Clinicopathological characteristics of endometrial carcinoma with different molecular subtypes and their correlation with lymph node metastasis.

Endometrial carcinoma (EC) is one of the three major malignancies of the female reproductive organs. With intense research of tumor molecular mechanisms and development of precision medicine in recent years, the traditional pathomorphological classification fails to meet the needs of clinical diagnosis and treatment for EC. This study aims to analyze the correlation of different Proactive Molecular Risk Classifier for Endometrial Cancer molecular subtypes with lymph node metastasis (LNM) and other clinical features in EC. 120 treatment-naive EC patients with surgery were enrolled in this study. The molecular subtypes of these patients were classified as follows by Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) molecular subtyping: mismatch repair deficiency (MMRd) in 22 cases (18.33%), polymerase epsilon exonuclease domain mutation (POLE EDM) in 2 cases (1.67%), p53 wild-type (p53-wt) in 64 cases (53.33%), and p53 abnormal (p53-abn) in 32 cases (26.67%). The clinicopathological features of 120 patients were retrospectively analyzed. Statistical significance was identified among the four molecular subtypes in terms of histological classification, International Federation of Gynecology and Obstetrics (FIGO) staging, pathological grading, and LNM. Among the enrolled cases, 26 had LNM and 94 had no lymph node involvement. According to the multivariate Logistic regression analysis, p53 wt (P=0.008, OR=0.078, 95% CI: 0.012-0.510) was a protective factor for LNM in EC patients, while poorly differentiated histology (P=0.001, OR=15.137, 95% CI: 3.013-76.044) was a risk factor. ProMisE classification system, being more objective and reproducible, can provide an important reference for preoperative decision-making. The patients with p53 wt by ProMisE had a low risk of LNM in preoperative diagnostic curettage specimens, while there was a higher risk of LNM among the patients with poorly differentiated EC.

Prognostic Significance of Disseminated Tumor Cells in Bone Marrow for Endometrial Carcinoma Patients.

Background: Until now, limited clinical significance had been reported for disseminated tumor cells (DTCs) in gynecologic malignancies. DTCs were previously reported not to be associated with established risk factors, L1CAM immunoreactivity, and outcome in endometrial carcinoma (EC). This study's primary objective was to investigate potential correlations of DTCs in the bone marrow (BM) of EC patients with disease-related survival, and a secondary objective was to evaluate associations between molecular classification of EC and DTCs. Methods: Patients treated for primary EC at Tuebingen University women's hospital between 2003 and 2016 were identified. A total of 402 patients with a complete set of BM cytology, molecular, and clinical data were evaluable. Results: DTC occurrence was distributed equally among all four molecular groups (p = 0.651). DTC positivity was associated with a less favorable disease-free survival (HR: 1.86, 95% CI: 1.03-3.36, p = 0.036) and progression-free survival (HR: 1.86, 95% CI: 1.01-3.44, p = 0.045). Presence of DTCs was associated with a higher frequency of distant disease recurrence (p = 0.017). Conclusions: In line with our previous findings, tumor cell dissemination is not associated with molecular features in our large cohort of primary EC patients. Since DTCs seem to be associated with survival and location of disease recurrence, further studies are needed to decisively define their role in EC survival.

Comprehensive molecular characterization of early stage grade 3 endometrioid endometrial adenocarcinoma.

