Novel Androgen Receptor Splice Variant 7 in Gynecologic Tumors.

Androgen receptor splicing variant 7 (AR-V7) is a truncated variant of the AR mRNA that may be a predictive biomarker for AR-targeted therapy. AR-V7 has been described in prostate, breast, salivary duct, and hepatocellular carcinomas as well as mammary and extra-mammary Paget disease. We report 2 gynecologic cancers occurring in the lower uterine segment and ovary and both harboring AR-V7 by targeted RNA sequencing. The uterine tumor was an undifferentiated carcinoma consisting of epithelioid cells and focally spindled cells arranged in sheets, nests, and cords associated with brisk mitotic activity and tumor necrosis. The ovarian tumor consisted of glands with cribriform and solid architecture and uniform cytologic atypia. ER and PR were positive in the ovarian tumor and negative in the uterine tumor. Both were positive for AR and negative for HER2, GATA3, and NKX3.1. DNA methylation profiling showed epigenetic similarity of the AR-V7-positive gynecologic cancers to AR-V7-positive breast cancers rather than to prostate cancers. AR-V7 may underpin rare gynecologic carcinomas with undifferentiated histology or cribriform growth reminiscent of prostatic adenocarcinoma and breast invasive ductal carcinoma.

Comparing survival in trial- versus routine-care advanced urothelial cancer patients on immune checkpoint blockade.

PURPOSE: Although recent trials involving first-line immune checkpoint inhibitors have expanded treatment options for patients with advanced urothelial carcinoma (aUC) who are ineligible for standard cisplatin-based chemotherapy, there exists limited evidence for whether trial efficacy translates into real-world effectiveness for patients seen in routine care. This retrospective cohort study compares differences in overall survival (OS) between KEYNOTE-052 trial participants and routine-care patients receiving first-line pembrolizumab monotherapy. METHODS: A routine-care patient cohort was constructed from the Flatiron Health database using trial eligibility criteria and was weighted to balance EHR and trial patient characteristics using matching-adjusted indirect comparisons. RESULTS: The routine-care cohort was older, more likely to be female, and more often cisplatin-ineligible due to renal dysfunction. ECOG performance status was comparable between the cohorts. Median OS was 9 months (95% CI 7-16) in the weighted routine-care cohort and 11.3 months (9.7-13.1) in the trial cohort. No significant differences between the Kaplan-Meier OS curves were detected (p = 0.76). Survival probabilities were similar between the weighted routine-care and trial cohorts at 12-, 24-, and 36- months (0.45 vs. 0.47, 0.31 vs. 0.31, 0.26 vs. 0.23, respectively). Notably, routine care patients had modestly lower survival at 3 months compared to trial participants (0.69 vs. 0.83, respectively). CONCLUSION: Our results provide reassurance that cisplatin-ineligible aUC patients receiving first-line immunotherapy in routine care experience similar benefits to those observed in trial patients.

Guiding Principles for Patient and Public Engagement in the Educational Missions of Medical Schools.

PURPOSE: The purpose of this research was to cocreate with patients and the public a set of evidence-informed guiding principles for their authentic, responsive, ongoing, and sustainable engagement in the mission, goals, curriculum, and delivery of medical education. METHOD: A set of guiding principles of relevance to medical education was identified from the literature. Eight focus groups with patients and community members representing a wide variety of perspectives were conducted in April and May 2022. Participants reviewed, prioritized, and discussed the principles and described successful engagement, resulting in 8 guiding principles in priority order. A summary report was circulated to participants for feedback. The principles were reviewed and endorsed by senior leaders in the medical school. RESULTS: The 8 focus groups were attended by 38 people (age range, mid-20s to postretirement; 7 male, 27 female, and 4 unknown gender). Accountability (19%), inclusion (18%), reciprocity (17%), and partnership and shared decision-making (14%) were chosen as the most important principles. They want evidence that their contributions are valued and have made a difference. They want the medical school to include and support a diversity of perspectives that reflect the populations being served by the health care system. They want the medical school to invest in building trusting and respectful long-term relationships with patients and the public. CONCLUSIONS: The guiding principles could be used by medical schools as a starting point to build relationships with their local communities to increase the authentic and sustainable engagement of patients and the public in the educational mission of the medical school.

Programming sp3 Quantum Defects along Carbon Nanotubes with Halogenated DNA.

