Perfusion-weighted imaging with dynamic contrast enhancement (PWI/DCE) morphologic, qualitative, semiquantitative, and radiomics features predicting undifferentiated pleomorphic sarcoma (UPS) treatment response.

Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft tissue sarcomas. This study determined the value of perfusion-weighted imaging with dynamic-contrast-enhancement (PWI/DCE) morphologic, qualitative, and semiquantitative features for predicting UPS pathology-assessed treatment effect (PATE). This retrospective study included 33 surgically excised extremity UPS patients with pre-surgical MRI. Volumetric tumor segmentation from PWI/DCE was obtained at Baseline (BL), Post-Chemotherapy (PC), and Post-Radiation Therapy (PRT). The surgical specimens' PATE separated cases into Responders (R) (≥ 90%, 16 patients), Partial-Responders (PR) (89 - 31%, 10 patients), and Non-Responders (NR) (≤ 30%, seven patients). Seven semiquantitative kinetic parameters and maps were extracted from time-intensity curves (TICs), and 107 radiomic features were derived. Statistical analyses compared R vs. PR/NR. At PRT, 79% of R displayed a "Capsular" morphology (P = 1.49 × 10-7), and 100% demonstrated a TIC-type II (P = 8.32 × 10-7). 80% of PR showed "Unipolar" morphology (P = 1.03 × 10-5), and 60% expressed a TIC-type V (P = 0.06). Semiquantitative wash-in rate (WiR) was able to separate R vs. PR/NR (P = 0.0078). The WiR radiomics displayed significant differences in the first_order_10 percentile (P = 0.0178) comparing R vs. PR/NR at PRT. The PWI/DCE TIC-type II curve, low WiR, and "Capsular" enhancement represent PRT patterns typically observed in successfully treated UPS and demonstrate potential for UPS treatment response assessment.

Are paediatric cardiology textbooks obsolete in the current digital era?

INTRODUCTION: With the rise of online references, podcasts, webinars, self-test tools, and social media, it is worthwhile to understand whether textbooks continue to provide value in medical education, and to assess the capacity they serve during fellowship training. METHODS: A prospective mixed-methods study based on surveys that were disseminated to seven paediatric cardiology fellowship programmes around the world. Participants were asked to read an assigned chapter of Anderson's Pediatric Cardiology 4th Edition textbook, followed by the completion of the survey. Open-ended questions included theming and grouping responses as appropriate. RESULTS: The survey was completed by 36 participants. When asked about the content, organisation, and utility of the chapter, responses were generally positive, at greater than 89%. The chapters, overall, were rated relatively easy to read, scoring at 6.91, with standard deviations plus or minus 1.72, on a scale from 1 to 10, with higher values meaning better results. When asked to rank their preferences in where they obtain educational content, textbooks were ranked the second highest, with in-person teaching ranking first. Several themes were identified including the limitations of the use of textbook use, their value, and ways to enhance learning from their reading. There was also a near-unanimous desire for more time to self-learn and read during fellowship. CONCLUSIONS: Textbooks are still highly valued by trainees. Many opportunities exist, nonetheless, to improve how they can be organised to deliver information optimally. Future efforts should look towards making them more accessible, and to include more resources for asynchronous learning.

Microwave-assisted solvothermal synthesis of nanostructured Ga-Doped Li7La3Zr2O12 solid electrolyte with enhanced densification and Li-ion conductivity.

Garnet-type Li7La3Zr2O12 (LLZO) Li-ion solid electrolytes are promising candidates for safe, next-generation solid-state batteries. In this study, we synthesize Ga-doped LLZO (Ga-LLZO) electrolytes using a microwave-assisted solvothermal method followed by low-temperature heat treatment. The nanostructured precursor (<50 nm) produced by the microwave-assisted solvothermal process has a high surface energy, facilitating the reaction for preparing garnet-type Ga-LLZO powders (<800 nm) within a short time (<5 h) at a low calcination temperature (<700 °C). Additionally, the calcined nanostructured Ga-LLZO powder can be sintered to produce a high-density pellet with minimized grain boundaries under moderate sintering conditions (temperature: 1150 °C, duration: 10 h). The optimal doping concentration was determined to be 0.4 mol% Ga, which resulted significantly increased the ionic conductivity (1.04 × 10-3 S cm-1 at 25 °C) and stabilized the cycling performance over 1700 h at 0.4 mA cm-2. This approach demonstrates the potential to synthesize oxide-type solid electrolyte materials with improved properties for solid-state batteries.

