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Two hundred student volunteers of 16-24 yrs were divided into two groups of 100 each, as children of hypertensive and children of normotensive parents. It was observed that there was no difference in resting SBP and DBP in both groups before CPT. After CPT, significant higher values of SBP after immersion, DBP after immersion, difference of SBP and difference of DBP were observed in children of hypertensive parents as compared to children of normotensive parents. This study can be used as a predictor of future development of hypertension for which early preventive measures can be taken to reduce the morbidity and mortality due to hypertensive complications.

Angiotensin II receptors, Type 1 (AT1R) and Type 2 (AT2R) are 7TM receptors that play critical roles in both the physiological and pathophysiological regulation of the cardiovascular system. While AT1R blockers (ARBs) have proven beneficial in managing cardiac, vascular and renal maladies they cannot completely halt and reverse the progression of pathologies. Numerous experimental and animal studies have demonstrated that β-arrestin biased AT1R-ligands (such as SII-AngII, S1I8, TRV023, and TRV027) offer cardiovascular benefits by blocking the G protein signaling while retaining the β-arrestin signaling. However, these ligands failed to show improvement in heart-failure outcome over the placebo in a phase IIb clinical trial. One major limitation of current β-arrestin biased AT1R-ligands is that they are peptides with short half-lives, limiting their long-term efficacy in patients. Additionally, β-arrestin biased AT1R-ligand peptides, may inadvertently block AT2R, a promiscuous receptor, potentially negating its beneficial effects in post-myocardial infarction (MI) patients. Therefore, developing a small molecule β-arrestin biased AT1R-ligand with a longer half-life and specificity to AT1R could be more effective in treating heart failure. This approach has the potential to revolutionize the treatment of cardiovascular diseases by offering more sustained and targeted therapeutic effects., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sadashiva S. Karnik reports financial support was provided by National Institutes of Health. Sadashiva S. Karnik reports financial support was provided by CLEVELAND CLINIC. If there are other authors, they 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 © 2024. Published by Elsevier Inc.)

Crop height and biomass are the two important phenotyping traits to screen forage population types at local and regional scales. This study aims to compare the performances of multispectral and RGB sensors onboard drones for quantitative retrievals of forage crop height and biomass at very high resolution. We acquired the unmanned aerial vehicle (UAV) multispectral images (MSIs) at 1.67 cm spatial resolution and visible data (RGB) at 0.31 cm resolution and measured the forage height and above-ground biomass over the alfalfa ( Medicago sativa L.) breeding trials in the Canadian Prairies. (1) For height estimation, the digital surface model (DSM) and digital terrain model (DTM) were extracted from MSI and RGB data, respectively. As the resolution of the DTM is five times less than that of the DSM, we applied an aggregation algorithm to the DSM to constrain the same spatial resolution between DSM and DTM. The difference between DSM and DTM was computed as the canopy height model (CHM), which was at 8.35 cm and 1.55 cm for MSI and RGB data, respectively. (2) For biomass estimation, the normalized difference vegetation index (NDVI) from MSI data and excess green (ExG) index from RGB data were analyzed and regressed in terms of ground measurements, leading to empirical models. The results indicate better performance of MSI for above-ground biomass (AGB) retrievals at 1.67 cm resolution and better performance of RGB data for canopy height retrievals at 1.55 cm. Although the retrieved height was well correlated with the ground measurements, a significant underestimation was observed. Thus, we developed a bias correction function to match the retrieval with the ground measurements. This study provides insight into the optimal selection of sensor for specific targeted vegetation growth traits in a forage crop.

Global agricultural production is significantly hampered by insect pests, and the demand for natural pragmatic pesticides with environmental concern remains unfulfilled. Ageratina adenophora (Spreng.) also known as Crofton weed, is an invasive perennial herbaceous plant that is known to possess multiple bioactive compounds. In our study, two isomers of ageraphorone metabolites i.e, 10 Hα-9-oxo-ageraphorone (10HA) and 10 Hβ-9-oxo-ageraphorone (10HB), were identified from Crofton weed, exhibiting potent antifeedant and larvicidal activities against Plutella xylostella. For antifeedant activity, the median effective concentration (EC 50 ) values for 10HA and 10HB in the choice method were 2279 mg/L and 3233 mg/L, respectively, and for the no choice method, EC 50 values were 1721 mg/L and 2394 mg/L, respectively. For larvicidal activity, lethal concentration (LC 50 ) values for 10HA and 10HB were 2421 mg/L and 4109 mg/L at 48 h and 2101 mg/L and 3550 mg/L at 72 h. Furthermore, both in- vivo and in-vitro studies revealed that the isomers 10HA and 10HB exhibited potent detoxifying enzymes inhibition activity such as carboxylesterase and glutathione S-transferases. Molecular docking and MD simulation analysis provide insight into the possible interaction between isomers of ageraphorone metabolites and Carboxylic Ester Hydrolase protein (Gene: pxCCE016b) of P. xylostella, which led to a finding that CarEH protein plays a significant role in the detoxification of the two compounds in P. xylostella. Finally, our findings show that the primary enzymes undergoing inhibition by isomers of ageraphorone metabolites, causing toxicity in insects, are Carboxylesterase and glutathione S-transferase., 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 © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Allosteric modulation is a central mechanism for metabolic regulation but has yet to be described for a gut microbiota-host interaction. Phenylacetylglutamine (PAGln), a gut microbiota-derived metabolite, has previously been clinically associated with and mechanistically linked to cardiovascular disease (CVD) and heart failure (HF). Here, using cells expressing β1- versus β2-adrenergic receptors (β1AR and β2AR), PAGln is shown to act as a negative allosteric modulator (NAM) of β2AR, but not β1AR. In functional studies, PAGln is further shown to promote NAM effects in both isolated male mouse cardiomyocytes and failing human heart left ventricle muscle (contracting trabeculae). Finally, using in silico docking studies coupled with site-directed mutagenesis and functional analyses, we identified sites on β2AR (residues E122 and V206) that when mutated still confer responsiveness to canonical β2AR agonists but no longer show PAGln-elicited NAM activity. The present studies reveal the gut microbiota-obligate metabolite PAGln as an endogenous NAM of a host GPCR., (© 2024. The Author(s).)