Atomic defect color centers in solid-state systems hold immense potential to advance various quantum technologies. However, the fabrication of high-quality, densely packed defects presents a significant challenge. Herein we introduce a DNA-programmable photochemical approach for creating organic color-center quantum defects on semiconducting single-walled carbon nanotubes (SWCNTs). Key to this precision defect chemistry is the strategic substitution of thymine with halogenated uracil in DNA strands that are orderly wrapped around the nanotube. Photochemical activation of the reactive uracil initiates the formation of sp3 defects along the nanotube as deep exciton traps, with a pronounced photoluminescence shift from the nanotube band gap emission (by 191 meV for (6,5)-SWCNTs). Furthermore, by altering the DNA spacers, we achieve systematic control over the defect placements along the nanotube. This method, bridging advanced molecular chemistry with quantum materials science, marks a crucial step in crafting quantum defects for critical applications in quantum information science, imaging, and sensing.

Characteristics and clinical outcomes of patients with kidney failure of unknown aetiology from ANZDATA registry.

INTRODUCTION: Kidney failure of unknown aetiology (uESKD) is also heavily location dependent varying between 27% in Egypt to 54% in Aguacalientes, Mexico. There is limited information about the characteristics of people with uESKD in Australia and New Zealand, as well as their clinical outcomes on kidney replacement therapy. METHODS: Data on people commencing kidney replacement therapy 1989-2021 were received from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. Primary exposure was cause of kidney failure-uESKD or non-uESKD (known-ESKD). Primary outcome was mortality. Secondary outcome was kidney transplantation. Dialysis and transplant cohorts were analysed separately. Cox Proportional Hazards Regression models were used to evaluate correlations between cause of kidney failure and mortality risk. Subgroup analyses were completed to compare mortality risk in people with uESKD to those with diabetic nephropathy, autosomal dominant polycystic kidney disease (ADPKD), glomerular disease and other kidney diseases. RESULTS: This study included 60,448 people on dialysis and 20,859 transplant recipients. 1-year, 3-year and 5-year mortality rates in people with uESKD on dialysis were 31.6%, 58.7% and 77.2%, respectively. 1-year, 3-year and 5-year mortality rates in transplant recipients with uESKD were 2.8%, 13.8% and 24.0%, respectively. People with uESKD on dialysis had a higher mortality risk compared to those without uESKD on univariable and multivariable analyses (adjusted hazard ratio [AHR] 1.10, 95% CI 1.06-1.16, p<0.001). Transplant recipients with uESKD have a higher mortality risk compared to those without uESKD on univariable and multivariable analyses (AHR 1.17, 95% CI 1.01-1.35, p<0.05). People with uESKD had similar likelihood of kidney transplantation compared to people with known-ESKD. CONCLUSION: People with uESKD on kidney replacement therapy have higher mortality risk compared to people with other kidney diseases. Further studies are required to identify contributing factors to these findings.

Patient/public perceptions on engagement with a medical school: What needs to happen to support authentic and sustained participation.

PURPOSE: Patient/public involvement in health professional education is increasing but remains episodic, narrowly focused, reliant on individual enthusiasts, and lacks supportive institutional infrastructure. There is little evidence-informed practical guidance on how to take a more strategic and formal approach. We undertook a qualitative study to learn from patients and the public how medical schools could engage in an authentic and sustainable way. METHODS: In 2022 we conducted eight focus groups with patients and members of community organizations. Participants were asked about experiences and perceptions of what needs to happen to enable and support them to participate in medical education, barriers to authentic engagement, and how they might be overcome. Recordings were transcribed and data coded inductively. A summary report was circulated to participants for validation of findings. RESULTS: The focus groups were attended by 38 participants representing a wide variety of perspectives. Participants provided practical suggestions that we categorized into six major themes: inviting participation; preparing for participation; supporting participation; increasing and supporting diversity; recognizing participation; institutional buy-in and support. CONCLUSIONS: Individual instructors can enhance authentic patient engagement through recruitment, support and recognition practices. Institutional commitment is required to sustain and widen participation through funding, policies and infrastructure.

A Scoping Review of Nutritional Biomarkers Associated with Food Security.

Food insecurity affects more than 40 million individuals in the United States and is linked to negative health outcomes due, in part, to poor dietary quality. Despite the emergence of metabolomics as a modality to objectively characterize nutritional biomarkers, it is unclear whether food security is associated with any biomarkers of dietary quality. This scoping review aims to summarize studies that examined associations between nutritional biomarkers and food security, as well as studies that investigated metabolomic differences between people with and without food insecurity. PubMed, Embase, Scopus, and AGRICOLA were searched through August 2022 for studies describing food insecurity and metabolic markers in blood, urine, plasma, hair, or nails. The 78 studies included consisted of targeted assays quantifying lipids, dietary nutrients, heavy metals, and environmental xenobiotics as biochemical features associated with food insecurity. Among those biomarkers which were quantified in at least five studies, none showed a consistent association with food insecurity. Although three biomarkers of dietary quality have been assessed between food-insecure versus food-secure populations, no studies have utilized untargeted metabolomics to characterize patterns of small molecules that distinguish between these two populations. Further studies are needed to characterize the dietary quality profiles of individuals with and without food insecurity.