Patient costs for drug-resistant TB diagnosis and pre-treatment evaluation in North India.

INTRODUCTION: India's National TB Elimination Programme (NTEP) aims to eliminate TB-related catastrophic expenditure by offering free diagnosis and treatment. However, 3.9% of TB patients have drug-resistant TB (DR-TB) and are facing higher costs. OBJECTIVE: To assess DR-TB patients' diagnosis and pre-treatment evaluation costs, catastrophic cost incidence, and its relation to patient characteristics. METHODS: The study included DR-TB patients from three District Drug-Resistant TB Centres in Delhi and Faridabad (October 2021-June 2022). Socio-economic and clinical characteristics and direct medical and non-medical costs from drug susceptibility testing eligibility to the start of DR-TB treatment were collected using patient interviews and records. Indirect costs were calculated via the human capital approach, defining catastrophic costs as expenses over 20% of household annual income. Multivariable regression was used to estimate the effects of patient characteristics on catastrophic costs. RESULTS: Of 158 patients, 37.3% were aged 19-30 years, and 55.7% were women. Median total cost was USD326.6 (IQR 132.7-666.7), with 48.2% for diagnosis and 66.0% indirect. 32% faced catastrophic costs, with manual labourers at higher risk (adjusted OR 4.4). CONCLUSION: Despite free diagnosis and treatment, a significant portion of DR-TB households in India incur catastrophic costs, mainly from indirect expenses, indicating a need for targeted policy and programme interventions.

INTRODUCTION: Le Programme national Indien d'élimination de la TB (NTEP) a pour objectif de réduire les dépenses catastrophiques liées à la TB en offrant un diagnostic et un traitement gratuits. Cependant, 3,9% des patients atteints de TB présentent une TB résistante aux médicaments (DR-TB) et doivent faire face à des coûts plus élevés. OBJECTIF: Évaluer les coûts de diagnostic et d'évaluation pré-thérapeutique chez les patients atteints de DR-TB, ainsi que l'impact des coûts catastrophiques et leur corrélation avec les caractéristiques des patients. MÉTHODES: L'étude a porté sur les patients atteints de DR-TB provenant de trois Centres de lutte contre la TB résistante aux médicaments des districts de Delhi et de Faridabad, Inde (octobre 2021­juin 2022). Les données relatives aux caractéristiques socio-économiques et cliniques, ainsi qu'aux coûts directs médicaux et non médicaux, ont été collectées lors de l'évaluation de l'éligibilité à l'antibiogramme au début du traitement de la DR-TB, à travers des entretiens avec les patients et l'analyse des dossiers. Les coûts indirects ont été évalués en utilisant l'approche du capital humain, définissant les coûts catastrophiques comme dépassant 20 % du revenu annuel du ménage. Une régression multivariable a été réalisée pour estimer l'impact des caractéristiques des patients sur les coûts catastrophiques. RÉSULTATS: Sur un échantillon de 158 patients, 37,3% avaient entre 19 et 30 ans et 55,7% étaient des femmes. Le coût médian total s'élevait à 326,6 USD (IQR 132,7­666,7), dont 48,2% pour le diagnostic et 66,0% pour les coûts indirects. En outre, 32% des patients ont été confrontés à des coûts catastrophiques, les travailleurs manuels étant les plus touchés (OR ajusté 4,4). CONCLUSION: Bien que le diagnostic et le traitement soient gratuits, de nombreux ménages indiens touchés par la DR-TB doivent faire face à des coûts élevés, en particulier des dépenses indirectes, soulignant ainsi le besoin d'interventions politiques et programmatiques ciblées.

Tubercular pyomyositis: A case series.

