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The essential oil of Mansoa alliacea (Lam.) A.H. Gentry was characterized on the basis of its gas chromatographymass spectrometry analysis, physico-chemical, antioxidant, and antifungal properties. M. alliacea essential oil (MAEO) had a complex mixture of eight major and minor components. The main constituents were disulfide, di-2-propenyl (cas) 1, 2-bis(allyl) disulfane (66.90%), trisulfide, di-2-propenyl (23.81%), and 1-Propene, 3,3'-thiobis- (cas) 4-thia-1,6-heptadiene (4.44%). The optical rotation and refractive index of oil were found to be 4.083 and 1.337, respectively. The oil showed potent antioxidant activity in 2, 2'- diphenyl-1-picrylhydazyl, β-carotene, and ABTS assays. Oil showed fungitoxic activity against nine fungal species. The investigations confirm that MAEO has promising potential to be used as a biopesticide and as a preservative agent in food and pharmaceutical systems. [ABSTRACT FROM AUTHOR]

This article presents the findings from a study on Land Use and Land Cover (LULC) predictions for Pathumthani province in 2028 and 2038. Utilizing Landsat satellite imagery data from 2013, 2018, and 2023, and employing the Cellular Authomata – Artificial Neural Network (CA-ANN) algorithm in MOLUSCE plugin in QGIS, the study simulated future LULC trends. The predictor variables used in the analysis are distance from main roads, distance sky train stations, distance from universities, and distance from markets. The overall accuracy and kappa coefficient of the prediction model validate its reliability for forecasting LULC changes. The results illustrate evolving urban landscapes and environmental dynamics, with vegetation predominating in the eastern and western regions of Pathumthani in 2028, while built-up areas concentrate along major transportation routes. By 2038, these trends persist, with notable expansion of built-up areas, particularly in Muang Pathumthani, Khlong Luang, and Lam Luk Ka districts. Significant urbanization is observed in Muang Pathumthani along the Chao Phraya River, driven by proximity to Nonthaburi. Lam Luk Ka experiences substantial development, supported by infrastructure and connectivity to Bangkok, while Thanyaburi sees urbanization along the Rangsit-Nakornnayok road. Khlong Luang emerges as an urban expansion hub, influenced by Highway No.1 and industrial estates. The study underscores the complex interplay of infrastructure, demographics, and environmental factors, emphasizing the need for sustainable planning to address future challenges. [ABSTRACT FROM AUTHOR]

Generative Adversarial Networks widely known as GANs, are deep learning models that has gained a lot of popularity in the last few years due to their promising nature. One of their major applications can be found in the healthcare sector for various purposes like image reconstruction, image enhancement, image segmentation, image processing, image analysis etc. The objective of this paper is to bring forward some of the recent research on the application of GANs in the health care domain during 2017 – 2022. A total of 168 papers were screened out of which 77 relevant to the present study were finalized for this study. Bibliometric analysis was also performed on these documents, to obtain an overall picture of Generative Adversarial Networks (GANs) in the healthcare domain. This analysis is expected to help the future researcher and developers in targeting the areas of the healthcare sector which are likely to grow in the coming future using GANs algorithms. [ABSTRACT FROM AUTHOR]

Plastics, particularly microplastics (MPs) and nanoplastics (NP), have become major environmental and health concerns due to their high chemical stability. The highly hydrophobic plastics enter living organisms through reversible interactions with biomolecules, forming biocoronas. Following recent reports on plastics breaching the blood-brain barrier, the binding behavior of human α-synuclein (hαSn) with polyethylene-based (PE) plastics was evaluated by using molecular dynamics simulations and experimental methods. The results provided three important findings: (i) hαSn transitions from an open helical to a compact conformation, enhancing intramolecular interactions, (ii) nonoxidized PE NPs (NPnonox) rapidly adsorb hαSn, as supported by experimental data from dynamic light scattering and adsorption isotherms, altering its structure, and (iii) the oxidized NP (NPox) failed to capture hαSn. These interactions were dominated by the N-terminal domain of hαSn, with major contributions from hydrophobic amino acids. These findings raise concerns about the potential pharmacological effects of NP-protein interactions on human health.

Introduction: Primary health care has regained its importance in global policy making. In 2018, the Government of India initiated the Ayushman Bharat - Comprehensive Primary Health Care (AB-CPHC) programme. It was based on upgrading the existing primary health facilities into Health and Wellness Centers (HWCs). The current study aimed to assess the readiness and performance of HWCs in providing comprehensive primary health care services in India's Chhattisgarh state., Methods: We conducted a cross-sectional health facility assessment with a state-representative sample of 404 HWCs. A standardized health facility survey tool was used to collect information on essential inputs and service outputs of HWCs. The expected population healthcare needs were estimated using secondary sources. The performance of HWCs was assessed by comparing the volume of services provided against the expected population need for outpatient care., Results: On an average, 358 outpatients including 128 non-communicable disease (NCD) patients were treated monthly at an HWC. HWCs were able to cover 31% of the total population's health need for outpatient care, 26% for hypertension, and 21% for diabetes care. In addition to services for reproductive and child health, HWCs provided services for common acute ailments (cold, cough, fever, aches and pains); infections of skin, eye, ear, and reproductive tract, and minor injuries. HWCs were also contributing significantly to national disease control programmes. Acute ailments followed by NCDs and communicable diseases had the largest share among services provided. The key gaps were in coverage of mental illnesses and chronic respiratory diseases. Most of the HWCs showed adequate readiness for the availability of required human resources, supplies, and infrastructure., Conclusion: HWCs were able to provide a comprehensive range of primary care services and able to cater to a sizable portion of the rural population's acute and chronic health care needs. The performance was made possible by the adequate availability of medicines, staff, training programmes and tele-consultation linkages. If HWCs in other states are able to reach a similar level of performance, the initiative will prove to be a game changer for equitable primary care in India., (© 2024. The Author(s).)

Drought stress is a universal crisis in sustaining the growth and production of major legumes, including the chickpea. Drought severely reduces the biomass of chickpea plants, with the effect on leaves appearing the most apparent. The aim of this study was to investigate, using various physiological and biochemical markers throughout the pod filling stage, how 78 desi chickpea genotypes tolerated drought stress. Most of the evaluated characteristics showed significant variations between control and drought treatments. The mean performance of most of the investigated parameters significantly decreased under moisture-stressed conditions. RWC, SWD, MSI, and CTD were investigated under terminal drought-stressed conditions. Except for saturated water deficit (SWD), all remaining characteristics declined with increasing stress. Genotypes SAGL152210, SAGL152252, SAGL152347, SAGL22-115, and JG11 were recognized as drought-tolerant based on physiological characteristics. Biochemical markers viz., protein content, total soluble sugar, lipid peroxidation, and proline content, had an impact on osmotic adjustment. Based on non-enzymatic biochemical traits, genotypes SAGL22-115, ICC4958, ICCV201108, ICCV201107, SAGL152252, and JG11 were identified for their capability to survive under drought-stressed conditions. H 2 O 2 content, CAT, SOD, POD, APX, and DPPH were considered antioxidant agents. Genotypes SAGL152208, SAGL22-105, SAGL22-112, ICC201108, SAGL152278, SAGL152252, SAGL162371, SAGL162390, ICC 4958, and JG315 may be considered drought-tolerant based on antioxidant activities. These genotypes are believed to be better equipped with physio-biochemical mechanisms and antioxidant defense systems at the cellular level and can be used in breeding programs to breed drought-tolerant cultivar(s). They can also be screened in the future, allowing the line(s) that have remained consistent over time to be recognized and registered as drought-tolerant donors.

The liquid chromatography-high resolution mass spectrometry (LC-HRMS) technique enables the detection of phytochemicals present in the extracts. LC-HRMS-generated mass list showed abundant compounds of interest, artifacts, and primary metabolites. The identification of a secondary metabolite of interest within the extract is very challenging. We hypothesized that identifying the "new metabolite" in the whole metabolome is more challenging than identifying it within the class of metabolites. The proposed prioritization strategy focused on the elimination of unknown and prioritizing the known class of secondary metabolites to identify new metabolites. The prioritization strategy demonstrated on Murraya paniculata for the identification of new metabolites. LC-HRMS-generated information is used as a filter to target the secondary metabolite and the new metabolites. This strategy successfully annotated the new coumarin and coumarin alkaloids from the mass list of 1448 metabolites. Varanasine ( 3 ), schroffanone ( 4 ), schroffanene ( 5 ), and O -methylmurraol ( 9 ) are new compounds, and coumarin ( 1 , 2 , and 6-8 ) are known. Varanasine ( 3 ) is the first naturally occurring 7-aminocoumarin with additional N -formyl functionality. The isolates were screened for cytotoxicity against the panel of cancer cell lines. Varanasine ( 3 ) and minumicrollin ( 6 ) showed significant cytotoxicity and apoptosis-inducing potential. The immunoblot analysis confirmed inhibition of apoptotic protein PARP-1 and caspase-3 expression by 3 and 6 .