Network Analysis for Formative Evaluation of Collaborative, Team Science Research Partnerships.

Cancer health disparities persist across the cancer care continuum despite decades of effort to eliminate them. Among the strategies currently used to address these disparities are multi-institution research initiatives that engage multiple stakeholders and change efforts. Endemic to the theory of change of such programs is the idea that collaboration-across institutions, research disciplines, and academic ranks-is necessary to improve outcomes. Despite this emphasis on collaboration, however, it is not often a focus of evaluation for these programs and others like them. In this paper we describe a method for evaluating collaboration within the Meharry-Vanderbilt-Tennessee State University Cancer Partnership using network analysis. Specifically, we used network analysis of co-authorship on academic publications to visualize the growth and patterns of scientific collaboration across partnership institutions, research disciplines, and academic ranks over time. We presented the results of the network analysis to internal and external advisory groups, creating the opportunity to discuss partnership collaboration, celebrate successes, and identify opportunities for improvement. We propose that basic network analysis of existing data along with network visualizations can foster conversation and feedback and are simple and effective ways to evaluate collaboration initiatives.

Automated model discovery for muscle using constitutive recurrent neural networks.

The stiffness of soft biological tissues not only depends on the applied deformation, but also on the deformation rate. To model this type of behavior, traditional approaches select a specific time-dependent constitutive model and fit its parameters to experimental data. Instead, a new trend now suggests a machine-learning based approach that simultaneously discovers both the best model and best parameters to explain given data. Recent studies have shown that feed-forward constitutive neural networks can robustly discover constitutive models and parameters for hyperelastic materials. However, feed-forward architectures fail to capture the history dependence of viscoelastic soft tissues. Here we combine a feed-forward constitutive neural network for the hyperelastic response and a recurrent neural network for the viscous response inspired by the theory of quasi-linear viscoelasticity. Our novel rheologically-informed network architecture discovers the time-independent initial stress using the feed-forward network and the time-dependent relaxation using the recurrent network. We train and test our combined network using unconfined compression relaxation experiments of passive skeletal muscle and compare our discovered model to a neo Hookean standard linear solid, to an advanced mechanics-based model, and to a vanilla recurrent neural network with no mechanics knowledge. We demonstrate that, for limited experimental data, our new constitutive recurrent neural network discovers models and parameters that satisfy basic physical principles and generalize well to unseen data. We discover a Mooney-Rivlin type two-term initial stored energy function that is linear in the first invariant I1 and quadratic in the second invariant I2 with stiffness parameters of 0.60 kPa and 0.55 kPa. We also discover a Prony-series type relaxation function with time constants of 0.362s, 2.54s, and 52.0s with coefficients of 0.89, 0.05, and 0.03. Our newly discovered model outperforms both the neo Hookean standard linear solid and the vanilla recurrent neural network in terms of prediction accuracy on unseen data. Our results suggest that constitutive recurrent neural networks can autonomously discover both model and parameters that best explain experimental data of soft viscoelastic tissues. Our source code, data, and examples are available at https://github.com/LivingMatterLab.

Folate receptor targeted nanoparticles containing niraparib and doxorubicin as a potential candidate for the treatment of high grade serous ovarian cancer.

Combination chemotherapy is an established approach used to manage toxicities while eliciting an enhanced therapeutic response. Delivery of drug combinations at specific molar ratios has been considered a means to achieve synergistic effects resulting in improvements in efficacy while minimizing dose related adverse drug reactions. The benefits of this approach have been realized with the FDA approval of Vyxeos®, the first liposome formulation to deliver a synergistic drug combination leading to improved overall survival against standard of care. In the current study, we demonstrate the synergistic potential of the PARP inhibitor niraparib and doxorubicin for the treatment of ovarian cancer. Through in vitro screening in a panel of ovarian cancer cell lines, we find that niraparib and doxorubicin demonstrate consistent synergy/additivity at the majority of evaluated molar ratio combinations. Further to these findings, we report formulation of a nanoparticle encapsulating our identified synergistic combination. We describe a rational design process to achieve highly stable liposomes that are targeted with folate to folate-receptor-alpha, which is known to be overexpressed on the surface of ovarian cancer cells. With this approach, we aim to achieve targeted delivery of niraparib and doxorubicin at a pre-determined synergistic molar ratio via increased receptor-mediated endocytosis.