The poly (ADP-ribose) polymerase-1 (PARP-1) enzyme is an important target in the treatment of breast cancer. Currently, treatment options include the drugs Olaparib, Niraparib, Rucaparib, and Talazoparib; however, these drugs can cause severe side effects including hematological toxicity and cardiotoxicity. Although in silico models for the prediction of PARP-1 activity have been developed, the drawbacks of these models include low specificity, a narrow applicability domain, and a lack of interpretability. To address these issues, a comprehensive machine learning (ML)-based quantitative structure-activity relationship (QSAR) approach for the informed prediction of PARP-1 activity is presented. Classification models built using the Synthetic Minority Oversampling Technique (SMOTE) for data balancing gave robust and predictive models based on the K-nearest neighbor algorithm (accuracy 0.86, sensitivity 0.88, specificity 0.80). Regression models were built on structurally congeneric datasets, with the models for the phthalazinone class and fused cyclic compounds giving the best performance. In accordance with the Organization for Economic Cooperation and Development (OECD) guidelines, a mechanistic interpretation is proposed using the Shapley Additive Explanations (SHAP) to identify the important topological features to differentiate between PARP-1 actives and inactives. Moreover, an analysis of the PARP-1 dataset revealed the prevalence of activity cliffs, which possibly negatively impacts the model's predictive performance. Finally, a set of chemical transformation rules were extracted using the matched molecular pair analysis (MMPA) which provided mechanistic insights and can guide medicinal chemists in the design of novel PARP-1 inhibitors., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Gastrointestinal stromal tumors (GISTs) are the mesenchymal tumors of the gastrointestinal tract. Extra Gastrointestinal stromal tumors (EGISTs) are rare neoplasms that occur outside the gastrointestinal tract [1]. Miettinen et al. [2] described the first EGIST in 1999. EGIST accounts for 10% of all GISTs [3]. The main distinction between GIST and EGIST is the site of origin of the primary tumor, as GIST occurs throughout the GI tract, from the esophagus to the anus, whereas EGIST is a tumor without any connection with the intestinal wall and are reported in the retroperitoneum, mesentery, and omentum [4]. Hu et al. [5] reported a first case report of EGIST of larynx.We present a second case report of Extra-gastrointestinal stromal tumor of larynx a 47-year-old male reported to ENT Department Command Hospital Central Command Lucknow with complaints of Hoarseness. On examination found to have right vocal cord growth for which he underwent excision of right vocal cord growth. Histopathological examination showed typical of a spindle-cell GIST, showing strong immunoreactivity for CD 117, DOG1, Vimentin and CD 99. 6 months follow up post surgery with no recurrence., Competing Interests: Conflict of interestThere are no conflicts of interest., (© Association of Otolaryngologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Transceptors, solute transporters that facilitate intracellular entry of molecules and also initiate intracellular signaling events, have been primarily studied in lower-order species. Ammonia, a cytotoxic endogenous metabolite, is converted to urea in hepatocytes for urinary excretion in mammals. During hyperammonemia, when hepatic metabolism is impaired, nonureagenic ammonia disposal occurs primarily in skeletal muscle. Increased ammonia uptake in skeletal muscle is mediated by a membrane-bound, 12 transmembrane domain solute transporter, Rhesus blood group-associated B glycoprotein (RhBG). We show that in addition to its transport function, RhBG interacts with myeloid differentiation primary response-88 (MyD88) to initiate an intracellular signaling cascade that culminates in activation of NFκB. We also show that ammonia-induced MyD88 signaling is independent of the canonical toll-like receptor-initiated mechanism of MyD88-dependent NFκB activation. In silico, in vitro, and in situ experiments show that the conserved cytosolic J-domain of the RhBG protein interacts with the Toll-interleukin-1 receptor (TIR) domain of MyD88. In skeletal muscle from human patients, human-induced pluripotent stem cell-derived myotubes, and myobundles show an interaction of RhBG-MyD88 during hyperammonemia. Using complementary experimental and multiomics analyses in murine myotubes and mice with muscle-specific RhBG or MyD88 deletion, we show that the RhBG-MyD88 interaction is essential for the activation of NFkB but not ammonia transport. Our studies show a paradigm of substrate-dependent regulation of transceptor function with the potential for modulation of cellular responses in mammalian systems by decoupling transport and signaling functions of transceptors., Competing Interests: Competing interests statement:The authors declare no competing interest.

