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Isothermal electrocaloric (EC) heat is a key—but rarely reported—parameter for cooling applications. Here, we employ calorimetry with large-area Peltiers (10 × 10 mm2) to study a multilayer capacitor (MLC) of well-ordered PbSc0.5Ta0.5O3 (PST) with a first-order ferroelectric phase transition. Our direct measurements of isothermal EC heat are consistent with complementary EC measurements of similar MLCs that display large EC effects, i.e., indirect EC measurements and direct measurements of adiabatic EC temperature change [Nair et al., Nature 575, 468 (2019)]. Using a field of 7.9 V μm−1, the EC heat associated with the electrically active PST peaks at 11 MJ m−3 near 300 K. At higher temperatures, as one approaches the critical point, the transition is seen to become less first order. Separately, we find that the inactive PST compromises quasi-direct EC measurements. In the future, isothermal EC heat should be directly measured as a matter of routine.

The present work describes the interaction between waves and currents utilizing a coupled ADCIRC+SWAN model for the very severe cyclonic storm Hudhud, which made landfall at Visakhapatnam on the east coast of India in October 2014. Model-computed wave and surge heights were validated with measurements near the landfall point. The Holland model reproduced the maximum wind speed of ≈ 54 m s−1 with the minimum pressure of 950 hPa. The modelled maximum surge of 1.2 m matches with the maximum surge of 1.4 m measured off Visakhapatnam. The two-way coupling with SWAN showed that waves contributed ≈ 0.25 m to the total water level during the Hudhud event. At the landfall point near Visakhapatnam, the East India Coastal Current speed increased from 0.5 to 1.8 m s−1 for a short duration ( ≈ 6 h) with net flow towards the south, and thereafter reversed towards the north. An increase of ≈ 0.2 m in Hs was observed with the inclusion of model currents. It was also observed that when waves travelled perpendicular to the coast after crossing the shelf area, with current towards the southwest, wave heights were reduced due to wave–current interaction; however, an increase in wave height was observed on the left side of the track, when waves and currents opposed each other.

There is growing interest in heat pumps based on materials that show thermal changes when phase transitions are driven by changes of electric, magnetic, or stress field. Importantly, regeneration permits sinks and loads to be thermally separated by many times the changes of temperature that can arise in the materials themselves. However, performance and parameterization are compromised by net heat transfer between caloric working bodies and heat-transfer fluids. Here, we show that this net transfer can be avoided—resulting in true, balanced regeneration—if one varies the applied electric field while an electrocaloric (EC) working body dumps heat on traversing a passive fluid regenerator. Our EC working body is represented by bulk PbSc_{0.5}Ta_{0.5}O_{3} near its first-order ferroelectric phase transition, where we record directly measured adiabatic temperature changes of up to 2.2 K. Indirectly measured adiabatic temperature changes of similar magnitude are identified, unlike normal, from adiabatic measurements of polarization, at nearby measurement set temperatures, without assuming a constant heat capacity. The resulting high-resolution field-temperature-entropy maps of our material, and a small clamped companion sample, are used to construct cooling cycles that assume the use of an ideal passive regenerator in order to span ≤20 K. These cooling cycles possess well-defined coefficients of performance that are bounded by well-defined Carnot limits, resulting in large (>50%) well-defined efficiencies that are not unduly compromised by a small field hysteresis. Our approach permits the limiting performance of any caloric material in a passive regenerator to be established, optimized, and compared; provides a recipe for true regeneration in prototype cooling devices; and could be extended to balance active regeneration.

Introduction: Legislative assemblies often provide a platform for legislators to question the government during question hours, which are crucial for governance However, question hours remain understudied, especially when addressing health policy and systems related issues in lower- and middle-income countries. This study assesses the 14th Kerala Legislative Assembly questions, focusing on health-related areas to provide insights for health policy formulation and decision-making processes. MATERIALS AND METHODS: We sourced and transcribed all starred questions (346) related to health that were answered by the health minister in the 14th Legislative Assembly between 2016 and 2021 from the archives of the assembly website. We conducted a thematic analysis of these questions and mapped them into various themes, guided by the World Health Organization building blocks framework. Results: About 7.8% of all questions (N = 4404) were related to health (N = 346). Of these questions, the majority were directly related to service delivery (43.4%), followed by health information (16.5%). Health financing, food safety, and human resources were the least discussed topics throughout the assessed period within the state. The legislators primarily focussed on health services and health information, with less attention given to health financing, food safety, and human resources regardless of constituency or political affiliation. Discussion: This study underscores the need for a balanced approach to public health issues, highlighting the importance of legislators to priortizing health services and information, while also addressing health financing, food safety, and human resources. This would enable a robust and resilient public health system to effectively address diverse health concerns.

Abstract We compared the risks and benefits of COVID-19 vaccines using a causal pathway analysis to weigh up possible risk factors of thromboembolic events post-vaccination. The self-controlled case series (SCCS) method examined the association between thromboembolic events and vaccination while a case-control study assessed the association between thromboembolic events and COVID-19, addressing under-reported infection data issues. The net vaccine effect was estimated using results from SCCS and case-control studies. We used electronic health record data from Corewell Health (16,640 subjects in SCCS and 106,143 in case-control). We found increased risks of thromboembolic events post-vaccination (incidence rate ratio: 1.19, 95% CI: [1.08, 1.31] after the first dose; 1.22, 95% CI: [1.11, 1.34] after the second dose). Vaccination attenuated infection-associated thromboembolic risks (odds ratio: 4.65, 95% CI: [4.18, 5.17] in unvaccinated vs 2.77, 95% CI: [2.40, 3.24] in vaccinated). After accounting for vaccine efficacy and protection against infection-associated thromboembolic events, vaccination decreases thromboembolic event risk, especially during high infection rate periods.