Mechanics of axon growth and damage: A systematic review of computational models.

Normal axon development depends on the action of mechanical forces both generated within the cytoskeleton and outside the cell, but forces of large magnitude or rate cause damage instead. Computational models aid scientists in studying the role of mechanical forces in axon growth and damage. These studies use simulations to evaluate how different sources of force generation within the cytoskeleton interact with each other to regulate axon elongation and retraction. Furthermore, mathematical models can help optimize externally applied tension to promote axon growth without causing damage. Finally, scientists also use simulations of axon damage to investigate how forces are distributed among different components of the axon and how the tissue surrounding an axon influences its susceptibility to injury. In this review, we discuss how computational studies complement experimental studies in the areas of axon growth, regeneration, and damage.

Youth and family engagement in childhood disability evidence syntheses: A scoping review.

Within the last decade, stakeholder engagement in research has become increasingly popular in childhood disability research; however, literature on the engagement of youth with neurodisabilities and their families in evidence syntheses is underdeveloped. Involving patients as partners in research has the potential to improve applicability and relevance of the research and benefit patient partners (e.g. enhanced self-esteem, increased research knowledge and skills); however, the methods, challenges, outcomes and recommendations of engaging youth with neurodisabilities and their families in evidence syntheses are unknown. Two parents of youth with complex disability needs were engaged as partners throughout this review. Following methods outlined by Arksey and O'Malley (2005), the primary research question in this scoping review is twofold: (i) what activities have youth with neurodisabilities and their families been engaged in as part of evidence syntheses and (ii) what were the outcomes of that engagement? After full text review of 369 articles, nine articles were included. Youth and families were engaged prior to the evidence synthesis and at every stage in the project, most often during data analysis where they contextualized the findings. Youth and family engagement were not formally evaluated; however, positive outcomes were reported by parents and researchers. Challenges such as increased time, sustaining engagement, and parents' dissatisfaction with their level of involvement were reported. Recommendations centred around providing partners with information, building relationships via social media, and openly communicating about roles, feedback and logistics. Childhood disability researchers should be aware of how they can increase engagement opportunities at all stages of evidence syntheses and how they might improve accessibility for youth with neurodisabilities and their families. Further research is needed to solidify a unified framework for conduct and reporting of youth and family engagement in evidence syntheses.

Image-based axon model highlights heterogeneity in initiation of damage.

Head injury simulations predict the occurrence of traumatic brain injury by placing a threshold on the calculated strains for axon tracts within the brain. However, a current roadblock to accurate injury prediction is the selection of an appropriate axon damage threshold. While several computational studies have used models of the axon cytoskeleton to investigate damage initiation, these models all employ an idealized, homogeneous axonal geometry. This homogeneous geometry with regularly spaced microtubules, evenly distributed throughout the model, overestimates axon strength because, in reality, the axon cytoskeleton is heterogeneous. In the heterogeneous cytoskeleton, the weakest cross section determines the initiation of failure, but these weak spots are not present in a homogeneous model. Addressing one source of heterogeneity in the axon cytoskeleton, we present a new semiautomated image analysis pipeline for using serial-section transmission electron micrographs to reconstruct the microtubule geometry of an axon. The image analysis procedure locates microtubules within the images, traces them throughout the image stack, and reconstructs the microtubule structure as a finite element mesh. We demonstrate the image analysis approach using a C. elegans touch receptor neuron due to the availability of high-quality serial-section transmission electron micrograph data sets. The results of the analysis highlight the heterogeneity of the microtubule structure in the spatial variation of both microtubule number and length. Simulations comparing this image-based geometry with homogeneous geometries show that structural heterogeneity in the image-based model creates significant spatial variation in deformation. The homogeneous geometries, on the other hand, deform more uniformly. Since no single homogeneous model can replicate the mechanical behavior of the image-based model, our results argue that heterogeneity in axon microtubule geometry should be considered in determining accurate axon failure thresholds.

Collaborating neuroscience online: The case of the Human Brain Project forum.

This paper analyzes user interactions on the public-access online forum of the Human Brain Project (HBP), a major European Union-funded neuroscience research initiative, to understand the utility of the Forum for collaborative problem solving. We construct novel data using discussion forum posts and detailed user profiles on the HBP Forum. We find that HBP Forum utilization is comparable to that of a leading general-interest coding platform, and that online usage metrics quickly recovered after an initial Covid-19-related dip. Regression results show that user interactions on the Forum are more active for questions on programming and in HBP core areas. Further, Cox proportional hazard analyses show that such problems are solved faster. Forum posts with users from different countries tend to be discussed more actively but solved slower. Higher shares of administrator support tend to solve problems faster. There are no clear patterns regarding gender and seniority. Our results suggest that building novel collaborative forums can support researchers working on complex topics in challenging times.

