibiotic resistance.

BackgroundThe Asthma Control Questionnaire (ACQ) is used to assess asthma symptom control. The relationship between the questionnaire items and symptom control has not been fully studied in severe asthmatic patients, and its validity for making comparisons between subgroups of patients is unknown.MethodsData was obtained from patients in the United Kingdom Severe Asthma Registry whose symptom control was assessed using the five-item ACQ (ACQ5) (n = 2,951). Confirmatory factor analysis determined whether a latent factor for asthma symptom control, as measured by the ACQ5, was consistent with the data. Measurement invariance was examined in relation to ethnicity, sex and age; this included testing for approximate measurement invariance using Bayesian Structural Equation Modelling (BSEM). The fitted models were used to estimate the internal consistency reliability of the ACQ5. Invariance of factor means across subgroups was assessed.ResultsA one-factor construct with residual correlations for the ACQ5 was an excellent fit to the data in all subgroups (Root Mean Square Error Approximation 0.03 [90%CI 0.02,0.05], p-close fit 0.93, Comparative Fit Index 1.00, Tucker Lewis Index 1.00}. Expected item responses were consistent for Caucasian and non-Caucasian patients with the same absolute level of symptom control. There was some evidence that females and younger adults reported wakening more frequently during the night than males and older adults respectively with the same absolute level of symptom control (pConclusionThe ACQ5 is informative in comparing levels of symptom control between severe asthmatic patients of different ethnicities, sexes and ages. It is important that analyses are replicated in other severe asthma registries to determine whether measurement invariance is observed.

Abstract Objective: The Beta-lactam Comprehensive Allergy Management Program (CAMP) was implemented to facilitate complete beta-lactam allergy history documentation in the electronic medical record (EMR) and increase beta-lactam utilization. The study objective was to assess the rate of complete allergy histories and days of antimicrobial therapy (DOT) before versus after CAMP implementation. Design: Quasi-experimental study with interrupted time-series analysis. Setting: Non-teaching, urban, and community medical center within a multi-hospital health system. Patients: Adult inpatients with a beta-lactam allergy receiving antimicrobial therapy. Methods: The multidisciplinary CAMP team screened, interviewed, and collected allergy history details of adult inpatients with a beta-lactam allergy receiving antimicrobial therapy starting January 4, 2021. Patients were stratified as high, moderate, or low risk of IgE-mediated allergy and referred to an allergist for skin testing or drug challenge. The EMR was updated with interview details and drug challenge or skin test results. The primary endpoint was rate of complete allergy history documentation before (12/1/18–4/1/19) compared to after (1/4/21–5/1/21) program implementation. The secondary endpoint was days of inpatient beta-lactam therapy. Implementation logistics, de-labeling rate, and antimicrobial therapy changes were evaluated. Results: The program evaluated 392 individuals, with 184 and 208 patients comprising the pre- and post-intervention groups, respectively. The post-intervention period was associated with an increase of 19.8% in complete allergy histories (0.359 PPc; R 2 0.26; p = 0.002) and 9.34 beta-lactam DOT per 1,000-days-present (1.106 PPc; R 2 0.194; p = 0.009). Conclusion: Implementation of a comprehensive beta-lactam allergy management program was associated with higher rates of complete beta-lactam allergy history and beta-lactam use.

Objectives The CanMEDS framework, an educational framework for physicians used in Canada, defined competencies that physicians require to meet patients’ needs, all of which can be cultivated through mentorship activities. The Advocacy Mentorship Initiative (AMI) at the University of Toronto used a cascading mentorship model (CMM), whereby resident mentors (RMs) mentored undergraduate medical student mentors (MSMs), who in turn mentored youth raised in at-risk environments. Both RMs and MSMs were mentored by the AMI programme lead, a staff psychiatrist, with expertise in child and adolescent psychiatry. The research question of this study was as follows: What were the merits of using a CMM in enhancing the knowledge, competencies and residency experiences of RMs in AMI?Design Qualitative interview study.Setting and participants RMs involved in AMI from January 2017 to December 2020 were invited to participate in the study. A total of 11 RMs agreed to participate.Methods Interviews were conducted to canvas participants about how AMI impacted them, and these were recorded, transcribed and anonymised. Braun and Clarke’s approach to thematic analysis was used to identify ‘subthemes’ and ‘themes’.Results Eleven RMs participated in the study. A major theme identified was how AMI enhanced the medical learner experience by augmenting the educational experience of MSMs, strengthening RMs’ values and attitudes, and strengthening RMs’ knowledge and competencies. The second theme captured was the effective facets of a mentorship programme in AMI, including the CMM, and collaborative and inclusive relationships between mentors and mentees.Conclusions RMs identified that the CMM of AMI cultivated CanMEDS competencies in medical learners; deepened medical learners’ understanding of social determinants of health; and offered a bidirectional approach to teaching and learning between MSMs and RMs. MSMs and RMs also learnt from the staff psychiatrist.

