Development of Magnesium Aluminate (MgAl2O4) Nanoparticles for refractory crucible application.

Ceramics are the oxides of metals and nonmetals with excellent compressive strength. Ceramics usually exhibit inert behavior at high temperatures. Magnesium aluminate (MgAl2O4), a member of the ceramic family, possesses a high working temperature up to 2000°C, low thermal conductivity, high strength even at elevated temperatures, and good corrosion resistance. Moreover, Magnesium Aluminate Nanoparticles (MANPs) can be used in the making of refractory crucible applications. This study focuses on the thermal behavior of Magnesium Aluminate Nanoparticles (MANPs) and their application in the making of refractory crucibles. The molten salt method is used to obtain MANPs. The presence of MANPs is seen by XRD peaks ranging from 66° to 67°. The determination of the smallest crystallite size of the sample is achieved by utilizing the Scherrer formula and is found to be 15.3 nm. The SEM micrographs provided further information, indicating an average particle size of 91.2 nm. At 600°C, DSC curves show that only 0.05 W/g heat flows into the material, and the TGA curve shows only 3% weight loss, which is prominent for thermal insulation applications. To investigate the thermal properties, crucibles of pure MANPs and the different compositions of MANPs and pure alumina are prepared. During the sintering, cracks appear on the crucible of pure magnesium aluminate. To explore the reason for crack development, tablets of MgAl2O4 are made and sintered at 1150°C. Ceramography shows the crack-free surfaces of all the tablets. Results confirm the thermal stability of MANPs at high temperatures and their suitability for melting crucible applications.

Rethinking HDL-C: An In-Depth Narrative Review of Its Role in Cardiovascular Health.

The interplay between HDL-C and LDL levels are closely intertwined with the cardiovascular system. High-Density Lipoprotein Cholesterol (HDL-C) is a well-known biomarker traditionally being interpreted as higher the HDL-C levels, minimal the risk of adverse cardiovascular disease (CVD) outcomes. However, recent research has unveiled a more complex relationship between HDL-C levels and cardiovascular outcomes, including genetic influences and potential risks associated with extremely high HDL-C levels. Intriguingly, extremely high HDL-C levels have been linked to unexpected cardiovascular risks. Up To date research suggests that individuals with genetically linked ultra-high HDL-C levels may depict an increased susceptibility to CVD, challenging the conventional realm that higher HDL-C is always beneficial. The mechanisms underlying this mystery are not fully understood but may involve HDL particle functionality and composition. In a nutshell, the relationship between HDL-C levels and cardiovascular outcomes is multifactorial. While low HDL-C remains a recognized risk factor for CVD, the genetic determinants of HDL-C levels add complexity to this association. Furthermore, extremely high HDL-C levels may not exhibit the expected protective benefits and may even pose unprecedented cardiovascular risks. A comprehensive understanding of these dynamics is essential for advancing our knowledge of CVD risk assessment and developing targeted therapeutic interventions. Further studies are needed to unravel the intricacies of HDL-C's role in cardiovascular health and disease.

Strengths and Limitations of Web-Based Cessation Support for Individuals Who Smoke, Dual Use, or Vape: Qualitative Interview Study.

BACKGROUND: Tobacco use has shifted in recent years, especially with the introduction of e-cigarettes. Despite the current variable and intersecting tobacco product use among tobacco users, most want to quit, which necessitates cessation programs to adapt to these variable trends (vs focusing on combustible cigarettes alone). The use of web-based modalities for cessation support has become quite popular in recent years and has been compounded by the COVID-19 pandemic. Therefore, understanding the current strengths and limitations of existing programs to meet the needs of current various tobacco users is critical for ensuring the saliency of such programs moving forward. OBJECTIVE: The purpose of this study was to understand the strengths and limitations of web-based cessation support offered through QuitNow to better understand the needs of a variety of end users who smoke, dual use, or vape. METHODS: Semistructured interviews were conducted with 36 nicotine product users in British Columbia. Using conventional content analysis methods, we inductively derived descriptive categories and themes related to the strengths and limitations of QuitNow for those who smoke, dual use, or vape. We analyzed the data with the support of NVivo (version 12; QSR International) and Excel (Microsoft Corporation). RESULTS: Participants described several strengths and limitations of QuitNow and provided suggestions for improvement, which fell under 2 broad categories: look and feel and content and features. Shared strengths included the breadth of information and the credible nature of the website. Individuals who smoke were particularly keen about the site having a nonjudgmental feeling. Moreover, compared with individuals who smoke, individuals who dual use and individuals who vape were particularly keen about access to professional quit support (eg, quit coach). Shared limitations included the presence of too much text and the need to create an account. Individuals who dual use and individuals who vape thought that the content was geared toward older adults and indicated that there was a lack of information about vaping and personalized content. Regarding suggestions for improvement, participants stated that the site needed more interaction, intuitive organization, improved interface esthetics, a complementary smartphone app, forum discussion tags, more information for different tobacco user profiles, and user testimonials. Individuals who vape were particularly interested in website user reviews. In addition, individuals who vape were more interested in an intrinsic approach to quitting (eg, mindfulness) compared with extrinsic approaches (eg, material incentives), the latter of which was endorsed by more individuals who dual use and individuals who smoke. CONCLUSIONS: The findings of this study provide directions for enhancing the saliency of web-based cessation programs for a variety of tobacco use behaviors that hallmark current tobacco use.