Cyclophane CP-1 demonstrates markedly distinct sensitivities toward Cholesterol sulfate (CH-S), Sodium Dodecyl Sulfate (SDS), and Sodium Dodecyl Benzene Sulfonate (SDBS) when the solvent is shifted minimally from a 95 % to a 98 % HEPES-DMSO mixture. In a 98:2 HEPES-DMSO mixture, CP-1 engages in highly selective self-assembly with CH-S, which is characterized by aggregation-induced emission enhancement (AIEE) in contrast to other steroidal sulfates such as pregnenolone sulfate (PRG-S), dehydroisoandrosterone sulfate (DIAND-S), taurocholic acid (TACH-S), and the surfactants SDS and SDBS. This assembly results in an approximate 40-fold increase in fluorescence intensity with three equivalents of CH-S and allows for the detection of concentrations as low as 200 nM under physiological conditions. Dynamic light scattering (DLS) studies illustrate the aggregation of CP-1 and CH-S, with the zeta potential of each shifting from negative values to nearly zero in a 1:2 CP-1:CH-S mixture, indicating self-assembly. This aggregation behavior is reversible, as demonstrated by a corresponding decrease and then increase in fluorescence intensity with temperature variations from 25 °C to 70 °C and back to 25 °C. Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) analyses show that CP-1 forms aggregates ranging from 100 to 180 nm, which increase to 150-250 nm upon interaction with CH-S. In a 95:5 HEPES-DMSO mixture, CP-1 exhibits a stronger AIEE response with SDS and SDBS compared to CH-S. Cyclophane CP-2, when dissolved in binary DMSO-water mixtures with water content exceeding 80 %, shows similar AIEE phenomena and undergoes selective fluorescence quenching with SDS and only a 50 % increase in fluorescence intensity with CH-S, irrespective of the HEPES concentration (95 % or 98 %)., 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 Elsevier B.V. All rights reserved.)

Background: Cabozantinib, a tyrosine kinase inhibitor (TKI), is a prevalent second-line (2 L) therapy and was approved for use after progression on TKIs. However, the 1 L treatment setting has changed since the approval of cabozantinib monotherapy in salvage therapy settings., Objective: To assess the differential effectiveness of cabozantinib after prior progression on 1 L ipilimumab with nivolumab (IPI + NIVO) compared to programmed death receptor-1 (PD-1) or PD-1 ligand (PD-L1) inhibitors (PD1/L1i) with TKIs., Methods: Utilizing a nationwide electronic health record (EHR)-derived de-identified database, we included patients with metastatic clear cell renal cell carcinoma (mccRCC) who received 1 L treatment with an immune checkpoint inhibitor (ICI)-based combination and 2 L treatment with cabozantinib monotherapy. These patients were categorized based on the type of 1 L ICI-based combination received: IPI + NIVO vs. PD1/L1i with TKI. Real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) were summarized using Kaplan-Meier curves and compared using Cox-proportional hazard models adjusted for International mRCC Database Consortium (IMDC) risk groups., Results: Among 12,285 patients with metastatic renal cell carcinoma, 237 were eligible and included. Median rwTTNT was 8 months for the IPI + NIVO subgroup and 7.5 months for the PD1/L1i + TKI subgroup (HR 1.05, 95% CI: 0.74-1.49, p  = 0.8). Median rwOS was 17 months for IPI + NIVO and 16 months for PD1/L1i + TKI subgroup (HR 0.79, 95% CI: 0.52-1.20, p  = 0.3)., Conclusions: Cabozantinib remains effective as a 2 L therapy for mccRCC independent of the type of prior 1 L ICI-based combination. Further research is needed to validate these findings and explore the ideal sequencing of therapies., Competing Interests: Dr. Agarwal: NA has received honorarium before May 2021 and during his lifetime for consulting to Astellas, AstraZeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics; and NA’s institution has received research funding during his lifetime from Arnivas, Astellas, AstraZeneca, Bavarian Nordic, Bayer, Bristol Meyers Squibb, Calithera, Celldex, Clovis, CRISPR Therapeutics, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. NA is a member of the editorial board of Kidney Cancer but was not involved in the peer-review process of this paper, nor had access to any information regarding its peer-review. Umang Swami, MD: US reports consultancy to Astellas, AstraZeneca, Adaptimmune, Exelixis, Gilead, Imvax, Pfizer, Seattle Genetics and Sanofi and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. Benjamin L. Maughan, MD: BLM has received financial compensation as a paid consultant/advisor to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, Xencor, NCCN and Peloton Therapeutics. Huntsman Cancer Institute has received research funding from Exelixis, Bavarian-Nordic, Clovis and Bristol-Myers Squibb on his behalf. AN, GB, NJ, VMT, HL, GGF, NS, CT, NT, BC, AS, CHC and BN have no conflicts of interest to report, (© 2024 – The authors. Published by IOS Press.)

Background: There is controversy about risk of malignant arrhythmias and stroke in patients with apical aneurysms in hypertrophic cardiomyopathy (HCM)., Objectives: The aim of this study was to estimate the associations of aneurysm size and major HCM risk factors with the incidence of lethal and potentially lethal arrhythmias and to estimate incidence of unexplained stroke., Methods: In 108 patients (age 57.4 ± 13.5 years, 37% female) from 3 HCM centers, we assessed American Heart Association/American College of Cardiology guidelines risk factors and initial aneurysm size by echocardiography and cardiac magnetic resonance imaging and assessed outcomes after median 5.9 (IQR: 3.7-10.0) years., Results: Implantable cardioverter defibrillator discharges or sudden cardiac death (SCD) occurred in 21 (19.4%) patients. Of patients with a risk factor, 55% subsequently had ventricular tachycardia (VT), ventricular fibrillation (VF), or SCD at follow-up, compared with 10% in those who did not ( P  < 0.001). The upper tercile of size had a 5-year cumulative risk of 35%, while the lower tercile had 5-year risk of 6% ( P  = 0.0046). In those with the smallest aneurysms <2 cm 2 and also without risk factors VT, VF, or SCD occurred in only 2.5%. Clinical atrial fibrillation (AF) was prevalent, occurring in 49 (45%). Stroke was commonly associated with AF. Stroke without conventional cause had an incidence of 0.5%/year. Surgery in 19% was effective in reducing symptoms. VT ablation and surgery were moderately effective in preventing recurrent VT., Conclusions: Risk factors and aneurysm size were associated with subsequent VT, VF, or SCD. Patients with aneurysms in the lowest tercile of size have a low cumulative 5-year risk. Clinical AF occurred frequently. Stroke prevalence in absence of known stroke etiologies is uncommon and comparable to risk of severe bleeding., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: India launched a national health insurance scheme named Ayushman Bharat Pradhan Mantri Jan Arogya Yojana (AB-PMJAY) in 2018 as a key policy for universal health coverage. The ambitious scheme covers 100 million poor households. None of the studies have examined its impact on the quality of care. The existing studies on the impact of AB-PMJAY on financial protection have been limited to early experiences of its implementation. Since then, the government has improved the scheme's design. The current study was aimed at evaluating the impact of AB-PMJAY on improving utilisation, quality, and financial protection for inpatient care after four years of its implementation., Methods: Two annual waves of household surveys were conducted for years 2021 and 2022 in Chhattisgarh state. The surveys had a sample representative of the state's population, covering around 15,000 individuals. Quality was measured in terms of patient satisfaction and length of stay. Financial protection was measured through indicators of catastrophic health expenditure at different thresholds. Multivariate adjusted models and propensity score matching were applied to examine the impacts of AB-PMJAY. In addition, the instrumental variable method was used to address the selection problem., Results: Enrollment under AB-PMJAY was not associated with increased utilisation of inpatient care. Among individuals enrolled under AB-PMJAY who utilised private hospitals, the proportion incurring catastrophic health expenditure at the threshold of 10% of annual consumption expenditure was 78.1% and 70.9% in 2021 and 2022, respectively. The utilisation of private hospitals was associated with greater catastrophic expenditure irrespective of AB-PMJAY coverage. Enrollment under AB-PMJAY was not associated with reduced out-of-pocket expenditure or catastrophic health expenditure., Conclusions: AB-PMJAY has achieved a large coverage of the population but after four years of implementation and an evidence-based increase in reimbursement prices for hospitals, it has not made an impact on improving utilisation, quality, or financial protection. The private hospitals contracted under the scheme continued to overcharge patients, and purchasing was ineffective in regulating provider behaviour. Further research is recommended to assess the impact of publicly funded health insurance schemes on financial protection in other low- and middle-income countries., (© 2024. The Author(s).)

