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Infectious diseases manifesting in the form of epidemics or pandemics do not only cause devastating impacts on public health systems but also disrupt the functioning of the socio-economic structure. Further, risks associated with pandemics and epidemics become exacerbated with coincident compound hazards. This study aims to develop a framework that captures key elements and components of epidemic and pandemic preparedness and response systems, focusing on a multi-hazard context. A systematic literature review was used to collect data through peer-reviewed journal articles using three electronic databases, and 17 experts were involved in the validation. Epidemiological surveillance and early detection, risk and vulnerability assessments, preparedness, prediction and decision making, alerts and early warning, preventive strategies, control and mitigation, response, and elimination were identified as key elements associated with epidemic and pandemic preparedness and response systems in a multi-hazard context. All elements appear integrated within three interventional phases: upstream, interface, and downstream. A holistic approach focusing on all interventional phases is required for preparedness and response to pandemics and epidemics to counter their cascading and systemic effects. Further, a paradigm shift in the preparedness for multi-hazards during an epidemic or pandemic is essential due to the multiple challenges posed by concurrent hazards.

Near-field (NF) integrated sensing and communication (ISAC) has the potential to revolutionize future wireless networks. It enables simultaneous communication and sensing operations on the same radio frequency (RF) resources using a shared hardware platform, maximizing resource utilization. NF-ISAC systems can improve communication and sensing performance compared to traditional far-field (FF) ISAC systems by exploiting the unique propagation characteristics of NF spherical waves with an additional distance dimension. Despite its potential, NF-ISAC research is still in its early stages, and a comprehensive survey of the technology is lacking. This paper systematically explores NF-ISAC technology, providing an in-depth analysis of both NF and FF systems, their applicability in various scenarios, and different channel models. It highlights the advantages and philosophies of ISAC, examining both narrow-band and wide-band NF-ISAC systems. Case studies and simulations offer deeper insights into NF-ISAC design philosophies. Additionally, the paper reviews the existing NF-ISAC literature, methodologies, potentials, and conclusions, and discusses future research areas, challenges, and applications.

Introduction: The practice of dentistry benefits greatly from cone beam computed tomography (CBCT) and advantages should be prioritized over hazards; even modest doses of X-rays have the potential to have cytotoxic effects, damage DNA through their clastogenic impact, and stimulate the creation of micronuclei along with further nuclear changes., Aims and Objectives: To assess the genotoxicity and cytotoxicity of X-rays in exfoliated oral mucosal cells from patients who underwent CBCT scans at different fields of view (FOV), and to examine and assess the extent of cytotoxicity and genotoxicity caused by X-rays in oral exfoliated cells of people who were subjected to CBCT at different fields of view (FOV)., Material and Methods: Following CBCT exposure, 66 patients were chosen from the Department of Oral Medicine and Radiology at the SVS Institute of Dental Sciences, Mahbubnagar. Cells from the buccal mucosa were then extracted using the exfoliative cytology method, and the samples were examined under a microscope to look for nuclear and cytological abnormalities., Results: A paired t-test analysis revealed that mean micronuclei increased significantly in each study group from before to after exposure. It increased in Group I from 93.59 to 96.05, in Group II from 83.27 to 91.86, and in Group III from 86.05 to 97.00. Various test analyses revealed an important relation between exposure status and the presence of karyorrhexis in Group III. There was no association in other groups., Conclusion: The study revealed a significant increase of micronuclei in subjects after exposure to radiation at various FOVs. There was an increased karyorrhexis following radiation exposure in all groups at various FOVs. The significant association between exposure and karyorrhexis in the larger size FOV group was noticed further potentiating the extent of increased damage as the size of FOV is increased., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. SVS Institute of Dental Sciences issued approval IEC/SVS/2022/253. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Vishwadha et al.)

Mycoplasma bovis is an important emerging pathogen of cattle and bison, but our understanding of the genetic basis of its interactions with its host is limited. The aim of this study was to identify genes of M. bovis required for interaction and survival in association with host cells. One hundred transposon-induced mutants of the type strain PG45 were assessed for their capacity to survive and proliferate in Madin-Darby bovine kidney cell cultures. The growth of 19 mutants was completely abrogated, and 47 mutants had a prolonged doubling time compared to the parent strain. All these mutants had a similar growth pattern to the parent strain PG45 in the axenic media. Thirteen genes previously classified as dispensable for the axenic growth of M. bovis were found to be essential for the growth of M. bovis in association with host cells. In most of the mutants with a growth-deficient phenotype, the transposon was inserted into a gene involved in transportation or metabolism. This included genes coding for ABC transporters, proteins related to carbohydrate, nucleotide and protein metabolism, and membrane proteins essential for attachment. It is likely that these genes are essential not only in vitro but also for the survival of M. bovis in infected animals., Importance: Mycoplasma bovis causes chronic bronchopneumonia, mastitis, arthritis, keratoconjunctivitis, and reproductive tract disease in cattle around the globe and is an emerging pathogen in bison. Control of mycoplasma infections is difficult in the absence of appropriate antimicrobial treatment or effective vaccines. A comprehensive understanding of host-pathogen interactions and virulence factors is important to implement more effective control methods against M. bovis . Recent studies of other mycoplasmas with in vitro cell culture models have identified essential virulence genes of mycoplasmas. Our study has identified genes of M. bovis required for survival in association with host cells, which will pave the way to a better understanding of host-pathogen interactions and the role of specific genes in the pathogenesis of disease caused by M. bovis ., Competing Interests: The authors declare no conflict of interest.

Background: Obesity and diabetes are known risk factors for severe dengue. Therefore, we sought to investigate the association of obesity with increased risk of hospitalization, as there is limited information., Methods and Findings: Children aged 10 to 18 years (n = 4782), were recruited from 9 districts in Sri Lanka using a stratified multi-stage cluster sampling method. Details of previous admissions to hospital due to dengue and anthropometric measurements were recorded and seropositivity rates for dengue were assessed. The body mass index (BMI) centile in children aged 10 to 18, was derived by plotting the values on the WHO BMI-for-age growth charts, to acquire the percentile ranking., Results: Although the dengue seropositivity rates were similar in children of the different BMI centiles, 12/66 (18.2%) seropositive children with a BMI centile >97th, had been hospitalized for dengue, compared to 103/1086 (9.48%) of children with a BMI centile of <97th. The logistic regression model suggested that BMI centiles 50th to 85th (OR = 1.06, 95% CI, 1.00 to 1.11, p = 0.048) and BMI centile of >97th (OR 2.33, 95% CI, 1.47 to 3.67, p = 0.0003) was significantly associated with hospitalization when compared to children in other BMI categories., Conclusions: Obesity appears to be associated with an increased risk of hospitalization in dengue, which should be further investigated in longitudinal prospective studies. With the increase in obesity in many countries, it would be important to create awareness regarding obesity and risk of severe disease and hospitalization in dengue., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Jeewandara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Lack of data on drug secretion in human milk is a concern for safe use of drugs during postpartum.Clinical studies are often difficult to perform; despite substantial improvements in computational methodologies such as physiologically based pharmacokinetic modelling, there is limited clinical data to validate such models for many drugs.Various factors that are likely to impact milk to plasma ratio were identified. A literature search was performed to gather available data on milk composition, total volume of milk produced per day, milk pH, haematocrit, and renal blood flow and glomerular filtration rate in various animal models.BLAST nucleotide and protein tools were used to evaluate the similarities between humans and animals in the expression and predominance of selected drug transporters, metabolic enzymes, and blood proteins.A multistep analysis of all the potential variables affecting drug secretion was considered to identify most appropriate animal model. The practicality of using the animal in a lab setting was also considered.Donkeys and goats were identified as the most suitable animals for studying drug secretion in milk and future studies should be performed in goats and donkeys to validate the preliminary observations.