This study assesses the reliability of resting-state dynamic causal modelling (DCM) of magnetoencephalography (MEG) under conductance-based canonical microcircuit models, in terms of both posterior parameter estimates and model evidence. We use resting-state MEG data from two sessions, acquired 2 weeks apart, from a cohort with high between-subject variance arising from Alzheimer's disease. Our focus is not on the effect of disease, but on the reliability of the methods (as within-subject between-session agreement), which is crucial for future studies of disease progression and drug intervention. To assess the reliability of first-level DCMs, we compare model evidence associated with the covariance among subject-specific free energies (i.e., the 'quality' of the models) with versus without interclass correlations. We then used parametric empirical Bayes (PEB) to investigate the differences between the inferred DCM parameter probability distributions at the between subject level. Specifically, we examined the evidence for or against parameter differences (i) within-subject, within-session, and between-epochs; (ii) within-subject between-session; and (iii) within-site between-subjects, accommodating the conditional dependency among parameter estimates. We show that for data acquired close in time, and under similar circumstances, more than 95% of inferred DCM parameters are unlikely to differ, speaking to mutual predictability over sessions. Using PEB, we show a reciprocal relationship between a conventional definition of 'reliability' and the conditional dependency among inferred model parameters. Our analyses confirm the reliability and reproducibility of the conductance-based DCMs for resting-state neurophysiological data. In this respect, the implicit generative modelling is suitable for interventional and longitudinal studies of neurological and psychiatric disorders., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Introduction: Pedicle screw placement plays a crucial role in treating various cases such as fractures, scoliosis, degenerative spine issues, and kyphosis, reinforcing all three spinal columns simultaneously. While three-dimensional navigation-assisted pedicle screw placement is considered superior, the freehand technique relies on anatomical landmarks and tactile feedback, with observed low complication rates., Materials and Methods: This was a prospective single-center study conducted over a period of 3 years. It included all patients of dorsal, lumbar, and sacral spinal instability of myriad etiology. Previously operated patients and sick obtunded patients were excluded from the study., Results: In our study, we included 102 patients including 62 (60.7%) males and 40 (39.2%) females. More than half of patients were young in the age group of 20-50 years. Our study population had a varied etiology with 43.1% of patients having vertebral column instability due to trauma. The other etiologies were spondylolisthesis and lumbar canal stenosis (39.2%), Pott's spine (11.7%), tumors (2.9%), and osteoporotic fractures (2.9%). Majority of patients (44.1%) presented with lower backache with radiculopathy. All the transpedicular screws inserted were evaluated by C-arm to assess for screw fixation. In the first year of our study, an average of 4 anteroposterior (AP) and 4 lateral C-arm X-ray shots were taken per screw placement. In the next year, an average of 3 AP and 3 lateral shots and finally in the last year of our study only 2 AP and 2 lateral C-arm X-ray shots were taken per screw placement. Out of 650 screws placed, 4 screws were identified to cause breach with maximum breaches in the lumbar spine fixation. In dorsal spine fixation, there was 1 lateral breach at D10. In lumbar spine fixation, there were 3 breaches: two medial one each at L4 and L5 and one anterior at L2 level. The various complications include wound infection, temporary and permanent neurological deficit, screw breakage, screw misplacement, cerebrospinal fluid leaks, nonunion, and spinal epidural hematoma., Conclusions: Our study has provided strong encouragement to persist with the freehand technique in transpedicular fixation surgeries after a certain number of cases given the minimal breaches and complications observed. There are subtle technical nuances as we increase the number of cases with less exposure of anatomical landmarks and X-rays. Success hinges on experience, adherence to technique, and thorough preoperative planning. Further research and extended follow-up periods are necessary to firmly establish this technique as the gold standard., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Craniovertebral Junction and Spine.)

Problem Definition: We quantify the increase in productivity in emergency departments (ED) from increasing nurse staff. We then estimate the associated revenue gains for the hospital and the associated welfare gains for society., Academic/practical Relevance: The United States is over a decade into the worst nursing shortage crisis in history, fueled by chronic under-investment. To demonstrate to hospital managers and policymakers the benefits of investing in nursing, we clarify the positive downstream effects of doing so in the ED setting., Methodology: We use a high-resolution data set of patient visits to the ED of a major U.S. academic hospital. Time-dependent hazard estimation methods (nonparametric and parametric) are used to study how the realtime service speed of a patient varies with the state of the ED, including the time-varying workloads of the assigned nurse. A counterfactual simulation is used to estimate the gains from increasing nurse staff in the ED., Results: We find that lightening a nurse's workload by one patient is associated with a 14% service speedup for every patient under the nurse's care. Simulation studies suggest that adding one more nurse to the busiest 12-hour shift of each day can shorten stays and avert $160,000 in lost patient wages per 10,000 visits. The reduction in service times also frees up capacity for treating more patients and generate $470,000 in additional net revenues for the hospital per 10,000 visits. Extensive sensitivity analyses suggest that our key message-investing in nursing will more than pay for itself-is likely to hold across a wide range of EDs., Managerial Implications: In determining whether to invest in more nursing resources, hospital managers need to look beyond whether payer reimbursements alone are sufficient to cover the upfront costs, to also account for the resulting downstream benefits.