Introduction: Rechallenge with antibodies targeting programmed cell death protein-1 or its ligand (PD-1/L1) after discontinuation or disease progression in solid tumors following a prior PD-1/L1 treatment is often practiced in clinic. This study aimed to investigate if adding PD-1/L1 inhibitors to cabozantinib, the most used second-line treatment in real-world patients with metastatic clear cell renal cell carcinoma (mccRCC), offers additional benefits., Methods: Using de-identified patient-level data from a large real-world US-based database, patients diagnosed with mccRCC, who received any PD-1/L1-based combination in first-line (1L) setting, followed by second-line (2L) therapy with either cabozantinib alone or in combination with PD-1/L1 inhibitors were included. Patients given a cabozantinib-containing regimen in 1L were excluded. The study end points were real-world time to next therapy (rwTTNT) and real-world overall survival (rwOS) by 2L., Results: Of 12,285 patients with metastatic renal cell carcinoma in the data set, 348 patients met eligibility and were included in the analysis. After propensity score matching weighting, cabozantinib with PD-1/L1 inhibitors versus cabozantinib (ref.) had similar rwTTNT and rwOS in the 2L setting. Hazard ratios and 95% confidence interval (CI) for rwTTNT and rwOS are 0.74 (95% CI, 0.49-1.12) and 1.15 (95% CI, 0.73-1.79), respectively., Conclusion: In this study, the results align with the phase 3 CONTACT-03 trial results, which showed no additional benefit of adding PD-L1 inhibitor to cabozantinib compared to cabozantinib alone in 2L following PD-1/L1-based therapies in 1L. These results from real-world patients strengthen the evidence regarding the futility of rechallenge with PD-1/L1 inhibitors., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Thromboembolic events (TE) are a common complication in patients with metastatic renal cell carcinoma (mRCC) and are associated with poorer clinical outcomes. However, the incidence of TE and clinical and genomic characteristics of patients with mRCC who develop this complication are poorly understood. Herein, we describe the incidence and clinical features of patients with mRCC with or without TE at our institution, and examine their association with the underlying genomic and transcriptomic characteristics of the tumor. This retrospective study included all consecutive cases of mRCC seen at our institution. A CLIA-certified lab performed tumor genomics and transcriptomics. Patients were classified based on the presence of a TE within the first year of diagnosis. Three hundred and seventy patients with mRCC were included in the study. TE was seen in 11% (42) of the patients. Patients with favorable International mRCC Database Consortium (IMDC) risk were less likely to develop a TE. In contrast, patients receiving combination treatment with a tyrosine kinase inhibitor (TKI) and an immune checkpoint inhibitor were more likely to develop a TE. No difference in overall survival among patients with or without TE was observed (52 vs. 55 months; HR 0.85, 95% CI 0.5574-1.293, p = 0.24). The most upregulated pathways in mRCC with TEs versus those without were the xenobiotic metabolism and mTORC1 signaling pathways. Our findings suggest potential biomarkers that, after external validation, could be used to better select patients who would benefit from prophylactic anticoagulation., Competing Interests: Neeraj Agarwal (lifetime disclosures): No personal COIs since April 15, 2021. Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to Neeraj Agarwal’s institution (lifetime): Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon. Umang Swami reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, Pfizer, AstraZeneca, and Gilead and research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics. Benjamin L. Maughan received financial compensation as a paid consultant/advisor to Abbive, Pfizer, AVEO oncology, Janssen, Astellas, Bristol-Myers Squibb, Clovis, Tempus, Merck, Exelixis, Bayer Oncology, Lilly, Sanofi, Telix, and Peloton Therapeutics; Huntsman Cancer Institute has received research funding from Exelixis, Bavarian-Nordic, Clovis, and Bristol-Myers Squibb on behalf of Benjamin L. Maughan. The rest of the authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright: Fortuna G.G., et al.)

Manually labeling data for supervised learning is time and energy consuming; therefore, lexicon-based models such as VADER and TextBlob are used to automatically label data. However, it is argued that automated labels do not have the accuracy required for training an efficient model. Although automated labeling is frequently used for stance detection, automated stance labels have not been properly evaluated, in the previous works. In this work, to assess the accuracy of VADER and TextBlob automated labels for stance analysis, we first manually label a Twitter, now X, dataset related to M-pox stance detection. We then fine-tune different transformer-based models on the hand-labeled M-pox dataset, and compare their accuracy before and after fine-tuning, with the accuracy of automated labeled data. Our results indicated that the fine-tuned models surpassed the accuracy of VADER and TextBlob automated labels by up to 38% and 72.5%, respectively. Topic modeling further shows that fine-tuning diminished the scope of misclassified tweets to specific sub-topics. We conclude that fine-tuning transformer models on hand-labeled data for stance detection, elevates the accuracy to a superior level that is significantly higher than automated stance detection labels. This study verifies that automated stance detection labels are not reliable for sensitive use-cases such as health-related purposes. Manually labeled data is more convenient for developing Natural Language Processing (NLP) models that study and analyze mass opinions and conversations on social media platforms, during crises such as pandemics and epidemics., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Perikli 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.)

Two different types of novel phenothiazine-embedded dithiasmaragdyrins containing one phenothiazine ring, two thiophene rings and two pyrrole rings connected via three meso carbons and two direct bonds in the macrocyclic framework were synthesized over the sequence of synthetic steps starting with phenothiazine. Three examples of phenothiazine-embedded dithiasmaragdyrins were synthesized by condensing appropriate phenothiazine-based pentapyrrane with pentafluorobenzaldehyde and two examples of phenothiazine sulfone embedded dithiasmaragdyrins were synthesized by condensing phenothiazine-based diol with appropriate meso-aryl dipyrromethane under mild acid-catalysed conditions. 1D&2D NMR studies revealed that the thiophene rings adopted inverted orientation in phenothiazine sulfone embedded dithiasmaragdyrins whereas in phenothiazine-embedded dithiasmaragdyrins, the thiophene rings were in normal orientation. Both types of macrocycles exhibit nonaromatic absorption features and showed panchochromic absorption features in its neutral and protonated forms. The electrochemical studies indicated that the phenothiazine-embedded dithiasmaragdyrins were more electron-rich compared to phenothiazine sulfone embedded dithiasmaragdyrins. DFT studies revealed that both types of dithiasmaragdyrins exhibit significantly distorted structures and TD-DFT studies support the experimental observations., (© 2024 Wiley-VCH GmbH.)

Importance: Targeted therapies based on underlying tumor genomic susceptible alterations have been approved for patients with metastatic prostate cancer (mPC) and advanced urothelial carcinoma (aUC)., Objective: To assess trends and disparities in next-generation sequencing (NGS) testing among patients with mPC and aUC., Design, Setting, and Participants: This retrospective cohort study used an electronic health record-derived database to extract deidentified data of patients receiving care from US physician practices, hospital-affiliated clinics, and academic practices. Patients diagnosed with mPC or aUC between March 1, 2015, and December 31, 2022, were included., Exposures: Social determinants of health evaluated by race and ethnicity, socioeconomic status (SES), region, insurance type, and sex (for aUC)., Main Outcomes and Measures: The primary outcomes were (1) NGS testing rate by year of mPC and aUC diagnosis using Clopper-Pearson 2-sided 95% CIs and (2) time to NGS testing, which considered death as a competing risk. Cumulative incidence functions were estimated for time to NGS testing. Disparities in subdistributional incidence of NGS testing were assessed by race and ethnicity, SES, region, insurance type, and sex (for aUC) using the Fine-Gray modified Cox proportional hazards model, assuming different subdistribution baseline hazards by year of mPC and aUC diagnosis., Results: A total of 11 927 male patients with mPC (167 Asian [1.6%], 1236 Black [11.6%], 687 Hispanic or Latino [6.4%], 7037 White [66.0%], and 1535 other [14.4%] among 10 662 with known race and ethnicity) and 6490 patients with aUC (4765 male [73.4%]; 80 Asian [1.4%], 283 Black [4.8%], 257 Hispanic or Latino [4.4%], 4376 White [74.9%], and 845 other [14.5%] among 5841 with known race and ethnicity) were eligible and included. Both cohorts had a median age of 73 years (IQR, 66-80 years), and most underwent NGS testing before first-line treatment in the mPC cohort (1502 [43.0%]) and before second-line treatment in the aUC cohort (1067 [51.3%]). In the mPC cohort, the rates of NGS testing increased from 19.0% in 2015 to 27.1% in 2022, but Black patients (hazard ratio [HR], 0.75; 95% CI, 0.67-0.84) and Hispanic or Latino patients (HR, 0.70; 95% CI, 0.60-0.82) were less likely to undergo NGS testing. Patients with mPC who had low SES (quintile 1: HR, 0.74 [95% CI, 0.66-0.83]; quintile 2: HR, 0.89 [95% CI, 0.80-0.99]), had Medicaid (HR, 0.53; 95% CI, 0.38-0.74) or Medicare or other government insurance (HR, 0.89; 95% CI, 0.82-0.98), or lived in the West (HR, 0.81; 95% CI, 0.70-0.94) also were less likely to undergo testing. In the aUC cohort, the NGS rate increased from 14.1% in 2015 to 46.6% in 2022, but Black patients (HR, 0.76; 95% CI, 0.61-0.96) and those with low SES (quintile 1: HR 0.77 [95% CI, 0.66-0.89]; quintile 2: HR, 0.87 [95% CI, 0.76-1.00]) or Medicaid (HR, 0.72; 95% CI, 0.53-0.97) or Medicare or other government insurance (HR, 0.88; 95% CI, 0.78-0.99) were less likely to undergo NGS testing. Patients with aUC living in the South were more likely to undergo testing (HR, 1.29; 95% CI, 1.12-1.49)., Conclusions and Relevance: These findings suggest that although NGS tumor testing rates improved over time, the majority of patients still did not undergo testing. These data may help with understanding current disparities associated with NGS testing and improving access to standard-of-care health care services.