Diabetes mellitus, linked with insulin resistance and hyperglycaemia, is a leading cause of mortality. Glucose uptake through glucose transporter type 4, especially in skeletal muscle, is crucial for maintaining euglycaemia and is a key pathway targeted by antidiabetic medication. Abrus precatorius is a medicinal plant with demonstrated antihyperglycaemic activity in animal models, but its mechanisms are unclear.This study evaluated the effect of a 50% ethanolic ( v/v ) A. precatorius leaf extract on (1) insulin-stimulated glucose uptake and (2) related gene expression in differentiated C2C12 myotubes using rosiglitazone as a positive control, and (3) generated a comprehensive phytochemical profile of A. precatorius leaf extract using liquid chromatography-high resolution mass spectrometry to elucidate its antidiabetic compounds. A. precatorius leaf extract significantly increased insulin-stimulated glucose uptake, and insulin receptor substrate 1 and Akt substrate of 160 kDa gene expression; however, it had no effect on glucose transporter type 4 gene expression. At 250 µg/mL A. precatorius leaf extract, the increase in glucose uptake was significantly higher than 1 µM rosiglitazone. Fifty-five phytochemicals (primarily polyphenols, triterpenoids, saponins, and alkaloids) were putatively identified, including 24 that have not previously been reported from A. precatorius leaves. Abrusin, precatorin I, glycyrrhizin, hemiphloin, isohemiphloin, hispidulin 4'- O - β -D-glucopyranoside, homoplantaginin, and cirsimaritin were putatively identified as known major compounds previously reported from A. precatorius leaf extract. A. precatorius leaves contain antidiabetic phytochemicals and enhance insulin-stimulated glucose uptake in myotubes via the protein kinase B/phosphoinositide 3-kinase pathway by regulating insulin receptor substrate 1 and Akt substrate of 160 kDa gene expression. Therefore, A. precatorius leaves may improve skeletal muscle insulin sensitivity and hyperglycaemia. Additionally, it is a valuable source of bioactive phytochemicals with potential therapeutic use for diabetes., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Background: The pandemic has put at risk the social and emotional development of children on account of the paucity of arenas for social interaction. This study from Kerala, India was conducted to assess the resilience factors, behavioural concerns, psychological distress symptoms among the children aged 3 to 5 years. We also tried to look into the lost opportunities that could have aided the social and emotional development of children like peer interaction, child care hours., Methods: The cross-sectional study was conducted among the children aged 3 to 5 years. A total of 535 children attending the immunisation clinics were enrolled by consecutive sampling. Devereux Early Childhood Assessment P2 (DECA P2) questionnaire was used to assess the levels of resilient factors and behavioural concerns in the study population., Results: We observed a high proportion of children in the area of need category of protective factors under DECA P2. The proportion of children falling under area of concern was 64.5%, 49%, 68.4% for attachment/relationship, self-regulation, and initiative respectively. 24.9% study subjects have a behavioural concern score that puts them in the area of need category. The logistic regression model we created identified 'Male Gender,' 'Mothers could spend only less time for child care' and 'electronic devices used as pacifier' as significant predictors for belonging to Area of need Behavioural Concerns T score category., Conclusion: A large proportion of children aged between 3 to 5 years with reported behavioural concerns and lack of protective factors for socioemotional development. This can be attributed partly to the ongoing pandemic and its associated restrictions. The increased child care hours invested by parents or grandparents could have sized down the full impact that the pandemic would have had on the socio emotional development of the child. Increased time spent using electronic devices coupled with dwindled opportunities for interaction with peers have been notable challenges., (© 2024. The Author(s).)

Background: There are no guidelines on individualized initial levothyroxine dosage in primary hypothyroidism. This prospective observational study was done to assess whether a predetermined dose of levothyroxine based on Thyroid Stimulating Hormone (TSH) levels would be able to make the patient euthyroid during a period of six weeks and to find other factors which influence the levothyroxine requirement., Materials and Methods: Newly diagnosed patients with primary hypothyroidism or those patients who were not on levothyroxine therapy were divided into TSH-based groups-Group 1, 5-9.99, Group 2, 10-29.99, Group 3, 30-99.99 and Group 4, >100 μIU/ml and treated with an initial levothyroxine dose of 25,50,75 and100 μg/day for next six weeks. Factors correlating with levothyroxine requirement were determined., Results: Of the 171 patients who were included 142 completed the study, 34,46,28 and 34 patients were included in groups 1 to 4, respectively. Normalization of TSH with the above criteria was achieved in 111 (78.7%) out of 141 patients, and 91%, 67%, 75%, and 82% respectively in the 4 groups. Among adequately replaced patients pre-treatment TSH level (r = 0.81), T4 level (r = 0.61), and body weight (r = 0.19) correlated with the levothyroxine requirement. Based on these factors predicted initial dose (μg/day) was found to be 0.54 (Body Weight [Kg]) +0.47 (TSH [μIU/m]) - 1.4 (Total T4 [μg/dl]) +17.79 or 0.27 (Body Weight) +0.553 (TSH) +21., Conclusion: Serum thyrotropin-based categorization for initial levothyroxine dose leads to euthyroidism in nearly four of five patients with primary hypothyroidism. The dose required for adequate replacement of levothyroxine has correlation with pre-treatment serum TSH levels serum thyroxine levels and body weight., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Background: Dengue shows high geographic heterogeneity within and across endemic countries. In the context of increasing burden and predicted outbreaks due to climate change, understanding the heterogeneity will enable us to develop region specific targeted interventions, including vaccination. World Health Organisation (WHO) suggests standard methodologies to study the burden and heterogeneity at national and subnational levels. Regional studies with robust and standard methodology to capture heterogeneity are scarce. We estimated the seroprevalence of dengue in children aged 9-12 years and the force of infection in Kerala, India, from where Zika cases also have been reported recently., Methods: We conducted a school-based cross-sectional survey in 38 clusters; selected by stratified random sampling, representing rural, urban, high burden and low-burden administrative units. Validation of Indirect IgG ELISA was done by Plaque Reduction Neutralization Test (PRNT 90 ) using the local isolates of all four serotypes. Force of infection (FOI) was estimated using the WHO-FOI calculator. We conducted a follow-up survey among a subsample of seronegative children, to estimate the rate of sero-conversion., Results: Among 5236 children tested, 1521 were positive for anti-dengue IgG antibody. The overall seroprevalence in the state was 29% (95% CI 24.1-33.9). The validity corrected seroprevalence was 30.9% in the overall sample, 46.9% in Thiruvananthapuram, 26.9% in Kozhikkode and 24.9% in Kollam. Age-specific seroprevalence increased with age; 25.7% at 9 years, 29.5% at 10 years, 30.9% at 11 years and 33.9% at 12 years. Seroprevalence varied widely across clusters (16.1%-71.4%). The estimated force of infection was 3.3/100 person-years and the seroconversion rate was 4.8/100 person-years. 90% of children who tested positive were not aware of dengue infection. All the four serotypes were identified in PRNT and 40% of positive samples had antibodies against multiple serotypes., Interpretation: The study validates the WHO methodology for dengue serosurveys and confirms its feasibility in a community setting. The overall seroprevalence in the 9-12 year age group is low to moderate in Kerala; there are regional variations; high burden and low burden clusters co-exist in the same districts. The actual burden of dengue exceeds the reported numbers. Heterogeneity in prevalence, the high proportion of inapparent dengue and the hyperendemic situation suggest the need for region-specific and targeted interventions, including vaccination., Funding: World Health Organization., Competing Interests: None., (© 2023 The Authors.)

Purpose: The reconstruction of defects around the knee and the proximal third of the leg necessitates thin, pliable skin with a stable and sensate soft tissue cover. This study analyzed the use of a proximally based sural artery flap for the coverage of such defects., Methods: This prospective clinical interventional study involved 10 patients who had soft tissue defects over the knee and the proximal third of the leg. These patients underwent reconstruction with a proximally based sural artery flap. The study analyzed various factors including age, sex, etiology, location and presentation of the defect, defect dimensions, flap particulars, postoperative complications, and follow-up., Results: There were 10 cases, all of which involved men aged 20 to 65 years. The most common cause of injury was trauma resulting from road traffic accidents. The majority of defects were found in the proximal third of the leg, particularly on the anterolateral aspect. Defect dimensions varied from 6×3 to 15×13 cm 2 , and extensive defects as large as 16 cm × 14 cm could be covered using this flap. The size of the flaps ranged from 7×4 to 16×14 cm 2 , and the pedicle length was 10 to 15 cm. In all cases, donor site closure was achieved with split skin grafting. This flap consistently provided a thin, pliable, stable, and durable soft tissue cover over the defect with no functional deficit and minimal donor site morbidity. Complications, including distal flap necrosis and donor site graft loss, were observed in two cases., Conclusions: The proximally based sural fasciocutaneous flap serves as the primary method for reconstructing medium to large soft tissue defects around the knee and the proximal third of the leg. This technique offers thin, reliable, sensate, and stable soft tissue coverage, and can cover larger defects with minimal complications., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (© 2023 The Korean Society of Traumatology.)

Purpose: Defects involving the ankle and foot are often the result of road traffic accidents. Many such defects are composite and require a flap for coverage, which is a significant challenge for reconstructive surgeons. Various locoregional options, such as reverse sural artery, reverse peroneal artery, peroneus brevis muscle, perforator-based, and fasciocutaneous flaps, have been used, but each flap type has limitations. In this study, we used the distally based lateral supramalleolar flap to reconstruct distal dorsal defects of the foot. The aim of this study was to analyze the efficacy of the flap in reconstructing distal dorsal defects of the foot. The specific objectives were to study the adequacy, reach, and utility of the lateral supramalleolar flap for distal defects of the dorsum of the foot; to observe various complications encountered with the flap; and to study the functional outcomes of reconstruction., Methods: The distal dorsal foot defects of 10 patients were reconstructed with distal lateral supramalleolar flaps over a period of 6 months at a tertiary care center, and the results were analyzed., Results: We were able to effectively cover distal foot defects in all 10 cases. Flap congestion was observed in two cases, and minor graft loss was seen in two cases., Conclusions: The distally based lateral supramalleolar flap is a good pedicled locoregional flap for the coverage of distal dorsal foot and ankle defects of moderate size, with relatively few complications and little morbidity. It can be used as a lifeboat or even substitute for a free flap., Competing Interests: Conflicts of interest The authors have no conflicts of interest to declare., (© 2023 The Korean Society of Traumatology.)