Current challenges and potential solutions to the use of digital health technologies in evidence generation: a narrative review.

Digital health is a field that aims to improve patient care through the use of technology, such as telemedicine, mobile health, electronic health records, and artificial intelligence. The aim of this review is to examine the challenges and potential solutions for the implementation and evaluation of digital health technologies. Digital tools are used across the world in different settings. In Australia, the Digital Health Translation and Implementation Program (DHTI) emphasizes the importance of involving stakeholders and addressing infrastructure and training issues for healthcare workers. The WHO's Global Task Force on Digital Health for TB aims to address tuberculosis through digital health innovations. Digital tools are also used in mental health care, but their effectiveness must be evaluated during development. Oncology supportive care uses digital tools for cancer patient intervention and surveillance, but evaluating their effectiveness can be challenging. In the COVID and post-COVID era, digital health solutions must be evaluated based on their technological maturity and size of deployment, as well as the quality of data they provide. To safely and effectively use digital healthcare technology, it is essential to prioritize evaluation using complex systems and evidence-based medical frameworks. To address the challenges of digital health implementation, it is important to prioritize ethical research addressing issues of user consent and addressing socioeconomic disparities in access and effectiveness. It is also important to consider the impact of digital health on health outcomes and the cost-effectiveness of service delivery.

Deciphering the binding mechanism of an anti-cancer phytochemical plumbagin with calf thymus DNA using biophysical and in silico techniques.

Plumbagin (PLM), a plant derivative, is well known for a wide range of therapeutic effects in humans including anti-cancer, anti-inflammatory, anti-oxidant, and anti-microbial. Cytotoxic and genotoxic potential of this phytochemical has been studied which demands further insight. DNA being a major target for several drugs was taken to study against PLM to understand its effects on the cellular system. UV-Vis spectroscopy has indicated the binding of PLM to ctDNA and dye displacement assays have confirmed the formation of PLM-ctDNA complex. The insignificant changes in circular dichroism spectra suggested that PLM is not affecting the structural makeup of the ctDNA, hence the binding could be peripheral and not intercalating. Further, the relative viscosity and minimal change in melting temperature upon the complex formation supported this finding and confirmed the groove binding of PLM. Molecular docking analysis and simulation studies also show PLM as a minor groove binder to DNA and provide details on the interaction dynamics of PLM-DNA complex. Docking followed by a 100 ns simulation reveals the negative Gibbs free energy change (∆G = -6.6 kcal mol-1), and the formation of a stable complex. The PLM- DNA complex with stable dynamics was further supported by different parameters including RMSD, RMSF, SASA, Rg, and the energy profile of interaction. This study provides an insight into the cytotoxic and genotoxic mechanism of PLM which can be a crucial step forward to exploit its therapeutic potential against several diseases including cancer.

Relational practices for meaningful inclusion in health research: Results of a deliberative dialogue study.