Background: Non-communicable diseases (NCDs) affect a large number of people globally and their burden has been growing. Healthcare for NCDs often involves high out-of-pocket expenditure and rising costs of providing services. Financing and providing care for NCDs have become a major challenge for health systems. Despite the high burden of NCDs in India, there is little information available on the costs involved in NCD care., Methods: The study was aimed at finding out the average monthly cost of outpatient care per NCD patient. The average cost was defined as all resources spent directly by government and citizens to get a month of care for a NCD patient. The cost borne by the government on public facilities was taken into account and activity-based costing was used to apportion it to the function of providing outpatient NCD care. For robustness, time-driven activity-based costing and sensitivity analyses were also performed. The study was conducted in Chhattisgarh State and involved a household survey and a facility survey, conducted simultaneously at the end of 2022. The surveys had a sample representative of the state, covering 3500 individuals above age of 30 years and 108 health facilities., Results: The average monthly cost per NCD patient was Indian Rupees (INR) 688 for public providers, INR 1389 for formal for-profit providers and INR 408 for informal private providers and they managed 53.5, 34.3 and 12.0% of NCD patients respectively. The disease profile of patients handled by different types of providers was similar. The average cost per patient was lowest for the primary care facilities in the public sector., Conclusions: The average direct cost of NCD care for government and citizens put together was substantially higher in case of formal for-profit providers compared with public facilities, even after taking into account the government subsidies to public sector. This has implications for allocative efficiency and the desired public-private provider mix in health systems., (© 2024. The Author(s).)

Aluminum (Al) overexposure damages various organ systems, especially the nervous system. Regularly administered aluminum chloride (AlCl 3 ) to rats causes dementia and pathophysiological alterations linked to Alzheimer's disease (AD). Taxifolin's neuroprotective effects against AlCl 3 -induced neurotoxicity in vitro and in vivo studies were studied. Taxifolin (0.1, 0.3, 1, 3, and 10 μM) was tested against AlCl 3 (5 mM)-induced neurotoxicity in C6 and SH-SY5Y cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Additionally, neural morphology was examined by confocal microscopy. Additionally, taxifolin's mode of binding with the co-receptor of toll-like receptor 4 (TLR4), human myeloid differentiation-2 ( h MD-2) was investigated. AlCl 3 (25 mg/kg/d, i.p. ) was administered to rats for 14 d, and from the eighth day, taxifolin (1, 2, and 5 mg/kg/d, i.p. ) was given along with AlCl 3 . This study assessed memory impairment using the Morris water maze, plus maze, and pole tests. This study also performed measurement of oxidant (malondialdehyde [MDA] and nitrite), antioxidant (reduced glutathione), and inflammatory (myeloperoxidase [MPO] activity, TLR4 expression) parameters in rats' brain in addition to histopathology. The docking score for taxifolin with h MD-2 was found to be -4.38 kcal/mol. Taxifolin treatment reduced the neurotoxicity brought on by AlCl 3 in both C6 and SH-SY5Y cells. Treatment with 10 μM taxifolin restored AlCl 3 -induced altered cell morphology. AlCl 3 administration caused memory loss, oxidative stress, inflammation (increased MPO activity and TLR4 expression), and brain atrophy. Taxifolin treatment significantly improved the AlCl 3 -induced memory impairment. Taxifolin treatment also mitigated the histopathological and neurochemical consequences of repeated AlCl 3 administration in rats. Thus, taxifolin may protect the brain against AD.

This study investigates the nanoscale self-assembly from mixtures of two symmetrical poly(ethylene oxide)-poly(propylene oxide)-pol(ethylene oxide) (PEO-PPO-PEO) block copolymers (BCPs) with different lengths of PEO blocks and similar PPO blocks. The blended BCPs (commercially known as Pluronic F88 and L81, with 80 and 10% PEO, respectively) exhibited rich phase behavior in an aqueous solution. The relative viscosity (η rel ) indicated significant variations in the flow behavior, ranging from fluidic to viscous, thereby suggesting a possible micellar growth or morphological transition. The tensiometric experiments provided insight into the intermolecular hydrophobic interactions at the liquid-air interface favoring the surface activity of mixed-system micellization. Dynamic light scattering (DLS) and small-angle neutron scattering (SANS) revealed the varied structural morphologies of these core-shell mixed micelles and polymersomes formed under different conditions. At a concentration of ≤5% w/v, Pluronic F88 exists as molecularly dissolved unimers or Gaussian chains. However, the addition of the very hydrophobic Pluronic L81, even at a much lower (<0.2%) concentration, induced micellization and promoted micellar growth/transition. These results were further substantiated through molecular dynamics (MD) simulations, employing a readily transferable coarse-grained (CG) molecular model grounded in the MARTINI force field with density and solvent-accessible surface area (SASA) profiles. These findings proved that F88 underwent micellar growth/transition in the presence of L81. Furthermore, the potential use of these Pluronic mixed micelles as nanocarriers for the anticancer drug quercetin (QCT) was explored. The spectral analysis provided insight into the enhanced solubility of QCT through the assessment of the standard free energy of solubilization (Δ G °), drug-loading efficiency (DL%), encapsulation efficiency (EE%), and partition coefficient ( P ). A detailed optimization of the drug release kinetics was presented by employing various kinetic models. The [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] MTT assay, a frequently used technique for assessing cytotoxicity in anticancer research, was used to gauge the effectiveness of these QCT-loaded mixed nanoaggregates.

Secondary aerosols constitute a significant fraction of atmospheric aerosols, yet our understanding of their formation mechanism and fate is very limited. In this work, the secondary organic aerosol (SOA) formation and aging of ambient air of Delhi are studied using a potential aerosol mass (PAM) reactor, an oxidation flow reactor (OFR), coupled with aerosol chemical speciation monitor (ACSM), proton transfer reaction time of flight mass spectrometer (PTR-ToF-MS), and scanning mobility particle sizer with counter (SMPS + C). The setup mimics atmospheric aging of up to several days with the generation of OH radicals. Variations in primary volatile organic compounds (VOCs) and oxygenated volatile organic compounds (OVOCs) as a function of photochemical age were investigated. Primary VOCs such as benzene, toluene, xylene, trimethyl benzene, etc. decrease and OVOCs like formic acid, formaldehyde, acetone, ethanol, etc. increase substantially upon oxidation in OFR. The highest organic aerosol (OA) enhancement was observed for the 4.2 equivalent photochemical days of aging i.e., 1.84 times the ambient concentration, and net OA loss was observed at very high OH exposure, typically after 8.4 days of photochemical aging due to heterogeneous oxidation followed by fragmentation/evaporation. In ambient air, OA enhancement is highest during nighttime due to the high concentrations of precursor VOCs in the atmosphere. SMPS + C results demonstrated substantial new particle formation upon aging and decrement in preexisting aerosol mass. This is the first experimental study conducting an in-situ evaluation of potential SOA mass generated from the ambient aerosols in India., 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 Elsevier Inc. All rights reserved.)