OBJECTIVE: The treatment for stage IB grade 3 endometrioid endometrial adenocarcinoma is challenging with variable practice. Molecular characterization may help identify adjuvant therapy strategies beyond stage. We aimed to better understand the molecular features of these tumors by characterizing them by ProMisE classification, mutational signature, and commonly mutated genes. METHODS: Patients with stage IB grade 3 EEC at two institutions were included. Immunohistochemistry and whole exome sequencing were performed on archival FFPE tissue sections to determine ProMisE classification. Personal Cancer Genome Reporter was used for somatic variant annotation, and mutational signatures were generated based on COSMIC single base substitution mutational signatures. RESULTS: 46 patients were included with variable adjuvant treatment. Nine patients recurred (19.6%), most with extra-abdominal disease (n = 5, or 55.6%). 10 had POLE mutations (21.7%), 18 were MMR deficient (39.1%), 6 had abnormal p53 (13.0%), and 12 were p53 wildtype (26.1%). There were no recurrences in the POLE subgroup. A dominant mutational signature was identified in 38 patients: 17 SBS5 signature (44.7%), 10 SBS15 or SBS44 signature (26.3%), 7 SBS10a or SBS10b signature (18.4%), 3 SBS14 signature (7.9%), and 1 SBS40 signature (2.6%). The six patients that recurred had a SBS5 signature. Frequently mutated genes included ARID1A (n = 30, 65%), PTEN (n = 28, 61%), MUC16 (n = 27, 59%), and PIK3CA (n = 25, 54%). CONCLUSIONS: This comprehensive evaluation found a molecularly diverse cohort of tumors, despite the same histology, stage and grade. Mutational signature SBS5 correlated with a high risk of recurrence. Further refining of endometrial cancer classification may enable more precise patient stratification and personalized treatment approaches.

Software cost estimation predication using a convolutional neural network and particle swarm optimization algorithm.

Over the past decades, the software industry has expanded to include all industries. Since stakeholders tend to use it to get their work done, software houses seek to estimate the cost of the software, which includes calculating the effort, time, and resources required. Although many researchers have worked to estimate it, the prediction accuracy results are still inaccurate and unstable. Estimating it requires a lot of effort. Therefore, there is an urgent need for modern techniques that contribute to cost estimation. This paper seeks to present a model based on deep learning and machine learning techniques by combining convolutional neural networks (CNN) and the particle swarm algorithm (PSO) in the context of time series forecasting, which enables feature extraction and automatic tuning of hyperparameters, which reduces the manual effort of selecting parameters and contributes to fine-tuning. The use of PSO also enhances the robustness and generalization ability of the CNN model and its iterative nature allows for efficient discovery of hyperparameter similarity. The model was trained and tested on 13 different benchmark datasets and evaluated through six metrics: mean absolute error (MAE), mean square error (MSE), mean magnitude relative error (MMRE), root mean square error (RMSE), median magnitude relative error (MdMRE), and prediction accuracy (PRED). Comparative results reveal that the performance of the proposed model is better than other methods for all datasets and evaluation criteria. The results were very promising for predicting software cost estimation.

Snakebite Management: The Need of Reassessment, International Relations, and Effective Economic Measures to Reduce the Considerable SBE Burden.

The sole treatment for snakebite envenomation (SBE), the anti-snake venom (ASV), suffers from considerable drawbacks, including side effects and limited species specificity. Additionally, despite its existence for more than a century, uniform availability of good quality ASV does not yet exist. The present review describes the journey of a SBE victim and highlights the global crisis of SBE management. A detailed analysis of the current ASV market has also been presented along with the worldwide snake distribution. The current production of country specific licensed ASV throughout the globe along with their manufacturers has been examined at the snake species level. Furthermore, a detailed analysis of on-ground situation of SBE management in antivenom manufacturing countries has been done using the most recent literature. Additionally, the export and import of different ASVs have been discussed in terms of procurement policies of individual countries, their shortcomings, along with the possible solution at the species level. It is interesting to note that in most countries, the existence of ASV is really either neglected or overstated, implying that it is there but unsuitable for use, or that it is not present but can be obtained from other countries. This highlights the urgent need of significant reassessment and international collaborations not just for development and production, but also for procurement, distribution, availability, and awareness. A PROMISE (Practical ROutes for Managing Indigenous Snakebite Envenoming) approach has also been introduced, offering simple, economical, and easy to adopt steps to efficiently alleviate the worldwide SBE burden.

Establishing a plan to improve pediatric patient comfort during PIV insertions and blood specimen collection: a quality improvement effort.