INTRODUCTION: The importance of including people affected by research (e.g., community members, citizens or patient partners) is increasingly recognized across the breadth of institutions involved in connecting research with action. Yet, the increasing rhetoric of inclusion remains situated in research systems that tend to reward traditional dissemination and uphold power dynamics in ways that centre particular (privileged) voices over others. In research explicitly interested in doing research with those most affected by the issue or outcomes, research teams need to know how to advance meaningful inclusion. This study focused on listening to voices often excluded from research processes to understand what meaningful inclusion looks and feels like, and asked what contributes to being or feeling tokenized. METHODS: In this deliberative dialogue study, 16 participants with experience of navigating social exclusions and contributing to research activities reflected on what makes for meaningful experiences of inclusion. Using a co-production approach, with a diversely representative research team of 15 that included patient and community partners, we used critically reflective dialogue to guide an inclusive process to study design and implementation, from conceptualization of research questions through to writing. RESULTS: We heard that: research practices, partnerships and systems all contribute to experiences of inclusion or exclusion; the insufficiency or absence of standards for accountability amplifies the experience of exclusion; and inclusive practices require intention, planning, reflection and resources. CONCLUSIONS: We offer evidence-informed recommendations for the deeply relational work and practices for inclusivity, focused on promising practices for cultivating welcoming systems, spaces and relationships. PATIENT OR PUBLIC CONTRIBUTION: This work reflects a co-production approach, where people who use and are affected by research results actively partnered in the research process, including study design, data-generating activities, analysis and interpretation, and writing. Several of these partners are authors of this manuscript.

Factors that influence decision-making among youth who vape and youth who don't vape.

Vaping rates among Canadian youth are significantly higher compared to adults. While it is acknowledged that various personal and socio-environmental factors influence the risk of school-aged youth for vaping uptake, we don't know which known behavior change factors are most influential, for whom, and how. The Unified Theory of Behavior (UTB) brings together theoretically-based behavior change factors that influence health risk decision making. We aimed to use this framework to study the factors that influence decision making around vaping among school-aged youth. Qualitative interviews were conducted with 25 youth aged 12 to 18 who were either vaped or didn't vape. We employed a collaborative and directed content analysis approach and the UTB constructs served as the coding framework for analysis. Gender differences were explored in the analysis. We found that multiple intersecting factors play a significant role in youth decision making to vape. Youth who vaped and those who did not vape reported similar mediating determinants that either reinforced or challenged their decision-making, such as easy access to vaping, constant exposure to vaping, and the temptation of flavors. Youth who didn't vape reported individual determinants that strengthened their intentions to not vape, including more negative behavioral beliefs (e.g., vaping is harmful) and normative beliefs (e.g., family disapproves), and strong self-efficacy (e.g. self-confidence). Youth who did vape, however, reported individual determinants that supported their intentions to vape, such as social identity, coolness, and peer endorsement. The findings revealed cohesion across multiple determinants, suggesting that consideration of multiple determinents when developing prevention messages would be beneficial for reaching youth.

A multitier virtual screening study of phytoconstituents as Myeloid Cell Leukemias 1 inhibitors.

Myeloid Cell Leukemia 1 (MCL1) is an anti-apoptotic protein that plays a critical role in regulating cell survival, particularly in cancer cells. It is a member of the BCL-2 family of proteins, which control the intrinsic pathway of apoptosis. MCL1 has emerged as a promising target for cancer therapy because it is overexpressed in a wide range of cancers, including breast, lung, prostate, and hematologic malignancies. Due to its remarkable role in cancer progression, it has been reflected as a promising drug target for cancer therapy. A few MCL1 inhibitors have been identified previously, but further research is needed to develop novel, effective and safe MCL1 inhibitors that can overcome resistance mechanisms and minimize toxicity in normal cells. In this study, we aim to search for compounds that target the critical binding site of MCL1 from phytoconstituent library from the IMPPAT database. To accomplish this, a multitier virtual screening approach involving molecular docking and molecular dynamics simulations (MDS) were used to evaluate their suitability for the receptor. Notably, certain screened phytoconstituents have appreciable docking scores and stable interactions toward the binding pocket of MCL1. The screened compounds underwent ADMET and bioactivity analysis to establish their anticancer properties. One phytoconstituent, Isopongaflavone, was identified that exhibiting higher docking and drug-likeness than the already reported MCL1 inhibitor, Tapotoclax. Isopongaflavone and and Tapotoclax, along with MCL1, were subjected to 100 nanoseconds (ns) MDS study to verify their stability inside the binding site of MCL1. The MDS findings demonstrated a strong binding affinity between Isopongaflavone and the MCL1 binding pocket, resulting in reduced conformational fluctuations. This investigation proposes Isopongaflavone as a promising candidate for the development of innovative anticancer therapeutics, pending the necessary validation procedures. Also, the findings provide valuable information for designing MCL1 inhibitors based on the protein's structure.Communicated by Ramaswamy H. Sarma.