Background: Health is an inseparable part of life and central to all life supporting systems. The reproductive and child health shares a major portion of public health cases that is crucial for socio-economic development. Studies on reproductive and child health have traditionally been focused on demographic aspects using socio-economic parameters. Given the emphasis of Sustainable Development Goal (SDG)-3 on health and well-being, it is imperative to understand the geo-spatial dimension with the visible transition of key health indicators of fertility, maternal and infant/child health in the high burdened districts within these high focus Empowered Action Group (EAG) states of Rajasthan, Madhya Pradesh, Uttar Pradesh and Bihar that make up nearly 40% of India's population with relatively laggard health status., Methodology: This paper aims to understand the status and trend of key reproductive and child health indicators and vital statistics based on the recent representative demographic surveys. We intend to undertake a district level spatio-temporal analysis by developing District Composite Health Profile (DCHP) using Composite Index Method on selected 13 equally weighted key reproductive and child health indicators. The study has been carried out using data from National Family Health Survey-4 (2015-16) and National Family Health Survey-5 (2019-21) survey rounds. We employed geo-spatial techniques i.e. Moran's-I, and univariate LISA to comprehend the geographical clustering of high and low health burden districts and their heterogeneities at the district level., Results/conclusions: The study highlights emerging inter-districts, and inter-state disparities over survey periods. With consistent improvement in the selected EAG states over time, the overall reproductive and child health status through DCHP along with each indicator was relatively better in the states of Rajasthan and worse in Bihar. Districts along the Terai belt in Uttar Pradesh and Bihar consistently performed sluggish during survey rounds. The geo-spatial clustering follows the political boundary of states, albeit with intra-state variations. Monitoring of key health indicators using composite index method provides a useful leverage for identifying priority districts/regions for universal health access that should also consider geographical space as an important policy dimension., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Pandey 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.)

Metastatic urinary tract cancer (mUTC) is challenging to treat in older adults due to comorbidities. We compared the clinical courses of younger and older (≥70 years) adults with mUTC receiving first-line (1L) systemic therapy in a tertiary cancer center. Baseline clinical characteristics, treatments received, tolerability, and survival outcomes were analyzed. Among 212 patients (103 older vs. 109 younger), the older patients had lower hemoglobin at baseline (84% vs. 71%, p = 0.03), the majority were cisplatin-ineligible (74% vs. 45%, p < 0.001), received more immunotherapy-based treatments in the 1L (52% vs. 36%, p = 0.01), received fewer subsequent lines of treatment (median 0 vs. 1, p = 0.003), and had lower clinical trial participation (30% vs. 18%, p = 0.05) compared to the younger patients. When treated with 1L chemotherapy, older patients required more dose adjustments (53.4% vs. 23%, p = 0.001) and received fewer cycles of chemotherapy (median 4 vs. 5, p = 0.01). Older patients had similar OS (11.2 months vs. 14 months, p = 0.06) and similar rates of treatment-related severe toxicity and healthcare visits, independent of the type of systemic treatment received, compared to younger patients. We conclude that select older adults with mUTC can be safely treated with immunotherapy and risk-adjusted regimens of chemotherapy with tangible survival benefits.

Background: Androgen deprivation therapy (ADT) intensification (ADTi) (i.e., ADT with androgen receptor pathway inhibitor or docetaxel, or both) has significantly improved survival outcomes of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, the impact of prior ADTi in the mHSPC setting on the disease presentation and survival outcomes in metastatic castration-resistant prostate cancer (mCRPC) is not well characterized. In this study, our objective was to compare the disease characteristics and survival outcomes of patients with new mCRPC with respect to receipt of intensified or nonintensified ADT in the mHSPC setting., Methods: In this institutional review board-approved retrospective study, eligibility criteria were as follows: patients diagnosed with mCRPC, treated with an approved first-line mCRPC therapy, and who received either intensified or nonintensified ADT in the mHSPC setting. Progression-free survival (PFS) was defined from the start of first-line therapy for mCRPC to progression per Prostate Cancer Working Group 2 criteria or death, and overall survival (OS) was defined from the start of first-line therapy for mCRPC to death or censored at the last follow-up. A multivariable analysis using the Cox proportional hazards model was used, adjusting for potential confounders., Results: Patients (n = 387) treated between March 20, 2008, and August 18, 2022, were eligible and included: 283 received nonintensified ADT, whereas 104 were treated with ADTi. At mCRPC diagnosis, patients in the ADTi group were significantly younger, had more visceral metastasis, lower baseline prostate-specific antigen (all p < 0.01), and lower hemoglobin (p = 0.027). Furthermore, they had significantly shorter PFS (median 4.8 vs. 8.4 months, adjusted hazard ratio [HR]: 1.46, 95% confidence interval [95% CI]: 1.07-2, p = 0.017) and OS (median 21.3 vs. 33.1 months, adjusted HR: 1.53, 95% CI: 1.06-2.21, p = 0.022) compared to patients in the nonintensified ADT group., Conclusion: Patients treated with ADTi in the mHSPC setting and experiencing disease progression to mCRPC had more aggressive disease features of mCRPC (characterized by a higher number of poor prognostic factors at mCRPC presentation). They also had shorter PFS on first-line mCRPC treatment and shorter OS after the onset of mCRPC compared to those not receiving ADTi in the mHSPC setting. Upon external validation, these findings may impact patient counseling, prognostication, treatment selection, and design of future clinical trials in the mCRPC setting. There remains an unmet need to develop novel life-prolonging therapies with new mechanisms of action to improve mCRPC prognosis in the current era., (© 2024 The Authors. The Prostate published by Wiley Periodicals LLC.)