HIGHLIGHTS: Patient comfort during peripheral intravenous (PIV) insertion and specimen collection was increased. The authors extended the contingency plan implemented for PICC insertion to include PIV insertion and specimen collection. The authors met their goals by using quality improvement methodology. Prioritizing patient comfort often requires institutional culture change. BACKGROUND: Needle procedures can cause pain and distress, especially in pediatric patients.1 Retrospective data collected at a freestanding pediatric facility revealed that approximately 30% of pediatric patients were not demonstrating sufficient levels of comfort during peripheral intravenous (PIV) catheter insertion and specimen collection (lab draws) even after successful implementation of comfort measures by the vascular access team (VAT) in an adjacent procedure (eg peripherally inserted central catheter placement). The current quality improvement project was implemented to support adaptation and expansion of previous lessons learned to PIVs and lab draws specifically. DESIGN AND METHODS: The VAT used the Pediatric Sedation State Scale,2 a standardized assessment tool integrated into the electronic medical record, to assess procedural comfort during PIVs and lab draws from February 2021 through April 2023. A total of 24 134 patients aged 0 to 18 years were included in the data collection. Interventions were delivered concurrently and included (1) reeducation/ongoing support for implementation of the Comfort Promise3 measures, (2) the creation and implementation of advanced comfort options, and (3) culture change. AIMS AND OBJECTIVES: The goal of the interventions was to improve the percentage of pediatric patients achieving adequate levels of comfort beginning at 68% in year 1 to 90% in year 2. RESULTS: From February 2021 to April 2023, the VAT team was able to improve procedural comfort scores from 68% to 90% of pediatric patients with adequate comfort for lab draws and/or PIV insertions. CONCLUSIONS: While standard comfort measures are a good first step in pain management during needle procedures, they are not sufficient for every pediatric patient. Nitrous, sedation, and the use of anxiolytics and analgesics can play an important role in reducing pain and anxiety during needle procedures and should be considered for patients not achieving adequate levels of comfort with standard comfort measures.

Implementation of endometrial cancer molecular subtyping into a hybrid community-academic practice.

OBJECTIVES: We sought to confirm utility of our institution's modified Proactive Molecular Risk Classifier for Endometrial Cancer protocol in our daily practice, which includes mismatch repair (MMR), p53, and L1 cell adhesion molecule (L1CAM) immunohistochemistry with in-house next-generation sequencing for POLE, TP53, and CTNNB1. METHODS: We conducted a retrospective review of all patients in our institution who underwent primary endometrial carcinoma resection from the year prior to protocol implementation (PRE; October 1, 2020, to September 30, 2021) through first year of implementation (POST; October 1, 2021, to September 30, 2022) to compare the distribution of molecular and traditional staging factors using GOG-249 criteria to assign clinical risk. RESULTS: In total, 136 of 260 PRE patients were classified as clinically low risk (LR), of whom 31 were MMR deficient. Of the 157 LR POST patients with endometrioid-type carcinoma, 45 were MMR deficient, 5 were POLE mutant, 5 were TP53 mutant, 56 were of no specific molecular profile (NSMP), and 46 did not receive full protocol testing. Of all 79 POST NSMP endometrioid-type cases, 18 were CTNNB1 mutated and 8 showed L1CAM expression. CONCLUSIONS: Our protocol identified 22 (14%) of 157 LR tumors that harbored incipient intermediate- to high-risk molecular aberrations in TP53, CTNNB1, or L1CAM. Moving forward, results of ongoing trials assessing adjuvant therapy decisions based on molecular classification are necessary to confirm protocol utility and identify appropriate modifications.

If we know better, why don't we do better? A rapid quality improvement project to increase utilization of comfort measures to reduce pain and distress in children in a COVID-19 mass vaccination clinic.