Abstract Wisdom is the hallmark of social judgment, but how people across cultures recognize wisdom remains unclear—distinct philosophical traditions suggest different views of wisdom’s cardinal features. We explore perception of wise minds across 16 socio-economically and culturally diverse convenience samples from 12 countries. Participants assessed wisdom exemplars, non-exemplars, and themselves on 19 socio-cognitive characteristics, subsequently rating targets’ wisdom, knowledge, and understanding. Analyses reveal two positively related dimensions—Reflective Orientation and Socio-Emotional Awareness. These dimensions are consistent across the studied cultural regions and interact when informing wisdom ratings: wisest targets—as perceived by participants—score high on both dimensions, whereas the least wise are not reflective but moderately socio-emotional. Additionally, individuals view themselves as less reflective but more socio-emotionally aware than most wisdom exemplars. Our findings expand folk psychology and social judgment research beyond the Global North, showing how individuals perceive desirable cognitive and socio-emotional qualities, and contribute to an understanding of mind perception.

Machining process involves numerous variables that can influence the desired outcomes, with surface roughness being a critical quality index for machined products. Surface roughness is often a technical requirement for mechanical products as it can lead to chatter and impact the functional performance of parts, especially those in contact with other materials. Therefore, predicting surface roughness is essential. This dataset comprises 7444 audio files containing acoustic signal samples recorded using a 44.1 kHz microphone during the milling of mild steel with a tungsten carbide tool on a BFW YF1 vertical milling machine. Various combinations of speed, feed and depth of cut were used, and surface roughness values measured using a Carl Zeiss E-35B profile-meter are provided for each combination. Additionally, an example workflow indicating the possible use of the data to estimate the surface roughness from the acoustic signals is presented. This dataset is the first publicly available resource for surface roughness measurement using sound signals in milling, offering significant potential for reuse in related research and applications.

Background This study sought to document and understand facilitators and barriers to producing, translating, and using modeled evidence in decision-making in Burkina Faso, Nigeria, India, and Kenya. We explored researcher-decision-maker engagement mechanisms as key facilitators of evidence use, with a focus on knowledge brokers and boundary organizations. Methods The study used sequential mixed methods drawing on data collected from surveys and key informant interviews, complemented by a rapid desk review to map modeling activities and actors. The survey was conducted online while the qualitative research entailed in-depth interviews with modelers, knowledge brokers, and decision-makers working in a representative variety of health fields, organizations, and levels of government. This study was approved by Health Media Lab IRB (Institutional Review Board) in the United States and a local IRB in each study country and conducted between September 2021 and June 2022. Results Informants interviewed for this study described a range of factors that facilitate and inhibit the use of modeled evidence in public health decision-making at the individual, organizational, and environmental levels. Key themes included the capacity to produce, translate, and use modeled evidence; the timing and relevance of modeling outputs; the existence of communications channels between modelers and decision-makers; the strength of underlying data systems; the role of sustained funding; and the impact of global crises. Conclusion This study highlights the importance of taking an ecosystem approach to supporting modeling activities, considering individual, organizational, and environmental factors and how different actors and interact to inform the production, translation, and use of modeled evidence. Structured interaction that promotes dialogue, debate, and joint sense making between the producers and users of evidence is critical to informing and influencing the use of evidence in decision-making.

Abstract Of all gynecologic cancers, epithelial-ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The precise mechanism by which leukemia inhibitory factor (LIF) and its receptor (LIFR) contribute to the progression of OCa remains unknown. Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using multiple primary and established OCa cell lines or tissues that represent five subtypes of epithelial-OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with LIFR inhibitor, EC359 significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5-50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo and in vivo models including cell-based xenografts, patient-derived explants, organoids, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells. Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.

Lane detection is a fundamental component of advanced driver assistance systems, facilitating critical functionalities like Lane Keep/Change Assistance, Lane Departure Warning, Adaptive Cruise Control, and Vehicle Localization. Despite significant advancements in camera-based lane detection, it continues to confront challenges that can be effectively addressed with LiDAR technology. This research contributes to the domain of LiDAR-based lane detection across three pivotal areas. Firstly, we introduce the BoostedDim Attention method, enhancing traditional Multi-Head Self-Attention (MHA) calculations within the shallow Vision Transformers-based K-Lane baseline model. This method excels, particularly in demanding scenarios, including unknown and nighttime conditions at short ranges (0–30 m) and daytime scenarios for long ranges (30–50 m). Secondly, we devise distance-based True Positive Rate (TPR) and Lateral Error evaluation metrics, providing a more precise and tailored approach to evaluating model performance compared to conventional metrics. These metrics consider sensor-specific and task-specific factors, offering a comprehensive assessment of LiDAR-based lane detection capabilities. Lastly, our investigation sheds light on the significance of calibrated reflectivity and intensity data, revealing their impact on lane detection under various lighting conditions. Notably, we highlight the positive influence of intensity data in low-light conditions for short ranges and its adverse effect during daytime for long ranges. These findings have significant implications for enhancing autonomous driving applications and other computer vision tasks.

Summary: Cancer cell populations comprise phenotypes distributed among the epithelial-mesenchymal (E-M) spectrum. However, it remains unclear which population-level processes give rise to the observed experimental distribution and dynamical changes in E-M heterogeneity, including (1) differential growth, (2) cell-state switching, and (3) population density-dependent growth or state-transition rates. Here, we analyze the necessity of these three processes in explaining the dynamics of E-M population distributions as observed in PMC42-LA and HCC38 breast cancer cells. We find that, while cell-state transition is necessary to reproduce experimental observations of dynamical changes in E-M fractions, including density-dependent growth interactions (cooperation or suppression) better explains the data. Further, our models predict that treatment of HCC38 cells with transforming growth factor β (TGF-β) signaling and Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/3) inhibitors enhances the rate of mesenchymal-epithelial transition (MET) instead of lowering that of E-M transition (EMT). Overall, our study identifies the population-level processes shaping the dynamics of spontaneous E-M heterogeneity in breast cancer cells.