Minimally Invasive Treatment Options for Hepatic Uveal Melanoma Metastases.

Uveal melanoma is one of the most common primary intraocular malignancies that accounts for about 85% of all ocular melanomas. The pathophysiology of uveal melanoma is distinct from cutaneous melanoma and has separate tumor profiles. The management of uveal melanoma is largely dependent on the presence of metastases, which confers a poor prognosis with a one-year survival reaching only 15%. Although a better understanding of tumor biology has led to the development of novel pharmacologic agents, there is increasing demand for minimally invasive management of hepatic uveal melanoma metastases. Multiple studies have already summarized the systemic therapeutic options available for metastatic uveal melanoma. This review covers the current research for the most prevalent locoregional treatment options for metastatic uveal melanoma including percutaneous hepatic perfusion, immunoembolization, chemoembolization, thermal ablation, and radioembolization.

Mission to Psyche: Including Undergraduates and the Public on the Journey to a Metal World.

The NASA Psyche mission's program to engage university undergraduates and the public in the mission is inspired by and built upon the extensive foundation of public engagement, educational outreach activities, and expertise of NASA and mission partner institutions. The program leverages the enthusiasm and contributions of undergraduates nationwide to the benefit of the mission, the students and their institutions and communities, and the broader public. Psyche Student Collaborations consists of four main programs, two (Psyche Capstone and Psyche Inspired) are available solely to undergraduates enrolled at universities or community colleges in the United States and its territories and two (Innovation Toolkit free online courses and Science Outreach Interns and Docents) invite broader participation by engaging the talents and creativity of undergraduate interns to help create content and events to reach the public and lifelong learners. Together, these offerings provide multiple entry points and a spectrum of intensity of experiences, numbers of participants, disciplinary diversity, and mode of delivery. Involving undergraduates in all phases of the program supports the development of the next generation of explorers, contributes to the nation's workforce preparation, and complements NASA's existing undergraduate offerings by providing long-term opportunities for students to participate with the mission through established postsecondary education structures like capstone courses.

Coating of chitosan on poly D,L-lactic-co-glycolic acid thymoquinone nanoparticles enhances the anti-tumor activity in triple-negative breast cancer.

Breast cancer is the second most common cancer around the world. Triple-negative breast cancer (TNBC) is characterized by the absence of three receptors: progesterone, estrogen, and human epidermal growth factor-2 receptor (HER2). Various synthetic chemotherapies have gained attention but they caused unwanted side effects. Therefore, some secondary therapies are now becoming famous against this disease. For instance, natural compounds have been extensively researched against many diseases. However, enzymatic degradation and low solubility remain a major concern. To combat these issues, various nanoparticles have been synthesized and optimized from time to time, which increases its solubility and hence therapeutic potential of a particular drug increases. In this study, we have synthesized Poly D,L-lactic-co-glycolic acid (PLGA) loaded thymoquinone (TQ) nanoparticle (PLGA-TQ-NPs) and then coated them by chitosan (CS) (PLGA-CS-TQ-NPs), which was characterized by different methods. Size of non-coated NPs was 105 nm with PDI value of 0.3 and the size of coated NPs was 125 nm with PDI value of 0.4. Encapsulation efficiency (EE%) and Drug loading (DL%) was found to be 70.5 ± 2.33 and 3.38 for non-coated and 82.3 ± 3.11 and 2.66 for coated NPs respectively. We have also analysed their cell viability against MDA-MB-231 and SUM-149 TNBC cell lines. The resultant, nanoformulations exhibit anti-cancerous activity in a dose and time-dependent manner for MDA-MB-231 and SUM-149 cell lines with an IC50 value of (10.31 ± 1.15, 15.60 ± 1.25, 28.01 ± 1.24) and (23.54 ± 1.24, 22.37 ± 1.25, 35 ± 1.27) for TQ free, PLGA-TQ-NPs and PLGA-CS-TQ-NPs respectively. For the first time, we have developed a nanoformulations of PLGA loaded TQ coated with CS NPs (PLGA-CS-TQ-NPs) against TNBC which led to their enhanced anti-cancerous effects.

Multimodal single-cell and whole-genome sequencing of small, frozen clinical specimens.