Objective: This study aims at understanding the level of knowledge, attitude, and practice of breastfeeding among mothers and the factors associated with good knowledge about breastfeeding., Materials and Methods: A cross-sectional study among 251 mothers of infants admitted in the pediatric wards of SAT Hospital, Thiruvananthapuram was conducted during November-December 2019. The mothers of infants born between 37 and 42 weeks of gestation and without major birth defects were included in the study. The data were entered into an MS Excel sheet and analyzed using Statistical Package of Social Sciences version 26.0. Significance of association was tested using Chi-square test and multivariate analysis was done using binary logistic regression test., Results: The mean age of the participants was 26.25 (SD 4) years. On multivariable analysis, higher education and older age were found to be significantly associated with good knowledge. Independent sample T-Test results show that there was a statistically significant difference between the mean age of mothers with good knowledge (26.4(±4), 25.14(±3.7)), p-0.015 and statistically significant association was found between the mean attitude scores (34.07(5.58)) with current breastfeeding practices (p=0.002). Chi-square test shows that exclusive breastfeeding was significantly associated with the mother's age (p=0.006); 64.2% of women practicing exclusive breastfeeding were less than 25 years of age. This study also demonstrated a significant association between the initiation of breastfeeding within an hour and exclusive breastfeeding (p=0.003)., Conclusion: This study shows that mothers with higher age and higher educational qualifications were significantly associated with good knowledge about breastfeeding. Even though mothers have good knowledge, nearly half the mothers only exclusively breastfeed their infants for six months. Improving the educational qualification of women and increasing awareness about the benefits of breastfeeding among young women will promote breastfeeding practices., Competing Interests: Conflict of Interests Authors declare no conflict of interests., (Copyright © 2023 Tehran University of Medical Sciences. Published by Tehran University of Medical Sciences.)

Background: The Angio-invasive Rhino-orbito-cerebral mucormycosis (ROCM) producing strokes is a less explored entity. Our hospital, a stroke-ready one, had an opportunity to manage mucormycosis when it was identified as the nodal center for mucormycosis management. We are sharing our experiences and mistakes in managing the cerebrovascular manifestations of ROCM., Methods: We conducted a prospective observational study during the second wave of the COVID-19 pandemic from 1st May 2021 to 30th September 2021, where consecutive patients aged more than 18 years with microbiologically confirmed cases of ROCM were included. Clinical details (timing of stroke onset after ROCM symptoms, GCS, NIHSS), imaging findings (ASPECTS, the territory of stroke, the pattern of infarct, hemorrhagic transformation, cavernous sinus thrombosis), angiogram findings, management details (IV thrombolysis), and outcomes (mRS at discharge and duration of hospital stay) were documented. We also compared the demographics, clinical features (NIHSS), radiological findings, treatment details, duration of hospital stay, and functional outcome at the discharge of the ROCM stroke patients with stroke patients without ROCM., Results: Stroke developed in 42% of patients with ROCM, predominantly anterior circulation border zone ischemic infarcts. Strokes occurred after a median of five days from the onset of ROCM symptoms. The most common vessel involved was the ophthalmic artery, followed by the cavernous ICA. We could not thrombolyse ROCM stroke patients. ROCM patients who developed stroke compared with patients without stroke had a more infiltrative fungal infection and higher inflammatory markers. Mucormycosis associated stroke patients had higher in-hospital mortality and poor functional outcomes., T Conclusion: Due to delayed recognition of stroke symptoms, none received reperfusion strategies, leading to poor functional outcomes. For early stroke detection, ROCM cases need frequent monitoring and education of patients and their relatives about the ALS acronym (loss of ambulation, limb weakness, and loss of speech)., Competing Interests: Disclosures None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The present study was initiated with PDB selection and validation where 11 acetylcholinesterase (AChE) and 4 N-methyl-D-aspartate receptor (NMDAR) proteins were considered for docking with Rivastigmine and Riluzole respectively. Out of the 15 proteins, selected significant binding was observed for AChE, with 5FPQ, and NMDA receptors with 5I2K. Molecular docking studies of 5FPQ/Rivastigmine complex displayed a binding score of -8.6 kcal/mol, and the predicted inhibitory concentration (Ki) was found to be 31 nM, whereas the 5I2K/Riluzole complex showed a binding score of -9.6 kcal/mol, with an inhibitory concentration (Ki) of 21 nM. Riluzole in complex with 5I2K formed predominant π-π stacking interactions with Tyr144, pi-alkyl interaction with Pro129, and conventional hydrogen bond with Phe130. In contrast, Rivastigmine in a complex with 5FPQ formed a hydrogen bond with Gln413 and pi-alkyl with Pro537. Molecular dynamics simulation study of both complexes 5FPQ/Rivastigmine and 5I2K/Riluzole exhibited stable RMSD, RMSF, Rg, and significant numbers of hydrogen bonds. From free energy landscape (FEL) analysis both complexes were observed to achieve global minima. Overall, molecular docking and MD simulation with subsequent binding free energies studies (MM-PBSA) elucidate the binding conformations and stability of these reprogrammed drugs in the AChE and NMDAR targets. From these in-silico predictions, it can be suggested that both Rivastigmine and Riluzole combination may provide better insights as a starting point combination therapy for the treatment of Alzheimer's disease.Communicated by Ramaswamy H. Sarma.

This study reports the design and synthesis of novel dialkyl (4-amino-5H-chromeno[2,3-d]pyrimidin-5-yl)phosphonates as potential antitumor agents against A549 (lung cancer), DU-145 (prostate cancer), PC-3 (prostate cancer), HeLa (cervical cancer) and MCF-7 (breast cancer), cell lines evidenced from the in vitro antitumor studies performed by MTT assay (across 10-30 μM concentrations). The structural eminence of these synthesized molecules has emanated by designing the structural core by uniting the chromene, pyrimidine and phosphonate moieties into one, which has augmented their novelty and made them unreported. Further the deep structural activity relationship study investigations articulated that the title compounds are promising drug-like compounds and potential inhibitor of histidine amino acid residue present on the respective enzymatic proteins [3QJZ (A549), 3VHE (DU-145), 3V49 (PC-3), 3F81 (HeLa), & 3R7Q (MCF-7)] of the cell lines screened and are identified as responsible for the multi-faceted antitumor activities predicted in vitro. The obtained results were further supported by molecular docking studies, QSAR, ADMET, and bioactivity studies which have supported them as potential BBB penetrable molecules and proficient CNS active neuro-protective agents during drug delivery., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Prof. Dr. C. Suresh Reddy has a patent #Application Number: 201741046873, Dated: 27/12/2017 and granted to Sri Venkateswara University, Tirupati 517 502, India on Dated: 27/06/2022; Patent No: 400076 (Document No: 044142395)., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Novel ethyl-4-(aryl)-6-methyl-2-(oxo/thio)-3,4-dihydro-1H-pyrimidine-5-carboxylates were synthesized from one-pot, three-component Biginelli reaction of aryl aldehydes, ethyl acetoacetate and urea/ thiourea by catalytic action of silica supported Bismuth(III) triflate, a Lewis acid. All the synthesized compounds were structurally characterized by spectral (IR, 1 H NMR & 13 C NMR spectroscopic and Mass spectrometric) and elemental (C, H & N) analyses. The present protocol has deserved novel as, formed the products in high yields with short reaction times, involved eco-friendly methodology and reusable heterogeneous Lewis acid catalyst. The title compounds were screened for in vitro DPPH free radical scavenging antioxidant activity and identified 4i, 4j, 4h & 4f as potential antioxidants. The obtained in vitro results were correlated with molecular docking, ADMET, QSAR, Bioactivity & toxicity risk studies and molecular finger print properties and found that in silico binding affinities were identified in good correlation with in vitro antioxidant activity and studied the structure activity relationship. The molecular docking study has disclosed strong hydrogen bonding interactions of title compounds with aspartic acid (ASP197) aminoacid residue of 2HCK, a complex enzyme of haematopoietic cell kinase and quercetin. Results of toxicology study evaluated for potential risks of compounds have revealed title compounds as safer drugs. In ultimate the study has established ligand's antioxidant potentiality as they effectively binds with ASP197 amino acid of Chain A hence confirms the inhibition of growth of reactive oxygen species in vivo. In addition, the title compounds have been identified as potential blood-brain barrier penetrable entities and efficient central nervous system (CNS) active neuro-protective antioxidant agents., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The present study intends to formulate, characterize and appraise the phospholipid-based nanovesicular system for enhanced delivery of Hesperetin (HT). The quality by design (QbD) approach was employed to prepare Hesperetin naturosomes (HTN) using the solvent evaporation technique and assessed for physicochemical and pharmacological attributes. The FTIR, DSC, and PXRD studies confirmed the successful formation of a vesicular drug-phospholipid complex, while photomicroscopy, SEM, and TEM analysis revealed the morphology of HTN. The functional attributes substantially enhanced the HT's aqueous solubility, drug release, and membrane permeation. The aqueous solubility of HTN was ~10-fold more than that of pure HT. Likewise, the in-vitro dissolution data of HTN showed better competence in releasing the HT (>93%) than the pure HT (~64%) or the physical mixture (~74%). Furthermore, HTN significantly altered HT permeation (>53%) when compared to pure HT (23%) or the physical mixture (28%). The current study showed that naturosomes are a promising way to improve the solubility in water, bioavailability, and therapeutic effectiveness of drugs., Competing Interests: The authors have declared that no competing interests exist.