This study was aimed to pursue the avenue of influence of the media in inciting violence and other such negative emotions and their impact on the realm of education. This study was directed at one hundred and thirty student participants of different age groups, natives, and fields of study. All the students assessed, gave anonymous data with consent. The questionnaire was self-developed, approved by professors, and scores were indexed to percentage value. The findings of the study revealed that media did incite fear and violence through their content and hampered the emotional balance and educational experience of students with the same. The study also concluded that a governing body must be formulated to check content provided by the media.

Malware detection is an ever-evolving area given that the strides in the detection capabilities being matched by radical attempts to bypass the detection. As the sophistication of malware continues to increase, the demand for innovative approaches to improve detection capabilities become paramount. Machine learning/Deep learning models are being increasingly used for Malware Detection, however one of the most important and frequently overlooked aspects of building such models is feature encoding. This research paper explores the importance of feature encoding to improve the efficiency of threat detection and proposes a novel entropy-based encoding scheme for the categorical features present in the data extracted from malicious inputs. The KDDCUP99, UNSW-NB15 and CIC-Evasive-PDFMal2022 datasets have been used to evaluate the effectiveness of the proposed encoding scheme. The results of the proposed encoding scheme are validated against seven other encoding schemes to ascertain the credibility and usability of the proposed scheme. The efficiency of the proposed system evaluated by applying different encoded versions of the datasets to train various machine learning models and determining the classification performance of the models on each dataset. The machine learning models trained with the proposed encoding scheme produced stable classification results and outperformed other encoding schemes when dimensionality reduction was applied on the data. The ensemble classifier trained using the proposed scheme was able to classify the data with an F1 score of 99.99% when the dimension-reduced entropy-encoded KDD Cup99 dataset was used to build the model. On the CIC-Evasive-PDFMal2022 dataset, the entropy encoding has exhibited a slightly improved classification parameters with the ensemble methods yielding a peak F1 score of 99.27%. We have also determined the feature importance values of the features present in the datasets to study the change in the contribution levels of the features when multiple categorical encoding schemes are applied upon the data.

Nanoemulsions (NEs) are submicron-sized heterogeneous biphasic liquid systems stabilized by surfactants. They are physically transparent or translucent, optically isotropic, and kinetically stable, with droplet sizes ranging from 20 to 500 nm. Their unique properties, such as high surface area, small droplet size, enhanced bioavailability, excellent physical stability, and rapid digestibility, make them ideal for encapsulating various active substances. This review focuses on recent advancements, future prospects, and challenges in the field of NEs, particularly in oral, parenteral, and ophthalmic delivery. It also discusses recent clinical trials and patents. Different types of in vitro and in vivo NE characterization techniques are summarized. High-energy and low-energy preparation methods are briefly described with diagrams. Formulation considerations and commonly used excipients for oral, ocular, and ophthalmic drug delivery are presented. The review emphasizes the need for new functional excipients to improve the permeation of large molecular weight unstable proteins, oligonucleotides, and hydrophilic drugs to advance drug delivery rapidly.

Introduction: Kerala, a south Indian state, has often been cited globally as a model for better health outcomes at low cost but faces unique challenges in achieving Universal Health Coverage (UHC). To propel the efforts in achieving UHC, the Government of Kerala announced the “Aardram” health reform initiative, emphasising improving the quality of primary care service delivery. The reforms started in 2017, and in the first stage, 170 of 848 Primary Health Centres (PHCs) were upgraded to Family Health Centres (FHCs). The facilities were provided with additional doctors, nurses, and paramedical staff; the working hours were extended, and the range of services offered increased. In support of these processes, we carried out a facility assessment to assess differences between upgraded FHCs and existing PHCs. Materials and Methods: We conducted a facility-based cross-sectional assessment in eight primary care facilities of Kerala, FHC (N=4) and PHCs (N=4) from June to October 2019. A structured questionnaire covering utilisation and coverage of selected priority services for various populations and health outcome data was filled out by health staff to report data for the financial year 2018-19. Data were analysed in Microsoft Excel spreadsheets for easy analysis and replication by state stakeholders. Results: Coverage indicators such as full antenatal care and full immunization coverage were not appreciably different in FHCs as compared to PHCs. However, key reform-related differences were observed. On average, FHCs had 0.8 medical officers and one staff nurse per 10,000 population, whereas PHCs had 0.7 medical officers and less than 0.4 staff nurses per 10,000 population, even as the size of populations served by these human resources varied greatly across both types of facilities. The number of outpatient department visits per 10,000 population annually was 11,343 persons in FHCs and 9,580 persons in PHCs. FHCs also provided additional services such as screening for depression and chronic obstructive pulmonary disorders. Conclusion: Aardram primary healthcare reforms are still in their early days and appear to be associated with improved service coverage at the institutional level. However, some patterns are uneven: reforms should be carefully documented, and population-level impacts monitored over time.

Tamil is one of the oldest existing languages, spoken by around 65 million people across India, Sri Lanka and South-East Asia. Countries such as Fiji and South Africa also have a significant population with Tamil ancestry. Tamil is a complex language and has 247 characters. A labelled dataset for Tamil Fingerspelling named TLFS23 has been created for research related to vision-based Fingerspelling translators for the Speech and hearing Impaired. The dataset would open up avenues to develop automated systems as translators and interpreters for effective communication between fingerspelling language users and non- users, using computer vision and deep learning algorithms. One thousand images representing each unique finger flexion motion for every Tamil character was collected overall constituting a large dataset with 248 classes with a total of 2,55,155 images. The images were contributed by 120 individuals from different age groups. The dataset is made publicly available at: https://data.mendeley.com/datasets/39kzs5pxmk/2.