Abstract Parkinson’s disease (PD) is characterized by rigidity, akinesia, postural instability and tremor. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) reduces tremor but the effects on postural instability are inconsistent. Another component of postural control is the postural strategy, traditionally referred to as the ankle or hip strategy, which is determined by the coupling between the joint motions of the body. We aimed to determine whether DBS STN and vision (eyes open vs. eyes closed) affect the postural strategy in PD in quiet stance or during balance perturbations. Linear motion was recorded from the knee, hip, shoulder and head in 10 patients with idiopathic PD with DBS STN (after withdrawal of other anti-PD medication), 25 younger adult controls and 17 older adult controls. Correlation analyses were performed on anterior–posterior linear motion data to determine the coupling between the four positions measured. All participants were asked to stand for a 30 s period of quiet stance and a 200 s period of calf vibration. The 200 s vibration period was subdivided into four 50 s periods to study adaptation between the first vibration period (30–80 s) and the last vibration period (180–230 s). Movement was recorded in patients with PD with DBS ON and DBS OFF, and all participants were investigated with eyes closed and eyes open. DBS settings were randomized and double-blindly programmed. Patients with PD had greater coupling of the body compared to old and young controls during balance perturbations (p ≤ 0.046). Controls adopted a strategy with greater flexibility, particularly using the knee as a point of pivot, whereas patients with PD adopted an ankle strategy, i.e., they used the ankle as the point of pivot. There was higher flexibility in patients with PD with DBS ON and eyes open compared to DBS OFF and eyes closed (p ≤ 0.011). During balance perturbations, controls quickly adopted a new strategy that they retained throughout the test, but patients with PD were slower to adapt. Patients with PD further increased the coupling between segmental movement during balance perturbations with DBS ON but retained a high level of coupling with DBS OFF throughout balance perturbations. The ankle strategy during balance perturbations in patients with PD was most evident with DBS OFF and eyes closed. The increased coupling with balance perturbations implies a mechanism to reduce complexity at a cost of exerting more energy. Strategic alterations of posture were altered by DBS in patients with PD and were delayed. Our findings therefore show that DBS does not fully compensate for disease-related effects on posture.

Abstract In this paper we present a detailed study of the four-body decay B 0 → K + π − ℓ + ℓ − , where tensions with the Standard Model predictions have been observed. Our analysis of the decay with P- and S-wave contributions to the K + π − system develops a complete understanding of the symmetries of the distribution, in the case of massless and massive leptons. In both cases, the symmetries determine relations between the observables in the B 0 → K + π − ℓ + ℓ − decay distribution. This enables us to define the complete set of observables accessible to experiments, including several that have not previously been identified. The new observables arise when the decay rate is written differentially with respect to m K π $$ {m}_{K_{\pi }} $$ . We demonstrate that experiments will be able to fit this full decay distribution with currently available data sets and investigate the sensitivity to new physics scenarios given the experimental precision that is expected in the future. The symmetry relations provide a unique handle to explore the behaviour of S-wave observables by expressing them in terms of P-wave observables, therefore minimising the dependence on poorly-known S-wave form factors. Using this approach, we construct two theoretically optimized S-wave observables and explore their sensitivity to new physics. By further exploiting the symmetry relations, we obtain the first bounds on the S-wave observables using two different methods and highlight how these relations may be used as cross-checks of the experimental methodology and the parametrization of the B 0 → K + π − ℓ + ℓ − differential decay rate. We identify a zero-crossing point that would be at a common dilepton invariant mass for a subset of P- and S-wave observables, and explore the information on new physics and hadronic effects that this zero point can provide.

Youth aging out of child welfare systems face an abrupt transition to adulthood and expectation for self-sufficiency with few supports. The current study represents a scoping review and narrative synthesis that sought to identify indicators used to measure the success of aging out youth and their corresponding methods of assessment. A database search was conducted and 150 articles were included in the review. Results revealed eight broad indicators of successful transitions, including: education, employment, basic needs, social support and relationships, conduct and victimization, health, general living skills, and resilience and psychological empowerment. As a larger category, health was broken down into five subdomains of physical, mental health symptoms, reproductive/sexual health, substance use, and access to care/service utilization. Findings highlight the need for comprehensive tools and strengths-based approaches to assessing transitional gaps earlier in the aging out process. Given the interdependency of indicator outcomes, fulsome measurement can provide a window into a youth’s future concerns.

Sidr honey is a valuable source of bioactive compounds with promising biological properties. In the present study, antimicrobial, antioxidant, and anti-quorum sensing properties of Saudi Sidr honey were assessed, along with phytochemical analysis, via gas chromatography–mass spectrometry (GC-MS). In silico study was also carried out to study the drug-likeness properties of the identified compounds and to study their affinity with known target proteins assessed using molecular docking approach. The results showed that Saudi Sidr honey exhibited promising antibacterial activity, with MIC values ranging from 50 to 400 mg/mL and MBC values from 50 to >450 mg/mL. Interestingly, the Saudi Sidr honey was active against Candida auris and Candida neoformans, with an MIC value of about 500 mg/mL. Moreover, the Sidr honey showed important antioxidant activities (ABTS assay: IC50 5.41 ± 0.045 mg/mL; DPPH assay: IC50 7.70 ± 0.065 mg/mL) and β-carotene bleaching test results (IC50 ≥ 20 mg/mL). In addition, the Saudi Sidr honey was able to inhibit biofilm formation on glass slides at 1/2 MIC by 77.11% for Bacillus subtilis, 70.88% for Staphylococcus aureus, 61.79% for Escherichia coli, and 56.64% for Pseudomonas aeruginosa. Similarly, violacein production by Chromobacterium violaceum was reduced by about 56.63%, while the production of pyocyanin by P. aeruginosa was decreased to 46.27% at a low concentration of Saudi Sidr honey. ADMET properties showed that five identified compounds, namely, 1-cyclohexylimidazolidin-2-one, 3-Butyl-3-methylcyclohexanone, 4-butyl-3-methoxy-2-cyclo penten-1-one, 2,2,3,3-Tetramethyl cyclopropane carboxylic acid, and 3,5-dihydroxy-2-(3-methylbut-2-en-1-yl showed promising drug-likeness properties. The compound 3,5-dihydroxy-2-(3-methylbut-2-en-1-yl exhibited the highest binding energy against antimicrobial and antioxidant target proteins (1JIJ, 2VAM, 6B8A, 6F86, 2CDU, and 1OG5). Overall, the obtained results highlighted the promising potential of Saudi Sidr honey as a rich source of bioactive compounds that can be used as food preservatives and antimicrobial, antioxidant, and anti-quorum sensing molecules.