Tuberculosis is one of the endemic diseases in India. Tuberculosis can involve almost every organ of the body, however isolated muscle involvement is considered rare. We hereby report a series of three cases of tubercular pyomyositis to highlight the importance of high clinical suspicion in endemic countries like India, in both immunocompetent and immunocompromised individuals, presenting with persistent fever and musculoskeletal symptoms. A timely diagnosis with effective drainage and antitubercular therapy helps in good functional recovery.

Enhancing liver tumor segmentation with UNet-ResNet: Leveraging ResNet's power.

BACKGROUND: Liver cancer poses a significant health challenge due to its high incidence rates and complexities in detection and treatment. Accurate segmentation of liver tumors using medical imaging plays a crucial role in early diagnosis and treatment planning. OBJECTIVE: This study proposes a novel approach combining U-Net and ResNet architectures with the Adam optimizer and sigmoid activation function. The method leverages ResNet's deep residual learning to address training issues in deep neural networks. At the same time, U-Net's structure facilitates capturing local and global contextual information essential for precise tumor characterization. The model aims to enhance segmentation accuracy by effectively capturing intricate tumor features and contextual details by integrating these architectures. The Adam optimizer expedites model convergence by dynamically adjusting the learning rate based on gradient statistics during training. METHODS: To validate the effectiveness of the proposed approach, segmentation experiments are conducted on a diverse dataset comprising 130 CT scans of liver cancers. Furthermore, a state-of-the-art fusion strategy is introduced, combining the robust feature learning capabilities of the UNet-ResNet classifier with Snake-based Level Set Segmentation. RESULTS: Experimental results demonstrate impressive performance metrics, including an accuracy of 0.98 and a minimal loss of 0.10, underscoring the efficacy of the proposed methodology in liver cancer segmentation. CONCLUSION: This fusion approach effectively delineates complex and diffuse tumor shapes, significantly reducing errors.

Machine learning-based energy management and power forecasting in grid-connected microgrids with multiple distributed energy sources.

The growing integration of renewable energy sources into grid-connected microgrids has created new challenges in power generation forecasting and energy management. This paper explores the use of advanced machine learning algorithms, specifically Support Vector Regression (SVR), to enhance the efficiency and reliability of these systems. The proposed SVR algorithm leverages comprehensive historical energy production data, detailed weather patterns, and dynamic grid conditions to accurately forecast power generation. Our model demonstrated significantly lower error metrics compared to traditional linear regression models, achieving a Mean Squared Error of 2.002 for solar PV and 3.059 for wind power forecasting. The Mean Absolute Error was reduced to 0.547 for solar PV and 0.825 for wind scenarios, and the Root Mean Squared Error (RMSE) was 1.415 for solar PV and 1.749 for wind power, showcasing the model's superior accuracy. Enhanced predictive accuracy directly contributes to optimized resource allocation, enabling more precise control of energy generation schedules and reducing the reliance on external power sources. The application of our SVR model resulted in an 8.4% reduction in overall operating costs, highlighting its effectiveness in improving energy management efficiency. Furthermore, the system's ability to predict fluctuations in energy output allowed for adaptive real-time energy management, reducing grid stress and enhancing system stability. This approach led to a 10% improvement in the balance between supply and demand, a 15% reduction in peak load demand, and a 12% increase in the utilization of renewable energy sources. Our approach enhances grid stability by better balancing supply and demand, mitigating the variability and intermittency of renewable energy sources. These advancements promote a more sustainable integration of renewable energy into the microgrid, contributing to a cleaner, more resilient, and efficient energy infrastructure. The findings of this research provide valuable insights into the development of intelligent energy systems capable of adapting to changing conditions, paving the way for future innovations in energy management. Additionally, this work underscores the potential of machine learning to revolutionize energy management practices by providing more accurate, reliable, and cost-effective solutions for integrating renewable energy into existing grid infrastructures.

Computational studies on the catalytic potential of the double active site for enzyme engineering.