Introduction: In patients with metastatic hormone-sensitive prostate cancer (mHSPC) undergoing intensified androgen deprivation therapy (ADT), not achieving an optimal PSA response, defined as PSA nadir >0.2 ng/ml (PSA subOR ) has been associated with worse survival outcomes in clinical trials (1)(10)(11) . Here, we externally evaluate, the impact of optimal PSA response on survival outcomes in these patients and provide absolute PFS and OS measures in those with PSA subOR in the context of ADT intensification in real world setting., Methods: In this retrospective study, all consecutive patients with mHSPC who underwent intensified ADT treated at our institution, and whose outcomes data were available, were included. We classified patients based on their PSA nadir on treatment: those with a on treatment PSA OR (PSA nadir ≤0.2 ng/ml) versus PSA subOR ., Results: A total of 205 patients were eligible: 136 (66.3%) patients achieved PSA OR versus 69 (33.7%) patients had PSA subOR . Patients who experienced a PSA OR had significantly improved PFS and OS from the start of intensified ADT versus who did not: PFS was not reached (NR) versus 11 months (hazard ratio (HR) 0.20, P < 0.001) and OS was NR versus 38.9 months (HR 0.21, P < 0.001). Survival outcomes were poor with PSA subOR regardless of intensification with docetaxel or an ARPI (absolute PFS and OS measures for each group are provided in the text)., Conclusion: Our study is the first to explore the negative impact of PSA subOR in patients with mHSPC undergoing intensified ADT in the real-world setting, and is the first to provide absolute PFS and OS in patients with PSA subOR receiving ADT intensification with ARPIs or docetaxel outside of clinical trial setting. These data will aid with prognostication, patient counseling, and for designing future clinical trials for patients with PSA subOR ., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background and Objective: It has been reported that patients with de novo metastatic castration-sensitive prostate cancer (dn-mCSPC) have worse prognosis and outcomes than those whose cancer relapses after prior local therapy (PLT-mCSPC). Our aim was to interrogate and validate underlying differences in tumor gene expression profiles between dn-mCSPC and PLT-mCSPC., Methods: The inclusion criteria were histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data for treatment-naïve primary prostate tissue. RNA sequencing was performed by Tempus or Caris Life Sciences, both of which have Clinical Laboratory Improvement Amendments certification. The Tempus cohort was used for interrogation, while the Caris cohort was used for validation. Differential gene expression analysis between the cohorts was conducted using the DEseq2 pipeline. The resulting gene expression profiles were further analyzed using Gene Set Enrichment software to identify pathways with enrichment in each cohort., Key Findings and Limitations: Overall, 128 patients were eligible, of whom 78 were in the Tempus cohort (dn-mCSPC 37, PLT-mCSPC 41) and 50 were in the Caris cohort (dn-mCSPC 30, PLT-mCSPC 20). Tumor tissues from patients with dn-mCSPC had higher expression of genes associated with inflammation pathways, while tissues from patients with PLT-mCSPC had higher expression of genes involved in oxidative phosphorylation, fatty acid metabolism, and androgen response pathways., Conclusions and Clinical Implications: Our study revealed upregulation of distinct genomic pathways in dn-mCSPC in comparison to PLT-mCSPC. These hypothesis-generating data could guide personalized therapy for men with prostate cancer and explain different survival outcomes for dn-mCSPC and PLT-mCSPC., Patient Summary: We measured gene expression levels in tumors from patients with metastatic castration-sensitive prostate cancer. In patients with metastatic disease at first diagnosis, inflammatory pathways were upregulated. In patients whose metastasis occurred on relapse after treatment, androgen response pathways were upregulated. These findings could help in personalizing therapy for prostate cancer and explaining differences in survival., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Importance: The treatment paradigm for advanced urothelial carcinoma (aUC) has undergone substantial transformation due to the introduction of effective, novel therapeutic agents. However, outcomes remain poor, and little is known about current treatment approaches and attrition rates for patients with aUC., Objectives: To delineate evolving treatment patterns and attrition rates in patients with aUC using a US-based patient-level sample., Design, Setting, and Participants: This retrospective cohort study used patient-level data from the nationwide deidentified electronic health record database Flatiron Health, originating from approximately 280 oncology clinics across the US. Patients included in the analysis received treatment for metastatic or local aUC at a participating site from January 1, 2011, to January 31, 2023. Patients receiving treatment for 2 or more different types of cancer or participating in clinical trials were excluded from the analysis., Main Outcomes and Measures: Frequencies and percentages were used to summarize the (1) treatment received in each line (cisplatin-based regimens, carboplatin-based regimens, programmed cell death 1 and/or programmed cell death ligand 1 [PD-1/PD-L1] inhibitors, single-agent nonplatinum chemotherapy, enfortumab vedotin, erdafitinib, sacituzumab govitecan, or others) and (2) attrition of patients with each line of therapy, defined as the percentage of patients not progressing to the next line., Results: Of the 12 157 patients within the dataset, 7260 met the eligibility criteria and were included in the analysis (5364 [73.9%] men; median age at the start of first-line treatment, 73 [IQR, 66-80] years). All patients commenced first-line treatment; of these, only 2714 (37.4%) progressed to receive second-line treatment, and 857 (11.8%) advanced to third-line treatment. The primary regimens used as first-line treatment contained carboplatin (2241 [30.9%]), followed by PD-1/PD-L1 inhibitors (2174 [29.9%]). The PD-1/PD-L1 inhibitors emerged as the predominant choice in the second- and third-line (1412 of 2714 [52.0%] and 258 of 857 [30.1%], respectively) treatments. From 2019 onward, novel therapeutic agents were increasingly used in second- and third-line treatments, including enfortumab vedotin (219 of 2714 [8.1%] and 159 of 857 [18.6%], respectively), erdafitinib (39 of 2714 [1.4%] and 28 of 857 [3.3%], respectively), and sacituzumab govitecan (14 of 2714 [0.5%] and 34 of 857 [4.0%], respectively)., Conclusions and Relevance: The findings of this cohort study suggest that approximately two-thirds of patients with aUC did not receive second-line treatment. Most first-line treatments do not include cisplatin-based regimens and instead incorporate carboplatin- or PD-1/PD-L1 inhibitor-based therapies. These data warrant the provision of more effective and tolerable first-line treatments for patients with aUC.

Purpose: An increased BMI is linked to increased prostate adenocarcinoma incidence and mortality. Baseline tumor gene expression profiling (GEP) can provide a comprehensive picture of the biological processes related to treatment response and disease progression. We interrogate and validate the underlying differences in tumor GEP on the basis of BMI in patients with prostate adenocarcinoma., Methods: The inclusion criteria consisted of histologically confirmed prostate adenocarcinoma and the availability of RNA sequencing data obtained from treatment-naïve primary prostate tissue. RNA sequencing was performed by a Clinical Laboratory Improvement Amendments-certified laboratory (Tempus or Caris Life Sciences). The Tempus cohort was used for interrogation and the Caris cohort for validation. Patients were stratified on the basis of BMI at the time of prostate cancer diagnosis: BMI-high (BMI H ; BMI ≥30) and BMI-low (BMI L ; BMI <30). Differential gene expression analysis between the two cohorts was conducted using the DEseq2 pipeline. The resulting GEPs were further analyzed using Gene Set Enrichment software to identify pathways that exhibited enrichment in each cohort., Results: Overall, 102 patients were eligible, with 60 patients in the Tempus cohort (BMI L = 38, BMI H = 22) and 42 patients in the Caris cohort (BMI L = 24, BMI H = 18). Tumor tissues obtained from patients in the BMI L group exhibited higher expression of genes associated with inflammation pathways. BMI H displayed increased expression of genes involved in pathways such as heme metabolism and androgen response., Conclusion: Our study shows the upregulation of distinct genomic pathways in BMI L compared with BMI H patients with prostate cancer. These hypothesis-generating data could explain different survival outcomes in both groups and guide personalized therapy for men with prostate cancer.

Introduction: India launched a national initiative named Health and Wellness Centres (HWCs) in 2018 to provide population-based primary care including for the non-communicable diseases (NCDs) in rural areas. The current study assesses whether operationalization of HWCs improved the detection of NCDs and increased the share of public sector facilities in providing NCD services., Methods: Two rounds of household surveys were conducted in rural Chhattisgarh in 2019 and 2022. With a focus on NCDs, the household survey covered a representative sample of individuals above the age of 30 years - 2760 individuals in 2019 and 2638 in 2022. Multi-variate regression analysis was carried out to determine effects of HWCs on identification of NCDs and utilization of public sector services., Results: The population covered by HWCs had 25% greater chance of being identified with NCDs as compared to the population without HWCs (AOR = 1.25, P = 0.03). The NCD patients living in areas covered by HWCs had 70% greater chance of utilizing the public healthcare facilities (AOR = 1.70, P = 0.01). In the population covered by HWCs, the share of the public sector in NCD care increased from 41.2% in 2019 to 62.1% in 2022, whereas the share of informal private providers dropped from 23.5% in 2019 to 8.4% in 2022., Conclusion: The HWCs showed effectiveness in increasing detection of NCDs at the population level and bringing a larger share of NCD patients to utilize public sector services. They can prove to be a crucial architectural correction for improving primary care service delivery for NCDs and other population health needs in India., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

The Genus Dysoxylum (Meliaceae) consists of approximately 80 species that are abundant in structurally diverse triterpenoids. The present study focused on isolating new triterpenoids from the bark of Dysoxylum malabaricum, one of the predominant species of Dysoxylum present in India. The methanol-dichloromethane bark extract was subjected to LCMS profiling followed by silica gel column chromatography and HPLC analysis to target new compounds. Two new ring A-modified cycloartane-type triterpenoids (1 and 2) were isolated from the bark extract. Spectroscopic methods like NMR, HRESIMS data, and electronic circular dichroism calculations elucidated the structuresandabsolute configurations of the isolated compounds. These compounds were evaluated for their cytotoxic potential against breast cancer cells and displayed notable cytotoxicity. Compound 1 exhibited the highest cytotoxicity against the MDA-MB-231 cells and induced apoptotic cell death. Also, it was able to inhibit glucose uptake and increase nitric oxide production in breast cancer cells., 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 Elsevier Inc. All rights reserved.)

Background and Objective: The impact of time of metastasis onset with respect toprimary renal cell carcinoma (RCC) diagnosis on survival outcomes is not well characterized in the era of immune checkpoint inhibitor (ICI)-based combinations. Herein, we assessed differences in clinical outcomes between synchronous and metachronous metastatic RCC (mRCC)., Methods: Data for patients with mRCC treated with first-line ICI-based combination therapies between 2014 and 2023 were retrospectively collected. Patients were categorized as having synchronous metastasis if present within 3 mo of RCC diagnosis; metachronous metastasis was defined as metastasis >3 mo after primary diagnosis. Time to treatment failure (TTF), overall survival (OS), and the disease control rate (DCR) were assessed., Key Findings and Limitations: Our analysis included 223 eligible patients (126 synchronous and 97 metachronous). Median TTF did not significantly differ between the synchronous and metachronous groups (9 vs 19.8 mo; p = 0.063). Median OS was significantly shorter in the synchronous group (28.0 vs 50.9 mo; p = 0.001). Similarly, patients with synchronous metachronous metastasis (58.7% vs. 78.4%; p = 0.002). On multivariable analyses, synchronous metastasis remained independently associated with worse OS and DCR., Conclusions and Clinical Implications: In this hypothesis-generating study, patients with mRCC with synchronous metastasis who were treated with first-line ICI-based combinations have a poorer OS and worse DCR than those with metachronous mRCC. If these results are externally validated, time to metastasis could be included in prognostic models for mRCC., Patient Summary: Our study demonstrates that patients treated with current first-line immunotherapies, who present with metastasis at the initial diagnosis of kidney cancer have worse overall survival compared to those who develop metastasis later. These results can help physicians and patients understand life expectancy., (Copyright © 2024. Published by Elsevier B.V.)