Homeless refugee youth experience high rates of traumatic and adverse experiences, a significant burden of mental health needs, and compounded barriers in accessing support services. Despite this, there is a paucity of literature exploring the unique intersections and vulnerabilities faced by this subgroup. This study of Youth Without Shelter (YWS), an emergency residence and referral agency serving homeless youth in Toronto, Canada was a qualitative study of homeless refugee youth. Research goals were to describe the mental health needs and identify the factors contributing to the resiliency of refugee youth experiencing homelessness. Data was collected through individual semi-structured interviews with YWS youth (n = 6) and analyzed using inductive thematic analysis with a realist lens. Results highlighted that the mental health of refugee youth experiencing homelessness was subject to system-level factors such as the immigration process (n = 6), housing insecurity (n = 5), finances (n = 5), education (n = 6), employment (n = 6) and sense of safety (n = 4), with acculturative stress, including culture shock (n = 3) and language (n = 4), also have negative effects. Goal directedness (n = 5), independence or responsibility (n = 4), and nurturing social connectedness with family (n = 5), peers (n = 6), and community (n = 4) contributed to participants' resilience. A model for planning future interventions was proposed and was informed by the lived experience of participants. This model focuses on initially on immediate and basic needs and reflected evidence gathered through this work to attend to long-term needs once individuals have integrated into society. Future efforts will be directed toward translating the lived experience of this population and developing practice guidelines to optimize care.

In recent years, bacterial pathogens have developed resistance to antimicrobial agents that have created a global threat to human health and environment. As a novel approach to combating antimicrobial resistance (AMR), targeting bacteria’s virulent traits that can be explained by quorum sensing (QS) is considered to be one of the most promising approaches. In the present study, biologically synthesized silver nanoparticles derived from Lactobacillus rhamnosus (AgNPs-LR) were tested against three Gram-negative bacteria to determine whether they inhibited the formation of biofilms and triggered the virulence factors controlled by QS. In C. violaceum and S. marcescens, a remarkable inhibition (>70%) of QS-mediated violacein and prodigiosin production was recorded, respectively. A dose-dependent decrease in virulence factors of P. aeruginosa (pyocyanin, pyoverdine, LasA protease, LasB elastase and rhamnolipid production) was also observed with AgNPs-LR. The biofilm development was reduced by 72.56%, 61.70%, and 64.66% at highest sub-MIC for C. violaceum, S. marcescens and P. aeruginosa, respectively. Observations on glass surfaces have shown remarkable reductions in biofilm formation, with less aggregation of bacteria and a reduced amount of extra polymeric materials being formed from the bacteria. Moreover, swimming motility and exopolysaccharides (EPS) was also found to reduce in the presence of AgNPs-LR. Therefore, these results clearly demonstrate that AgNPs-LR is highly effective in inhibiting the development of biofilms and the QS-mediated virulent traits of Gram-negative bacteria. In the future, AgNPs-LR may be used as an alternative to conventional antibiotics for the treatment of bacterial infections after careful evaluation in animal models, especially for the development of topical antimicrobial agents.

Homeostasis between protein synthesis and degradation is a critical biological function involving a lot of precise and intricate regulatory systems. The ubiquitin-proteasome pathway (UPP) is a large, multi-protease complex that degrades most intracellular proteins and accounts for about 80% of cellular protein degradation. The proteasome, a massive multi-catalytic proteinase complex that plays a substantial role in protein processing, has been shown to have a wide range of catalytic activity and is at the center of this eukaryotic protein breakdown mechanism. As cancer cells overexpress proteins that induce cell proliferation, while blocking cell death pathways, UPP inhibition has been used as an anticancer therapy to change the balance between protein production and degradation towards cell death. Natural products have a long history of being used to prevent and treat various illnesses. Modern research has shown that the pharmacological actions of several natural products are involved in the engagement of UPP. Over the past few years, numerous natural compounds have been found that target the UPP pathway. These molecules could lead to the clinical development of novel and potent anticancer medications to combat the onslaught of adverse effects and resistance mechanisms caused by already approved proteasome inhibitors. In this review, we report the importance of UPP in anticancer therapy and the regulatory effects of diverse natural metabolites, their semi-synthetic analogs, and SAR studies on proteasome components, which may aid in discovering a new proteasome regulator for drug development and clinical applications.

Abstract Background Physicians are in a position of great influence to advocate for health equity. As such, it is important for physicians-in-training to develop the knowledge and skills necessary to fulfil this role. Although various undergraduate medical programs have implemented health advocacy training, they often lack experiential learning and physician involvement. These aspects are foundational to the Advocacy Mentorship Initiative (AMI) which utilizes cascading mentorship as a novel approach to advocacy training. Medical students develop advocacy competency as peer mentors to youth raised in at-risk environments, while also being mentored themselves by physician residents. We aim to determine whether there are specific advantages to utilizing cascading mentorship to facilitate the attainment of advocacy competencies in undergraduate medical education. Methods Medical students participating in AMI between 2017 to 2020 completed pre- and post-exposure questionnaires. Questionnaires assessed confidence in advocacy-related skills and knowledge of youth advocacy concepts, as well as learning goals, skills gained, benefits of AMI and resident mentors, and impact on future career. Sign tests were utilized to analyze quantitative results, and content analysis was used for open-ended responses. A triangulation protocol was also utilized. Results Fifty mentors participated, 24 (48%) of which completed both pre- and post-exposure questionnaires. Participants gained confidence in advocacy-related skills (p