INTRODUCTION: Many evidence-based tools exist to address pain and distress associated with injections; however, there remains a large gap between the knowledge of these tools and their utilization. Our hospital began a quality improvement (QI) project prior to COVID-19, with the goal of increasing the utilization of Comfort Promise measures during needle procedures. When COVID-19 vaccinations were approved, our mass vaccination clinics provided an opportunity to rapidly increase utilization across the institution. The primary aim was to increase the percentage of comfort measures (CM) offered with COVID-19 vaccinations. METHODS: Through this QI project, nurses and other professionals implemented CMs during COVID mass vaccination clinics. Clinics occurred in 3 age-based waves. Waves served as Plan-Do-Study-Act (PDSA) cycles. Families completed post-vaccination surveys to determine what CMs were offered and intention for future use with vaccinations. RESULTS: Uptake of CMs (PainEase, ShotBlockers, Comfort Positioning, Alternative Focus, Topical Lidocaine, and Breastfeeding/Sucrose) throughout the waves increased and generally remained stable. CMs also seemed to decrease pain/distress with vaccinations (70.5 to 88.7%), and children/caregivers intended to use some combination for future vaccinations (82.5 to 98.5%). CONCLUSIONS: Fast-paced mass vaccination clinics provided an ideal opportunity to significantly increase utilization of CMs. Across age groups CMs yielded high satisfaction and interest in future utilization. Clinic nurses returned to their own sub-specialties and became change agents. IMPLICATIONS: If all healthcare providers can work together to achieve consensus while incorporating comfort measures into daily practice, sustained change with incorporation of these evidence-based tools can be achieved. Future directions are discussed.

Time-Dependent Prediction Models for Individual Prognosis of Chronic Postsurgical Pain following Knee Replacement Based on an Extensive Multivariable Data Set.

(1) Background: Clinically useful prediction models for chronic postsurgical pain (CPSP) in knee replacement (TKA) are lacking. (2) Methods: In our prospective, multicenter study, a wide-ranging set of 91 variables was collected from 933 TKA patients at eight time points up to one year after surgery. Based on this extensive data pool, simple and complex prediction models were calculated for the preoperative time point and for 6 months after surgery, using least absolute shrinkage and selection operator (LASSO) 1se and LASSO min, respectively. (3) Results: Using preoperative data only, LASSO 1se selected age, the Revised Life Orientation Test on pessimism, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC)-subscore pain and the Timed "Up and Go" Test for prediction, resulting in an area under the curve (AUC) of 0.617 and a Brier score of 0.201, expressing low predictive power only. Using data up to 6 months after surgery, LASSO 1se included preoperative Patient Health Questionnaire-4, Knee Injury and Osteoarthritis Outcome Score (KOOS)-subscore pain (pain) 3 months after surgery (month), WOMAC pain 3 and 6 months, KOOS subscore symptoms 6 months, KOOS subscore sport 6 months and KOOS subscore Quality of Life 6 months. This improved the predictive power to an intermediate one (AUC 0.755, Brier score 0.168). More complex models computed using LASSO min did little to further improve the strength of prediction. (4) Conclusions: Even using multiple variables and complex calculation methods, the possibility of individual prediction of CPSP after TKA remains limited.

A single-institution retrospective exploratory analysis on the effectiveness and safety of lenvatinib plus pembrolizumab for advanced endometrial cancer: insights from ProMisE molecular classification system.

BACKGROUND: The Proactive Molecular Risk Classifier for Endometrial Cancer has identified four risk groups for the prognosis of endometrial cancer. Lenvatinib plus pembrolizumab was recently approved as a second-line treatment for unresectable endometrial cancer, but reports in clinical practice are lacking. The relationship between the efficacy of lenvatinib/pembrolizumab and Proactive Molecular Risk Classifier for Endometrial Cancer classification is unclear. METHODS: This single-centre retrospective study included patients who underwent lenvatinib/pembrolizumab therapy at Iwate Medical University Hospital between January 2022 and March 2023. Formalin-fixed paraffin-embedded specimens obtained from patients before treatment were collected and classified into the mismatch repair-deficient, p53 abnormal and no specific molecular profile subtypes using immunohistochemistry. The response rate, progression-free survival and adverse events were evaluated using electronic medical records. The study was approved by the hospital's ethics committee (approval number: MH2022-093). RESULTS: This study enrolled 20 patients, who underwent a median follow-up of 17.8 months (95% confidence interval: 16.6-18.9). The best overall response rate was 60.0% (36.1-80.9), and the median progression-free survival was 11.6 months (2.9-20.3). The median progression-free survival in the p53 abnormal group (n = 9) was 3.4 months (3.0-3.8); however, progression-free survival did not reach the median (P < 0.001) in the mismatch repair-deficient/no specific molecular profile group (n = 11). Symptomatic immune-related adverse events (except hypothyroidism) occurred in 4/20 (25.0%) patients, and partial responses were observed in all cases. No treatment-related deaths occurred. CONCLUSION: The p53abn group in the Proactive Molecular Risk Classifier for Endometrial Cancer classification has a poor prognosis even after treatment with lenvatinib/pembrolizumab.