Purpose: This feasibility study aimed to investigate the use of exhaled breath analysis to capture and quantify relative changes of metabolites during resolution of acute diabetic ketoacidosis under insulin and rehydration therapy., Methods: Breath analysis was conducted on 30 patients of which 5 with DKA. They inflated Nalophan bags, and their metabolic content was subsequently interrogated by secondary electrospray ionization high-resolution mass spectrometry (SESI-HRMS)., Results: SESI-HRMS analysis showed that acetone, pyruvate, and acetoacetate, which are well known to be altered in DKA, were readily detectable in breath of participants with DKA. In addition, a total of 665 mass spectral features were found to significantly correlate with base excess and prompt metabolic trajectories toward an in-control state as they progress toward homeostasis., Conclusion: This study provides proof-of-principle for using exhaled breath analysis in a real ICU setting for DKA monitoring. This non-invasive new technology provides new insights and a more comprehensive overview of the effect of insulin and rehydration during DKA treatment., Competing Interests: PS is co-founder of Deep Breath Intelligence AG Switzerland, which develops breath-based diagnostic tools. KDS and JZ are consultants for Deep Breath Intelligence AG Switzerland. The University Children’s Hospital Basel is a shareholder of Deep Breath Intelligence AG Switzerland. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Awchi, Singh, Brenner, Burckhardt, Hess, Zeng, Datta, Frey, Zumsteg, Szinnai and Sinues.)

Edible insects possess several health enhancing properties and play an important role in human nutrition. Coridius chinensis is an edible insect that is considered food and claimed as traditional medicine. In the present study, nutritional contents, chemical composition, antioxidant, and anti-inflammatory properties of C. chinensis were analyzed. It was found that the insect sample contains 50.46% moisture, 44.65% protein, 4.45% carbohydrate, 39.42% crude fats, 3.53% ash and 576.11 (Kcal/100 g) energy. Our study highlighted the presence of a significant amount of phenol and flavonoids. The C. chinensis hydro-alcoholic extract showed high antioxidant property and anti-inflammatory activity. GCMS analysis identified 61 volatile compounds. LC-MS analysis of hydroalcoholic extract of C. chinensis revealed the presence of compounds such as etodolac glucuronide, morphine 3-glucuronide, ecgonine, ecgonine methyl ester, sufentanil, and palmitoyl ethanololamide. These findings suggest that C. chinensis species can be employed as a valuable food source with excellent therapeutic properties., (© 2024. The Author(s).)

Insects are the largest group of arthropods with the highest faunal diversity of over a million species. Apart from many other roles in the environment, the aspect of several insects being used for human consumption (entomophagy) and as traditional medicine (entomotherapy) by different communities of the world holds special significance for countering global food crisis. The enormous insect resources contribute a reasonable share in improving the livelihoods of many entomophagy practicing communities. Considering this significance, the present review emphasizes the bio-economic potential of insect resources. An overview of entomophagy practices in India; benefits towards the environment, humans and animals; insect species used in entomophagy along with therapeutic importance, nutritional, physical, chemical, and microbiological hazards; farming and mass production technologies; legal status and socio-economic implications in Indian scenario have been presented. Traditionally tested and accepted therapeutic use of edible insects have been reported to cure various disease conditions and calls for scientific exploration and validation to rediscover promising medical products of modern medicine. Edible insects as an alternative food need to be popularized in India with a new policy or regulation to harvest and sell insect-derived food products with proper safe consumption demonstrations. Considering the facts that insects reproduce in large numbers at a faster rate, require less land, water and other resources for farming, and economically and ecologically sustainable harvesting can be done in a short time, insect farming can offer revenue and rural job opportunities in developing countries, especially in India. Therefore, the traditional use of insects as food and medicine has tremendous potential to enhance the economy and living standards., (© 2024. The Author(s).)

Drug addiction is a complex disease affected by numerous genetic and environmental factors. Brain regions in reward pathway, neuronal adaptations, genetic and epigenetic interactions causing transcriptional enhancement or repression of multiple genes induce different addiction phenotypes for varying duration. Addictive drug use causes epigenetic alterations and similarly epigenetic changes induced by environment can promote addiction. Epigenetic mechanisms include DNA methylation and post-translational modifications like methylation, acetylation, phosphorylation, ubiquitylation, sumoylation, dopaminylation and crotonylation of histones, and ADP-ribosylation. Non-coding RNAs also induce epigenetic changes. This review discusses these above areas and stresses the need for exploring epidrugs as a treatment alternative and adjunct, considering the limited success of current addiction treatment strategies. Epigenome editing complexes have lately been effective in eukaryotic systems. Targeted DNA cleavage techniques such as CRISPR-Cas9 system, CRISPR-dCas9 complexes, transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) have been exploited as targeted DNA recognition or anchoring platforms, fused with epigenetic writer or eraser proteins and delivered by transfection or transduction methods. Efficacy of epidrugs is seen in various neuropsychiatric conditions and initial results in addiction treatment involving model organisms are remarkable. Epidrugs present a promising alternative treatment for addiction., 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 © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Although many genetic risk factors for psychiatric and neurodevelopmental disorders have been identified, the neurobiological route from genetic risk to neuropsychiatric outcome remains unclear. 22q11.2 deletion syndrome (22q11.2DS) is a copy number variant (CNV) syndrome associated with high rates of neurodevelopmental and psychiatric disorders including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia. Alterations in neural integration and cortical connectivity have been linked to the spectrum of neuropsychiatric disorders seen in 22q11.2DS and may be a mechanism by which the CNV acts to increase risk. In this study, magnetoencephalography (MEG) was used to investigate electrophysiological markers of local and global network function in 34 children with 22q11.2DS and 25 controls aged 10-17 years old. Resting-state oscillatory activity and functional connectivity across six frequency bands were compared between groups. Regression analyses were used to explore the relationships between these measures, neurodevelopmental symptoms and IQ. Children with 22q11.2DS had altered network activity and connectivity in high and low frequency bands, reflecting modified local and long-range cortical circuitry. Alpha and theta band connectivity were negatively associated with ASD symptoms while frontal high frequency (gamma band) activity was positively associated with ASD symptoms. Alpha band activity was positively associated with cognitive ability. These findings suggest that haploinsufficiency at the 22q11.2 locus impacts short and long-range cortical circuits, which could be a mechanism underlying neurodevelopmental and psychiatric vulnerability in this high-risk group., (© 2023. The Author(s).)