For the first time, we reported the phytochemical composition of the volatile oil from Thymus musilii Velen (T. musilii). The antioxidant and antimicrobial activities against various food-borne and clinical pathogenic microorganisms were also tested. The thyme oil was particularly rich in thymol (67.697 ± 0.938%), and thymyl acetate (12.993 ± 0.221%). The strongest antioxidant activity of the essential oil was registered with the tests: ABTS (IC50 = 5.6 × 10−4 mg/mL) and β-carotene/linoleic acid (IC50 = 3.2 × 10−3 mg/mL). This thymol-chemotype oil was active against all microorganisms tested with an inhibition growth zone ranging from 21.33 ± 1.52 mm for Proteus mirabilis (P. mirabilis) to 37.33 ± 1.15 mm for Candida vaginalis (C. vaginalis) strain. Overall, the tested oil exhibited bactericidal and fungicidal activities and only a small quantity of the tested essential oil was found to be sufficient for inhibiting the growth of the tested microorganisms. Furthermore, molecular docking results implies that, among the bioactive compounds, β-caryophyllene interacted strongly with the active site residues of TyrRS, GLMS and Gyrase enzymes and consequently support our in vitro results with the highest inhibition potential of this essential oil against tested pathogens, especially Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). Our results suggested that essential oil of T. musiliii exhibited strong biological activities with a promising source of various natural compounds.

Though the immunity to malaria has been associated with cellular immune responses, the exact function of the phenotypic cell population is still unclear. This study investigated the host immune responses elicited during the pre-erythrocytic stage, post-Plasmodium yoelii sporozoite infection in Swiss mice model. For this purpose, we analyzed the dynamics of different subsets of immune cells population and cytokine levels in the hepatic mononuclear and splenic cells population during pre-erythrocytic liver-stage infection. We observed a significant reduction in the effectors immune cells population including CD8+ T cell, F4/80+ macrophage and in plasmacytoid dendritic cells (CD11c+ B220+). Interestingly, substantial down-regulation was also noted in pro-inflammatory cytokines (i.e. IFN-γ, TNF-α, IL-12, IL-2, IL-17 and iNOS), while, up-regulation of anti-inflammatory cytokines (i.e. IL-10, IL-4 and TGF-β) during asymptomatic pre-erythrocytic liver-stage infection. Collectively, this study demonstrated that during pre-erythrocytic development, Plasmodium yoelii sporozoite impaired the host activators of innate and adaptive immune responses by regulating the immune effector cells, gene expression and cytokines levels for the establishment of infection and subsequent development in the liver and spleen. The results in this study provided a better understanding of the events leading to malarial infection and will be helpful in supportive treatment and vaccine development strategy.

Abstract Background Tremor is a cardinal symptom of Parkinson’s disease (PD) that may cause severe disability. As such, objective methods to determine the exact characteristics of the tremor may improve the evaluation of therapy. This methodology study aims to validate the utility of two objective technical methods of recording Parkinsonian tremor and evaluate their ability to determine the effects of Deep Brain Stimulation (DBS) of the subthalamic nucleus and of vision. Methods We studied 10 patients with idiopathic PD, who were responsive to L-Dopa and had more than 1 year use of bilateral subthalamic nucleus stimulation. The patients did not have to display visible tremor to be included in the study. Tremor was recorded with two objective methods, a force platform and a 3 dimensional (3D) motion capture system that tracked movements in four key proximal sections of the body (knee, hip, shoulder and head). They were assessed after an overnight withdrawal of anti-PD medications with DBS ON and OFF and with eyes open and closed during unperturbed and perturbed stance with randomized calf vibration, using a randomized test order design. Results Tremor was detected with the Unified Parkinson’s Disease Rating Scale (UPDRS) in 6 of 10 patients but only distally (hands and feet) with DBS OFF. With the force platform and the 3D motion capture system, tremor was detected in 6 of 10 and 7 of 10 patients respectively, mostly in DBS OFF but also with DBS ON in some patients. The 3D motion capture system revealed that more than one body section was usually affected by tremor and that the tremor amplitude was non-uniform, but the frequency almost identical, across sites. DBS reduced tremor amplitude non-uniformly across the body. Visual input mostly reduced tremor amplitude with DBS ON. Conclusions Technical recording methods offer objective and sensitive detection of tremor that provide detailed characteristics such as peak amplitude, frequency and distribution pattern, and thus, provide information that can guide the optimization of treatments. Both methods detected the effects of DBS and visual input but the 3D motion system was more versatile in that it could detail the presence and properties of tremor at individual body sections.

Medicinal plants are an essential source of traditional curatives for numerous skin diseases. Polyalthia longifolia (Sonn.) Thwaites (Annonaceae family) is a medicinal plant used to cure skin illnesses. P. longifolia is usually applied in folkloric therapeutical systems to treat skin diseases. The methicillin-resistant Staphylococcus aureus (MRSA) bacteria is among the essential bacteria contributing to skin diseases. Hence, to verify the traditional medicinal claim of P. longifolia usage in skin disease treatment, the current research was performed to study the synergistic antibacterial activity of standardized Polyalthia longifolia methanol leaf extract (MEPL) against MRSA bacteria. The synergistic antimicrobial activity result of ceftriaxone, when mixed with MEPL, against MRSA was investigated by the disc diffusion method, broth microdilution method, checkerboard dilution test, and modulation of mecA gene expression by multiplex polymerase chain reaction (multiplex PCR). The MEPL extract exhibited good synergistic antimicrobial activity against MRSA. Using the checkerboard method, we confirmed the synergistic effect of MEPL from P. longifolia and ceftriaxone (2:1) for MRSA with a marked reduction of the MIC value of the ceftriaxone from 8000 µg/mL to 1000 µg/mL. Moreover, the combination of MEPL with ceftriaxone significantly (p < 0.05) inhibited the presence of the resistant mecA gene in the tested strain. The LC–ESI–MS/MS analysis identified compounds that were reported to exhibit antimicrobial activity. Conclusively, the MEPL extract, an important etiological agent for skin diseases, showed worthy synergistic antimicrobial action against MRSA bacteria, thus supporting the traditional use of P. longifolia.