Una investigación etnográfica sobre la violencia médica en los centros de salud de Nepal / Ethnographic Investigation into Medical Violence in Nepali Healthcare Facilities / Uma investigação etnográfica da violência médica em centros de saúde no Nepal

Introducción: la violencia no es un subproducto inherente de las relaciones humanas, pero los con-flictos sí lo son. En este artículo se examinan los factores y circunstancias que conducen a la tensión y los conflictos entre las personas que buscan atención médica y los establecimientos médicos nepalíes y los miembros del personal que trabajan allí. Desarrollo: embebido con una revisión de la literatura relevante, a través del análisis de datos etnográficos generada a partir de la investigación de campo y el análisis de contenido de la representación de noticias seleccionada, el artículo se desarrolla en cuatro secciones diferentes. La primera parte trata sobre el contexto de las consultas médicas que resultan en el desarrollo de una relación problemática. A esto le sigue el examen de los diferentes tipos de violencia, enfrentamientos y protestas que surgen a través de tales relaciones. En la tercera parte se analizan las implicaciones de las crecientes promesas médicas y el consiguiente aumento de las expectativas, mien-tras que la última parte destaca cómo las prácticas médicas típicas que existen en los propios hospitales nepaleses aumentan la posibilidad de enfrentamientos y violencia. Conclusión: la frecuente ocurrencia de peleas y violencia médica tanto en hospitales públicos como privados en Nepal sugiere que hay una bre-cha de comunicación entre los proveedores de servicios y el paciente debido a la naturaleza esotérica de la medicina. El conflicto y la violencia hacia los proveedores de servicios también pueden prosperar en el contexto de un modelo explicativo diferencial de las dos partes. La creciente animosidad también indica una disminución de la confianza entre los proveedores de atención médica y los solicitantes en Nepal

Introduction: Violence is not an inherent by-product of human relationships, but conflicts are. This arti-cle examines the factors and circumstances that lead to tension and conflicts between health seekers, and their counterpart Nepali medical establishments, and their staff members. Development: The article is divided into four sections by embedding a relevant literature review, analyzing ethnographic data generated from field research, and analyzing the content analysis of selected news portrayals. The first section discusses the context of the medical consultations that lead to the development of a problematic relationship. This is followed by examining the various types of violence, confrontations, and protests that arise from such relationships. The implications of rising medical promises and resulting height-ened expectations are discussed in the third section. The last section focuses on how common medical practices in Nepali hospitals increase the possibility of confrontations and violence. Conclusions: The prevalence of tussles and medical violence in Nepal's public and private hospitals suggests that they can occur in any hospital, regardless of ownership. Because of the esoteric nature of medicine, there is always a communication gap between service providers and patients. Conflict and violence against service providers can thrive in the context of a two-sided differential explanatory model. The growing hostility also indicates a decline in trust between healthcare providers and patients in Nepal