Curcumin, an organic phenolic molecule that is extracted from the rhizomes of Curcuma longa Linn, has undergone extensive evaluation for its diverse biological activities in both animals and humans. Despite its favorable characteristics, curcumin encounters various formulation challenges and stability issues that can be effectively addressed through the application of nanotechnology. Nano-based techniques specifically focused on enhancing solubility, bioavailability, and therapeutic efficacy while mitigating toxicity, have been explored for curcumin. This review systematically presents information on the improvement of curcumin’s beneficial properties when incorporated, either individually or in conjunction with other drugs, into diverse nanosystems such as liposomes, nanoemulsions, polymeric micelles, dendrimers, polymeric nanoparticles, solid-lipid nanoparticles, and nanostructured lipid carriers. Additionally, the review examines ongoing clinical trials and recently granted patents, offering a thorough overview of the dynamic landscape in curcumin delivery. Researchers are currently exploring nanocarriers with crucial features such as surface modification, substantial loading capacity, biodegradability, compatibility, and autonomous targeting specificity and selectivity. Nevertheless, the utilization of nanocarriers for curcumin delivery is still in its initial phases, with regulatory approval pending and persistent safety concerns surrounding their use.

The nose-to-brain drug-delivery system has emerged as a promising strategy to overcome the challenges associated with conventional drug administration for central nervous system disorders. This emerging field is driven by the anatomical advantages of the nasal route, enabling the direct transport of drugs from the nasal cavity to the brain, thereby circumventing the blood–brain barrier. This review highlights the significance of the anatomical features of the nasal cavity, emphasizing its high permeability and rich blood supply that facilitate rapid drug absorption and onset of action, rendering it a promising domain for neurological therapeutics. Exploring recent developments and innovations in different nanocarriers such as liposomes, polymeric nanoparticles, solid lipid nanoparticles, dendrimers, micelles, nanoemulsions, nanosuspensions, carbon nanotubes, mesoporous silica nanoparticles, and nanogels unveils their diverse functions in improving drug-delivery efficiency and targeting specificity within this system. To minimize the potential risk of nanoparticle-induced toxicity in the nasal mucosa, this article also delves into the latest advancements in the formulation strategies commonly involving surface modifications, incorporating cutting-edge materials, the adjustment of particle properties, and the development of novel formulations to improve drug stability, release kinetics, and targeting specificity. These approaches aim to enhance drug absorption while minimizing adverse effects. These strategies hold the potential to catalyze the advancement of safer and more efficient nose-to-brain drug-delivery systems, consequently revolutionizing treatments for neurological disorders. This review provides a valuable resource for researchers, clinicians, and pharmaceutical-industry professionals seeking to advance the development of effective and safe therapies for central nervous system disorders.

Background This study sought to document and understand facilitators and barriers to producing, translating, and using modeled evidence in decision-making in Burkina Faso, Nigeria, India, and Kenya. We explored researcher-decision-maker engagement mechanisms as key facilitators of evidence use, with a focus on knowledge brokers and boundary organizations. Methods The study used mixed methods drawing on analysis from key informant interviews and surveys, complemented by a rapid desk review to map modeling activities and actors. The survey was conducted online while the qualitative research entailed in-depth interviews with modelers, knowledge brokers, and decision-makers working in a representative variety of health fields, organizations, and levels of government. This study was approved by Health Media Lab IRB (Institutional Review Board) in the United States and a local IRB in each study country and conducted between September 2021 and June 2022. Results Informants interviewed for this study described a range of factors that facilitate and inhibit the use of modeled evidence in public health decision-making at the individual, organizational, and environmental levels. Key themes included the capacity to produce, translate, and use modeled evidence; the timing and relevance of modeling outputs; the existence of communications channels between modelers and decision-makers; the strength of underlying data systems; the role of sustained funding; and the impact of global crises. Conclusion This study highlights the importance of taking an ecosystem approach to supporting modeling activities, considering individual, organizational, and environmental factors and how different actors and interact to inform the production, translation, and use of modeled evidence. Structured interaction that promotes dialogue, debate, and joint sense making between the producers and users of evidence is critical to informing and influencing the use of evidence in decision-making.

The design of an experimental approach, the Box–Behnken design, was implemented to optimize the chromatographic condition to develop a rapid HPLC procedure for quantification of a ternary mixture of metoprolol (MET), telmisartan (TEL), and amlodipine (AML) from the formulation. The perturbation plots, contour, and 3D response surface pictures were developed to study the impact of each variable on the analytes’ retention time and the probable interaction between the parameters with fewer chromatographic runs. The optimized HPLC method separated the three analytes within 5 min with excellent selectivity and peak shape on a Zorbax C18 HPLC column using acetonitrile and phosphate buffer (20 mM, pH 5.8) with isocratic elution at a 1.1 mL/min flowrate. A wavelength 230 nm was utilized to monitor the elute. The validation of proposed method demonstrated a wide linearity range of 10–200 µg/mL for MET and TEL and 5–50 µg/mL for AML along with an excellent correlation coefficient. The correctness of the HPLC approach was further confirmed by excellent recovery of the added amount of analytes utilizing the standard addition technique. The recommended HPLC approach was employed safely for quality assurance of the formulation, because the evaluation of the method’s greenness and whiteness confirmed the environmentally friendly nature of the approach.

PURPOSEThis study aims to investigate the factors that influence total procedure time when performing computed tomography (CT)-guided percutaneous core-needle lung biopsies.METHODSThis is a cross-sectional study of 673 patients, who underwent a CT-guided percutaneous coreneedle biopsy at a tertiary care center from March 2014 to August 2016. Data on patient, nodule, and procedural factors and outcomes were collected retrospectively. Univariate linear regression and a multivariate stepwise linear regression were utilized for analysis.RESULTSFactors most strongly associated with prolonged procedure duration include 20-gauge needle use when compared with 18-gauge needle use (estimated difference in time=1.19), collecting additional core biopsies (estimated difference in time=1.10), decubitus nodule side up (DNSU; estimated difference in time=1.42), and supine positioning (estimated difference in time=1.16) relative to decubitus nodule side down positioning, and increased nodule distance from the skin surface (estimated difference in time=1.03). Increased nodule length (estimated difference in time=0.93) was associated with reductions in procedure duration. Prolonged procedure time was associated with an increased rate of pneumothorax (odds ratio (OR)=1.02; P < .0001) and decreased rate of pulmonary hemorrhage (OR=0.97; P < .0001).CONCLUSIONThe use of 20-gauge biopsy needle, collecting additional core biopsies, DNSU and supine positioning, smaller nodule size, and increasing nodule distance from the skin surface were associated with increased procedure time for CT-guided core needle biopsies of lung nodules. Prolonged procedure time is associated with a higher rate of pneumothorax and a lower rate of pulmonary hemorrhage.