The proteinaceous compounds produced by lactic acid bacteria are called bacteriocins and have a wide variety of bioactive properties. However, bacteriocin’s commercial availability is limited due to short stability periods and low yields. Therefore, the objective of this study was to synthesize bacteriocin-derived silver nanoparticles (Bac10307-AgNPs) extracted from Lactobacillus acidophilus (L. acidophilus), which may have the potential to increase the bioactivity of bacteriocins and overcome the hurdles. It was found that extracted and purified Bac10307 had a broad range of stability for both temperature (20–100 °C) and pH (3–12). Further, based on Sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS–PAGE) analysis, its molecular weight was estimated to be 4.2 kDa. The synthesized Bac10307-AgNPs showed a peak of surface plasmon resonance at 430 nm λmax. Fourier transform infrared (FTIR) confirmed the presence of biological moieties, and transmission electron microscopy (TEM) coupled with Energy dispersive X-Ray (EDX) confirmed that AgNPs were spherical and irregularly shaped, with a size range of 9–20 nm. As a result, the Bac10307-AgNPs displayed very strong antibacterial activity with MIC values as low as 8 μg/mL for Staphylococcus aureus (S. aureus) and Pseudomonas aeruginosa (P. aeruginosa), when compared to Bac10307 alone. In addition, Bac10307-AgNPs demonstrated promising in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 116.04 μg/mL) and in vitro cytotoxicity against human liver cancer cells (HepG2) (IC50 = 135.63 μg/mL), more than Bac10307 alone (IC50 = 139.82 μg/mL against DPPH and 158.20 μg/mL against HepG2). Furthermore, a protein–protein molecular docking simulation study of bacteriocins with target proteins of different biological functions was also carried out in order to ascertain the interactions between bacteriocins and target proteins.

The seventh human coronavirus was discovered and reported primarily in Wuhan, China. After intense seasons with repercussions in all areas of humanity, the pandemic demonstrates a new perspective. In Brazil, the pandemic concept had impacts in vast areas, including healthcare hospitals. This present study aims to describe and synthesize data from a determined period from the year 2021 that correlate the symptoms of passive and/or active patients for COVID-19 and their respective results of IgG/IgM serological tests in hospitals in the city of Cruzeiro, São Paulo, Brazil. The form had been applied to 333 people and obtained conclusive results and several symptoms were presented; in addition, asymptomatic cases were also analyzed and directed in the genomic study of variants of concern, as well as vaccination data in the study region.

In the wake of the emergence and worldwide respread of a viral infection called Monkeypox (Mpox), there is a serious threat to the health and safety of the global population. This viral infection was endemic to the western and central parts of Africa, but has recently spread out of this endemic area to various countries, including the United Kingdom (UK), Portugal, Spain, the United States of America (USA), Canada, Sweden, Belgium, Italy, Australia, Germany, France, the Netherlands, Israel, and Mexico. This is a timely review focusing on recent findings and developments in the epidemiology, clinical features, therapeutic targets, diagnosis, prevention mechanisms, research challenges and possible treatment for Mpox. To date (29 November 2022), there have been around 81,225 reported cases of Mpox. In most cases, this illness is mild; however, there is a fatality rate ranging from 1 to 10%, which might be increased due to associated complications and/or secondary infections. There is a real challenge in the diagnosis of Mpox, since its symptoms are very similar to those of other infections, including smallpox and chickenpox. Generally, to prevent/limit the risk and transmission of Mpox, the detection and isolation of infected individuals, as well as hand hygiene and cleanliness, are essential and effective approaches to control/combat this viral infection. Nevertheless, updated information about Mpox from different angles is lacking. Thus, this review provides updated and comprehensive information about the Mpox illness, which should highlight the global burden, pathogenicity, symptoms, diagnosis, prevention measures and possible treatment of this emerging disease.

Thymus musilii Velen. is a rare plant species cultivated in the Ha’il region (Saudi Arabia) under greenhouse conditions. In this work, we described, for the first time, the phytochemical composition, antimicrobial, antioxidant, anti-quorum sensing, and anticancer activities of T. musilii methanolic extract using both experimental and computational approaches. The obtained results showed the identification of eight small-like peptides and eighteen phyto-compounds by using high-resolution liquid chromatography–mass spectrometry (HR-LCMS) dominated mainly by compounds belonging to isoprenoid, fatty acyl, flavonoid, and alkaloid classes. The tested extracts exhibited high antifungal and antibacterial activity with the mean diameter of growth inhibition zones ranging from 12.33 ± 0.57 mm (Pseudomonas aeruginosa ATCC 27853) to 29.33 ± 1.15 mm (Candida albicans ATCC 10231). Low minimal inhibitory concentrations were recorded for the tested micro-organisms ranging from 0.781 mg/mL to 12.5 mg/mL. While higher doses were necessary to completely kill all tested bacterial and fungal strains. Thyme extract was able to scavenge DPPH•, ABTS•+, β-carotene, and FRAP free radicals, and the IC50 values were 0.077 ± 0.0015 mg/mL, 0.040 ± 0.011 mg/mL, 0.287 ± 0.012 mg/mL, and 0.106 ± 0.007 mg/mL, respectively. The highest percentage of swarming and swimming inhibition was recorded at 100 µg/mL with 39.73 ± 1.5% and 25.18 ± 1%, respectively. The highest percentage of biofilm inhibition was recorded at 10 mg/mL for S. typhimurium ATCC 14028 (53.96 ± 4.21%) and L. monocytogenes ATCC 7644 (49.54 ± 4.5 mg/mL). The in silico docking study revealed that the observed antimicrobial, antioxidant, and anticancer activities of the constituent compounds of T. musilii are thermodynamically feasible, notably, such as those of the tripeptides (Asn-Met-His, His-Cys-Asn, and Phe-His-Gln), isoprenoids (10-Hydroxyloganin), and diterpene glycosides (4-Ketoretinoic acid glucuronide).