Background: The role of local self-government (LSG) bodies in planning community-level interventions for noncommunicable diseases (NCD) control is critical. An understanding of how much priority is given to NCD in decentralized health planning is needed., Objective: The objective of this study is to analyze the pattern of budgetary allocation for health sector projects at different levels of LSGs in Thiruvananthapuram, Kerala, with specific reference to NCD control., Materials and Methods: Secondary data analysis was done on economic review reports and reports on health sector projects obtained from LSG department with permission. The pattern of budgetary allocation of health projects in both urban and rural local bodies of Thiruvananthapuram district for 2019-2020 was studied., Results: The proportion of NCD projects in terms of number and budget allocation, respectively, among health sector projects for gram panchayaths (GP) was 47 projects (5.25%) and 63.19 lakhs (1.8%). Figures for block panchayaths (BP) were 13 (9%) and 98.10 lakhs (10.94%), for district panchayath (DP), 1 (0.9%) and 48 lakhs (3%), for municipalities 1 (1.6%) and 4.66 lakhs (1.2%), and for corporation were 1 (1.4%) and 3 lakhs (0.16%). Only 29 (40%) GP and 5 (45%) BP had at least one NCD project. At the GP level, 21% of projects were community-based interventions and 15% of projects were for cancer screening, mental health, and hospital-based NCD clinics each. Among local bodies with lower allocation for NCD projects, the amount allocated for construction and maintenance work in health institutions was higher., Conclusion: Decision-making in decentralized health planning needs an evidence-based realignment of priorities toward NCD., Competing Interests: None

Background: In the context of the largest dengue outbreak in the state of Kerala, India in 2017, along with global evidence of changing epidemiology of dengue virus and its distribution, this study was planned to understand the epidemiological pattern of dengue infection and contemplate the clinical presentations of different serotypes., Methods: This cross-sectional study was conducted in the Thiruvananthapuram and Kollam districts of Kerala, India, spanning 3 y from 2017 to 2019. We recruited adult patients based on the World Health Organization case definition of probable dengue fever to study their virological, spatial and clinical characteristics., Results: Dengue infection was identified in 113 (33.9%) of the 333 probable dengue patients recruited. Dengue virus 1 (DENV1), along with its combinations (59.09%), was the predominant serotype during 2017, followed by DENV2. There was a marked increase in the proportion of DENV4 cases (34.56%) and concurrent infections (26%) in 2019. DENV3 infections were more likely to present with warning signs (adjusted relative risk 6.14 [95% confidence interval 1.3 to 29.4]) and a significantly lower platelet count (p=0.02)., Conclusions: The results highlight the hyperendemicity of dengue infection in the state and the changing pattern of dengue virus predominance along with redominance. The rise in DENV4 and concurrent infections put forth the possibility of a more severe future outbreak., (© The Author(s) 2022. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

Introduction and Aims: The COVID-19 pandemic poses an ongoing risk to health workers globally. This is particularly true in low- and middle-income countries (LMICs) where resource constraints, ongoing waves of infection, and limited access to vaccines disproportionately burden health systems. Thus, infection prevention and control (IPC) training for COVID-19 remains an important tool to safeguard health workers. We report on the implementation of evidence-based and role-specific COVID-19 IPC training for health workers in a hospital and public health field setting in Sri Lanka., Methods: We describe the development of training materials, which were contextualized to local needs and targeted to different staffing categories including support staff. We describe development of role- and context-specific IPC guidelines and accompanying training materials and videos during the first year of the COVID-19 pandemic. We describe in-person training activities and an overview of session leadership and participation., Results: Key to program implementation was the role of champions in facilitating the training, as well as delivery of training sessions featuring multi-media videos and role play to enhance the training experience. A total of 296 health workers participated in the training program sessions. Of these, 198 were hospital staff and 98 were from the public health workforce. Of the 296 health workers who participated in a training session, 277 completed a pre-test questionnaire and 256 completed post-test questionnaires. A significant increase in knowledge score was observed among all categories of staff who participated in training;however, support staff had the lowest pre-test knowledge on IPC practices at 71%, which improved to only 77% after the formal class., Conclusion: Implementing an IPC training program during a complex health emergency is a challenging, yet necessary task. Leveraging champions, offering training through multiple modalities including the use of videos and role play, as well as inclusion of all staff categories, is crucial to making training accessible., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the University of Adelaide, Joanna Briggs Institute.)

Identifying the right accessories for installing the dental implant is a vital element that impacts the sustainability and the reliability of the dental prosthesis when the medical case of a patient is not comprehensive. Dentists need to identify the implant manufacturer from the x-ray image to determine further treatment procedures. Identifying the manufacturer is a high-pressure task under the scaling volume of patients pending in the queue for treatment. To reduce the burden on the doctors, a dental implant identification system is built based on a new proposed thinner VGG model with an on-demand client-server structure. We propose a thinner version of VGG16 called TVGG by reducing the number of neurons in the dense layers to improve the system's performance and gain advantages from the limited texture and patterns in the dental radiography images. The outcome of the proposed system is compared with the original pre-trained VGG16 to verify the usability of the proposed system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Tsai, Xue, Wu, Van, Kaluarachchi, Dang and Chintha.)

Background: There are limited data regarding the safety and immunogenicity of the Sinopharm/BBIBP-CorV vaccine in pregnancy. Therefore, we sought to investigate the antibody responses and maternal and fetal adverse events following this vaccine in pregnant mothers in Sri Lanka., Methods and Findings: SARS-CoV-2 receptor binding domain (RBD) specific total antibodies and ACE2 blocking antibodies were measured by ELISA in pregnant mothers (n = 94) who received the vaccine in the first (n = 2), second (n = 57) and third (n = 33) trimester of pregnancy. Data regarding adverse events and fetal and maternal outcomes were obtained from the women once they delivered. No adverse maternal or fetal complications reported such as miscarriage, thrombotic events, hypertensive disorders, fetal death, preterm delivery, or congenital anomalies were reported. 58/94 (61.7%) had RBD binding antibodies and were found to be seropositive at the time of recruitment. All women seroconverted after the second dose and 31/36 previously uninfected women and 57/58 previously infected women gave a positive response to ACE2 blocking antibodies. The RBD binding antibody levels (p = 0.0002) and ACE2 blocking antibodies (p<0.0001) were significantly higher in previously infected individuals post-second dose compared to uninfected individuals., Conclusions: The Sinopharm/ BBIBP-CorV vaccine appeared safe and induced high seroconversion rates and ACE2 blocking antibodies in pregnant mothers in the second and third trimester in pregnancy. However, the RBD binding antibodies and ACE2 blocking antibodies post-second dose were significantly higher in previously infected pregnant mothers post-second dose, suggesting that two doses of the vaccine are likely to be less immunogenic in previously unexposed individuals., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 Jeewandara et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Mycoplasma bovis ( M. bovis ) can cause a multitude of diseases in cattle, with detrimental effects on the farm economy and the welfare of both adult and young cattle. The objective of this study was to determine the prevalence of M. bovis in adult cows and calves in the south-west region of Western Australia. A cross-sectional study was conducted on 29 dairy farms with 699 apparently healthy adult lactating cows and 495 young calves during 2019-2020. Nasal swabs and blood samples collected from the animals and bulk tank milk (BTM) samples were assessed for M. bovis -specific proteins and antibodies by using polymerase chain reaction (PCR) and Mycoplasma immunogenic lipase A- Enzyme-Linked Immune Sorbent Assay (MilA ELISA). A seroprevalence of 42.5% (95% CI: 38.9-46.2) and 61% (95% CI: 56.6-65.2) was found in adult lactating cows and calves, respectively. The herd-level seroprevalence of M. bovis ranged from 4% (95% CI: 07-19.5) to 92% (95% CI: 75.0-97.8) in adult lactating cows and 25% (95% CI: 10.2-49.5) to 87% (95% CI: 67.9-95.5) for calves in these farms. None of the BTM and nasal swab samples were positive for M. bovis , indicating an absence of any current active infections on the farms. The female calves and pure Holstein-Friesian animals are twice as likely to be seropositive for M. bovis compared to male calves (OR 2.4; 95% CI: 1.7-3.5) and Holstein-Friesian crossbred calves (OR 2.4; 95% CI: 1.7-3.5). The high seroprevalence in both adult and young cattle in the southwest dairy farms of Western Australia warrants more effective farm biosecurity measures and further evaluation of the current prevention and management measures practiced on the farms.