Single-cell genomics enables dissection of tumor heterogeneity and molecular underpinnings of drug response at an unprecedented resolution1-11. However, broad clinical application of these methods remains challenging, due to several practical and preanalytical challenges that are incompatible with typical clinical care workflows, namely the need for relatively large, fresh tissue inputs. In the present study, we show that multimodal, single-nucleus (sn)RNA/T cell receptor (TCR) sequencing, spatial transcriptomics and whole-genome sequencing (WGS) are feasible from small, frozen tissues that approximate routinely collected clinical specimens (for example, core needle biopsies). Compared with data from sample-matched fresh tissue, we find a similar quality in the biological outputs of snRNA/TCR-seq data, while reducing artifactual signals and compositional biases introduced by fresh tissue processing. Profiling sequentially collected melanoma samples from a patient treated in the KEYNOTE-001 trial12, we resolved cellular, genomic, spatial and clonotype dynamics that represent molecular patterns of heterogeneous intralesional evolution during anti-programmed cell death protein 1 therapy. To demonstrate applicability to banked biospecimens of rare diseases13, we generated a single-cell atlas of uveal melanoma liver metastasis with matched WGS data. These results show that single-cell genomics from archival, clinical specimens is feasible and provides a framework for translating these methods more broadly to the clinical arena.

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration: ClinicalTrials.gov Identifier: NCT04354701.

Association of Liver Function Test with Severity of Dengue Fever in Suburbs of Islamabad.

Aim: This study aimed to identify the key parameters to assist the early diagnosis of Dengue Infection to prevent severe outcomes. Methodology: A cross-sectional study was conducted from June 2022 to December 2022 at a tertiary care hospital. 149 patients who presented with dengue symptoms for less than 5 days were enrolled in the study. Hepatic functioning was assessed by monitoring Serum Alanine Transaminase (ALT) (normal = 7-56 IU/L), and serum Aspartate Transaminase (AST) (normal = 10-40 IU/L) levels. Abdominal ultrasound and chest X-Ray were performed, and findings were recorded. Statistical analysis was done using SPSS Version 24. Results: 81 patients (54.36%) were found to have Classical DF, while 46 patients (45.64%) were diagnosed with DHF or DSS. Dengue fever is more common in males than in females, and it disproportionately affects those under the age of 30. Only 81 (54.63%) of the total 149 individuals developed DF, but of those, 79 (74.4%) had normal ALT levels and 2 (4.26%) had elevated ALT levels. Among the 68 patients with DHF (45.64%), 41 (87.23%) had elevated ALT, while only 23 (22.55%) had normal ALT and all 4 (8.51%) with DSS did as well. The p-value for the correlation between platelet count and elevated ALT levels is 0.007, which is statistically significant. Conclusion: Management of dengue disease requires close monitoring of hepatic enzyme levels, particularly ALT and AST, along with the platelet count. It will aid in reducing the severity of the dengue virus. In addition, there should be particular outdoor exposure guidelines, particularly during dengue season evenings, i.e., monsoon.

Intermittent MEK inhibition for the treatment of metastatic uveal melanoma.

Introduction: Uveal melanoma (UM) is associated with poor outcomes in the metastatic setting and harbors activating mutations resulting in upregulation of MAPK signaling in almost all cases. The efficacy of selumetinib, an oral allosteric inhibitor of MEK1/2, was limited when administered at a continual dosing schedule of 75 mg BID. Preclinical studies demonstrate that intermittent MEK inhibition reduces compensatory pathway activation and promotes T cell activation. We hypothesized that intermittent dosing of selumetinib would reduce toxicity, allow for the administration of increased doses, and achieve more complete pathway inhibition, thus resulting in improved antitumor activity. Methods: We conducted a phase Ib trial of selumetinib using an intermittent dosing schedule in patients with metastatic UM. The primary objective was to estimate the maximum tolerated dose (MTD) and assess safety and tolerability. Secondary objectives included assessment of the overall response rate (RR), progression-free survival (PFS) and overall survival (OS). Tumor biopsies were collected at baseline, on day 3 (on treatment), and between days 11-14 (off treatment) from 9 patients for pharmacodynamic (PD) assessments. Results: 29 patients were enrolled and received at least one dose of selumetinib across 4 dose levels (DL; DL1: 100 mg BID; DL2: 125 mg BID; DL3: 150 mg BID; DL4: 175 mg BID). All patients experienced a treatment-related adverse event (TRAE), with 5/29 (17%) developing a grade 3 or higher TRAE. Five dose limiting toxicities (DLT) were observed: 2/20 in DL2, 2/5 in DL3, 1/1 in DL4. The estimated MTD was 150 mg BID (DL3), with an estimated probability of toxicity of 29% (90% probability interval 16%-44%). No responses were observed; 11/29 patients achieved a best response of stable disease (SD). The median PFS and OS were 1.8 months (95% CI 1.7, 4.5) and 7.1 months (95% CI 5.3, 11.5). PD analysis demonstrated at least partial pathway inhibition in all samples at day 3, with reactivation between days 11-14 in 7 of those cases. Conclusions: We identified 150 mg BID as the MTD of intermittent selumetinib, representing a 100% increase over the continuous dose MTD (75 mg BID). However, no significant clinical efficacy was observed using this dosing schedule.