In the present study, the chemical composition of the volatile oil and methanolic extract from Ducrosia flabellifolia Boiss. was investigated. The antimicrobial, antioxidant, and anticancer activities of the methanolic extract from D. flabellifolia aerial parts were screened using experimental and computational approaches. Results have reported the identification of decanal (28.31%) and dodecanal (16.93%) as major compounds in the essential oil obtained through hydrodistillation. Farnesyl pyrophosphate, Methyl 7-desoxypurpurogallin-7-carboxylate trimethyl ether, Dihydro-Obliquin, Gummiferol, 2-Phenylaminoadenosine, and 2,4,6,8,10-dodecapentaenal, on the other hand, were the dominant compounds in the methanolic extract. Moreover, the tested extract was active against a large collection of bacteria and yeast strains with diameter of growth inhibition ranging from 6.67 ± 0.57 mm to 17.00 ± 1.73 mm, with bacteriostatic and fungicidal activities against almost all tested microorganisms. In addition, D. flabellifolia methanolic extract was dominated by phenolic compounds (33.85 ± 1.63 mg of gallic acid equivalent per gram of extract) and was able to trap DPPH• and ABTS•+ radicals with IC50 about 0.05 ± 0 mg/mL and 0.105 ± 0 mg/mL, respectively. The highest percentages of anticancer activity were recorded at 500 µg/mL for all cancer cell lines with IC50 about 240. 56 µg/mL (A-549), 202.94 µg/mL (HCT-116), and 154.44 µg/mL (MCF-7). The in-silico approach showed that D. flabellifolia identified compounds bound 1HD2, 2XCT, 2QZW, and 3LN1 with high affinities, which together with molecular interactions and the bond network satisfactorily explain the experimental results using antimicrobial, antioxidant, and anticancer assays. The obtained results highlighted the ethnopharmacological properties of the rare desertic D. flabellifolia plant species growing wild in Hail region (Saudi Arabia).

Listeria monocytogenes (L. monocytogenes) is a serious food-borne pathogen that can cause listeriosis, an illness caused by eating food contaminated with this pathogen. Currently, the treatment or prevention of listeriosis is a global challenge due to the resistance of bacteria against multiple commonly used antibiotics, thus necessitating the development of novel green antimicrobials. Scientists are increasingly interested in microbial surfactants, commonly known as “biosurfactants”, due to their antimicrobial properties and eco-friendly nature, which make them an ideal candidate to combat a variety of bacterial infections. Therefore, the present study was designed to use a network pharmacology approach to uncover the active biosurfactants and their potential targets, as well as the signaling pathway(s) involved in listeriosis treatment. In the framework of this study, 15 biosurfactants were screened out for subsequent studies. Among 546 putative targets of biosurfactants and 244 targets of disease, 37 targets were identified as potential targets for treatment of L. monocytogenes infection, and these 37 targets were significantly enriched in a Gene Ontology (GO) analysis, which aims to identify those biological processes, cellular locations, and molecular functions that are impacted in the condition studied. The obtained results revealed several important biological processes, such as positive regulation of MAP kinase activity, protein kinase B signaling, ERK1 and ERK2 cascade, ERBB signaling pathway, positive regulation of protein serine/threonine kinase activity, and regulation of caveolin-mediated endocytosis. Several important KEGG pathways, such as the ERBBB signaling pathway, TH17 cell differentiation, HIF-1 signaling pathway, Yersinia infection, Shigellosis, and C-type lectin receptor signaling pathways, were identified. The protein–protein interaction analysis yielded 10 core targets (IL2, MAPK1, EGFR, PTPRC, TNF, ITGB1, IL1B, ERBB2, SRC, and mTOR). Molecular docking was used in the latter part of the study to verify the effectiveness of the active biosurfactants against the potential targets. Lastly, we found that a few highly active biosurfactants, namely lichenysin, iturin, surfactin, rhamnolipid, subtilisin, and polymyxin, had high binding affinities towards IL2, MAPK1, EGFR, PTPRC, TNF, ITGB1, IL1B, ERBB2, SRC, and mTOR, which may act as potential therapeutic targets for listeriosis. Overall, based on the integrated network pharmacology and docking analysis, we found that biosurfactants possess promising anti-listeriosis properties and explored the pharmacological mechanisms behind their effect, laying the groundwork for further research and development.