Objectives: Endometrial cancer is the most common gynecologic malignancy in women. Of the two histological subtypes of endometrial cancer described, Type II tumors are biologically more aggressive and convey a less favorable prognosis when compared to Type I tumors. Novel therapeutics for treatment of Type II endometrial cancer are needed. Leukemia Inhibitory Factor Receptor (LIFR) and its ligand, LIF, play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Our recent studies revealed high levels of LIF and its receptor LIFR are associated with poor survival in endometrial cancer patients. We evaluated the efficacy of EC359, a novel small molecule inhibitor of the LIF receptor, against Type II Endometrial cancer cells. Methods: Primary and established cell lines were utilized in this study. Established cell lines were purchased from the American Type Culture Collection (ATCC CRL-1622). All primary samples were collected through the UT Health San Antonio tumor registry under IRB approval. The recently developed LIFR inhibitor, EC359, was used to elucidate the therapeutic utility of targeting the LIF/LIFR pathway in Type II endometrial cancer. In vitro activity was tested using MTT, colony formation, invasion, and apoptosis assays. Mechanistic studies were conducted using Western blot, reporter gene assays, and RT-qPCR analysis. Patient-derived xenograft (PDX) models were used for preclinical evaluation and toxicity. Results: Treatment of established and primary endometrial cancer cells with the LIFR inhibitor EC359 significantly reduced cell viability, long-term cell survival, invasion, and promoted apoptosis. Treatment with EC359 attenuated the activation of LIF/LIFR driven pathways including STAT3, mTOR, and AKT. EC359 significantly reduced tumor progression in patient derived xenograft model. Conclusions: These data support EC359 as a potential novel small molecule therapeutic for treatment of Type II Endometrial cancer.

Orodispersible films (ODFs) are thin, mechanically strong, and flexible polymeric films that are designed to dissolve or disintegrate rapidly in the oral cavity for local and/or systemic drug delivery. This review examines various aspects of ODFs and their potential as a drug delivery system. Recent advancements, including the detailed exploration of formulation components, such as polymers and plasticizers, are briefed. The review highlights the versatility of preparation methods, particularly the solvent-casting production process, and novel 3D printing techniques that bring inherent flexibility. Three-dimensional printing technology not only diversifies active compounds but also enables a multilayer approach, effectively segregating incompatible drugs. The integration of nanoparticles into ODF formulations marks a significant breakthrough, thus enhancing the efficiency of oral drug delivery and broadening the scope of the drugs amenable to this route. This review also sheds light on the diverse in vitro evaluation methods utilized to characterize ODFs, ongoing clinical trials, approved marketed products, and recent patents, providing a comprehensive outlook of the evolving landscape of orodispersible drug delivery. Current patient-centric approaches involve developing ODFs with patient-friendly attributes, such as improved taste masking, ease of administration, and enhanced patient compliance, along with the personalization of ODF formulations to meet individual patient needs. Investigating novel functional excipients with the potential to enhance the permeation of high-molecular-weight polar drugs, fragile proteins, and oligonucleotides is crucial for rapid progress in the advancing domain of orodispersible drug delivery.

The therapeutic effectiveness of paliperidone in the treatment of schizophrenia has been limited by its poor oral bioavailability; hence, an alternative route could be appropriate. This study investigates the feasibility of developing a buccal film impregnated with paliperidone-loaded nanostructured lipid carriers (NLCs) and assesses the potential to enhance its bioavailability. Box–Behnken-based design optimization of NLCs was performed by examining the particles’ physical characteristics. The polymeric film was used to load optimized NLCs, which were then assessed for their pharmaceutical properties, permeability, and pharmacokinetics. The optimization outcomes indicated that selected formulation variables had a considerable (p < 0.05) impact on responses such as particle size, entrapment efficiency, and % drug release. Desired characteristics such as a negative charge, higher entrapment efficiency, and nanoparticles with ideal size distribution were shown by optimized NLC dispersions. The developed film demonstrated excellent physico-mechanical properties, appropriate texture, good drug excipient compatibility (chemically stable formulation), and amorphous drug nature. A sustained Weibull model drug release (p < 0.0005) and superior flux (~5-fold higher, p < 0.005) were seen in NLC-loaded film compared to plain-drug-loaded film. The pharmacokinetics profile in rabbits supports the goal of buccal therapy as evidenced by significantly higher AUC0–12 (p < 0.0001) and greater relative bioavailability (236%) than the control. These results support the conclusion that paliperidone-loaded NLC buccal film has the potential to be an alternate therapy for its effective administration in the treatment of schizophrenia.

A new, host specific digenetic trematode, Neogonapodasmius hemirhamphi n. gen., n.sp. from the half beak, Hemirhamphus xanthopterus (Val.) off the Southwest (Trivandrum) coast of India is described. The parasite is found encysted on the anterior dorsal fin of the fish. Each cyst usually contains one female worm. Occasionally, however, one male also occurs along with the female, in a cyst. A comparison of the characters of the known forms of the family Didymozoidae with those of the present specimen showed significant differences prompting the erection of a new genus Neogonapodasmius, to contain the new specimen.