Vacuum frying technology has proven to be one of the best methods to produce snack products with higher retention of health-promoting/protecting nutraceuticals with reduced-fat content. In this work, application and optimization of vacuum frying process for purple sweet potato have used response surface methodology-based Box-Behnken design to produce low-fat and anthocyanin-rich purple sweet potato vacuum fried chips. The study showed the significant impact of frying temperature, vacuum pressure, and frying time on the chip's moisture and oil content, level of anthocyanin, visual impressions like color and texture. The selection of optimized frying parameters was carried out using a numerical optimizer and found to be 105°C for 7.08 min at a reduced pressure of 14.79 kPa. Compared to the atmospheric deep-fried chips, the vacuum fried chips showed 86% retention of anthocyanin content and a 35.6% decline in oil content with a lower breaking force of 0.69 N. Overall, the study confirmed that vacuum fried purple sweet potato chips could be a viable option to produce snacks with high functional value to meet the current consumer demands. PRACTICAL APPLICATION: Purple sweet potatoes have the potential to produce healthy snack chips with lower fat content and higher functional characteristics when vacuum frying technology is used with optimized processing variables., (© 2022 Institute of Food Technologists®.)

For the first time a new flavonoid compound is isolated from the seeds of Celastrus paniculatus (CP) using different chromatographic techniques and it's structure is predicted as "3-(3,4-dimethoxyphenyl)-1-(4-methoxyphenyl)prop-2-en-1-one" by employing various spectroscopic studies. The neuroprotective potential of this flavonoid was evaluated against ketamine-induced cognitive deficits with special reference to cholinergic system in vivo . The compound has exhibited significant neuroprotective property against ketamine-induced cholinergic alterations in different brain regions of rat which are restored to normal during the treatment with the compound on par with the reference compound, clozapine. Moreover, the isolated compound was found to be non-toxic to the animal during the treatment which indicates its safety in any human health related applications and can add value to the new drug development. In conclusion, this is the first study of new flavonoid compound of CP and its protective efficacy against schizophrenia.

Ethnopharmacological Relevance: Chandamarutha Chenduram (CC), an Indian traditional Siddha preparation officially recorded in the Siddha formulary of India and its composition are widely used in the Siddha practice of neurological disorders like stroke/paralysis in India. However, the scientific validation and mechanistic evidence is lacking and yet to be elucidated., Aim of the Study: To establish the scientific evidences and to explore the possible neuroprotective mechanism of CC in cerebral ischemia., Materials and Methods: Chemical standardization of the CC was performed using atomic absorption spectroscopy and gravimetric analysis. Acute toxicity study for CC in mice was performed in accordance with OECD 423 guidelines. CC (5 mg/kg) and CC (10 mg/kg) were investigated in bilateral common carotid occlusion (BCCAo) model in mice. After, behavioral assessments, the brain samples were collected and the hippocampus region was micro-dissected for neurotransmitter, neurobiochemicals and inflammatory cytokines estimation. The excitatory amino acid transporter-2 (EAAT-2) expressions was analyzed by RT-PCR to understand the possible molecular mechanism. In addition, hematoxylin and eosin staining of CA1 hippocampal brain region was performed to support the neuroprotective effect of CC in ischemic condition., Results: Chemical standardization analysis showed that CC has acceptable range of mercury (0.82 ppm) and elemental sulphur (11% w/w). Also, other heavy metal limits were found to be less or not detectable. Toxicity study also evidenced the safety profile of CC. CC has significantly reversed the behavioral dysfunctions (p < 0.001) in global ischemic mice. Treatment with CC has attenuated the excitatory neurotransmitter glutamate, lipid peroxide, nitric oxide, cytokines (IL-1β, TNF-α) (p < 0.001) and increased the antioxidant enzymes (SOD, CAT, GSH) and EAAT-2 expression level (p < 0.001) in ischemic brain. The hematoxylin and eosin staining in CA1 region of hippocampus also evidence the neuroprotective effect exhibited by CC., Conclusions: Treatment with CC has exhibited dose dependent effect and CC10 has shown significant protective effect in comparison to CC5 in most of the parameters studied. CC prevented further degeneration of neurons in cerebral ischemic mice through ameliorating inflammatory cytokines and oxy-radicals mediated EAAT-2 dysfunction and subsequent excitotoxicity in neurons., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Abstract: Appropriate monitoring of opioid use in patients with pain conditions is paramount, yet it remains a very challenging task. The current work examined the use of a wearable sensor to detect self-administration of opioids after dental surgery using machine learning. Participants were recruited from an oral and maxillofacial surgery clinic. Participants were 46 adult patients (26 female) receiving opioids after dental surgery. Participants wore Empatica E4 sensors during the period they self-administered opioids. The E4 collected physiological parameters including accelerometer x-, y-, and z-axes, heart rate, and electrodermal activity. Four machine learning models provided validation accuracies greater than 80%, but the bagged-tree model provided the highest combination of validation accuracy (83.7%) and area under the receiver operating characteristic curve (0.92). The trained model had a validation sensitivity of 82%, a specificity of 85%, a positive predictive value of 85%, and a negative predictive value of 83%. A subsequent test of the trained model on withheld data had a sensitivity of 81%, a specificity of 88%, a positive predictive value of 87%, and a negative predictive value of 82%. Results from training and testing model of machine learning indicated that opioid self-administration could be identified with reasonable accuracy, leading to considerable possibilities of the use of wearable technology to advance prevention and treatment., (Copyright © 2021 International Association for the Study of Pain.)

Ligand coated nanoparticles are complex objects consisting of a metallic or semiconductor core with organic ligands grafted on their surface. These organic ligands provide stability to a nanoparticle suspension. In solutions, the effective interactions between such nanoparticles are mediated through a complex interplay of interactions between the nanoparticle cores, the surrounding ligands, and the solvent molecules. While it is possible to compute these interactions using fully atomistic molecular simulations, such computations are too expensive for studying self-assembly of a large number of nanoparticles. The problem can be made tractable by removing the degrees of freedom associated with the ligand chains and solvent molecules and using the potentials of mean force (PMF) between nanoparticles. In general, the functional dependence of the PMF on the inter-particle distance is unknown and can be quite complex. In this article, we present a method to model the two-body and three-body PMF between ligand coated nanoparticles through a linear combination of symmetry functions. The method is quite general and can be extended to model interactions between different types of macromolecules.

Background: Despite being the first Indian state with a dedicated Non-Communicable Disease (NCD) program, glycemic control among a large proportion of patients is low in Kerala. This study tries to find evidence for a standardized non-pharmacological strategy delivered through Junior Public Health Nurses (JPHNs) in achieving and maintaining glycemic control among diabetic patients registered with NCD clinics of primary health care settings. Design: A cluster randomized controlled trial was conducted among adult patients with Diabetes Mellitus attending NCD clinics of primary care settings of South Kerala, India. JPHNs of the intervention group received additional module-based training while standard management continued in the control group. Sequence generation was done by random permuted blocks method and a cluster of 12 patients was selected from each of the 11 settings by computer-generated random numbers. Patients were followed up for 6 months with monthly monitoring of Fasting Blood Sugar (FBS), Post-Prandial Blood Sugar (PPBS), blood pressure, Body Mass Index (BMI), and health-related behaviors. Knowledge and skills/practice of JPHNs were also evaluated. Analysis of Covariance was done to study the final outcome adjusting for the baseline values and a model for glycemic control was predicted using multilevel modeling. Results: We analyzed 72 participants in the intervention group and 60 participants in the control group according to the intention-to-treat principle. The intervention was associated with a significant reduction in FBS ( p < 0.001) and PPBS ( p < 0.001) adjusting for the baseline values. The achievement of glycemic control was 1.5 (95% CI: 1.05-2.3) times better with intervention and they showed a better trend of maintenance of glycemic control (FBS, p = 0.003 and PPBS, p = 0.039). Adjusting for clustering and the baseline values, the intervention showed a significant effect on FBS (B = -3.1, SE = 0.57; p < 0.001) and PPBS (B = -0.81, SE = 0.3; p < 0.001) with time. Drug adherence score ( p < 0.001), hours of physical activity ( p < 0.001), BMI ( p = 0.002), fruit intake ( p = 0.004), and green leafy vegetable intake ( p = 0.01) were the major predictors of FBS control. The practice/skills score of the JPHNs significantly improved with intervention ( p < 0.001) adjusting for baseline values. Conclusion: A well-designed health worker intervention package incorporated into the existing health system can translate into attitude change and skill development in the health workers which can reflect in the improvement of glycemic control among the patients. Trial registration: [URL: http://www.ctri.nic.in], identifier [CTRI/2017/11/010622]., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rahul, Chintha, Anish, Prajitha and Indu.)