Honey exhibited potential antimicrobial activity against multidrug resistant (MDR) bacteria that continues to be a serious health problem. We reported the in-vitro activity of Saudi Sumra honey against clinical pathogenic bacteria and fungi, antibiofilm, anti-quorum-sensing (QS) and antioxidant activities in relation to its phytochemical composition assessed by gas chromatography-mass spectrometry (GC-MS). Broth dilution method and scavenging activities against 2,2-diphenyl-1-picryl-hydrazyl-hydrate (DPPH) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and β-carotene bleaching assays were performed. The GC-MS analysis of Sumra honey showed that 2,4-dihydroxy-2,5-dimethyl-3(2H)-furan-3-one 1-methylcyclopropanemethanol were the major identified phytoconstituents. Sumra honey showed a minimum inhibitory concentration (MIC) to clinical isolates of Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) at 300 mg/mL, Pseudomonas aeruginosa (250 mg/mL), Escherichia coli (350 mg/mL) and Acinetobacter baumannii (250 mg/mL); clinical fungal isolates—Candida auris (600 mg/mL) and Cryptococcus neoformans (>1000 mg/mL); wild type fungal isolates—Candida krusei (>1000 mg/mL) and Candida albicans (700 mg/mL). In addition, Sumra honey demonstrated promising inhibition targeting biofilm formation by 59% for Bacillus subtilis, 48% for S. aureus, 38% for E. coli, and 33.63% for P. aeruginosa. The violacein production in Chromobacterium violaceum was reduced to 68%, whereas pyocyanin production in P. aeruginosa was reduced to 54.86% at ½ MIC. Furthermore, Sumra honey exhibited strong antioxidant activities (DPPH − IC50 = 7.7 mg/mL; ABTS − IC50 = 5.4 mg/mL; β-carotene − IC50 = >20 mg/mL). Overall, obtained data highlighted the promising potential therapeutic use of Sumra honey treating infections caused by MDR bacteria and fungi. Moreover, Sumra honey can be a good candidate as an inhibitor agent for bacterial cellular communication in strains of P. aeruginosa and C. violaceum.

Ilimaquinone (IQ), a metabolite found in marine sponges, has been reported to have a number of biological properties, including potential anticancer activity against colon cancer. However, no clear understanding of the precise mechanism involved is known. The aim of this study was to examine the molecular mechanism by which IQ acts on HCT-116 cells. The anticancer activity of IQ was investigated by means of a cell viability assay followed by the determination of induction of apoptosis by means of the use of acridine orange–ethidium bromide (AO/EB) staining, Annexin V/PI double staining, DNA fragmentation assays, and TUNEL assays. The mitochondrial membrane potential (ΔΨm) was detected using the JC-1 staining technique, and the apoptosis-associated proteins were analyzed using real-time qRT-PCR. A molecular docking study of IQ with apoptosis-associated proteins was also conducted in order to assess the interaction between IQ and them. Our results suggest that IQ significantly suppressed the viability of HCT-116 cells in a dose-dependent manner. Fluorescent microscopy, flow cytometry, DNA fragmentation and the TUNEL assay in treated cells demonstrated apoptotic death mode. As an additional confirmation of apoptosis, the increased level of caspase-3 and caspase-9 expression and the downregulation of Bcl-2 and mitochondrial dysfunction were observed in HCT-116 cells after treatment with IQ, which was accompanied by a decrease in mitochondrial membrane potential (ΔΨm). Overall, the results of our studies demonstrate that IQ could trigger mitochondria-mediated apoptosis as demonstrated by a decrease in ΔΨm, activation of caspase-9/-3, damage of DNA and a decrease in the proportion of Bcl-2 through the mitochondrial-mediated apoptosis pathway.

This study aimed at optimizing conditions for increased withanolide production in Withania somnifera. The elicitors used for the foliar spray on the aerial parts of the plant were salicylic acid, jasmonic acid, and chitosan for the enhancement of withanolides in Withania somnifera under different environmental regimes. Three different elicitors, i.e., chitosan, jasmonic acid and salicylic acid, were applied on the plants through foliar route every 15th day for 6 months, and later plants were used for sample preparation. Further, the elicitors were used in different concentration, i.e., jasmonic acid (50, 200 and 400 ppm), chitosan (10, 50 and 100 ppm) and salicylic acid (0.5, 1 and 2 ppm). The elicitors were sprayed on the foliar parts of the plant between 10:00–11:00 a.m. on application days. For elicitor spray, a calibrated sprayer was used. The withanolide A/withaferin A was quantified through HPLC. It was found that in an open environment, maximum withaferin A content, i.e., 0.570 mg/g (DW), was recorded with jasmonic acid (50 ppm) treatment in comparison to control (0.067 mg/g DW). Thus, there was an 8.5-fold increase in the withaferin A content. Maximum withanolide A content of 0.352 mg/g (DW) was recorded when chitosan (50 ppm) was sprayed, while in the control, withanolide A content was recorded to be 0.031 mg/g (DW); thus, chitosan application increased the production of withanolide A by 11.3-fold. Under controlled conditions, maximum withaferin A content of 1.659 mg/g (DW) was recorded when plants were sprayed with chitosan (100 ppm), which was 8.1 times greater than the control content of 0.203 mg/g (DW). Maximum withanolide A content of 0.460 mg/g (DW) was recorded when chitosan (100 ppm) was applied, whereas in the control, withanolide A content was found to be 0.061 mg/g (DW). Thus, foliar spraying of elicitors in very low concentrations can serve as a low-cost, eco-friendly, labor-intensive and elegant alternative approach that can be practiced by farmers for the enhancement, consistent production and improved yield of withanolide A/withaferin A. This can be a suitable way to enhance plant productivity, thus increasing the availability of withanolide A and withaferin A for the health and pharma industry.

The Hague Convention is an international intergovernmental agreement that facilitates the return of abducted children to lawful parents across international borders. Children may not be returned if it can be established that the return would result in harm to the child. Forensic psychiatrists may be called upon to provide an expert opinion regarding the potential harm to come to a child, as well as various other psycholegal issues. We discuss interpretations and precedents regarding this law and the possible contributions of forensic psychiatrists. We also discuss two hybridized case examples involving international child abduction and proceedings before the Hague Convention. We will discuss issues that arose after psychiatric evaluations in each case.