Streptococcus mutans bacteria form a biofilm called plaque that causes oral diseases, including tooth decay. Therefore, inhibition of biofilm formation is essential to maintaining good oral health. The health and nutritional benefits of Cynodon dactylon are well documented, but very little is known about its use to treat against oral diseases. The aim of this study was to detect the adhesion strength of the S. mutans bacterial biofilm in 100 cases in the Rajshahi region and evaluate the inhibitory activity of different compound extracts of C. dactylon on the S. mutans bacterial biofilm by determining the composition of isolated compounds using phytochemical analysis. Nuclear magnetic resonance (NMR) spectroscopy confirmed that three specific compounds from C. dactylon were discovered in this study: 3,7,11,15 tetramethyl hexadec-2-4dien 1-o1, compound 3,7,11,15 tetramethylhexadec-2-en-1-o1 from phytol derivatives, and stigmasterol. Results indicated that the compound of 3,7,11,15-tetramethyl-hexadec-2-en-1-ol exhibited higher antibiofilm activities on S. mutans than those of the other compound extracts. A lower level of minimum inhibitory concentration was exposed by 3, 7, 11,15 tetramethyl hexadeca-2-en-1-o1 (T2) on S. mutans at 12.5 mL. In this case, the compound of 3,7,11,15 tetramethyl hexadec 2en-1-o1 was used, and patients showed a mean value and standard error reduced from 3.42 ± 0.21 to 0.33 ± 0.06 nm. The maximum inhibition was (80.10%) in the case of patient no. 17, with a value of p < 0.05 found for S. mutans to which 12.5 μL/mL ethyl acetate extract was applied. From these findings, it may be concluded that C. dactylon extracts can be incorporated into various oral preparations to prevent tooth decay.

Leflunomide (LEF), a disease-modifying anti-rheumatic drug, has been widely explored for its anti-inflammatory potential in skin disorders such as psoriasis and melanoma. However, its poor stability and skin irritation pose challenges for topical delivery. To surmount these issues, LEF-loaded solid lipid nanoparticles (SLNs) integrated with hydrogels have been developed in the present investigation. SLNs developed by microemulsion techniques were found ellipsoidal with 273.1 nm particle size and −0.15 mV zeta potential. Entrapment and total drug content of LEF-SLNs were obtained as 65.25 ± 0.95% and 93.12 ± 1.72%, respectively. FTIR and XRD validated the successful fabrication of LEF-SLNs. The higher stability of LEF-SLNs (p < 0.001) compared to pure drug solution was observed in photostability studies. Additionally, in vitro anti-inflammatory activity of LEF-SLNs showed good potential in comparison to pure drugs. Further, prepared LEF-SLNs loaded hydrogel showed ideal rheology, texture, occlusion, and spreadability for topical drug delivery. In vitro release from LEF-SLN hydrogel was found to follow the Korsmeyer-Peppas model. To assess the skin safety of fabricated lipidic formulation, irritation potential was performed employing the HET-CAM technique. In conclusion, the findings of this investigation demonstrated that LEF-SLN hydrogel is capable of enhancing the photostability of the entrapped drug while reducing its skin irritation with improved topical delivery characteristics.

The efficacy of topical antifungal therapy in onychomycosis has been hindered by the failure of the antimycotic to permeate the nail plate. This research aims to design and develop a transungual system for the effective delivery of efinaconazole utilizing constant voltage iontophoresis. Seven prototype drug-loaded hydrogel formulations (E1–E7) were prepared to assess the influence of solvent (ethanol) and cosolvent (Labrasol®) on transungual delivery. Optimization was performed to evaluate the effect of three independent variables; voltage, solvent-to-cosolvent ratio, and penetration enhancer (PEG 400) concentration on critical quality attributes (CQAs), such as drug permeation and loading into the nail. The selected hydrogel product was characterized for pharmaceutical properties, efinaconazole release from the nail, and antifungal activity. Preliminary data indicates ethanol, Labrasol®, and voltage influence the transungual delivery of efinaconazole. Optimization design indicates a significant impact by applied voltage (p-0.0001) and enhancer concentration (p-0.0004) on the CQAs. Excellent correlation between selected independent variables and CQAs was confirmed by the high desirability value (0.9427). A significant (p < 0.0001) enhancement in the permeation (~78.59 µg/cm2) and drug loading (3.24 µg/mg) was noticed in the optimized transungual delivery with 10.5 V. FTIR spectral data indicates no interaction between the drug and excipients, while the DSC thermograms confirmed the amorphous state of the drug in the formulation. Iontophoresis produces a drug depot in the nail that releases above the minimum inhibitory concentration level for an extended period, potentially reducing the need for frequent topical treatment. Antifungal studies further substantiate the release data and have shown remarkable inhibition of Trichophyton mentagrophyte. Overall, the promising results obtained here demonstrate the prospective of this non-invasive method for the effective transungual delivery of efinaconazole, which could improve the treatment of onychomycosis.

The clinical usefulness of doxorubicin (DOX) is limited by its serious adverse effects, such as cardiotoxicity. Pregnenolone demonstrated both anti-inflammatory and antioxidant activity in animal models. The current study aimed to investigate the cardioprotective potential of pregnenolone against DOX-induced cardiotoxicity. After acclimatization, male Wistar rats were randomly grouped into four groups: control (vehicle-treated), pregnenolone (35 mg/kg/d, p.o.), DOX (15 mg/kg, i.p, once), and pregnenolone + DOX. All treatments continued for seven consecutive days except DOX, which was administered once on day 5. The heart and serum samples were harvested one day after the last treatment for further assays. Pregnenolone ameliorated the DOX-induced increase in markers of cardiotoxicity, namely, histopathological changes and elevated serum levels of creatine kinase-MB and lactate dehydrogenase. Moreover, pregnenolone prevented DOX-induced oxidative changes (significantly lowered cardiac malondialdehyde, total nitrite/nitrate, and NADPH oxidase 1, and elevated reduced glutathione), tissue remodeling (significantly decreased matrix metalloproteinase 2), inflammation (significantly decreased tumor necrosis factor-α and interleukin 6), and proapoptotic changes (significantly lowered cleaved caspase-3). In conclusion, these findings show the cardioprotective effects of pregnenolone in DOX-treated rats. The cardioprotection achieved by pregnenolone treatment can be attributed to its antioxidant, anti-inflammatory, and antiapoptotic actions.