Background: COVID 19 is associated with the development of post COVID syndrome usually manifested as fatigue, anxiety, joint pain, headache, chest pain, dementia, depression, and dyspnea. Documented evidence of post COVID syndrome among patients with asymptomatic or mild infections, especially from India is less., Methodology: A community based prospective cohort study was conducted among 154 patients admitted in CFLTCs of coastal Thiruvananthapuram, Kerala during May-August 2020. They were enrolled at the time of their admission to CFLTCs and were followed up for three months after discharge. The discharged patients were followed up at regular intervals of three weeks and three months by telephonic interview using a structured proforma., Results: Out of the 154 patients followed up, 57 (37%) were men and 97 (63%) were women. The mean (SD) age of study participants was 31.49 (18.4) years. At least one symptom was present in 120 (78.0%) patients at the time of admission. Cough (29, 18.8%), fever (26, 16.8%), headache (25, 16.2%), rhinitis (23,14.9%) and sore throat (18, 11.7%) were the major symptoms reported at the time of admission. At the end of three weeks, 11 (7.1%) patients and at the end of three months 18 (11.7%) patients reported to have symptoms. Fatigue (5.8%), headache (5.8%) myalgia (3.2%) joint pain (2.5%) and exertional dyspnea (2.5%) were the predominant symptoms. Presence of fatigue, cough and breathlessness at the time of admission, and presence of another COVID positive family member were significantly associated with the appearance of post COVID symptoms., Conclusion: Post COVID syndrome is not uncommon in COVID 19 patients with minimal symptoms. Understanding long term consequences of COVID 19 is as important as management of acute COVID 19 due to its multisystem involvement and its implications on health and well-being., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Background: Poisoning has been and still is a major problem faced throughout the globe. But its patterns are different and changing in different parts of the world due to local influences. This calls for a study to explore the issue in this unique South Indian state., Methods: A cross-sectional exploratory study was conducted to analyse the patterns of poisoning and the socio-demographic characteristics of the patients. Subgroups were compared using Fisher-Freeman-Halton exact test and further analysed by multivariate logistic regression., Results: 48% of cases were of pharmaceutical drug poisoning. 27.5% of these cases involved polymedication and Paracetamol (Acetaminophen) turned out to be the single most drug used. Suicide was the most common circumstance. 10% of patients had co-diagnoses of psychiatric disorders. Univariate analysis separately showed that females (p < 0.001), higher educated (p = 0.149), higher socioeconomic strata (p = 0.136) and non-addicts (p = 0.002) were more exposed to drugs whereas males, lower educated, lower socioeconomic strata and addicts are skewed to pesticides for poisoning. Most repeat suicide attempts were with the same poisonous agent. 70% of patients with a diagnosed psychiatric disorder have attempted suicide before using some drugs (p < 0.001)., Conclusion: Our study highlights the importance of a region-wise, targeted approach in policymaking to curb poisoning., (Copyright © 2021 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Epilepsy is a related chronic neurological condition of a predisposition for recurrent epileptic seizures, with various manifestations and causes. Although there are antiepileptic drugs, complementary natural therapies are widely used. The purpose of this systematic review was to analyze the antiepileptic/anticonvulsant pharmacological properties of plant-food derived bioactive molecules. In this regard, a systematic review of the PubMed database was made based on the inclusion criteria. Natural compounds/herbs with scientifically proven antiepileptic properties were selected. Experimental pharmacological studies in vitro and in vivo have shown that flavonoids, alkaloids and terpenoids may have anticonvulsant mechanisms similar to the new generation antiepileptic drugs. The relationships of structure-anticonvulsant effect, pharmacological models, seizure-inducing factors and response, effective dose were also analyzed and discussed. The results of in vitro and in vivo pharmacological studies analyzed in this systematic review support the clinical importance of plant-food-derived bioactive molecules for the complementary treatment of epilepsy. Thus, are opened new perspectives to develop new natural anticonvulsant drugs., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To evaluate the therapeutic efficacy and underlying molecular mechanisms of Bauhiniastatin-1 (BSTN1) to alleviate adiposity in diet-induced obese rodent model and in 3T3-L1 cells. Methods: BSTN1 was purified and confirmed through HPLC. In-vitro experiments such as MTT assay, Oil Red-O (ORO) stain, cellular lipid content, glycerol release and RT-PCR analysis were performed in 3T3-L1 cells in the presence and absence of BSTN1. In animal experiments, rats were divided into Group-I: normal pellet diet-fed, Group-II: HFD-fed, Groups-III, IV and V: HFD-fed BSTN1 (1.25, 2.5, and 5 mg/kg.b.wt./day/rat)-treated and Group-VI: HFD-fed Orlistat-treated. The rats were fed either normal diet or high fat diet (HFD) for 18 weeks and water ad-libitum . BSTN1 was orally administered from 13th week onwards to the selected HFD-fed groups. Body composition parameters, biochemical assays, histopathology examination and western blot analysis were performed to identify the predicted targets related to obesity. Molecular docking studies threw light on the binding interactions of BSTN1 against PPAR-γ, FAS and AMPK. Results: BSTN1 at 20 μM significantly ( p < 0.001) inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 cells. A conspicuous down-regulation in the mRNA expression levels of PPAR-γ, FAS and SREBP1 was observed but AMPK expression remained unchanged in BSTN1 treated 3T3-L1 cells. A substantial decrease in body weight gain, fat percent, total body fat, serum and liver lipid profile (except high-density lipoprotein), glucose, insulin and insulin resistance in BSTN1 treated rats was noticed in a dose dependent manner. In BSTN1 (5 mg/kg.b.wt.)-treated groups significantly ( p < 0.01) elevated plasma adiponectin level but reduced leptin level as well as fall in serum AST and ALT were noticed. Further, the disturbed structural integrity and architecture of adipose and hepatic tissues due to high fat diet feeding were considerably recovered with BSTN1 treatment. Down-regulation in the protein expression level of PPAR-γ and activation of AMPK through phosphorylation was observed in BSTN1 treated rats than the untreated. Molecular docking studies revealed strong binding interactions of BSTN1 against PPAR-γ and AMPK and thus supported the experimental results. Conclusion: Taken together, the results suggest that BSTN1 could be a promising pharmacological molecule in the treatment of obesity and dyslipidemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Karunakaran, Lokanatha, Muni Swamy, Venkataramaiah, Muni Kesavulu, Appa Rao, Badri and Balaji.)

Objective: To understand the structures and strategies that helped Kerala in fighting the COVID-19 pandemic, the challenges faced by the state and how it was tackled., Design: Qualitative descriptive study using focus group discussions and in-depth interviews., Setting: State of Kerala, India., Participants: 29 participants: four focus group discussions and eight in-depth interviews. Participants were chosen purposively based on their involvement in decision-making and implementation of COVID-19 control activities, from the department of health and family welfare, police, revenue, local self-government and community-based organisations. Districts, panchayats (local bodies) and primary health centres (PHCs) were selected based on epidemiological features of the area like the intensity of disease transmission and preventive/containment activities carried out in that particular area to capture the wide range of activities undertaken in the state., Results: The study identified five major themes that can inform best practices viz social capital, robust public health system, participation and volunteerism, health system preparedness, and challenges. This study was a real-time exploration of the intricacies of COVID-19 management in a low/middle-income country and the model can serve as an example for other states and nations to emulate or adjust accordingly., Conclusion: The study shows the impact of synergy of these themes towards more effective solutions; however, further research is much needed in examining the relationship between these factors and their relevance in policy decisions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Different kinds of secondary metabolites present in the medicinal plants play an important role to alleviate different human ailments including neurodegenerative disorders such as Parkinson's, Alzheimer's, epilepsy and schizophrenia etc. Recently we have isolated and characterized a novel bioactive compound viz. 3-(3,4-dimethoxy phenyl)-1-4(methoxy phenyl)prop-2-en-1-one from the methanolic extract of Celastrus paniculatus (CP) which has been widely used for the treatment of neurodegenerative diseases. The present investigation is mainly aimed to evaluate the neuroprotective potential of the above bioactive compound against ketamine-induced schizophrenia with particular reference to catecholaminergic metabolism using in vivo and in silico methods. Ketamine-induced schizophrenia caused significant elevation in biogenic amines (epinephrine, nor epinephrine, dopamine and 5-HT) and monoamine oxidase activity levels which were restored to normal during the treatment with the bioactive compound akin to the reference compound, clozapine. In addition, the compound has shown highest binding score against all the biogenic amine receptors viz. D1, D2, D3, D4 and serotonin receptor, 5-HT 2A with lowest inhibition constant values than the reference compound, clozapine. The present findings suggest that modulation of CNS monoamine neurotransmitter system might partly contribute to the impairments associated with schizophrenia and the plant compound alleviates the monoaminergic abnormalities associated with the neurological dysfunction.Communicated by Ramaswamy H. Sarma.