Introdução: a violência não é um subproduto inerente às relações humanas, mas o conflito é. Este artigo examina os fatores e circunstâncias que levam à tensão e ao conflito entre as pessoas que pro-curam cuidados médicos e os estabelecimentos médicos nepaleses e os funcionários que aí trabalham. Desenvolvimento: incorporada a uma revisão da literatura relevante, através da análise de dados etno-gráficos gerados a partir da pesquisa de campo e da análise de conteúdo da representação noticiosa selecionada, o artigo desenvolve-se em quatro seções distintas. A primeira parte trata do contexto das consultas médicas que resultam no desenvolvimento de uma relação problemática. Em seguida, exa-minamos os diferentes tipos de violência, confrontos e protestos que surgem através de tais relações. A parte três discute as implicações das crescentes promessas médicas e o consequente aumento das expectativas, enquanto a última parte destaca como as práticas médicas típicas que existem nos próprios hospitais nepaleses aumentam o potencial de confrontos e violência. Conclusão: a frequente ocorrência de brigas e violência médica em hospitais públicos e privados no Nepal sugere-nos que podem ocorrer em qualquer hospital, independentemente do proprietário. Sempre existe uma lacuna de comunicação entre os prestadores de serviços e o paciente devido à natureza esotérica da medicina. O conflito e a vio-lência contra os prestadores de serviços também podem florescer no contexto de um modelo explicativo diferencial das duas partes. A crescente animosidade também indica um declínio na confiança entre os prestadores de cuidados de saúde e os requerentes no Nepal

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting. METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage. RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026. CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

Corrigendum: Standardized classification schemes in reporting oncologic PET/CT.

[This corrects the article DOI: 10.3389/fmed.2022.1051309.].

Simplifying Barley Leaf Rust Research: An Easy and Reproducible Infection Protocol for Puccinia hordei on a Small Laboratory Scale.

Barley (Hordeum vulgare) is one of the most important agricultural crops in the world, but pathogen infections regularly limit its annual yield. A major threat is the infection with the biotrophic leaf rust fungus, Puccinia hordei. Rust fungi have a complex life cycle, and existing resistances can be easily overcome. To address this problem, it is crucial to develop barley varieties with improved and durable resistance mechanisms. An essential step towards this goal is a simple and reproducible infection protocol to evaluate potential resistance phenotypes in the lab. However, available protocols sometimes lack detailed procedure or equipment information, use spore application methods that are not suitable for uniform spore dispersion, or require special mineral oils or engineered fluids. In addition, they are often optimized for pathogen-dedicated greenhouses or phytochambers, which may not be available to every research institute. Here, we describe an easy and user-friendly procedure to infect barley with Puccinia hordei on a small laboratory scale. This procedure utilizes inexpensive and simple tools to evenly split and apply spores to barley leaves. The treated plants are incubated in affordable and small phytocabinets. Our protocol enables a quick and reproducible infection of barley with leaf rust, a method that can easily be transferred to other rust fungi, including stripe rust, or to other plant species. Key features Step-by-step infection protocol established for barley cv. Golden Promise, the gold standard genotype for genetic transformation Plant age-independent protocol Precise spore application by using inexpensive pipe cleaners for uniform symptom formation and increased reproducibility No specialized equipment needed Includes simple spore harvesting method Protocol is applicable to other biotrophic pathogens (stripe rust or powdery mildew) and other plants (e.g., wheat) Protocol is also applicable for a detached leaf assay Graphical overview.

Harmonized molecular classification; assessment of a single-test ProMisE NGS tool.

OBJECTIVES: Despite recommendations for integrating molecular classification of endometrial cancers (EC) into pathology reporting and clinical management, uptake is inconsistent. To assign ProMisE subtype, all molecular components must be available (POLE mutation status, mismatch repair (MMR) and p53 immunohistochemistry (IHC)) and often these are assessed at different stages of care and/or at different centres resulting in delays in treatment. We assessed a single-test DNA-based targeted next generation sequencing (NGS) molecular classifier (ProMisE NGS), comparing concordance and prognostic value to the original ProMisE classifier. METHODS: DNA was extracted from formalin-fixed paraffin embedded (FFPE) ECs that had previously undergone ProMisE molecular classification (POLE sequencing, IHC for p53 and MMR). DNA was sequenced using the clinically validated Imagia Canexia Health Find It™ amplicon-based NGS gene panel assay to assess for pathogenic POLE mutations (unchanged from original ProMisE), TP53 mutations (in lieu of p53 IHC), and microsatellite instability (MSI) (in lieu of MMR IHC),with the same order of segregation as original ProMisE used for subtype assignment. Molecular subtype assignment of both classifiers was compared by concordance metrics and Kaplan-Meier survival statistics. RESULTS: The new DNA-based NGS molecular classifier (ProMisE NGS) was used to determine the molecular subtype in 164 ECs previously classified with ProMisE. 159/164 cases were concordant with a kappa statistic of 0.96 and an overall accuracy of 0.97. Prognostic differences in progression-free, disease-specific and overall survival between the four molecular subtypes were observed for the new NGS classifier, recapitulating the survival curves of the original ProMisE classifier. ProMisE NGS was 100% concordant between matched biopsy and hysterectomy samples. CONCLUSION: ProMisE NGS is feasible on standard FFPE material, demonstrates high concordance with the original ProMisE classifier and maintains prognostic value in EC. This test has the potential to facilitate implementation of molecular classification of EC at the time of first diagnosis.