Characterizing metastatic uveal melanoma patients who develop symptomatic brain metastases.

Metastatic uveal melanoma (mUM) is an advanced ocular malignancy characterized by a hepatotropic pattern of spread. As the incidence of brain metastases (BM) in mUM patients has been thought to be low, routine CNS surveillance has not been recommended. Notably, no formal assessment of BM incidence in mUM has to date been published to support this clinical practice. We aimed to determine the true rate of BM in mUM and to clarify the clinical and genomic risk factors associated with BM patients through a collaborative multicenter, retrospective research effort. Data collected from 1,845 mUM patients in databases across four NCI-designated comprehensive cancer centers from 2006-2021 were retrospectively analyzed to identify patients with BM. Brain imaging in most cases were performed due to onset of neurological symptoms and not for routine surveillance. An analysis of demographics, therapies, gene expression profile, tumor next generation sequencing (NGS) data, time to metastasis (brain or other), and survival in the BM cohort was completed. 116/1,845 (6.3%) mUM patients were identified with BM. The median age at time of UM diagnosis was 54 years old (range: 18-77). The median time to any metastasis was 4.2 years (range: 0-30.8). The most common initial metastatic site was the liver (75.9%). 15/116 (12.9%) BM patients presented with BM at the time of initial metastatic diagnosis. Median survival after a diagnosis of BM was 7.6 months (range: 0.4-73.9). The median number of organs involved at time of BM diagnosis was 3 (range: 1-9). DecisionDX-UM profiling was completed on 13 patients: 10-Class 2, 2-Class 1B, and 1-Class 1A. NGS and cytogenetic data were available for 34 and 21 patients, respectively. BM was identified in 6.3% of mUM cases and was associated with high disease burden and a median survival of under 8 months once diagnosed. Since most patients in this cohort were symptomatic, the incidence of asymptomatic BM remains unknown. These data suggest the use of routine brain imaging in all mUM patients at risk for developing BM for early detection.

Education During Ward Rounds: Systematic Review.

BACKGROUND: Enhancing the educational experience provided by ward rounds requires an understanding of current perceptions of the educational value of rounds. OBJECTIVE: This systematic review examines perceptions of education in ward rounds, educational activities in ward rounds, barriers to learning, and perceptions of simulation-based ward rounds. METHODS: The 2020 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. MEDLINE (EBSCO), Cochrane, and Scopus were searched on May 29, 2022, for studies assessing learning during ward rounds. The search terms included "ward rounds," "education," and "trainees." Then, the selected articles were reference searched. In total, 354 articles were retrieved. The articles were assessed for eligibility by 2 independent reviewers who screened titles, abstracts, and full-length texts. Articles addressing trainees' education in all ward rounds were included. Articles were excluded if they were specific to certain disciplines, were reviews, were not published in scholarly journals, were published before 2015, were published in languages other than English, or did not concern human participants. Following the removal of 63 duplicates, a total of 268 articles were excluded. The risk of bias within the selected articles was also assessed via the Critical Appraisal Skills Programme checklist for qualitative research. Qualitative data were used to describe results in a narrative synthesis and in tables. RESULTS: A total of 23 articles were included. Perceptions of teaching in rounds were addressed by 6 studies, of which 3 showed negative perceptions among participants, 2 reported ambivalent perceptions, and 1 showed positive perceptions. Perceived barriers to teaching during rounds were assessed by 7 studies. The reported barriers included time constraints, workloads, schedules, interruptions, the service-oriented nature of rounds, the lack of feedback, hierarchies, the lack of opportunities to ask questions and be engaged in patient management, and divergent learner needs. Further, 8 studies identified types of educational activities, including observation, patient-specific teaching, and discussion. Perceptions of learning through simulated ward rounds were assessed by 8 studies, and a consensus of satisfaction was noted among learners. The interventions that were explored to improve education included using teaching frameworks, involving clinical librarians, and changing the setting of ward rounds. CONCLUSIONS: The main limitations of this review are the predominant use of qualitative data in the included articles and the lack of standardization for the educational compositions of ward rounds among articles, which made the articles hard to compare. In conclusion, learning opportunities in ward rounds are often missed, and trainees perceive rounds to have low educational value. It is important to recognize the barriers to education during ward rounds and address them to maximize the benefits of ward rounds. Finally, there is a need to develop plans that incorporate teaching regularly during ward rounds in the inpatient setting. TRIAL REGISTRATION: PROSPERO CRD42022337736; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=337736.