Clinical application of treprostinil in pulmonary arterial hypertension is hampered by adverse effects caused by its high dosing frequency. The objective of this investigation was to Formulate an adhesive-type transdermal patch of treprostinil and evaluate it both in vitro and in vivo. A 32-factorial design was utilized to optimize the selected independent variables (X1: drug amount, X2: enhancer concentration) on the response variables (Y1: drug release, Y2: transdermal flux). The optimized patch was evaluated for various pharmaceutical properties, skin irritation, and pharmacokinetics in rats. Optimization results signify considerable influence (p < 0.0001) of X1 on both Y1 and Y2, as compared to X2. The optimized patch possesses higher drug content (>95%), suitable surface morphology, and an absence of drug crystallization. FTIR analysis revealed compatibility of the drug with excipients, whereas DSC thermograms indicate that the drug exists as amorphous in the patch. The adhesive properties of the prepared patch confirm adequate adhesion and painless removal, while the skin irritation study confirms its safety. A steady drug release via Fickian diffusion and greater transdermal delivery (~23.26 µg/cm2/h) substantiate the potential of the optimized patch. Transdermal therapy resulted in higher treprostinil absorption (p < 0.0001) and relative bioavailability (237%) when compared to oral administration. Overall, the results indicate that the developed drug in the adhesive patch can effectively deliver treprostinil through the skin and could be a promising treatment option for pulmonary arterial hypertension.

Natural plants and their products continue to be the major source of phytoconstituents in food and therapeutics. Scientific studies have evidenced the benefits of sesame oil and its bioactives in various health conditions. Various bioactives present in it include sesamin, sasamolin, sesaminol, and sesamol; among these, sesamol represents a major constituent. This bioactive is responsible for preventing various diseases including cancer, hepatic disorders, cardiac ailments, and neurological diseases. In the last decade, the application of sesamol in the management of various disorders has attracted the increasing interest of the research community. Owing to its prominent pharmacological activities, such as antioxidant, antiinflammatory, antineoplastic, and antimicrobial, sesamol has been explored for the above-mentioned disorders. However, despite the above-mentioned therapeutic potential, its clinical utility is mainly hindered owing to low solubility, stability, bioavailability, and rapid clearance issues. In this regard, numerous strategies have been explored to surpass these restrictions with the formulation of novel carrier platforms. This review aims to describe the various reports and summarize the different pharmacological activities of sesamol. Furthermore, one part of this review is devoted to formulating strategies to improve sesamol’s challenges. To resolve the issues such as the stability, low bioavailability, and high systemic clearance of sesamol, novel carrier systems have been developed to open a new avenue to utilize this bioactive as an efficient first-line treatment for various diseases.

Glycyrrhiza glabra L. (belonging to the family Leguminosae), commonly known as Licorice, is a popular medicinal plant that has been used in traditional medicine worldwide for its ethnopharmacological efficacy in treating several ailments. Natural herbal substances with strong biological activity have recently received much attention. The main metabolite of glycyrrhizic acid is 18β-glycyrrhetinic acid (18βGA), a pentacyclic triterpene. A major active plant component derived from licorice root, 18βGA has sparked a lot of attention due to its pharmacological properties. The current review thoroughly examines the literature on 18βGA, a major active plant component obtained from Glycyrrhiza glabra L. The current work provides insight into the pharmacological activities of 18βGA and the potential mechanisms of action involved. The plant contains a variety of phytoconstituents such as 18βGA, which has a variety of biological effects including antiasthmatic, hepatoprotective, anticancer, nephroprotective, antidiabetic, antileishmanial, antiviral, antibacterial, antipsoriasis, antiosteoporosis, antiepileptic, antiarrhythmic, and anti-inflammatory, and is also useful in the management of pulmonary arterial hypertension, antipsychotic-induced hyperprolactinemia, and cerebral ischemia. This review examines research on the pharmacological characteristics of 18βGA throughout recent decades to demonstrate its therapeutic potential and any gaps that may exist, presenting possibilities for future drug research and development.

Poor aqueous solubility besides extensive hepatic first effect significantly decreases the oral absorption of levosulpiride, which in turn minimizes its therapeutic effectiveness. Niosomes have been extensively investigated as a transdermal vesicular nanocarrier to increase the delivery of low permeable compounds into and across the skin. This research work was to design, develop and optimize levosulpiride-loaded niosomal gel and to evaluate its prospects for transdermal delivery. The Box-Behnken design was used to optimize niosomes by analyzing the impact of three factors (cholesterol; X1, Span 40; X2, and sonication time; X3) on the responses (particle size, Y1, and entrapment efficiency, Y2). Optimized formulation (NC) was incorporated into gel and evaluated for pharmaceutical properties, drug release study, ex vivo permeation, and in vivo absorption. The design experiment data suggest that all three independent variables influence both response variables significantly (p < 0.01). Pharmaceutical characteristics of NC vesicles showed the absence of drug excipient interaction, nanosize (~102.2 nm), narrow distribution (~0.218), adequate zeta potential (−49.9 mV), and spherical shape, which are suitable for transdermal therapy. The levosulpiride release rates varied significantly (p < 0.01) between niosomal gel formulation and control. Greater flux (p < 0.01) was observed with levosulpiride-loaded niosomal gel than with control gel formulation. Indeed, the drug plasma profile of niosomal gel was significantly higher (p < 0.005), with ~3 folds higher Cmax and greater bioavailability (~500% higher; p < 0.0001) than its counterpart. Overall, these findings imply that the use of an optimized niosomal gel formulation can increase the therapeutic efficacy of levosulpiride and may represent a promising alternative to conventional therapy.