Research and Evaluation in a Child-Focused Place-Based Initiative: West Philly Promise Neighborhood.

Place-based initiatives attempt to reduce persistent health inequities through multisectoral, cross-system collaborations incorporating multiple interventions targeted at varying levels from individuals to systems. Evaluations of these initiatives may be thought of as part of the community change process itself with a focus on real-time learning and accountability. We described the design, implementation, challenges, and initial results of an evaluation of the West Philly Promise Neighborhood, which is a comprehensive, child-focused place-based initiative in Philadelphia, Pennsylvania. Priorities for the evaluation were to build processes for and a culture of ongoing data collection, monitoring, and communication, with a focus on transparency, accountability, and data democratization; establish systems to collect data at multiple levels, with a focus on multiple uses of the data and future sustainability; and adhere to grant requirements on data collection and reporting. Data collection activities included the compilation of neighborhood-level indicators; the implementation of a program-tracking system; administrative data linkage; and neighborhood, school, and organizational surveys. Baseline results pointed to existing strengths in the neighborhood, such as the overwhelming majority of caregivers reporting that they read to their young children (86.9%), while other indicators showed areas of need for additional supports and were programmatic focuses for the initiative (e.g., about one-quarter of young children were not engaged in an early childhood education setting). Results were communicated in multiple formats. Challenges included aligning timelines, the measurement of relationship-building and other process-focused outcomes, data and technology limitations, and administrative and legal barriers. Evaluation approaches and funding models that acknowledge the importance of capacity-building processes and allow the development and measurement of population-level outcomes in a realistic timeframe are critical for measuring the success of place-based approaches.

QTL mapping of shoot and seed traits impacted by Drought in Barley using a recombinant inbred line Population.

BACKGROUND: With ongoing climate change, drought events are severely limiting barley production worldwide and pose a significant risk to the malting, brewing and food industry. The genetic diversity inherent in the barley germplasm offers an important resource to develop stress resiliency. The purpose of this study was to identify novel, stable, and adaptive Quantitative Trait Loci (QTL), and candidate genes associated with drought tolerance. A recombinant inbred line (RIL) population (n = 192) developed from a cross between the drought tolerant 'Otis' barley variety, and susceptible 'Golden Promise'(GP) was subjected to short-term progressive drought during heading in the biotron. This population was also evaluated under irrigated and rainfed conditions in the field for yields and seed protein content. RESULTS: Barley 50k iSelect SNP Array was used to genotype the RIL population to elucidate drought-adaptive QTL. Twenty-three QTL (eleven for seed weight, eight for shoot dry weight and four for protein content) were identified across several barley chromosomes. QTL analysis identified genomic regions on chromosome 2 and 5 H that appear to be stable across both environments and accounted for nearly 60% variation in shoot weight and 17.6% variation in seed protein content. QTL at approximately 29 Mbp on chromosome 2 H and 488 Mbp on chromosome 5 H are in very close proximity to ascorbate peroxidase (APX) and in the coding sequence of the Dirigent (DIR) gene, respectively. Both APX and DIR are well-known key players in abiotic stress tolerance in several plants. In the quest to identify key recombinants with improved tolerance to drought (like Otis) and good malting profiles (like GP), five drought tolerant RILs were selected for malt quality analysis. The selected drought tolerant RILs exhibited one or more traits that were outside the realms of the suggested limits for acceptable commercial malting quality. CONCLUSIONS: The candidate genes can be used for marker assisted selection and/or genetic manipulation to develop barley cultivars with improved tolerance to drought. RILs with genetic network reshuffling necessary to generate drought tolerance of Otis and favorable malting quality attributes of GP may be realized by screening a larger population.

