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BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.

Background: Nursing students from diverse or equity backgrounds are less likely to possess the required skills to ensure success in their studies. This research explores the impact of embedded support on student learning in a first-year foundational subject, Contexts of Nursing, in an undergraduate nursing degree.t., Methods: The Embedded Tutor Program offers specialised tutoring support for first-year undergraduate students. Embedded tutors, with backgrounds as registered nurses and academics, provided online one-on-one feedback to students on draft assessment tasks. Outreach contact was provided to students at risk of failing. A Pearson's Chi-squared test was used to assess the impact of tutor support on grade distribution and a paired student t-test was used to assess the difference in cumulative marks for students from equity backgrounds. Statistical significance was set at p < 0.05. Feedback provided by students, tutors and staff in an online anonymous survey was thematically analysed., Results: There was a significant grade shift for the 267 students who met with an embedded tutor (p < 0.05). Students who were a member of an Australian Government identified equity group had a significant increase in their cumulative mark if they met with a tutor of 9-17 % (p < 0.05). This improvement in cumulative mark was maintained for students with cumulative equity factors. The overwhelming majority of students who were identified as at risk of failing and met with a tutor following outreach support received a passing grade. Students reported growing skills and confidence in academic literacy was a key benefit of the program., Conclusion: A shared approach to delivering education has a positive effect on the experience of learning. The combined efforts of the subject convenor, embedded tutors, and extended student service roles within the University resulted in outcomes that were positive for student learning. Determining student capacity for learning extended beyond a student's consideration of grades or their progression in the program to include the development of self-efficacy., Competing Interests: Declaration of competing interest All authors declare no competing interests directly or indirectly related to the content of the article submitted for publication., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Determining early-stage prognostic markers and stratifying patients for effective treatment are two key challenges for improving outcomes for melanoma patients. Previous studies have used tumour transcriptome data to stratify patients into immune subgroups, which were associated with differential melanoma specific survival and potential predictive biomarkers. However, acquiring transcriptome data is a time-consuming and costly process. Moreover, it is not routinely used in the current clinical workflow. Here, we attempt to overcome this by developing deep learning models to classify gigapixel haematoxylin and eosin (H&E) stained pathology slides, which are well established in clinical workflows, into these immune subgroups. We systematically assess six different multiple instance learning (MIL) frameworks, using five different image resolutions and three different feature extraction methods. We show that pathology-specific self-supervised models using 10x resolution patches generate superior representations for the classification of immune subtypes. In addition, in a primary melanoma dataset, we achieve a mean area under the receiver operating characteristic curve (AUC) of 0.80 for classifying histopathology images into 'high' or 'low immune' subgroups and a mean AUC of 0.82 in an independent TCGA melanoma dataset. Furthermore, we show that these models are able to stratify patients into 'high' and 'low immune' subgroups with significantly different melanoma specific survival outcomes (log rank test, P< 0.005). We anticipate that MIL methods will allow us to find new biomarkers of high importance, act as a tool for clinicians to infer the immune landscape of tumours and stratify patients, without needing to carry out additional expensive genetic tests., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: The rationale for oophorectomy during female cystectomy is not adequately supported. The co-occurrence and timing of bladder cancer (BC) and ovarian cancer (OC) in females harboring OC germline mutations remain unclear. Our objective was to determine the frequency and temporal occurrence of OC germline variants among females with BC., Methods: We used genetic and phenotypic data from the UK Biobank (UKB). The study cohort was defined using ICD-10/ICD-9 codes for BC and further stratified to identify 1347 females. Analysis was restricted to variants with high/moderate impact for initial regression. ClinVar was used to interpret pathogenicity. Pathogenic/likely