Worldwide, the primary problem today is the proliferation of cancer and secondary bacterial infections caused by biofilms, as they are the principal causes of death due to the lack of effective drugs. A great deal of biological activities of silver nanoparticles (AgNPs) have made them a brilliant choice for the development of new drugs in recent years. The present study was conducted to evaluate the anticancer, antibacterial, anti-QS, and antibiofilm effects of AgNPs synthesized from Eruca sativa (E. sativa) leaf extract. The ultraviolet–visible (UV–Vis) spectra showed a peak of surface plasmon resonance at 424 nm λmax, which corresponded to AgNP formation. The Fourier transform infrared spectroscopy (FT-IR) confirmed that biological moieties are involved for the development of AgNPs. Moreover, transmission electron microscopy (TEM) analyses confirmed the spherical shape and uniform size (8.11 to 15 nm) of the AgNPs. In human lung cancer cells (A549), the anticancer potential of AgNPs was examined by the MTT [3-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, scratch assay, and invasion assay. The results indicated that AgNPs inhibit the migration of A549 cells. The synthesized AgNPs showed MIC values of 12.5 µg/mL against Chromobacterium violaceum (C. violaceum) and 25 µg/mL against Pseudomonas aeruginosa (P. aeruginosa), which demonstrated their antibacterial abilities. Biological compounds that disable the QS system are being investigated as potential strategies for preventing bacterial infections. Thus, we analyzed the potential effectiveness of synthesized AgNPs in inhibiting QS-regulated virulence factors and biofilm formation in both strains of bacteria. In C. violaceum, the synthesized AgNPs significantly inhibited both violacein (85.18% at 1/2 × MIC) and acyl homoserine lactone (78.76% at 1/2 × MIC). QS inhibitory activity was also demonstrated in P. aeruginosa at a sub-MIC concentration (1/2 × MIC) by a reduction in pyocyanin activity (68.83%), total protease (68.50%), LasA activity (63.91%), and LasB activity (56.40%). Additionally, the exopolysaccharide production was significantly reduced in both C. violaceum (65.79% at 1/2 × MIC) and P. aeruginosa (57.65% at 1/2 × MIC). The formation of biofilm was also significantly inhibited at 1/2 × MIC in C. violaceum (76.49%) and in P. aeruginosa (65.31%). Moreover, a GC–MS analysis confirmed the presence of different classes of bioactive phytochemical constituents present in the leaf extract of E. sativa. On the basis of our results, we conclude that biologically synthesized AgNPs showed numerous multifunctional properties and have the potential to be used against human cancer and bacterial biofilm-related infections.

Parkinson's disease (PD) can produce postural abnormalities of the standing body position such as kyphosis. We investigated the effects of PD, deep brain stimulation (DBS) in the subthalamic nucleus (STN), vision and adaptation on body position in a well-defined group of patients with PD in quiet standing and during balance perturbations. Ten patients with PD and 25 young and 17 old control participants were recruited. Body position was measured with 3D motion tracking of the ankle, knee, hip, shoulder and head. By taking the ankle as reference, we mapped the position of the joints during quiet standing and balance perturbations through repeated calf muscle vibration. We did this to explore the effect of PD, DBS in the STN, and vision on the motor learning process of adaptation in response to the repeated stimulus. We found that patients with PD adopt a different body position with DBS ON vs. DBS OFF, to young and old controls, and with eyes open vs. eyes closed. There was an altered body position in PD with greater flexion of the head, shoulder and knee (p≤0.042) and a posterior position of the hip with DBS OFF (p≤0.014). With DBS ON, body position was brought more in line with the position taken by control participants but there was still evidence of greater flexion at the head, shoulder and knee. The amplitude of movement during the vibration period decreased in controls at all measured sites with eyes open and closed (except at the head in old controls with eyes open) showing adaptation which contrasted the weaker adaptive responses in patients with PD. Our findings suggest that alterations of posture and greater forward leaning with repeated calf vibration, are independent from reduced movement amplitude changes. DBS in the STN can significantly improve body position in PD although the effects are not completely reversed. Patients with PD maintain adaptive capabilities by leaning further forward and reducing movement amplitude despite their kyphotic posture.

Quorum sensing (QS) controls the expression of diverse biological traits in bacteria, including virulence factors. Any natural bioactive compound that disables the QS system is being considered as a potential strategy to prevent bacterial infection. Various biological activities of biosurfactants have been observed, including anti-QS effects. In the present study, we investigated the effectiveness of a biosurfactant derived from Lactiplantibacillus plantarum on QS-regulated virulence factors and biofilm formation in Pseudomonas aeruginosa and Chromobacterium violaceum. The structural analogues of the crude biosurfactant were identified using gas chromatography–mass spectrometry (GC–MS). Moreover, the inhibitory prospects of identified structural analogues were assessed with QS-associated CviR, LasA, and LasI ligands via in silico molecular docking analysis. An L. plantarum-derived biosurfactant showed a promising dose-dependent interference with the production of both violacein and acyl homoserine lactone (AHL) in C. violaceum. In P. aeruginosa, at a sub-MIC concentration (2.5 mg/mL), QS inhibitory activity was also demonstrated by reduction in pyocyanin (66.63%), total protease (60.95%), LasA (56.62%), and LasB elastase (51.33%) activity. The swarming motility and exopolysaccharide production were also significantly reduced in both C. violaceum (61.13%) and P. aeruginosa (53.11%). When compared with control, biofilm formation was also considerably reduced in C. violaceum (68.12%) and P. aeruginosa (59.80%). A GC–MS analysis confirmed that the crude biosurfactant derived from L. plantarum was a glycolipid type. Among all, n-hexadecanoic acid, oleic acid, and 1H-indene,1-hexadecyl-2,3-dihydro had a high affinity for CviR, LasI, and LasA, respectively. Thus, our findings suggest that the crude biosurfactant of L. plantarum can be used as a new anti-QS/antibiofilm agent against biofilm-associated pathogenesis, which warrants further investigation to uncover its therapeutic efficacy.