Proteins possessing double active sites have the potential to revolutionise enzyme design strategies. This study extensively explored an enzyme that contains both a natural active site (NAS) and an engineered active site (EAS), focusing on understanding its structural and functional properties. Metadynamics simulations were employed to investigate how substrates interacted with their respective active sites. The results revealed that both the NAS and EAS exhibited similar minimum energy states, indicating comparable binding affinities. However, it became apparent that the EAS had a weaker binding site for the substrate due to its smaller pocket and constrained conformation. Interestingly, the EAS also displayed dynamic behaviour, with the substrate observed to move outside the pocket, suggesting the possibility of substrate translocation. To gain further insights, steered molecular dynamics (SMD) simulations were conducted to study the conformational changes of the substrate and its interactions with catalytic residues. Notably, the substrate adopted distinct conformations, including near-attack conformations, in both the EAS and NAS. Nevertheless, the NAS demonstrated superior binding minima for the substrate compared to the EAS, reinforcing the observation that the engineered active site was less favourable for substrate binding due to its limitations. The QM/MM (Quantum mechanics and molecular mechanics) analyses highlight the energy disparity between NAS and EAS. Specifically, EAS exhibited elevated energy levels due to its engineered active site being located on the surface. This positioning exposes the substrate to solvents and water molecules, adding to the energy challenge. Consequently, the engineered enzyme did not provide a significant advantage in substrate binding over the single active site protein. Further, the investigation of internal channels and tunnels within the protein shed light on the pathways facilitating transport between the two active sites. By unravelling the complex dynamics and functional characteristics of this double-active site protein, this study offers valuable insights into novel strategies of enzyme engineering. These findings establish a solid foundation for future research endeavours aimed at harnessing the potential of double-active site proteins in diverse biotechnological applications.

Significantly enhanced critical current density and pinning force in nanostructured, (RE)BCO-based, coated conductor.

High-temperature superconducting wires have many large-scale, niche applications such as commercial nuclear fusion as well as numerous other large-scale applications in the electric power industry and in the defense, medical and transportation industries. However, the price/performance metric of these coated conductor wires is not yet favorable to enable and realize most large-scale applications. Here we report on probing the limits of Jc (H, T) possible via defect engineering in heteroepitaxially deposited high-temperature superconducting thin-films on coated conductor substrates used for long-length wire fabrication. We report record values of Jc (H, T) and pinning force, Fp (H, T) in (RE)BCO films with self-assembled BaZrO3 nanocolumns deposited on a coated conductor substrate. A Jc of ~190 MA/cm2 at 4.2 K, self-field and ~90 MA/cm2, at 4.2 K, 7 T was measured. At 20 K, Jc of over 150 MA/cm2 at self-field and over 60 MA/cm2 at 7 T was observed. A very high pinning force, Fp, of ~6.4 TN/m3 and ~4.2 TN/m3 were observed at 7 T, 4.2 K and 7 T, 20 K respectively. We report on the highest values of Jc and Fp obtained to date for all fields and operating temperatures from 4.2 K to 77 K. These results demonstrate that significant performance enhancements and hence far more favorable price/performance metrics are possible in commercial high-temperature superconducting wires.

Noma Masquerading as Squamous Cell Carcinoma - A Case Report in an AIDS Patient.

Rationale: Cancrum oris, also known as noma, is a rare and rapidly progressing gangrenous infection affecting the oral cavity, commonly seen in malnourished children. We discuss the clinical presentation, diagnostic dilemma and management in a 54-year-old male human immunodeficiency virus-positive patient with oral ulceration clinically resembling squamous cell carcinoma (SCC). Patient Concerns: The patient had severe oral ulceration with pain and difficulty eating food. Diagnosis: Histopathological examination was misleading as it revealed features akin to early invasion of SCC. Immunohistochemistry findings were not in favour of SCC. Treatment: Antiretroviral therapy was started owing to the decreased CD4 cell count. Outcomes: Lesions began to show signs of healing on follow-up. Take-away Lessons: This case aims to highlight the unique challenges of diagnosing and emphasises the importance of considering opportunistic infections in immunocompromised patients presenting with oral ulcerations to prevent misdiagnosis and maltreatment.

Comparative Evaluation of Polymethyl Methacrylate and Thermoforming Crowns as Semipermanent Crowns in Primary Molars: An In Vivo Study.