pathogenic (P/LP) variants were assessed by age of presentation, family history, and concomitant malignancies. Statistical analysis was performed using UKB DNAnexus JupyterLab and RStudio., Key Findings and Limitations: Some 3.4% of the patients had at least one of 15 variants for OC. CHEK2 and PALB2 mutations represented the highest ratio of overall/pathogenic variants (15.8% and 6.6%). Although females with P/LP OC mutations had a higher risk of OC, diagnosis of OC preceded BC by 11.3 yr (±12.5 yr) in the group with mutations and by 15.6 yr (±11.3 yr) in the group without mutations. The group with P/LP variants had higher rates of maternal (14.63% vs 8.12%; p = 0.04) and sibling (9.76% vs 3.98%; p = 0.02) breast cancer and of maternal colon cancer (9.76% vs 4.21%), and lower maternal life expectancy (75.34 vs 68.15 yr; p = 0.0014). UKB provides limited staging/treatment history and its exome sequencing platform may miss variants or provide insufficient coverage for genotyping., Conclusions and Clinical Implications: This study provides evidence against routine oophorectomy for reducing OC risk in females with BC. The results highlight that the development of OC occurred 11 yr before diagnosis of BC for patients with OC mutations and 15 yr before diagnosis of BC for patients without OC mutations., Patient Summary: Although removal of the ovaries in women with bladder cancer is common, no studies have shown that this strategy has a benefit. Our study of women diagnosed with bladder cancer who had genetic mutations associated with ovarian cancer shows that their risk of developing ovarian cancer after bladder cancer is low. These findings provide evidence against removal of the ovaries when the bladder is being removed as treatment for bladder cancer., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: This scoping review was undertaken to obtain conceptual clarification about how racism and cultural safety are understood by interdisciplinary health professionals globally in the aged care sector in regional, rural and remote areas. There is evidence in Australia and internationally that racism is a factor impacting significantly on the health of First Peoples and other racialised minorities. Recent policy changes in Australia have required health professionals to integrate cultural safety into their practice to mitigate racism and improve the health of older First Nations Australians and older people from diverse ethnic and cultural groups., Methods: This review consisted of literature published in English from 1990, including published primary studies; systematic, integrative and narrative reviews; meta-analyses; theses; policy documents; guidelines; position statements; and government literature. Ovid (MEDLINE), CINAHL Plus with Full Text, Scopus, Proquest Nursing and Allied Health Database, and Informit were used in the full search. The most recent search of all databases was undertaken on 9 May 2022. Ten papers were included in the review, following the exclusion of 376 papers. A title and abstract search of the reference lists of papers included in the review identified no additional papers., Results: Ten papers were included in the review from Australia, Canada, the US, Norway and England. The literature reviewed suggests that health professionals in the aged care sector in regional, rural and remote areas in Australia, Canada, the US, Norway and England use alternative terms to 'racism' and 'racist', such as 'institutional marginalisation'., Discussion: The absence of explicit reference to racism aligns with critical race research that argues implicit bias and institutional racism are often separated from an individualised understanding of racism. That is, practitioners may understand racism as something that is perpetrated by individuals in an otherwise 'neutral' health setting. There is also a lack of clarity on how culturally safe care is understood, even though individual care plans are viewed as instrumental in establishing the needs and preferences of the consumers. Within the literature surveyed, barriers to providing quality and culturally inclusive care include disengaged management, insufficient human and material resources, language barriers and a lack of education focused on the needs of older individuals and groups with various cultural and spiritual needs. Additionally, the review does not clearly illuminate what health professionals understand to be racist thinking or behaviour and how it is responded to in practice. Likewise, there is limited information about health professionals' understanding of cultural safety and how to provide culturally inclusive care., Conclusion: While work is beginning on developing standards for cultural safety training in an Australian context, there are also opportunities to consider how these should be applied or adapted to residential and community aged care to best meet the needs of a diverse consumer base and workforce.