During the past few years, there has been exponential growth in the field of ethnopharmacology in the treatment of different human ailments, including neurological disorders. In our previous study, we isolated, characterized, and reported a novel bioactive compound with therapeutic efficacy in vivo, which was used in the current study. This study was designed to investigate the pharmacological effect and therapeutic mechanism of the natural plant compound 3-(3,4-dimethoxy phenyl)-1-(4-methoxy phenyl)prop-2-en-1-one against ketamine-induced toxicity in PC 12 cell lines. Cell death was induced in PC 12 cell lines by incubating with ketamine, and the protection offered by the compound at different concentrations was studied during pretreatment. The therapeutic efficacy was screened through MTT assay, LDH assay, DCF-DA assay, clonogenic assay, RT-PCR, and densitometric analysis. The bioactive compound caused a significant elevation in cell viability up to approximately 80%, down-regulation of cell damage, reduction in free radical damage caused by intracellular reactive oxygen species, and up-regulation of cell survival ability, which was dysregulated during ketamine induction. In addition, RT-PCR analysis of DOPA-related genes suggests that the compound exerted significant inhibition in the expression of these genes, which were overexpressed during ketamine induction. The current findings provide new insight into the neuroprotective mediation of bioactive factors as a prospective therapy for neurological disorders.

Glutamate and dopamine hypotheses are leading theories of the pathophysiology of schizophrenia. Multiple lines of evidence suggest that dopaminergic and glutamatergic dysfunction is an underlying mechanism in schizophrenia. Since currently available antipsychotic drugs have significant untoward side effects, identification of new neuroprotective compounds from the medicinal plants may prove beneficial in neurodegenerative disorders. In our previous investigation we have isolated, characterized and reported a novel bioactive compound viz. 3-(3, 4-dimethoxy phenyl)-1-(4-methoxy phenyl) prop-2-en-1-one from the Celastrus paniculatus (CP) is used for the current clinical intervention of schizophrenia disease. The present study is mainly aimed to evaluate the neuroprotective potential of the above bioactive compound against ketamine-induced schizophrenia with particular reference to glutamate metabolism using in vivo and in silico methods. The decrease in glutamine content and the activity levels of glutamate dehydrogenase, glutamine synthetase, and glutaminase in different regions of the rat brain suggests lowered oxidative deamination and lowered mobilization of glutamate towards glutamine formation during ketamine-induced schizophrenia. Pre-treatment with the plant compound reversed the alterations in glutamate metabolism and restored the normal glutamatergic neurotransmission akin to the reference drug, clozapine. In addition, the compound has shown strong interaction and exhibited the highest binding energies against selected NMDA receptors with the lowest inhibition constant than the reference drug. Recoveries of these parameters during anti-schizophrenic treatment suggest that administration of plant compound might offer neuroprotection by interrupting the pathological cascade of glutamatergic neurotransmission that occurs during schizophrenia., (Copyright © 2021. Published by Elsevier Masson SAS.)

A series of gold(I) complexes with the general formula [Au( L2 )( L' )] ( L2 =4-phenyl- N -(prop-2-yn-1-yl)quinazoline-2-carboxamide, L' =PPh 3 (triphenylphosphine), 1 ; TPA (1,3,5-triaza-7-phosphaadamantane), 2 , and Me 2 -imy (1,3-dimethylimidazol-2-ylidene), 3 ) were synthesized and fully characterized by spectroscopic methods. The alkynyl ligand L2 belongs to the quinazoline carboxamide class of ligands that are known to bind to the translocator protein (TSPO) at the outer mitochondrial membrane. 1 and 2 exert cytotoxic effects in bladder cancer cells with IC 50 values in the low micromolar range. Further mechanistic analysis indicated that the two complexes both act by inducing reactive oxygen species and caspase-mediated apoptosis. The complexes inhibit thioredoxin reductase, an established target of anticancer gold(I) complexes. Docking studies confirmed that after ligand exchange the free ligand L2 can interact with the TSPO binding site., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. European Journal of Inorganic Chemistry published by Wiley-VCH GmbH.)

Background and Objectives: The morbidity and mortality spectrum of the south Indian state of Kerala is dominated by chronic non-communicable diseases, yet febrile illnesses because of neglected tropical diseases and emerging viral infections are often reported. As fever deaths are mostly avoidable, understanding the determinants of mortality is essential for implementing preventive measures., Methods: A case-control study was done during an ongoing dengue outbreak in Thiruvananthapuram district, Kerala during 2017-18. Cases included all fever deaths from the line list of Integrated Disease Surveillance Program (IDSP). Data were obtained from hospital case records and by interviewing patients or care givers. The theoretical model for determinants of mortality was constructed at three levels namely sociodemographic factors, access to health care and health seeking behavior, and clinical determinants., Results: This study confirmed association of mortality with age above 40 years ( P = 0.010, OR = 3.48), being heavy built ( P = 0.029, OR = 13.25), clinical symptoms of breathlessness ( P < 0.001, OR = 24.89), restlessness ( P < 0.001, OR = 97.26), clinical signs of drowsiness ( P = 0.024, OR = 7.97), hypotension ( P < 0.001, OR = 42.22), complications such as ARDS ( P = 0.047, OR = 171.56), and myocarditis ( P = 0.012, OR = 16.59). A low occupation status of semiskilled work or less ( P = 0.012, OR = 0.30), choosing a nearby hospital for treatment ( P = 0.018, OR = 0.48) and shortening the time gap between onset of symptom and final diagnosis ( P = 0.044, OR = 0.72) was found to be protective., Conclusion: Along with biological and clinical factors, distal determinants like social factors, health seeking behavior, and health system factors are associated with fever mortality., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Inositol-requiring enzyme 1 (IRE1) is a bifunctional serine/threonine kinase and endoribonuclease that is a major mediator of the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Tumour cells experience ER stress due to adverse environmental cues such as hypoxia or nutrient shortage and high metabolic/protein-folding demand. To cope with those stresses, cancer cells utilise IRE1 signalling as an adaptive mechanism. Here, we report the discovery of the FDA-approved compounds methotrexate, cefoperazone, folinic acid and fludarabine phosphate as IRE1 inhibitors. These were identified through a structural exploration of the IRE1 kinase domain using IRE1 peptide fragment docking and further optimisation and pharmacophore development. The inhibitors were verified to have an impact on IRE1 activity in vitro and were tested for their ability to sensitise human cell models of glioblastoma multiforme (GBM) to chemotherapy. We show that all molecules identified sensitise glioblastoma cells to the standard-of-care chemotherapy temozolomide (TMZ)., (© 2020 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Enzyme assays have widespread applications in drug discovery from plants to natural products. The appropriate use of blanks in enzyme assays is important for assay baseline-correction, and the correction of false signals associated with background matrix interferences. However, the blank-correction procedures reported in published literature are highly inconsistent. We investigated the influence of using different types of blanks on the final calculated activity/inhibition results for three enzymes of significance in diabetes and obesity; α-glucosidase, α-amylase, and lipase. This is the first study to examine how different blank-correcting methods affect enzyme assay results. Although assays targeting the above enzymes are common in the literature, there is a scarcity of detailed published protocols. Therefore, we have provided comprehensive, step-by-step protocols for α-glucosidase-, α-amylase- and lipase-inhibition assays that can be performed in 96-well format in a simple, fast, and resource-efficient manner with clear instructions for blank-correction and calculation of results., Results: In the three assays analysed here, using only a buffer blank underestimated the enzyme inhibitory potential of the test sample. In the absorbance-based α-glucosidase assay, enzyme inhibition was underestimated when a sample blank was omitted for the coloured plant extracts. Similarly, in the fluorescence-based α-amylase and lipase assays, enzyme inhibition was underestimated when a substrate blank was omitted. For all three assays, method six [Raw Data - (Substrate + Sample Blank)] enabled the correction of interferences due to the buffer, sample, and substrate without double-blanking, and eliminated the need to add substrate to each sample blank., Conclusion: The choice of blanks and blank-correction methods contribute to the variability of assay results and the likelihood of underestimating the enzyme inhibitory potential of a test sample. This highlights the importance of standardising the use of blanks and the reporting of blank-correction procedures in published studies in order to ensure the accuracy and reproducibility of results, and avoid overlooked opportunities in drug discovery research due to inadvertent underestimation of enzyme inhibitory potential of test samples resulting from unsuitable blank-correction. Based on our assessments, we recommend method six [RD - (Su + SaB)] as a suitable method for blank-correction of raw data in enzyme assays.