Allium hookeri (F: Liliaceae), an indigenous plant of Manipur, India, is traditionally used to treat various diseases and disorders like diabetes, hypertension, and stomach ache. In our previous study, the methanol extract of the plant showed significant antidiabetic potential in rats. In the present study, we evaluated the antidiabetic potential of a flavonoid compound named MEA isolated from the methanolic leaf extract of A. Hookeri in rats. Additionally, we assessed the compound's mode of action through the molecular docking study. The MEA reduced the blood glucose level from 317±12.8 to 99.4±6.67 mg/dl after 21 days of treatment. Besides, MEA also restored the body weights and other biochemical parameters including lipid profile significantly compared to the diabetic group (p<0.001). The histoarchitecture of the pancreatic tissues of the MEA treated group was also improved compared to the diabetic group. In the docking study, the compound showed good binding affinity in the active binding site of the two structures of pancreatic beta-cell SUR1 (Sulfonylurea Receptor 1) subunit with CDocker energy -31.556 kcal/mol and -39.703 kcal/mol, respectively. The compound MEA was found to be drug-like with non-carcinogenic, non-mutagenic and non-irritant properties. These findings indicate the antidiabetic potential of MEA, which might act by modulating the pancreatic beta-cell SUR1 subunit present in the K ATP channel. Hence, the MEA would be a promising lead molecule to develop new antidiabetic drug candidates of the future., (© 2023 Wiley-VHCA AG, Zurich, Switzerland.)

Secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) is an established technique in the field of breath analysis characterized by its short analysis time, as well as high levels of sensitivity and selectivity. Traditionally, SESI-HRMS has been used for real-time breath analysis, which requires subjects to be at the location of the analytical platform. Therefore, it limits the possibilities for an introduction of this methodology in day-to-day clinical practice. However, recent methodological developments have shown feasibility on the remote sampling of exhaled breath in Nalophan® bags prior to measurement using SESI-HRMS. To further explore the range of applications of this method, we conducted a proof-of-concept study to assess the impact of the storage time of exhaled breath in Nalophan® bags at different temperatures (room temperature and dry ice) on the relative intensities of the compounds. In addition, we performed a detailed study of the storage effect of 27 aldehydes related to oxidative stress. After 2 h of storage, the mean of intensity of all m/z signals relative to the samples analyzed without prior storage remained above 80% at both room temperature and dry ice. For the 27 aldehydes, the mean relative intensity losses were lower than 20% at 24 h of storage, remaining practically stable since the first hour of storage following sample collection. Furthermore, the mean relative intensity of most aldehydes in samples stored at room temperature was higher than those stored in dry ice, which could be related to water vapor condensation issues. These findings indicate that the exhaled breath samples could be preserved for hours with a low percentage of mean relative intensity loss, thereby allowing more flexibility in the logistics of off-line SESI-HRMS studies., (Creative Commons Attribution license.)

Human individuality is likely underpinned by the constitution of functional brain networks that ensure consistency of each person's cognitive and behavioral profile. These functional networks should, in principle, be detectable by noninvasive neurophysiology. We use a method that enables the detection of dominant frequencies of the interaction between every pair of brain areas at every temporal segment of the recording period, the dominant coupling modes (DoCM). We apply this method to brain oscillations, measured with magnetoencephalography (MEG) at rest in two independent datasets, and show that the spatiotemporal evolution of DoCMs constitutes an individualized brain fingerprint. Based on this successful fingerprinting we suggest that DoCMs are important targets for the investigation of neural correlates of individual psychological parameters and can provide mechanistic insight into the underlying neurophysiological processes, as well as their disturbance in brain diseases., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

The Concise Guide to PHARMACOLOGY 2023/24 is the sixth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of approximately 1800 drug targets, and about 6000 interactions with about 3900 ligands. There is an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes almost 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.16177. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2023, and supersedes data presented in the 2021/22, 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate., (© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.)

Therapeutic drug monitoring (TDM) of medications with a narrow therapeutic window is a common clinical practice to minimize toxic effects and maximize clinical outcomes. Routine analyses rely on the quantification of systemic blood concentrations of drugs. Alternative matrices such as exhaled breath are appealing because of their inherent non-invasive nature. This is especially the case for pediatric patients. We have recently showcased the possibility of predicting systemic concentrations of valproic acid (VPA), an anti-seizure medication by real-time breath analysis in two real clinical settings. This approach, however, comes with the limitation of the patients having to physically exhale into the mass spectrometer. This restricts the possibility of sampling from patients not capable or available to exhale into the mass spectrometer located on the hospital premises. In this work, we developed an alternative method to overcome this limitation by collecting the breath samples in customized bags and subsequently analyzing them by secondary electrospray ionization coupled to high-resolution mass spectrometry (SESI-HRMS). A total of n = 40 patients (mean ± SD, 11.5 ± 3.5 y.o.) diagnosed with epilepsy and taking VPA were included in this study. The patients underwent three measurements: (i) serum concentrations of total and free VPA, (ii) real-time breath analysis and (iii) off-line analysis of exhaled breath collected in bags. The agreement between the real-time and the off-line breath analysis methods was evaluated using Lin's concordance correlation coefficient (CCC). CCC was computed for ten mass spectral predictors of VPA concentrations. Lin's CCC was >0.6 for all VPA-associated features, except for two low-signal intensity isotopic peaks. Finally, free and total serum VPA concentrations were predicted by cross validating the off-line data set. Support vector machine algorithms provided the most accurate predictions with a root mean square error of cross validation of 29.0 ± 7.4 mg l -1 and 3.9 ± 1.4 mg l -1 for total and free VPA (mean ± SD), respectively. As a secondary analysis, we explored whether exhaled metabolites previously associated with side-effects and response to medication could be rendered by the off-line analysis method. We found that five features associated with side effects showed a CCC > 0.6, whereas none of the drug response-associated peaks reached this cut-off. We conclude that the clinically relevant free fraction of VPA can be predicted by this combination of off-line breath collection with rapid SESI-HRMS analysis. This opens new possibilities for breath based TDM in clinical settings., (Creative Commons Attribution license.)