Background: Advanced penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy with limited success of immune-checkpoint inhibitors (ICIs). Approximately half of pSCC cases are associated with human papillomavirus (HPV) infection., Methods: Evaluation was done retrospectively of the landscape of somatic alterations and ICI-related biomarkers in pSCC by using the Caris Life Sciences data set with the aim to establish signatures for HPV-dependent oncogenesis. The pSCC tumors were analyzed by using next-generation sequencing (NGS) of DNA and RNA. Programmed death ligand 1 (PD-L1) expression was evaluated by immunohistochemistry (IHC). Microsatellite instability (MSI) was tested by fragment analysis, IHC (SP142; ≥1%), and NGS. Tumor mutational burden (TMB)-high was defined as ≥10 mutations/Mb. HPV16/18 status was determined by using whole-exome sequencing (WES) when available. Significance was adjusted for multiple comparisons (q value < .05)., Results: NGS of the overall cohort (N = 108) revealed TP53 (46%), CDKN2A (26%), and PIK3CA (25%) to be the most common mutations. Overall, 51% of tumors were PD-L1+, 10.7% had high TMB, and 1.1% had mismatch repair-deficient (dMMR)/MSI-high status. Twenty-nine patients had their HPV status made available by WES (HPV16/18+, n = 13; HPV16/18-, n = 16). KMT2C mutations (33% vs. 0%) and FGF3 amplifications (30.8% vs. 0%) were specific to HPV16/18+ tumors, whereas CDKN2A mutations (0% vs. 37.5%) were exclusive to HPV16/18- tumors. TMB-high was exclusively found in the HPV16/18+ group (30.8%). The two groups had comparable PD-L1 and dMMR/MSI-H status., Conclusions: In a large and comprehensive NGS-based evaluation of somatic alterations in pSCC, HPV16/18+ versus HPV16/18- pSCCs were molecularly distinct tumors. Our finding that TMB-high is exclusive to HPV16/18+ tumors requires confirmation in larger data sets., Plain Language Summary: Penile squamous cell carcinoma (pSCC) is a rare and aggressive malignancy in the advanced setting, with poor prognosis and little success with immune-checkpoint inhibitors (ICIs) in an unselected patient approach. Human papillomavirus (HPV) infection is a known risk factor for pSCC; its impact on genomic tumor profiling is less defined. Using next-generation sequencing, we explored the genetic landscape and ICI-related biomarkers of pSCC and HPV-driven oncogenic molecular signatures. Our results indicate that HPV-positive and HPV-negative pSCCs are molecularly distinct tumors. Increased tumor mutational burden is associated with HPV-positive tumors, and could serve as a biomarker for predicting therapeutic response to ICI-based therapies. Our results support the growing literature indicating that HPV status in pSCC can be used to guide patient stratification in ICI-based clinical trials., (© 2023 American Cancer Society.)

Purpose: Technetium-99m-sestamibi single-photon emission CT/x-ray CT is an emerging clinical tool to differentiate oncocytic tumors from renal cell carcinomas. We report data from a large institutional cohort of patients who underwent technetium-99m-sestamibi scans during evaluation of renal masses., Materials and Methods: Patients who underwent technetium-99m-sestamibi single-photon emission CT/x-ray CT between February 2020 and December 2021 were included in the analysis. Scans were defined as "hot" for oncocytic tumor when technetium-99m-sestamibi uptake was qualitatively equivalent or higher between the mass of interest and normal renal parenchyma, suggesting oncocytoma, hybrid oncocytic/chromophobe tumor, or chromophobe renal cell carcinoma. Demographic, pathological, and management strategy data were compared between "hot" and "cold" scans. For individuals who underwent diagnostic biopsy or extirpative procedures, the concordance between radiological findings and pathology was indexed., Results: A total of 71 patients (with 88 masses) underwent technetium-99m-sestamibi imaging with 60 (84.5%) patients having at least 1 "cold" mass on imaging and 11 (15.5%) patients exhibiting only "hot" masses. Pathology was available for 7 "hot" masses, with 1 biopsy specimen (14.3%) being discordant (clear cell renal cell carcinoma). Five patients with "cold" masses underwent biopsy. Out of 5 biopsied masses, 4 (80%) were discordant oncocytomas. Of the extirpated specimens, 35/40 (87.5%) harbored renal cell carcinoma and 5/40 (12.5%) yielded discordant oncocytomas. In sum, 20% of pathologically sampled masses that were "cold" on technetium-99m-sestamibi imaging still harbored oncocytoma/hybrid oncocytic/chromophobe tumor/chromophobe renal cell carcinoma., Conclusions: Further work is needed to define utility of technetium-99m-sestamibi in real-world clinical practice. Our data suggest this imaging strategy is not yet ready to replace biopsy.