Aim: The present randomized clinical trial is aimed at evaluating clinical efficiency of two different types of esthetic crowns-polymethyl methacrylate crowns and vacuum formed thermoformed crown as an alternative to full-coverage coronal restoration for deciduous molars. Materials and methods: A total of 45 primary molars in pediatric patients were selected using randomization and split into three groups based on the technique used for preparation of crowns: group I-polymethyl methacrylate crowns; group II-thermoformed crown; and group III-stainless steel crowns (SSC). All crowns were clinically and radiographically evaluated at baseline, 1st month, and 3rd month for gingival health, retention, marginal integrity, proximal contacts, occlusion, alignment, and staining. Statistical analysis: The data was tabulated and analyzed by Statistical Package for the Social Sciences (SPSS) Version 23.0 software. The intergroup comparison was done by Kruskal-Wallis test, analysis of variance (ANOVA), and Mann-Whitney U test for continuous data. The intragroup comparison was done by Friedman test and Wilcoxon signed-rank test for categorical data. All p-values < 0.05 were considered statistically significant. Results: With regard to the parameters of plaque score, gingival index score, occlusion, interproximal contacts, retention, alignment, and marginal adaptation, no statistical significance was noted between the three groups. However, with regard to the discoloration (staining) when the polymethyl methacrylate acrylic (PMMA) group was compared with thermoforming group, statistical significance was noted in 1st month with p-values of 0.04 and 0.03, respectively. On intragroup comparison, statistically significant values were obtained in SSC group for plaque score and thermoforming group for gingival index score. Clinical significance: The study concluded that the PMMA and thermoforming crowns can be used as an alternative to SSC for restoring the primary molars as they showed equivalent results to that of standard SSC. How to cite this article: Matha N, Kumar KS, Reddy BVT, et al. Comparative Evaluation of Polymethyl Methacrylate and Thermoforming Crowns as Semipermanent Crowns in Primary Molars: An In Vivo Study. Int J Clin Pediatr Dent 2024;17(S-1):S43-S54.

Factors Affecting Survival in Severe and Very Severe COPD after Admission in ICUs of Tertiary Care Centers of India (FAST COPD): Study Protocol for a Multicentric Cohort Study.

Background: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. However, there is a lack of comprehensive data from low- and middle-income countries (LMICs) regarding factors influencing COPD outcomes, particularly in regions where biomass exposure is prevalent. Objective: The Factors Affecting Survival in Severe and Very Severe COPD Patients Admitted to Tertiary Centers of India (FAST) study aims to address this gap by evaluating factors impacting survival and exacerbation rates among COPD patients in LMICs like India, with a specific focus on biomass exposure, clinical phenotypes, and nutritional status in patients admitted to the Intensive Care Unit (ICU). Methods: The FAST study is an observational cohort study conducted in university teaching hospitals across India. The study aims to enroll 1000 COPD patients admitted to the ICU meeting specific inclusion criteria, with follow-up assessments conducted every 6 months over a 2-year period. Data collection includes demographic information, clinical manifestations, laboratory investigations, pulmonary function tests, medications, nutritional status, mental health, and health-related quality of life. Adjudication of exacerbations and mortality will also be undertaken. The FAST study seeks to provide crucial insights into COPD outcomes in LMICs, informing more precise management strategies and mitigating the burden of COPD in these settings. By evaluating factors such as biomass exposure, clinical phenotypes, and nutritional status, the study aims to address key knowledge gaps in COPD research. How to cite this article: Arunachala S, Devapal S, Swamy DSN, Greeshma MV, Ul Hussain I, Siddaiah JB, et al. Factors Affecting Survival in Severe and Very Severe COPD after Admission in ICUs of Tertiary Care Centers of India (FAST COPD): Study Protocol for a Multicentric Cohort Study. Indian J Crit Care Med 2024;28(6):552-560.

Comparative Evaluation of Periodontal Ligament-associated Protein-1/Asporin Levels in Periodontal Tissue in Health and Disease.