Dolutegravir’s therapeutic effectiveness in the management of neuroAIDS is mainly limited by its failure to cross the blood–brain barrier. However, lipid-based nanovesicles such as nanoemulsions have demonstrated their potential for the brain targeting of various drugs by intranasal delivery. Thus, the purpose of this study was to develop a Dolutegravir-loaded nanoemulsion-based in situ gel and evaluate its prospective for brain targeting by intranasal delivery. Dolutegravir-loaded nanoemulsions were prepared using dill oil, Tween® 80, and Transcutol® P. Optimization of the nanoemulsion particle size and drug release was carried out using a simplex lattice design. Formulations (F1–F7 and B1–B6) were assessed for various pharmaceutical characteristics. Ex vivo permeation and ciliotoxicity studies of selected in situ gels (B1) were conducted using sheep nasal mucosa. Drug targeting to the brain was assessed in vivo in rats following the nasal delivery of B1. The composition of oil, surfactant, and cosurfactant significantly (p < 0.05) influenced the dependent variables (particle size and % of drug release in 8 h). Formulation B1 exhibits pharmaceutical characteristics that are ideal for intranasal delivery. The mucosal steady-state flux noticed with BI was significantly greater (p < 0.005) than for the control gel. A histopathology of nasal mucosa treated with BI showed no signs of toxicity or cellular damage. Intranasal administration of B1 resulted in greater Cmax (~six-fold, p < 0.0001) and AUC0−α (~five-fold, p < 0.0001), and decreased Tmax (1 h) values in the brain, compared to intravenous administration. Meantime, the drug level in the plasma was relatively low, suggesting less systemic exposure to Dolutegravir through intranasal delivery. In summary, the promising data observed here signifies the prospective of B1 to enhance the brain targeting of Dolutegravir by intranasal delivery and it could be used as a feasible and practicable strategy for the management of neuroAIDS.

Multi-layered thermal barrier coatings (TBCs) are deposited on gas turbine metallic components to protect them against high temperatures, oxidation, and corrosion. However, TBCs have limited working temperatures and lifetimes due to their material properties. Several approaches are tested to increase TBC topcoats' phase stability and properties. Increasing entropy to stabilize phases is a concept introduced in 2004 and required decreasing the Gibbs free energy. Many high entropy ceramics are developed for structural and functional applications, and different types of high entropy oxides (HEOs) are promising TBC ceramics due to their unique characteristics. HEOs are single-phase solid solutions that contain five or more cations, usually a mixture of transition metals and rare-earth elements. Due to the cocktail effect, the final material has a different behavior from its constituents, making it a viable method to improve the properties of traditional materials. Generally, high entropy materials are characterized by three additional phenomena: sluggish diffusion, severe lattice distortion, and high entropy. A review of possible improvements in the lifetime of TBC topcoats using different HEOs in terms of their composition, properties, and stability is presented here. Different HEOs are then examined, and various thermophysical properties, high-temperature stability, and sintering resistance are discussed. [ABSTRACT FROM AUTHOR]

In recent times, frequent occurrences of natural disasters have been the cause of widespread disruptions to life and property. Albeit attempts to prevent such disasters may be a lost cause, emerging technologies can be resorted to, for minimization of their impact. This study proposes a deep learning-based computer vision and crowdsourcing methodology for the detection and estimation of flood depths, one of the most intense disruptive disasters. State-of-the-art flood detection systems work off of satellite or radar images. This research deals with processing images, captured at random, from flood ravaged zones, by smartphones or digital cameras. The crowdsourced image collection of the flood scenes afford better coverage and diverse perspectives, for assessments of the flood devastation. This paper proffers a fuzzy logic-based algorithm, and image segmentation based on color, to estimate the extent of flooding by analysis of crowdsourced images. Deployment of these methods helps in classification of the flooded areas into high, medium, or low level of flooding, to facilitate cost-effective, time-critical rescue operations. This algorithm yielded an accuracy of 83.1% on our dataset. [ABSTRACT FROM AUTHOR]

ObjectiveTo evaluate the significance of non-deletional α gene variants identified in neonates during newborn screening for sickle cell disorders.Methods1534 newborn babies were screened in the last 2 years for sickle cell disease using a targeted screening approach. Investigations included a complete blood count, high performance liquid chromatography analysis, cellulose acetate electrophoresis (pH 8.9), heat stability test, restriction digestion and Amplified Refractory Mutation System for confirmation of sickle haemoglobin (Hb S), α genotyping by multiplex PCR and DNA sequencing.ResultsThree non-deletional α gene variants, Hb Fontainebleau, Hb O Indonesia and Hb Koya Dora, were identified in heterozygous condition in newborns. This is the first report of Hb Fontainebleau in association with Hb S. The baby had anaemia at birth (Hb 11.4 g/dl) with no cyanosis, icterus or need for transfusion. She had occipital encephalocoele and was operated on day 24 to remove the mass. The baby diagnosed with Hb O Indonesia in combination with Hb S also had a low haemoglobin level of 12.7 g/dl.ConclusionNewborn screening for sickle cell disorders also enabled us to identify three α globin chain variants. Two babies who inherited Hb Fontainebleau and Hb O Indonesia along with Hb S had reduced Hb levels at birth and need to be followed up. [ABSTRACT FROM AUTHOR]

Isolated left ventricular non-compaction is a rare, morphologically distinct primary genetic cardiomyopathy, which was first described in children, but is becoming increasingly recognised in adults. The most common clinical manifestations include heart failure, arrhythmias and embolic events, and in children it may be associated with facial dysmorphisms and Wolff–Parkinson–White syndrome. Misdiagnosis may occur through lack of awareness of the condition, but with increased vigilance detailed cardiac imaging can reliably differentiate isolated left ventricular non-compaction from other pathological causes of left ventricular dysfunction. This is important because the condition may be associated with significant morbidity and mortality, and genetic counselling and echocardiographic screening of first-degree relatives is recommended to detect asymptomatic cases. [ABSTRACT FROM AUTHOR]