Background: The Heartmate 3 (HM3) risk score (HM3RS) was derived and validated internally from within the Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial population and provides 1- and 2-year mortality risk prediction for patients in those before HM3 left ventricular assist device (LVAD) implantation. We aimed to evaluate the HM3RS in nontrial unselected patients, including those not meeting inclusion criteria for MOMENTUM 3 trial enrollment., Methods: Patients who underwent HM3 LVAD implant at 1 of 7 US centers between 2017 and 2021, with at least 1-year follow-up, were included in this analysis. Patients were retrospectively assessed for their eligibility for the MOMENTUM 3 trial based on study inclusion and exclusion criteria. HM3RS risk discrimination was evaluated using time-dependent receiver operating characteristic curve analysis for 1-year mortality for all patients and further stratified by MOMENTUM 3 trial eligibility. Kaplan-Meier curves were constructed using the HM3RS-based risk categories., Results: Of 521 patients included in the analysis, 266 (51.1%) would have met enrollment criteria for MOMENTUM 3. The 1- and 2-year survival for the total cohort was 85% and 81%, respectively. There was no statistically significant difference in survival between those who met and did not meet enrollment criteria at 1 (87% vs 83%; p = 0.21) and 2 years postimplant (80% vs 78%; p = 0.39). For the total cohort, HM3RS predicted 1-year survival with an area under the curve (AUC) of 0.63 (95% confidence interval [CI]: 0.57-0.69, p < 0.001). HM3RS performed better in the subset of patients meeting enrollment criteria: AUC 0.69 (95% CI:0.61-0.77, p < 0.001) compared to the subset that did not: AUC 0.58 (95% CI: 0.49-0.66, p = 0.078)., Conclusions: In this real-world evidence, multicenter cohort, 1- and 2-year survival after commercial HM3 LVAD implant was excellent, regardless of trial eligibility. The HM3RS provided adequate risk discrimination in "trial-like" patients, but predictive value was reduced in patients who did not meet trial criteria., (Copyright © 2023 International Society for the Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Natural lactones have been used in traditional and folklore medicine for centuries owing to their anti-inflammatory properties. The study uses a multifaceted approach to identify lead anti-inflammatory lactones from the SISTEMATX natural products database. The study analyzed the natural lactone database, revealing 18 lactones linked to inflammation targets. The primary targets were PTGES, PTGS1, COX-2, ALOX5 and IL1B. STX 12273 was the best hit, with the lowest binding energy and potential for inhibiting the COX-2 enzyme. The study suggested natural lactone, STX 12273, from the SISTEMATX database with anti-inflammatory potential and postulated its use for inflammation treatment or prevention.Communicated by Ramaswamy H. Sarma.

The compound 2,3-dehydrosilychristin, a flavonolignan linked to silychristin and silymarin, remains intriguing due to its challenging isolation from silymarin. While silymarin has been the exclusive source of flavonolignans - silybin, silychristin and silydianin - 2,3-dehydrosilychristin is reported in this study from Vitex negundo Linn. leaves. 2,3-Dehydrosilychristin ( 7 ) and 14 other compounds were isolated through focused extraction. Its subsequent pharmacological evaluation demonstrated potent antioxidant and in-vitro anti-inflammatory effects, notably inhibiting cytokines TNF-α, IL-6, IL-8 and VEGF. In in-vivo assessments, 2,3-dehydrosilychristin ( 7 ) revealed remarkable hepatoprotective potential by reducing liver enzyme levels AST and ALT. These findings expand the potential of 2,3-dehydrosilychristin and suggest bioprospecting Vitex species as alternate sources of bioactive flavonolignans.

Boronic acid-containing molecules are substantially popularized in chemical biology and medicinal chemistry due to the broad spectrum of covalent conjugations as well as interaction modules offered by the versatile boron atom. Apparently, the WGA peptide (wheat germ agglutinin, 62-73), which shows a considerably low binding affinity to sialic acid, turned into a selective and >5 folds potent binder with the aid of a suitable boronic acid probe installed chemoselectively. In silico studies prompted us to install BA probes on the cysteine residue, supposedly located in close proximity to the bound sialic acid. In vitro studies revealed that the tailored boronopeptides show enhanced binding ability due to the synergistic recognition governed by selective non-covalent interactions and cis-diol boronic acid conjugation. The intense binding is observed even in 10 % serum, thus enabling profiling of sialyl-glycan on cancer cells, as compared with the widely used lectin, Sambucus nigra. The synergistic binding mode between the best boronopeptide (P3) binder and sialic acid was analyzed via 1 H and 11 B NMR., (© 2023 Wiley-VCH GmbH.)

Psoralea corylifolia (syn. Cullen corylifolium), commonly called bawachi, is a medicinal plant extensively used for skin conditions like leukoderma, vitiligo, and psoriasis. It is notably rich in valuable bioactive compounds, particularly coumarins and furanocoumarins. This study isolated fourteen coumarins from P. corylifolia which were tested for cytotoxicity using the MTT assay, with compound 10 showing good cytotoxicity against A549 cells (IC 50 0.9 μM), while compound 1, compound 2, and compound 3 displaying potential cytotoxicity against MDA-MB-231 cells (IC 50 0.49 μM, 0.56 μM, and 0.84 μM respectively). Additionally, the compounds' interaction with Epidermal Growth Factor Receptor (EGFR) protein, highly expressed in both cell lines, was investigated through molecular modeling studies, that aligned well with cytotoxicity results. The findings revealed the remarkable cytotoxic potential of four coumarins 1, 2, 3, and 10 against A549 and MDA-MB-231 cell lines., (© 2024 Wiley-VHCA AG, Zurich, Switzerland.)