Adjuvant crizotinib in high-risk uveal melanoma following definitive therapy.

Introduction: Approximately 40% of patients with uveal melanoma (UM) will develop metastatic disease. Tumors measuring at least 12mm in basal diameter with a class 2 signature, as defined by a widely used gene expression-profiling test, are associated with significantly higher risk of metastasis, with a median time to recurrence of 32 months. No therapy has been shown to reduce this risk. Materials and Methods: This was a single-arm, multicenter study in patients with high-risk UM who received definitive treatment of primary disease and had no evidence of metastasis. Patients were consecutively enrolled to receive 12 four-week cycles of adjuvant crizotinib at a starting dose of 250mg twice daily and were subsequently monitored for 36 months. The primary outcome of this study was to assess recurrence-free survival (RFS) of patients with high-risk UM who received adjuvant crizotinib. Results: 34 patients enrolled and received at least one dose of crizotinib. Two patients were unevaluable due to early withdrawal and loss to follow-up, leaving 32 patients evaluable for efficacy. Eight patients (25%) did not complete the planned 48-week course of treatment due to disease recurrence (n=5) or toxicity (n=3). All patients experienced at least one adverse event (AE), with 11/34 (32%) experiencing a Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or 4 AE. After a median duration of follow up of 47.1 months, 21 patients developed distant recurrent disease. The median RFS was 34.9 months (95% CI (Confidence Interval), 23-55 months), with a 32-month recurrence rate of 50% (95% CI, 33-67%). Analysis of protein contents from peripheral blood extracellular vesicles in a subset of patient samples from baseline, on-treatment, and off-treatment, revealed a change in protein content associated with crizotinib exposure, however without a clear association with disease outcome. Conclusions: The use of adjuvant crizotinib in patients with high-risk UM did not result in improved RFS when compared to historical controls. Analysis of blood extracellular vesicles revealed changes in protein content associated with treatment, raising the possibility of future use as a biomarker. Further investigation of adjuvant treatment options are necessary for this challenging disease.

On the move: spatial ecology and habitat use of red fox in the Trans-Himalayan cold desert.

Red fox (Vulpes vulpes) is the most widespread wild carnivore globally, occupying diverse habitats. The species is known for its adaptability to survive in dynamic anthropogenic landscapes. Despite being one of the most extensively studied carnivores, there is a dearth of information on red fox from the Trans-Himalayan region. We studied the home range sizes of red fox using the different estimation methods: minimum convex polygon (MCP), kernel density estimator (KDE), local convex hull (LoCoH) and Brownian-bridge movement model (BBMM). We analysed the daily movement and assessed the habitat selection with respect to topographic factors (ruggedness, elevation and slope), environmental factor (distance to water) and anthropogenic factors (distance to road and human settlements). We captured and GPS-collared six red fox individuals (three males and three females) from Chiktan and one female from Hemis National Park, Ladakh, India. The collars were programmed to record GPS fixes every 15-min. The average BBMM home range estimate (95% contour) was 22.40 ± 12.12 SD km2 (range 3.81-32.93 km2) and the average core area (50% contour) was 1.87 ± 0.86 SD km2 (range 0.55-2.69 km2). The estimated average daily movement of red fox was 17.76 ± 8.45 SD km/d (range 10.91-34.22 km/d). Red fox significantly selected lower elevations with less rugged terrain and were positively associated with water. This is the first study in the Trans-Himalayan landscape which aims to understand the daily movement of red fox at a fine temporal scale. Studying the movement and home range sizes helps understand the daily energetics and nutritional requirements of red fox. Movement information of a species is important for the prioritisation of areas for conservation and can aid in understanding ecosystem functioning and landscape management.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.