Background: Periodontal ligament-associated protein-1 (PLAP-1)/asporin is an extracellular matrix protein that plays a protective role in the pathogenesis of periodontitis. There is a paucity of information about the association between PLAP-1/asporin and periodontitis in human PDL. Thus, in this study, PLAP-1/asporin levels between participants with healthy periodontium and chronic periodontitis were compared and correlated with periodontal parameters. Materials and Methods: Fifty participants were recruited and divided into 25 in each group: Group 1 (control) and Group 2 (test). Probing pocket depth (PPD) and clinical attachment level (CAL) were recorded. Periodontal ligament (PDL) samples were collected from extracted teeth for estimating PLAP-1/asporin levels using the Human Asporin Enzyme-Linked Immunoassay Kit. Results: A statistically significant difference (P = 0.001) in the PLAP-1/asporin levels was observed between Group 1 and Group 2. A weak negative correlation was observed between PLAP-1/asporin levels and periodontal parameters (PPD and CAL) in both groups. Conclusion: In this study, higher PLAP-1/asporin levels in participants with healthy periodontium highlight the protective role of PLAP-1/asporin in maintaining periodontal homeostasis.

Source attribution of carbon monoxide over Northern India during crop residue burning period over Punjab.

National Capital Territory of Delhi and its satellite cities suffer from poor air quality during the post-monsoon months of October-November. In this study, a novel attempt is made to estimate the contribution of different emission sources (industrial, residential, power generation, transportation, biomass burning, photochemical production, lateral transport, etc.) towards the criteria air pollutant carbon monoxide (CO) concentration over North India. Multiple simulations of the WRF-Chem model with a tagged tracer approach with different inputs (6 anthropogenic emission inventories and 3 biomass burning emission inventories) were used. The model performance was evaluated against the MOPITT retrieved CO surface concentration. Analysis of model simulated CO over North India suggests that anthropogenic emissions contribute around 32-49% to surface CO concentration while crop residue burning contributes 27-44% of which 80% originates from Punjab. For Delhi, the contribution from anthropogenic sources is dominant (53-77%) of which 10-28% is from the domestic sector and 14-55% is from the transport sector. Agricultural waste burning contributes about 15-30% to Delhi's surface CO concentration (of which 75% originates from Punjab). Crop residue burning emission is a chief source of CO over Punjab with a contribution of about 56-76%. The results suggest that industrial, transport, and domestic sector activities are more responsible for increased CO levels over New Delhi and surrounding regions than crop residue burning over Punjab. Furthermore, critical meteorological parameters like 10 m wind speed, boundary layer height, 2 m temperature, total precipitation, and relative humidity were evaluated against CO concentration to understand their impact on CO distribution. Results conclude that deteriorating air quality over the North Indian region is caused by a combination of prevailing meteorological factors (such as slow winds, shallow mixing layer, and cold temperatures) and man-made emissions.

The analytical study of double diffusive convection in a rectangular enclosure bounded by porous lining with thermal radiation.

The current analytical study is dedicated to the boundary layer regime where heat and mass transfer rates are ruled by natural convection. A rectangular enclosure filled with a combination of an arbitrary buoyancy ratio has an Oseen-linear solution, and the position of Beavers and Joseph's condition is employed at the porous fluid interface. Thermal radiation's interaction with a porous lining influences overall heat transfer in a system. Porous linings and radiation are employed in many applications, such as furnaces, insulation, heat exchangers, solar energy collecting and storage, and heat control in electronics. The effect of slip and radiation is to increase the flow rate because of the reduction in friction at the surface. It indicates the fact that temperature and concentration are rapidly lowering. As the slip parameter and radiation parameter increase, the heat and mass transport increase due to the rise in velocity. The Nusselt and Sherwood numbers reach their maximum when the radiation parameter, Rayleigh number, and slip parameter are increased. The findings of the Nusslet number and Sherwood numbers are related to the finite situations of the slip parameter tending to infinity, the radiation parameter going to zero and the angle 90°.

Expert Consensus on Dipeptidyl Peptidase-4 Inhibitor-Based Therapies in the Modern Era of Type 2 Diabetes Mellitus Management in India.