The extremely rapid assembly of the earliest galaxies during the first billion years of cosmic history is a major challenge for our understanding of galaxy formation physics 1-5 . The advent of the James Webb Space Telescope (JWST) has exacerbated this issue by confirming the existence of galaxies in substantial numbers as early as the first few hundred million years 6-8 . Perhaps even more surprisingly, in some galaxies, this initial highly efficient star formation rapidly shuts down, or quenches, giving rise to massive quiescent galaxies as little as 1.5 billion years after the Big Bang 9,10 . However, due to their faintness and red colour, it has proven extremely challenging to learn about these extreme quiescent galaxies, or to confirm whether any existed at earlier times. Here we report the spectroscopic confirmation of a massive quiescent galaxy, GS-9209, at redshift, z = 4.658, just 1.25 billion years after the Big Bang, using the JWST Near-Infrared Spectrograph (NIRSpec). From these data we infer a stellar mass of M *  = 3.8 ± 0.2 × 10 10  M ⊙ , which formed over a roughly 200 Myr period before this galaxy quenched its star-formation activity at [Formula: see text], when the Universe was approximately 800 Myr old. This galaxy is both a likely descendent of the highest-redshift submillimetre galaxies and quasars, and a likely progenitor for the dense, ancient cores of the most massive local galaxies., (© 2023. The Author(s).)

Abdominal aortic aneurysm (AAA) is a pathologic enlargement of the infrarenal aorta with an associated risk of rupture. However, the responsible mechanisms are only partially understood. Based on murine and human samples, a heterogeneous distribution of characteristic pathologic features across the aneurysm circumference is expected. Yet, complete histologic workup of the aneurysm sac is scarcely reported. Here, samples from five AAAs covering the complete circumference partially as aortic rings are investigated by histologic means (HE, EvG, immunohistochemistry) and a new method embedding the complete ring. Additionally, two different methods of serial histologic section alignment are applied to create a 3D view. The typical histopathologic features of AAA, elastic fiber degradation, matrix remodeling with collagen deposition, calcification, inflammatory cell infiltration and thrombus coverage were distributed without recognizable pattern across the aneurysm sac in all five patients. Analysis of digitally scanned entire aortic rings facilitates the visualization of these observations. Immunohistochemistry is feasible in such specimen, however, tricky due to tissue disintegration. 3D image stacks were created using open-source and non-generic software correcting for non-rigid warping between consecutive sections. Secondly, 3D image viewers allowed visualization of in-depth changes of the investigated pathologic hallmarks. In conclusion, this exploratory descriptive study demonstrates a heterogeneous histomorphology around the AAA circumference. Warranting an increased sample size, these results might need to be considered in future mechanistic research, especially in reference to intraluminal thrombus coverage. 3D histology of such circular specimen could be a valuable visualization tool for further analysis., (© 2023. The Author(s).)