Introduction: Quality counseling can positively impact maternal, infant and young child nutrition (MIYCN) behaviors linked to poor nutrition outcomes. Global guidance includes 93 recommendations on MIYCN counseling., Methods: A desk review and key informant interviews sought to assess compliance to the recommendations, reach and quality, systemic gaps and opportunities for MIYCN counseling in seven South Asian countries. Ninety-three (93) policies and guidelines, 180 counseling materials and over 50 documents were reviewed; 115 key informant interviews were conducted. Information synthesis captured eight domains. Data from national surveys were analyzed to determine MIYCN counseling reach, quality and association with nutrition behaviors., Results: Results showed that national guidelines were inconsistent with global recommendations for seven thematic areas. Coverage of contacts points like antenatal and postnatal care (ANC, PNC) with potential to deliver MIYCN counseling was highly variable. Having at least four ANC contacts was significantly associated with consumption of 100+ iron folic acid tablets in all countries. Rates of early initiation of breastfeeding (18% Pakistan to 90% Sri Lanka) were lower than institutional delivery rates, except for Bangladesh and Sri Lanka. PNC contact within 48 h of birth was positively correlated with exclusive breastfeeding in India, Pakistan and Sri Lanka (OR 1.4, 3.1, 3.2). Health worker contacts and wealth status equally influenced child's dietary diversity in India. MIYCN services were add-on roles for community-based workers, except in India. Supervision mechanisms exist but were not focused on quality of MIYCN services. Counseling resources were predominantly paper based (>70%), had rural-focused messaging on diets and mainly targeted women. Platforms to engage men were largely missing. Health management information systems included indicators on maternal contact points in all countries but not for children. Assessing funding for MIYCN counseling was challenging as costs were subsumed across several budget line-items., Discussion: The research findings can be used to (1) align country guidance with global recommendations, (2) review workforce responsibilities and capacity building with supervision, (3) assess the need for new counseling materials based on coverage of content, service providers and audience, (4) integrate MIYCN counseling indicators in information systems and (5) include MIYCN counseling services with activities and budget in country plans., 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 © 2023 Bhanot, Sethi, Murira, Singh, Ghosh and Forissier.)

Bone metabolism is a key factor for successful osseointegration, and low vitamin D levels may negatively impact the process of osseointegration after implant placement. The study was aimed at evaluating the relation of vitamin D levels with dental implant osseointegration and subsequently the success or failure of the implant. The focused questions were-What is the effect of vitamin D levels on successful dental implant osseointegration and what is the effect of vitamin D supplementation on successful implant osseointegration? A search was conducted on PubMed and Google Scholar using the terms "vitamin D," "cholecalciferol," "1,25(OH) D," "dental implant," "osseointegration," and "bone implant contact" for a period of 10 years from 2011 to 2020. Clinical trials, cross-sectional studies, case series, and case reports were included. A total of ten studies were included after the screening process. Five of these studies evaluated the effect of vitamin D supplementation on osseointegration, whereas five only evaluated the effect of vitamin D deficiency on dental implant osseointegration. Only five of these studies reported dental implant failure varying from 7% to 13% in vitamin D deficient/insufficient groups. Positive relationship exists between serum vitamin D levels and dental implant osseointegration; however, few studies failed to report any relation. More prospective clinical research studies as well as randomized controlled trials are needed to show a significant correlation between decreased serum levels of vitamin D and increased risk of dental implant failure in perspective of vitamin D supplementation which can promote the osseointegration of dental implants., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 National Journal of Maxillofacial Surgery.)

Dendritic cells (DCs) actively sample and present antigen to cells of the adaptive immune system and are thus vital for successful immune control and memory formation. Immune cell metabolism and function are tightly interlinked, and a better understanding of this interaction offers potential to develop immunomodulatory strategies. However, current approaches for assessing the immune cell metabolome are often limited by end-point measurements, may involve laborious sample preparation, and may lack unbiased, temporal resolution of the metabolome. In this study, we present a novel setup coupled to a secondary electrospray ionization-high resolution mass spectrometric (SESI-HRMS) platform allowing headspace analysis of immature and activated DCs in real-time with minimal sample preparation and intervention, with high technical reproducibility and potential for automation. Distinct metabolic signatures of DCs treated with different supernatants (SNs) of bacterial cultures were detected during real-time analyses over 6 h compared to their respective controls (SN only). Furthermore, the technique allowed for the detection of 13 C-incorporation into volatile metabolites, opening the possibility for real-time tracing of metabolic pathways in DCs. Moreover, differences in the metabolic profile of naı̈ve and activated DCs were discovered, and pathway-enrichment analysis revealed three significantly altered pathways, including the TCA cycle, α-linolenic acid metabolism, and valine, leucine, and isoleucine degradation.