India has a high prevalence of type 2 diabetes mellitus (T2DM) with unique clinical characteristics compared to other populations. Despite advancements in diabetes therapy, a significant number of patients in India still experience poor glycemic control and complications. Dipeptidyl peptidase-4 (DPP-4) inhibitors continue to be an important component of T2DM treatment due to their favorable efficacy and tolerability profile. Given the current scenario, there is a need to revisit the role of DPP-4 inhibitors in T2DM management in Indian patients. This consensus paper aims to provide guidance on the utilization of DPP-4 inhibitors in T2DM management from an Indian perspective. A consensus group of 100 experts developed recommendations based on an extensive literature review and discussions. The expert group emphasized the importance of timely glycemic control, combination therapy, and targeting the underlying pathophysiology of T2DM. The combinations of DPP-4 inhibitors with metformin and/or sodium-glucose transport protein-2 inhibitors are rationalized in this paper, considering their complementary mechanisms of action. This paper provides valuable insights for clinicians in optimizing the management of T2DM in the Indian population with the use of DPP-4 inhibitors and proposes an algorithm for selecting DPP-4 inhibitor-based therapies.

Data-driven dentistry: Computational revelations redefining pulp capping.

Introduction: Pulpal and periradicular diseases stem from immune reactions to microbiota, causing inflammation. Limited blood supply hampers dental pulp self-healing. Managing inflammation involves eliminating bacteria and reducing pro-inflammatory mediators especially MMP-9, which has a significant correlation with pulpitis. s. Flavonoids like Hesperidin, Baicalein, Epigallocatechin gallate, Genistein, Icariin, and Quercetin show potential for pulp capping. Aim: This in-silico study compares various Flavonoids for their anti-inflammatory effects on MMP-9, with Chlorhexidine as a control, a known MMP-9 inhibitor. Materials and Methods: Protein and Ligand Preparation: The human MMP-9 catalytic domain (PDB ID: 4XCT) structure was retrieved, and necessary modifications were made. Flavonoids from PubChem database were prepared for docking using AutoDock Vina. A grid for docking was created, and molecular dynamics simulations were conducted using Gromacs-2019.4 with GROMOS96 force field. Trajectory analysis was performed, and MM-PBSA calculation determined binding free energies. Results: Analysis of MMP-9 and ligand interactions revealed Hesperidin's high binding affinity, forming numerous hydrogen bonds with specific amino acids. Molecular dynamics simulations confirmed stability, with RMSD, RMSF, Rg, and SASA indicating consistent complex behaviour over 100 ns. MM-PBSA calculation affirmed favourable energy contributions in MMP-9-Hesperidin interactions. Conclusion: MMP-9 plays a crucial role in prognosis of pulpitis. Incorporating MMP-9 inhibitors into pulp capping agents may enhance therapeutic efficacy. Hesperidin emerges as a potent MMP-9 inhibitor, warranting further in vivo validation against other agents.

A phase II study (AARDVARC) of AZD4635 in combination with durvalumab and cabazitaxel in patients with progressive, metastatic, castration-resistant prostate cancer.

BACKGROUND: This phase II nonrandomized study evaluated the efficacy and safety of AZD4635 in combination with durvalumab (Arm A) or durvalumab plus cabazitaxel (Arm B) in patients with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel and ≥1 novel hormonal agent. PATIENTS AND METHODS: The primary endpoint was radiographic progression-free survival (rPFS) per RECIST v1.1 (soft tissue) or the Prostate Cancer Clinical Trials Working Group 3 (bone). Secondary endpoints included safety, tolerability, overall survival, confirmed prostate-specific antigen (PSA50) response, pharmacokinetics, and objective response rate. Enrollment in Arm A was stopped following a sponsor decision unrelated to safety. The study was stopped based on the planned futility analysis due to low PSA50 response in Arm B. RESULTS: In the final analysis (1 November 2021), 30 patients were treated (Arm A, n = 2; Arm B, n = 28). The median rPFS in Arm B was 5.8 months (95% confidence interval 4.2-not calculable). Median rPFS was 5.8 months versus 4.2 months for patients with high versus low blood-based adenosine signature. The most common treatment-related adverse events in Arm B were nausea (50.0%), diarrhea (46.4%), anemia and neutropenia (both 35.7%), asthenia (32.1%), and vomiting (28.6%). Overall, AZD4635 in combination with durvalumab or AZD4635 in combination with cabazitaxel and durvalumab showed limited efficacy in patients with mCRPC. CONCLUSIONS: Although the safety profile of both combinations was consistent with known safety data of the individual agents, the results of this trial do not support further development of the combinations.