Background: The application of next-generation sequencing techniques has enabled characterization of urinary tract microbiome. Although many studies have demonstrated associations between the human microbiome and bladder cancer (BC), these have not always reported consistent results, thereby necessitating cross-study comparisons. Thus, the fundamental questions remain how we can utilize this knowledge., Objective: The aim of our study was to examine the disease-associated changes in urine microbiome communities globally utilizing a machine learning algorithm., Design, Setting, and Participants: Raw FASTQ files were downloaded for the three published studies in urinary microbiome in BC patients, in addition to our own prospectively collected cohort., Outcome Measurements and Statistical Analysis: Demultiplexing and classification were performed using the QIIME 2020.8 platform. De novo operational taxonomic units were clustered using the uCLUST algorithm and defined by 97% sequence similarity and classified at the phylum level against the Silva RNA sequence database. The metadata available from the three studies included were used to evaluate the differential abundance between BC patients and controls via a random-effect meta-analysis using the metagen R function. A machine learning analysis was performed using the SIAMCAT R package., Results and Limitations: Our study includes 129 BC urine and 60 healthy control samples across four different countries. We identified a total of 97/548 genera to be differentially abundant in the BC urine microbiome compared with that of healthy patients. Overall, while the differences in diversity metrics were clustered around the country of origin (Kruskal-Wallis, p < 0.001), collection methodology was a driver of microbiome composition. When assessing dataset from China, Hungary, and Croatia, data demonstrated no discrimination capacity to distinguish between BC patients and healthy adults (area under the curve [AUC] 0.577). However, inclusion of samples with catheterized urine improved the diagnostic accuracy of prediction for BC to AUC 0.995, with precision-recall AUC = 0.994. Through elimination of contaminants associated with the collection methodology among all cohorts, our study identified increased abundance of polycyclic aromatic hydrocarbon (PAH)-degrading bacteria Sphingomonas, Acinetobacter, Micrococcus, Pseudomonas, and Ralstonia to be consistently present in BC patients., Conclusions: The microbiota of the BC population may be a reflection of PAH exposure from smoking, environmental pollutants, and ingestion. Presence of PAHs in the urine of BC patients may allow for a unique metabolic niche and provide necessary metabolic resources where other bacteria are not able to flourish. Furthermore, we found that while compositional differences are associated with geography more than with disease, many are driven by the collection methodology., Patient Summary: The goal of our study was to compare the urine microbiome of bladder cancer patients with that of healthy controls and evaluate any potential bacteria that may be more likely to be found in patients with bladder cancer. Our study is unique as it evaluates this across multiple countries, to find a common pattern. After we removed some of the contamination, we were able to localize several key bacteria that are more likely to be found in the urine of bladder cancer patients. These bacteria all share their ability to break down tobacco carcinogens., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Purpose: We evaluated oncologic risks in a large cohort of patients with radiographic cystic renal masses who underwent active surveillance or intervention., Materials and Methods: A single-institutional database of 4,340 kidney lesions managed with either active surveillance or intervention between 2000-2020 was queried for radiographically cystic renal masses. Association of radiographic tumor characteristics and high-grade pathology was evaluated., Results: We identified 387 radiographically confirmed cystic lesions in 367 patients. Of these, 247 were resected (n=240) or ablated (n=7; n=247, 203 immediate vs 44 delayed intervention). Pathologically, 23% (n=56) demonstrated high-grade pathology. Cystic features were explicitly described by pathology in only 18% (n=33) of all lesions and in 7% (n=4) of high-grade lesions. Of the intervention cohort, African American race, male gender, and Bosniak score were associated with high-grade pathology ( P < .05). On active surveillance (n=184), Bosniak IV lesions demonstrated faster growth rates than IIF and III lesions (2.7 vs 0.6 and 0.5 mm/y, P ≤ .001); however, growth rates were not associated with high-grade pathology ( P = .5). No difference in cancer-specific survival was identified when comparing intervention vs active surveillance at 5 years (99% vs 100%, P = .2). No difference in recurrence was observed between immediate intervention vs delayed intervention ( P > .9)., Conclusions: A disconnect between "cystic" designation on imaging and pathology exists for renal lesions. Over 80% of radiographic Bosniak cystic lesions are not described as "cystic" on pathology reports. More than 1 in 5 resected cystic renal lesions demonstrated high-grade disease. Despite this finding, judiciously managed active surveillance ± delayed intervention is a safe and effective management option for most radiographic cystic renal masses.