Background: Institutional quarantine centres were set up in all districts in Kerala as a novel strategy in the fight against novel COVID-19 virus. These were meant for returnees from affected areas, for whom home quarantine was not possible due to lack of facilities. This research aims to evaluate facilities and services of Institutional quarantine centres in Thiruvananthapuram district, Kerala state and to study profile of persons under quarantine in these centres., Methods: A cross-sectional study was conducted to evaluate institutional quarantine centres established in Thiruvananthapuram district of Kerala in April 2020. Evaluation was done using a checklist based on standard operating procedures for functioning of centres issued by Health department. Inspection of facilities and registers was done. Details of a subset of inmates were collected by telephonic interviews using a semi-structured questionnaire., Results: Two (0.41%) inmates in the centre turned positive on testing while in quarantine. Both of them were foreign returnees and were asymptomatic. There was not a single case of transmission of infection between inmates or to staff and volunteers. The adherence to infection control practices was satisfactory in all centres. One third of inmates were from listed highly affected countries and were mandatorily quarantined., Conclusion: Institutional quarantine centres were functioning effectively to provide quarantine facilities for high-risk individuals and thereby controlling the spread of COVID-19. Selection of facilities, staffing pattern and day to day functioning of these centres is a model which can be replicated at other COVID-19 affected areas., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

Polyherbal compound (Bronco-T) has been extensively used as a traditional medicine for various therapies. However, very few report studies on anti-inflammatory and lung regeneration properties are evidenced. In the present study, we evaluated the beneficial actions and anti-inflammatory properties of polyherbal medicine, Bronco-T, exhibited by treating the lungs of rats exposed to formaldehyde to evaluate the beneficial properties. For this study, we divided into five groups': i.e. Group-I served as a control and the other four groups such as II, III, IV, and V are experimental. All animals maintained by regular feed and water ad libitum during the study. Formaldehyde vapors exposure at a single period of time (1 hour) daily (40%formaldehyde at room temperature) for 21 days period exposed all groups. The Bronco-T extracts about 50 mg/kg BW administered to experimental groups and group IV rats treated with 500μ grams/Kg BW salbutamol. To understand the impact of formaldehyde exposure on the beneficial effects of Bronco-T, we evaluated hematological parameters, bronchoalveolar lavage (BAL), histamine levels, and histological alterations of lung architecture. Formaldehyde-induced adverse effects in lung and increased histamine levels in BAL compared to Bronco-T-treated rats act as a preventive immunological role in blood toxicity and recovery of lung architecture in Bronco-T-treated rats. This study showed the evaluation of antihistamine levels through HPLC analysis. Bronco-T has antioxidant and anti-histamine properties as the widest therapeutic window, and we continue to evaluate the pharmacological evaluations needed in our further studies., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Outstanding increase of oral absorption, bioavailability, and antiviral efficacy of phosphorylated nucleosides and basic antiviral influence of abacavir is the central idea for the development of new series of phosphorylated abacavir (ABC) derivatives. The designed compounds were primarily screened for antiviral nature against HN protein of NDV and VP7 protein of BTV using the molecular environment approach. Out of all the designed compounds, the compounds which are having higher binding energies against these two viral strains were prompted for the synthesis of the target compounds (5A-K). Among the synthesized title compounds (5A-K), the compounds which have exhibited higher dock scores akin to the rest of the compounds were then selected and screened for the antiviral activity against NDV and BTV infected embryonated eggs and BHK 21 cell lines through the in ovo and in vitro approaches. The results revealed that all the designed compounds have formed higher binding energies against both the targets. Among all, the compounds which are selected based on their dock scores such as 5A, 5F, 5G, 5H, 5I, and 5K against NDV and 5J, 5E, 5I, 5C, 5A, and 5K against BTV have shown significant antiviral activity against HN protein of NDV, VP7 protein of Bluetongue virus in both NDV- and BTV-treated embryonated eggs and BHK 21 cell lines. Hence, it is concluded that, the best lead compounds will stand as the potential antiviral agents and prompted them as virtuous therapeutics against NDV and BTV in future.

A new class of phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[ d ]isoxazole were synthesized in good to excellent yields (78-96%) by an in situ , three-step process. All the synthesized molecules were evaluated for anti-bacterial and anti-fungal activities using in vitro and in silico methods. The results revealed that the compounds 4b , 4d , 4h , 4i , and 4j exhibited the most promising anti-bacterial activity against S. aureus , B. subtilis , K. pneumoniae , S. typhi and P. mirabilis and anti-fungal activity against A. niger and A. flavus when compared with the standard drugs Norfloxacin and Nystatin at concentrations of 25, 50, 75 and 100 µg/mL. The rest of the title compounds have shown moderate activity against all the bacterial and fungal strains. Molecular docking studies revealed that the synthesized compounds have exhibited significant binding modes with high dock scores ranging from -7.2 to -9.5 against 3V2B protein when compared with the standard drugs Norfloxacin (-5.8) and Nystatin (-6.6) respectively. Hence, it is suggested that the synthesized phosphoramidate derivatives of 6-fluoro-3-(piperidin-4-yl)benzo[ d ]isoxazole will stand as the promising antimicrobial drug candidates in future.

The design, synthesis, characterization, and biological activity of a series of platinum(IV) prodrugs containing the axial ligand 3-(4-phenylquinazoline-2-carboxamido)propanoate ( L3 ) are reported. L3 is a derivative of the quinazolinecarboxamide class of ligands that binds to the translocator protein (TSPO) at the outer mitochondrial membrane. The cytotoxicities of cis , cis , trans -[Pt(NH 3 ) 2 Cl 2 ( L3 )(OH)] ( C-Pt1 ), cis , cis , trans -[Pt(NH 3 ) 2 Cl 2 ( L3 )(BZ)] ( C-Pt2 ), trans -[Pt(DACH)(OX)( L3 )(OH)] ( C-Pt3 ), and trans -[Pt(DACH)(OX)( L3 )(BZ)] ( C-Pt4 ) (DACH: R , R -diaminocyclohexane, BZ: benzoate, OX: oxalate) in MCF-7 breast cancer and noncancerous MCF-10A epithelial cells were assessed and compared with those of cisplatin, oxaliplatin, and the free ligand L3 . Moreover, the cellular uptake, ROS generation, DNA damage, and the effect on the mitochondrial function, mitochondrial membrane potential, and morphology were investigated. Molecular interactions of L3 in the TSPO binding site were studied using molecular docking. The results showed that complex C-Pt1 is the most effective Pt(IV) complex and exerts a multimodal mechanism involving DNA damage, potent ROS production, loss of the mitochondrial membrane potential, and mitochondrial damage.

Among the major neurodegenerative disorders (NDDs), Alzheimer's disease (AD) and Parkinson's disease (PD), are a huge socioeconomic burden. Over many centuries, people have sought a cure for NDDs from the natural herbals. Many medicinal plants and their secondary metabolites are reported with the ability to alleviate the symptoms of NDDs. The major mechanisms identified, through which phytochemicals exert their neuroprotective effects and potential maintenance of neurological health in ageing, include antioxidant, anti-inflammatory, antithrombotic, antiapoptotic, acetylcholinesterase and monoamine oxidase inhibition and neurotrophic activities. This article review the mechanisms of action of some of the major herbal products with potential in the treatment of NDDs according to their molecular targets, as well as their regional sources (Asia, America and Africa). A number of studies demonstrated the beneficial properties of plant extracts or their bioactive compounds against NDDs. Herbal products may potentially offer new treatment options for patients with NDDs, which is a cheaper and culturally suitable alternative to conventional therapies for millions of people in the world with age-related NDDs., Competing Interests: The authors declare no conflict of interest.

Schizophrenia is a devastating illness and displays a wide range of psychotic symptoms. Accumulating evidence indicate impairment of bioenergetic pathways including energy storage and usage in the pathogenesis of schizophrenia. Although well-established synthetic drugs are being used for the management of schizophrenia, most of them have several adverse effects. Hence, natural products derived from medicinal plants represent a continuous major source for ethnomedicine-derived pharmaceuticals for different neurological disorders including schizophrenia. In the present study, we have investigated the neuroprotective effect of the novel bioactive compound i.e. "3-(3,4-dimethoxy phenyl) -1- (4-methoxyphenyl) prop-2-en-1-one" of Celastrus paniculata against ketamine-induced schizophrenia with particular reference to the activities of ATPase using in vivo and in silico methods. Ketamine-induced schizophrenia caused significant reduction in the activities of all three ATPases (Na + /K + , Ca 2+ and Mg 2+ ) in different regions of brain which reflects the decreased turnover of ATP, presumably due to the inhibition of oxidoreductase system and uncoupling of the same from the electron transport system. On par with the reference compound, clozapine, the activity levels of all three ATPases were restored to normal after pretreatment with the compound suggesting recovery of energy loss that was occurred during ketamine-induced schizophrenia. Besides, the compound has shown strong interaction and exhibited highest binding energies against all the three ATPases with a lowest inhibition constant value than the clozapine. The results of the present study clearly imply that the compound exhibit significant neuroprotective and antischizophrenic effect by modulating bioenergietic pathways that were altered during induced schizophrenia.

In the present study, a new series of α -Aminophosphonates bearing 6-amino-1,3-dimethyluracil was synthesized in good to excellent yields (78-95%) by one-pot, three-component reaction of 6-amino-1,3-dimethyluracil, aromatic aldehydes and diethylphosphite via Kabachnik-Fields reaction by using an eco-friendly Eaton's reagent. All the compounds were screened for in vitro antioxidant studies by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and hydrogen peroxide (H 2 O 2 ) methods. Among the synthesized bioactive molecules, 4a , 4d , 4g , and 4h exhibited promising antioxidant activity compared with the standard drug Ascorbic acid. Furthermore, in order to support the biological results of the compounds, molecular docking studies were performed against Aromatase enzyme for four compounds which revealed that the compounds 4a , 4d , 4g , and 4h have significant binding modes, with docking scores of -8.6, -8.4, -8.1 and -8.1 respectively and the compound 4b specifically has equal dock score of -8.0 when compared with the standard drug Exemestane.