Global drug diffusion and innovation with the medicines patent pool.

This paper studies the impact of the first joint licensing platform for patented drugs, the Medicines Patent Pool, on global drug diffusion and innovation. The pool allows generic firms worldwide to license drug bundles cheaply and conveniently for sales in a set of developing countries. I construct a novel dataset from licensing contracts, public procurement, clinical trials, and drug approvals. Using difference-in-differences methods, I find that the pool leads to substantial increases in the generic supply of drugs purchased, particularly in countries with stronger patent protection. In addition, there are some positive increases in clinical trials and drug product approvals after a compound enters the pool, mostly by firms outside the pool.

Automatic question answering for multiple stakeholders, the epidemic question answering dataset.

One of the effects of COVID-19 pandemic is a rapidly growing and changing stream of publications to inform clinicians, researchers, policy makers, and patients about the health, socio-economic, and cultural consequences of the pandemic. Managing this information stream manually is not feasible. Automatic Question Answering can quickly bring the most salient points to the user's attention. Leveraging a collection of scientific articles, government websites, relevant news articles, curated social media posts, and questions asked by researchers, clinicians, and the general public, we developed a dataset to explore automatic Question Answering for multiple stakeholders. Analysis of questions asked by various stakeholders shows that while information needs of experts and the public may overlap, satisfactory answers to these questions often originate from different information sources or benefit from different approaches to answer generation. We believe that this dataset has the potential to support the development of question answering systems not only for epidemic questions, but for other domains with varying expertise such as legal or finance.

U.S. State approaches to cannabis licensing.

U.S. states have taken varied approaches to licensing cannabis businesses under federal prohibition, but up to now there is limited research on cross-state licensing approaches. This paper provides a systematic analysis of the current licensing strategies taken by all states that have passed medical cannabis laws (MCLs)/recreational cannabis laws (RCLs). We construct comprehensive data on cannabis business licenses offered in each state, as well as metrics for license categories, cost, and issuance volume. We then analyze patterns between these metrics, also considering how long ago states implemented MCLs/RCLs, qualitative licensing aspects, state ideology and voting preference, and state cannabis taxation data. We observe that states tend to license medical cannabis more restrictively than adult-use cannabis: i.e., by offering licenses in fewer categories, at higher cost, in lower issuance volume, and more often mandating vertical integration. Additionally, states that implemented MCLs/RCLs earlier tend to offer licenses in more categories, at lower cost, and in greater volumes. Further, though states that implemented MCLs recently lean conservative and Republican, we do not observe clear relationships between ideology or voting preference and licensing policy. In our supporting results, we observe that a greater share of states with complex licensing structures impose non-retail price cannabis taxes than states overall, and we discuss how states have changed their licensing policies over time.

Myoepithelial carcinoma of soft tissue is a diagnostic challenge on fine-needle aspiration: Case report and review of literature.

Myoepithelial carcinoma (MEC) of soft tissue, also known as malignant myoepithelial tumor, is an uncommon malignancy. Cytologic diagnosis of this entity is challenging due to its rarity and heterogeneous morphology. We report a case of MEC in a 22-year-old man, who presented with a 6.5 cm soft tissue mass on his right distal forearm that has been enlarging over the past 3 months. Ultrasound-guided fine-needle aspiration (FNA) revealed abundant isolated neoplastic cells ranging from spindled cells to epithelioid and plasmacytoid morphology in a myxoid background. These cells showed moderate cytologic atypia characterized by high-nuclear/cytoplasmic ratio, irregular nuclear contours, and prominent nucleoli. The cytoplasm varied from dense to vacuolated and occasionally rhabdoid with intracytoplasmic inclusions. Scattered bi- and multinucleated cells were identified. A diagnosis of high-grade malignancy was made with the differential diagnosis including rhabdomyosarcoma and melanoma. A subsequent core biopsy of the tumor showed immunoreactivity for pan-cytokeratins, calponin, p63, and smooth muscle actin. INI-1 was lost. SOX-10 and Melan-A were negative. Molecular studies showed loss of SMARCB1 (INI-1) and CDKN2A. Gene fusion studies did not detect any fusion. A diagnosis of soft tissue MEC was made which is a challenge on FNA due to several cytologic mimickers including rhabdomyosarcoma, epithelioid sarcoma, extrarenal rhabdoid tumor, extra-axial chordoma and melanoma. Recognition of the biphasic cell population in a myxoid background and a battery of immunohistochemical stains are crucial for accurate diagnosis.