Neoadjuvant cisplatin-based chemotherapy (NACC) followed by radical cystectomy is the standard treatment for localized muscle-invasive bladder cancer (MIBC). Patients who achieve a complete pathological response following NACC have better overall survival than those with residual disease. However, a subset of patients does not derive benefit from NACC while experiencing chemotherapy-related side effects that may delay cystectomy, which can be detrimental. There is a need for predictive and prognostic biomarkers to better stratify patients who will derive benefits from NACC. This review summarizes the currently available literature on various predictors of response to neoadjuvant chemotherapy. Covered predictors include clinical factors, treatment regimens (including chemotherapy and immunotherapy), histological predictors, and molecular predictors such as DNA repair genes, p53, FGFR3, ERBB2, Bcl-2, EMMPRIN, survivin, choline-phosphate cytidylyltransferase-α, epigenetic markers, immunological markers, other molecular predictors and gene expression profiling. Further, we elaborate on the potential role of neoadjuvant immunotherapy and the correlative biomarkers of response., Competing Interests: Declaration of Competing Interest Sumati Gupta: SG reports research funding to institute from Mirati Therapeutics, Novartis, Pfizer, Viralytics, Hoosier Cancer Research Network, Rexahn Pharmaceuticals, Five Prime Therapeutics, Incyte, MedImmune, Merck, Bristol Myers Squibb, Clovis Oncology, LSK BioPharma, QED Therapeutics, Daiichi Sankyo/Lilly, Immunocore, Seattle Genetics, Astellas, Acrotech and Astra Zenec. Umang Swami: US reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, Pfizer, AstraZeneca and Gilead and research funding to institute from Janssen, Exelixis and Astellas/Seattle Genetics. NT, GGF, GG, ED, and VMT have no conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Somatic or germline homologous recombination repair (HRR) pathway gene mutations are commonly detected in prostate cancer, especially in advanced disease, and are associated with response to poly (ADP-ribose) polymerase (PARP) inhibitors. In this study, we evaluated whether histological patterns are predictive of HRR pathway gene mutations. The study population comprised 130 patients with advanced prostate carcinoma who underwent comprehensive genomic profiling (CGP) of tumor tissue at a CLIA-certified laboratory. HRR genes in the study included BRCA1, BRCA2, ATM, BARD1, BRIP, CHEK2, MRE11A, NBN, PALB2, RAD51C, RAD51D, EMSY, ATR, CHEK1, and FAM175A. Overall, 38 patients had mutations in BRCA1/2, 36 in other HRR genes, and 56 were negative for HRR mutations. All cases were re-reviewed and quantified by two genitourinary pathologists blinded to mutational status for the following histological patterns of prostate carcinoma: cribriform, ductal, intraductal carcinoma (IDC), small cell carcinoma, signet ring-like pattern, and lobular carcinoma-like pattern. Discordances were resolved by consensus review. Histologic patterns were analyzed for any correlation with mutations in HRR pathway genes (grouped as BRCA1/2 mutated or non-BRCA1/2 mutated) compared to tumors without mutations in HRR genes by Chi-square testing. Patterns with >20 % and >30 % of tumor volume were additionally evaluated for correlation with mutational status. We found no significant association between HRR pathway mutations and cribriform pattern, IDC, ductal carcinoma, small cell carcinoma, signet ring-like pattern, or lobular carcinoma-like patterns. Tumors with >20 % or >30 % histologic patterns by volume also demonstrated no significant association with mutational status. This study suggests that histopathologic examination alone is insufficient to distinguish prostate cancer with germline or somatic mutations in HRR pathway genes, highlighting the continuing importance of ancillary molecular diagnostics in guiding therapy selection for prostate cancer patients who may benefit from PARP inhibitors., Competing Interests: Declaration of competing interest N. A. (lifetime disclosures): Consultancy to Astellas, Astra Zeneca, Aveo, Bayer, Bristol Myers Squibb, Calithera, Clovis, Eisai, Eli Lilly, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead, Janssen, Merck, MEI Pharma, Nektar, Novartis, Pfizer, Pharmacyclics, and Seattle Genetics. Research funding to Neeraj Agarwal's institution: Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol-Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon.U.S. reports consultancy to Astellas, Exelixis, Seattle Genetics, Imvax, Sanofi, AstraZeneca, and Gilead. Reports research funding to institute from Janssen, Exelixis, and Astellas/Seattle Genetics. Other authors have not conflicts to disclose., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Virtual screening (VS) is an important approach in drug discovery and relies on the availability of a virtual library of synthetically tractable molecules. Ugi reaction (UR) represents an important multi-component reaction (MCR) that reliably produces a peptidomimetic scaffold. Recent literature shows that a tactically assembled Ugi adduct can be subjected to further chemical modifications to yield a variety of rings and scaffolds, thus, renewing the interest in this old reaction. Given the reliability and efficiency of UR, we collated an UR derived library (URDL) of small molecules (total = 5773) for VS. The synthesis of the majority of URDL molecules may be carried out in 1-2 pots in a time and cost-effective manner. The detailed analysis of the average property and chemical space of URDL was also carried out using the open-source Datawarrior program. The comparison with FDA-approved oral drugs and inhibitors of protein-protein interactions (iPPIs) suggests URDL molecules are 'clean', drug-like, and conform to a structurally distinct space from the other two categories. The average physicochemical properties of compounds in the URDL library lie closer to iPPI molecules than oral drugs thus suggesting that the URDL resource can be applied to discover novel iPPI molecules. The URDL molecules consist of diverse ring systems, many of which have not been exploited yet for drug design. Thus, URDL represents a small virtual library of drug-like molecules with unexplored chemical space designed for VS. The structures of all molecules of URDL, oral drugs, and iPPI compounds are being made freely accessible as supplementary information for broader application., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

A series of phenothiazine embedded heteroporphyrins containing one phenothiazine unit, two pyrrole rings and one heterocycle such as furan, thiophene, selenophene and tellurophene connected via four meso carbons were synthesized. The macrocycles were synthesized by condensing the phenothiazine based tripyrrane with corresponding 2,5-bis(hydroxymethyl)heterocycle under BF 3  ⋅ OEt 2 catalyzed conditions and compared the structural, spectral, and electrochemical properties with the reported phenothiazinophyrins. The studies showed that the phenothiazine embedded heteroporphyrins were nonaromatic and electronic properties were significantly altered by replacing the pyrrole ring from phenothiazinophyrin with different heterocycles. The X-ray structure of phenothiazine embedded thiaporphyrin revealed that the macrocycle was distorted with an inverted thiophene ring. Both mono-protonated and diprotonated derivatives of macrocycles were generated by the controlled addition of trifluoroacetic acid to the macrocycles. The macrocyclic protons experienced upfield/downfield shifts in protonated derivatives compared to their corresponding neutral phenothiazine embedded heteroporphyrins. However, the heterocyclic ring in both mono- and diprotonated derivatives retained its inverted conformation. The macrocycles in their neutral and protonated form exhibit nonaromatic absorption features. The studies indicated the electron rich nature of macrocycles and DFT/TD-DFT studies were carried out to justify the experimental observations., (© 2023 Wiley-VCH GmbH.)

Dengue is a viral disease that clinically presents with fever, thrombocytopenia-related haemorrhagic complications and shock in its severest form. This female patient in her 40s primarily presented to the emergency department of the cardiac centre as syncopal attacks with a complete atrioventricular block. Temporary cardiac pacing as an emergency procedure helped to maintain cardiac rhythm and haemodynamics. A history of recent onset fever helped us to suspect and confirmed by serology for dengue pathology. Normal sinus rhythm was restored after 2 days, and we removed the temporary pacing. Cardiac arrhythmia did not recur in 6 months of follow-up. The aetiology for dengue-related cardiac arrhythmia is still not established. In the recovery phase from fever, complete heart block may show up as a primary presentation in the emergency. Its timely diagnosis and temporary pacing may allow spontaneous recovery. The inclusion of electrocardiography in dengue patient guidelines should help clinicians to dictate its treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In this recent investigation, the focus centred on exploring the potential phytoconstituents within the bark of Dysoxylum malabaricum . A profiling strategy employing LC-HRMS (Liquid Chromatography-High Resolution Mass Spectrometry) was implemented for the rapid identification of compounds from the bark extract. The crude extract underwent fractionation, resulting in the isolation of four previously known compounds ( 1-4 ) and a novel cycloartane triterpenoid named Mahamanalactone A ( 5 ). Compound 5 represents a cycloartane triterpenoid with a modified ring-A, featuring £-caprolactone fusion at positions 4 and 5, distinguishing it from other reported compounds where £-caprolactone is typically fused at positions 3 and 4. Cytotoxicity assessment revealed that the newly identified compound 5 exhibited a moderate cytotoxic profile (IC 50 29 to 78 µM) against a panel of cancer cell lines.

Objective: The purpose of this study was to find data proving the influence of the Haemophilus influenzae type b (Hib) conjugate vaccination on the frequency of invasive Hib illness., Methodology: A systematic literature search was conducted on the PubMed database to identify peerreviewed publications pertaining to the epidemiology of Haemophilus influenzae meningitis, both before and after the introduction of Haemophilus influenzae type b (Hib) conjugate vaccines. The search query employed a combination of relevant keywords, including "invasive," " Haemophilus," "influenzae, " "meningitis," and specific serotype b (Hib). Additionally, terms related to epidemiology, burden, risk factors, impact, Hib vaccine, Hib conjugate vaccine, combination vaccine, vaccine production, efficacy, immunisation coverage, surveillance, review, clinical aspects, outcomes, and various age groups (adults and children) were incorporated., Result: The search encompassed articles published till now. Subsequently, relevant research papers concerning Haemophilus influenzae meningitis were subjected to a comprehensive review and analysis., Conclusion: The Hib conjugate vaccination has shown to be extremely effective when administered to the entire population. However, changes to the immunisation protocol appear to be required in order to effectively manage invasive Hib illness., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Patients with synchronous (de novo) metastatic castration-sensitive prostate cancer appear to have worse survival outcomes and shorter time to develop castration resistance than patients with metachronous disease. However, the impact of synchronous metastasis on outcomes in metastatic castration-resistant prostate cancer (mCRPC) setting is unknown in patients without prior exposure to androgen receptor pathway inhibitors (ARPIs). In this study, we assessed the impact of initial timing of metastasis (synchronous vs metachronous) on survival outcomes of patients with new-onset mCRPC in a real-world population treated with first-line abiraterone or enzalutamide., Methods: Data were collected retrospectively from 323 patients with a confirmed diagnosis of mCRPC who received ARPIs as first-line therapy and had no prior exposure to ARPIs. The study endpoints were progression-free survival and overall survival., Results: The results showed that median overall survival was significantly shorter in patients with synchronous disease than those with metachronous disease (26 vs 38.7 months, HR 1.42, 95% CI 1.09-1.86, P = .011). However, there was no difference in median progression-free survival., Conclusions: The initial presentation with synchronous metastasis remained an independent factor associated with shorter OS in the multivariable analysis. These hypothesis-generating data, after external validation, may have implications in patient counseling, prognostication, and design of future clinical trials in the new-onset mCRPC setting.