Background: Maternal health care financing is key to the smooth functioning of health systems in a country. In India, maternal health care still persists as a major public health issue. Adequate health insurance could transform the utilization of maternal health care services. Therefore, we aim to examine the health insurance policies that cover maternal health and their performance in India., Methods: The unit-level data of social consumption on health by the National Sample Survey Organizations, conducted in India (2017-18), are used. Bivariate analysis, logistic regression and propensity scoring matching are applied., Results: About 14.1% women are covered by health insurance support at the national level. Uninsured women are less likely to receive full antenatal care (ANC) services and institutional delivery. Socio-economic characteristics play a significant role in utilizing maternal health care benefits through health insurance support., Conclusions: Our study concludes that the health insurance coverage is the most significant contributor to the better utilization of full ANC and institutional delivery at the national level and hindrances in accessing them. There is a need for proactive and inclusive policy development by the Government of India to incentivize public financing through health insurance, which can shrink the challenges of public health burden and reduce the health risk., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Breast cancer treatment with PARP-1 inhibitors remains challenging due to emerging toxicities, drug resistance, and unaffordable costs of treatment options. How do we invent strategies to design better anti-cancer drugs? A part of the answer is in optimized compound properties, desirability functions, and modern computational drug design methods that drive selectivity and toxicity and have not been reviewed for PARP-1 inhibitors. Nonetheless, comparisons of these compound properties for PARP-1 inhibitors are not available in the literature. In this review, we analyze the physchem, PKPD space to identify inherent desirability functions characteristic of approved drugs that can be valuable for the design of better candidates. Recent literature utilizing ligand, structure-based drug design strategies and matched molecular pair analysis (MMPA) for the discovery of novel PARP-1 inhibitors are also reviewed. Thus, this perspective provides valuable insights into the medchem and multiparameter optimization of PARP-1 inhibitors that might be useful to other medicinal chemists., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Anila Nuthi reports that financial support was provided by Ministry of Electronics and Information Technology., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Research studies based on tractography have revealed a prominent reduction of asymmetry in some key white-matter tracts in schizophrenia (SCZ). However, we know little about the influence of common genetic risk factors for SCZ on the efficiency of routing on structural brain networks (SBNs). Here, we use a novel recall-by-genotype approach, where we sample young adults from a population-based cohort (ALSPAC:N genotyped = 8,365) based on their burden of common SCZ risk alleles as defined by polygenic risk score (PRS). We compared 181 individuals at extremes of low (N = 91) or high (N = 90) SCZ-PRS under a robust diffusion MRI-based graph theoretical SBN framework. We applied a semi-metric analysis revealing higher SMR values for the high SCZ-PRS group compared with the low SCZ-PRS group in the left hemisphere. Furthermore, a hemispheric asymmetry index showed a higher leftward preponderance of indirect connections for the high SCZ-PRS group compared with the low SCZ-PRS group (PFDR < 0.05). These findings might indicate less efficient structural connectivity in the higher genetic risk group. This is the first study in a population-based sample that reveals differences in the efficiency of SBNs associated with common genetic risk variants for SCZ., (© The Author(s) 2022. Published by Oxford University Press.)

Real-time breath analysis using secondary electrospray ionization coupled with high-resolution mass spectrometry is a fast and noninvasive method to access the metabolic state of a person. However, it lacks the ability to unequivocally assign mass spectral features to compounds due to the absence of chromatographic separation. This can be overcomed by using exhaled breath condensate and conventional liquid chromatography-mass spectrometry (LC-MS) systems. In this study, to the best of our knowledge, we confirm for the first time the presence of six amino acids (GABA, Oxo-Pro, Asp, Gln, Glu, and Tyr) previously reported to be involved in response to and side effects from antiseizure medications in exhaled breath condensate and by extension in exhaled human breath. Raw data are publicly available at MetaboLights with the accession number MTBLS6760.

The Last four decades have witnessed the banning of several synthetic insecticides mainly due to the development of resistance to the target pests and due to hazardous effects on humans and the environment. Hence, the development of a potent insecticide with biodegradable and eco-friendly nature is the need of the hour. In the present study, the fumigant property, and biochemical effects of Dillenia indica L. (Dilleniaceae) were studied against three coleopterans stored-products insects. The bioactive enriched fraction (sub-fraction-III) was isolated from ethyl acetate extracts of D. indica leaves and found toxic to rice weevil, Sitophilus oryzae (L.) (Coleoptera); lesser grain borer Rhyzopertha dominica (L.) (Coleoptera) and red flour beetle, Tribolium castaneum (Herbst.) (Coleoptera) with the LC 50 values of 101.887, 189.908 and 115.1 µg/L respectively after 24 h exposure. The enriched fraction was found to inhibit the function of acetylcholinesterase (AChE) enzyme when tested against S. oryzae, T. castaneum , and R. dominica with LC 50 value of 88.57 µg/ml, 97.07 µg/ml, and 66.31 µg/ml respectively, in in-vitro condition. It was also found that the enriched fraction caused a significant oxidative imbalance in the antioxidative enzyme system such as superoxide dismutase, catalase, DPPH (2,2-diphenyl-1-picrylhydrazyl), and glutathione-S-transferase (GST). GCMS analysis of the enriched fraction indicates three major compounds namely, 6-Hydroxy-4,4,7a-trimethyl-5,6,7,7a-tetrahydrobenzofuran-2(4H)-one, 1,2-Benzisothiazol-3(2H)-one, and Benzothiazole, 2-(2-hydroxyethylthio)-. Finally, we concluded that the enriched fraction of D. indica has insecticidal properties and the toxicity may be due to the inhibition of the AChE enzyme in association with oxidative imbalance created on the insect's antioxidant enzyme systems., 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 © 2023 Singh, Koijam, Bharali and Rajashekar.)