Test-retest repeatability of organ uptake on PSMA-targeted 18 F-DCFPyL PET/CT in patients with prostate cancer.

OBJECTIVES: We evaluated 18 F-DCFPyL test-retest repeatability of uptake in normal organs. METHODS: Twenty-two prostate cancer (PC) patients underwent two 18 F-DCFPyL PET scans within 7 days within a prospective clinical trial (NCT03793543). In both PET scans, uptake in normal organs (kidneys, spleen, liver, and salivary and lacrimal glands) was quantified. Repeatability was determined by using within-subject coefficient of variation (wCOV), with lower values indicating improved repeatability. RESULTS: For SUVmean , repeatability was high for kidneys, spleen, liver, and parotid glands (wCOV, range: 9.0%-14.3%) and lower for lacrimal (23.9%) and submandibular glands (12.4%). For SUVmax , however, the lacrimal (14.4%) and submandibular glands (6.9%) achieved higher repeatability, while for large organs (kidneys, liver, spleen, and parotid glands), repeatability was low (range: 14.1%-45.2%). CONCLUSION: We found acceptable repeatability of uptake on 18 F-DCFPyL PET for normal organs, in particular for SUVmean in the liver or parotid glands. This may have implications for both PSMA-targeted imaging and treatment, as patient selection for radioligand therapy and standardized frameworks for scan interpretation (PROMISE, E-PSMA) rely on uptake in those reference organs.

Clinical characteristics and prognostic characterization of endometrial carcinoma: a comparative analysis of molecular typing protocols.

BACKGROUND: Endometrial carcinoma (EC) is one of the most common gynecological malignancies in China and globally, accounting for the fourth-prevalent cancer in women. Although numerous studies have confirmed prognostic value of The Cancer Genome Atlas (TCGA) molecular subgroups, it is unclear how they are combined with histological features. The main objective of this study was to compare ProMisE and TCGA classification for the rapid and accurate prediction of prognosis within EC patients, together with the provision of a revised strategy for individualized diagnosis and treatment of patients. METHODS: Within this study, 70 patients with EC from Beijing Tsinghua Changgeng Hospital (affiliated to Tsinghua University) were retrospectively examined between July 2015 and December 2021. Samples were processed for determination of clinical markers, together with ProMisE and TCGA classification. RESULTS: Comparative analysis across four TCGA types (POLE, Low-CN, High-CN, and MSI-H) and age, was statistically significant (χ²= 7.000, p = 0.029). There was no significant difference observed among the four TCGA types and FIGO stage, vascular invasion and depth of invasion, or lymph node metastasis and tumor area. There was no significant association between the expression of Vimentin, Ki-67, PTEN, MSH2, PAX-8, ß-catenin, CD10, ER, PR, P16, MLH1, and PMS2 with the four TCGA types. In addition, p63 expression (χ²= 11.09, p = 0.029) and p53 expression (χ²= 11.585, p = 0.005) were statistically significant. Numerous models demonstrated that patients with POLE mutations and low-CN had higher progression free survival (PFS) and overall survival (OS), whereas those with high-CN had lowest values. The log-rank test revealed that the survival rate of PR-positive and ER-positive patients was significantly higher (p < 0.001). CONCLUSION: Overall, these results can be of additional benefit for clinical applications, in comparison to the ProMisE classification method. In addition, PR, ER, vascular infiltration, hyperlipidemia and atherosclerosis were found to be the key factors affecting EC prognosis.