Background: Aortic aneurysm (AA) is a "silent killer" human disease with no effective treatment. Although the therapeutic potential of various pharmacological agents have been evaluated, there are no reports of β-arrestin-biased AT1R (angiotensin-II type-1 receptor) agonist (TRV027) used to prevent the progression of AA., Methods: We tested the hypothesis that TRV027 infusion in AngII (angiotensin II)-induced mouse model of AA prevents AA. High-fat-diet-fed ApoE (apolipoprotein E gene)-null mice were infused with AngII to induce AA and co-infused with TRV027 and a clinically used AT1R blocker Olmesartan to prevent AA. Aortas explanted from different ligand infusion groups were compared with assess different grades of AA or lack of AA., Results: AngII produced AA in ≈67% male mice with significant mortality associated with AA rupture. We observed ≈13% mortality due to aortic arch dissection without aneurysm in male mice. AngII-induced AA and mortality was prevented by co-infusion of TRV027 or Olmesartan, but through different mechanisms. In TRV027 co-infused mice aortic wall thickness, elastin content, new DNA, and protein synthesis were higher than untreated and Olmesartan co-infused mice. Co-infusion with both TRV027 and Olmesartan prevented endoplasmic reticulum stress, fibrosis, and vasomotor hyper responsiveness., Conclusions: TRV027-engaged AT1R prevented AA and associated mortality by distinct molecular mechanisms compared with the AT1R blocker, Olmesartan. Developing novel β-arrestin-biased AT1R ligands may yield promising drugs to combat AA.

In present study, the acute and sub-acute toxicities of Dihydro- p -coumaric acid isolated from the leaves of Tithonia diversifolia (Hemsl.) A. Gray was studied for safety issues in mammals . For acute toxicity tests, isolated compound was administered orally in both male and female BALB/c mice at the doses of 200, 800, and 1,600 mg/kg body weight for 7 days. In sub-acute toxicity study 50 and 500 mg/kg bw of the compound was orally administered for 14 days. Toxicity induced behavioural changes, haematological parameters, biochemical markers and histopathological sections were studied after Dihydro- p -coumaric acid administration. The vital organs like heart, kidney, uterus and testis revealed no adverse effects at doses of upto 1,600 mg/kg bw and 500 mg/kg bw. Slight hepatotoxicity was however demonstrated by ALT and AST assay but histopathological section did not concur as much. The study demonstrated insignificant difference in the percentage of feed intake, water intake, weight gain, haematological parameters and histopathological changes, with no toxicity signs and mortality. Dihydro- p -coumaric acid can be regarded as safe in both acute and sub-acute toxicity assay in both sexes. This indicates Dihydro- p -coumaric acid as a viable alternative to synthetic pesticides., 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 Devi, Jena, Patra, Singh, Chawla, Raina, Koijam, Parida and Rajashekar.)

Exhaled breath contains valuable information at the molecular level and offers promising potential for precision medicine. However, few breath tests transition to routine clinical practice, partly because of the missing validation in multicenter trials. Therefore, we developed and applied an interoperability framework for standardized multicenter data acquisition and processing for breath analysis with secondary electrospray ionization-high resolution mass spectrometry. We aimed to determine the technical variability and metabolic coverage. Comparison of multicenter data revealed a technical variability of ∼20% and a core signature of the human exhaled metabolome consisting of ∼850 features, corresponding mainly to amino acid, xenobiotic, and carbohydrate metabolic pathways. In addition, we found high inter-subject variability for certain metabolic classes (e.g., amino acids and fatty acids), whereas other regions such as the TCA cycle were relatively stable across subjects. The interoperability framework and overview of metabolic coverage presented here will pave the way for future large-scale multicenter trials., Competing Interests: P.S. and M.K. are co-founders of Deep Breath Intelligence AG (Switzerland). K.S. and F.S. are consultants for Deep Breath Intelligence AG (Switzerland). P.S., K.S., A.G., M.K., U.F., and M.O. hold a patent on data processing for breath analysis by SESI-HRMS. P.S. and K.S. hold a patent on a system suitability test for SESI-HRMS. All other authors declare no competing interests., (© 2022 The Authors.)

Early detection of pathogenic bacteria is needed for rapid diagnostics allowing adequate and timely treatment of infections. In this study, we show that secondary electrospray ionization-high resolution mass spectrometry (SESI-HRMS) can be used as a diagnostic tool for rapid detection of bacterial infections as a supportive system for current state-of-the-art diagnostics. Volatile organic compounds (VOCs) produced by growing S . aureus or S . pneumoniae cultures on blood agar plates were detected within minutes and allowed for the distinction of these two bacteria on a species and even strain level within hours. Furthermore, we obtained a fingerprint of clinical patient samples within minutes of measurement and predominantly observed a separation of samples containing live bacteria compared to samples with no bacterial growth. Further development of this technique may reduce the time required for microbiological diagnosis and should help to improve patient's tailored treatment., Competing Interests: P.S. is cofounder of Deep Breath Initiative A.G. (Switzerland), which develops breath-based diagnostic tools. K.D.S. is consultant for Deep Breath Initiative A.G. (Switzerland)., (© 2022 The Author(s).)