The current subjective histopathological assessment of cutaneous melanoma is challenging. The application of image analysis algorithms to histological images may facilitate improvements in workflow and prognostication. To date, several individual algorithms applied to melanoma histological images have been reported with variations in approach and reported accuracies. Histological digital images can be created using a camera mounted on a light microscope, or through whole slide image (WSI) generation using a whole slide scanner. Before any such tool could be integrated into clinical workflow, the accuracy of the technology should be carefully evaluated and summarised. Therefore, the objective of this review was to evaluate the accuracy of existing image analysis algorithms applied to digital histological images of cutaneous melanoma. Database searching of PubMed and Embase from inception to 11th March 2022 was conducted alongside citation checking and examining reports from organisations. All studies reporting accuracy of any image analysis applied to histological images of cutaneous melanoma, were included. The reference standard was any histological assessment of haematoxylin and eosin-stained slides and/or immunohistochemical staining. Citations were independently deduplicated and screened by two review authors and disagreements were resolved through discussion. The data was extracted concerning study demographics; type of image analysis; type of reference standard; conditions included and test statistics to construct 2 × 2 tables. Data was extracted in accordance with our protocol and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Diagnostic Test Accuracy (PRISMA-DTA) Statement. A bivariate random-effects meta-analysis was used to estimate summary sensitivities and specificities with 95% confidence intervals (CI). Assessment of methodological quality was conducted using a tailored version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. The primary outcome was the pooled sensitivity and specificity of image analysis applied to cutaneous melanoma histological images. Sixteen studies were included in the systematic review, representing 4,888 specimens. Six studies were included in the meta-analysis. The mean sensitivity and specificity of automated image analysis algorithms applied to melanoma histological images was 90% (CI 82%, 95%) and 92% (CI 79%, 97%), respectively. Based on limited and heterogeneous data, image analysis appears to offer high accuracy when applied to histological images of cutaneous melanoma. However, given the early exploratory nature of these studies, further development work is necessary to improve their performance., (© 2023. The Author(s).)

While multiple mechanisms have been hypothesized to explain the therapeutic effect of lymph node (LN) yield in patients with urothelial cell carcinoma (UCC) undergoing radical cystectomy (RC), the effect of stage migration, commonly known as the Will Rogers effect, is often discounted. We reviewed the National Cancer Database for patients with UCC undergoing RC with pathologically node-negative (pN0) disease from 2004 to 2016. We tested for an adjusted association between LN yield and overall survival using multivariable Cox proportional-hazard models. Median survival was estimated using the Kaplan-Meier method. We identified 19 939 patients with pN0 UCC treated with RC. After adjustment, patients in the highest quantile for LN yield (≥26 LNs) had a 34% lower risk of death in comparison to patients in the lowest quantile (≤5 LNs). As we increased the threshold for LN yield for dichotomization from >5 to >15 to >25 LNs, median survival increased from 83 to 95 to 103 mo. The pN0 group with higher LN yield appeared to live longer in this analysis owing to the mathematical artifact of how patients are indexed. Resection of a greater number of negative LNs will lead to higher fidelity for pN0 cohorts being evaluated, as the likelihood of contamination by pN+ cases that were missed will be lower., Patient Summary: A strategy to dissect a high number of lymph nodes in patients undergoing removal of their bladder for bladder cancer can be associated with side effects, and the benefit in terms of cancer control or survival remains uncertain. Urologists and their patients should engage in shared decision-making and consider the risks and benefits of more extensive lymph node dissection during surgery., (© 2022 The Author(s).)

Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV - ) head and neck squamous cancer (HNSC), associated with an immune-cold tumor microenvironment (TME) signal, and recent evidence suggested that this TME-cold phenotype was greatly enhanced with 9p21 deletion size, notably encompassing band 9p24.1 (3). Here, we report multi-omic, -threshold and continuous-variable dissection of 9p21 and 9p24 loci (including depth and degree of somatic alteration of each band at each locus, and each gene at each band) and TME of four HPV - HNSC cohorts. Preferential 9p24 deletion, CD8 T-cell immune-cold associations were observed, driven by 9p24.1 loss, and in turn by an essential telomeric regulatory gene element, JAK2-CD274 . Surprisingly, same genetic region gains were immune hot. Related 9p21-TME analyses were less evident. Inherent 9p-band-level influences on anti-PD1 ICT survival rates, coincident with TME patterns, were also observed. At a 9p24.1 whole-transcriptome expression threshold of 60th percentile, ICT survival rate exceeded that of lower expression percentiles and of chemotherapy; below this transcript threshold, ICT survival was inferior to chemotherapy, the latter unaffected by 9p24.1 expression level ( P- values < 0.01, including in a PD-L1 immunohistochemistry-positive patient subgroup). Whole-exome analyses of 10 solid-tumor types suggest that these 9p-related ICT findings could be relevant to squamous cancers, in which 9p24.1 gain/immune-hot associations exist.

Purpose: Estrogen receptor 1 (ESR1) mutations and fusions typically arise in patients with hormone receptor-positive breast cancer after aromatase inhibitor therapy, whereby ESR1 is constitutively activated in a ligand-independent manner. These variants can impact treatment response. Herein, we characterize ESR1 variants among molecularly profiled advanced breast cancers., Methods: DNA next-generation sequencing (592-gene panel) data from 9860 breast cancer samples were retrospectively reviewed. Gene fusions were detected using the ArcherDx fusion assay or whole transcriptome sequencing (n = 344 and n = 4305, respectively). Statistical analyses included Chi-square and Fisher's exact tests., Results: An ESR1 ligand-binding domain (LBD) mutation was detected in 8.6% of tumors evaluated and a pathogenic ESR1 fusion was detected in 1.6%. Most ESR1 LBD mutations/fusions were from estrogen receptor (ER)-positive samples (20.1% and 4.9%, respectively). The most common ESR1 LBD mutations included D538G (3.3%), Y537S (2.3%), and E380Q (1.1%) mutations. Among biopsy sites, ESR1 LBD mutations were most observed in liver metastases. Pathogenic ESR1 fusions were identified in 76 samples (1.6%) with 40 unique fusion partners. Evaluating co-alterations, ESR1 variant (mutation/fusion) samples more frequently expressed androgen receptor (78.0% vs 58.6, P < 0.0001) and less frequently immune checkpoint proteins than ESR1 wild-type (PD-1 20.0% vs 53.4, P < 0.05; immune cell PD-L1 10.0% vs 30.2, P < 0.0001)., Conclusion: We have described one of the largest series of ESR1 fusions reported. ESR1 LBD mutations were commonly identified in ER-positive disease. Limited data exists regarding the clinical impact of ESR1 fusions, which could be an area for future therapeutic exploration., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Anti-programmed cell death 1 (anti-PD-1) and PD ligand 1 (PD-L1) immune checkpoint therapies (ICTs) provided durable responses only in a subset of cancer patients. Thus, biomarkers are needed to predict nonresponders and offer them alternative treatments. We recently implicated discoidin domain receptor tyrosine kinase 2 (DDR2) as a contributor to anti-PD-1 resistance in animal models; therefore, we sought to investigate whether this gene family may provide ICT response prediction., Methods: We assessed mRNA expression of DDR2 and its family member DDR1. Transcriptome analysis of bladder cancer (BCa) models in which DDR1 and 2 were perturbed was used to derive DDR1- and DDR2-driven signature scores. DDR mRNA expression and gene signature scores were evaluated using BCa-The Cancer Genome Atlas (n = 259) and IMvigor210 (n = 298) datasets, and their relationship to BCa subtypes, pathway enrichment, and immune deconvolution analyses was performed. The potential of DDR-driven signatures to predict ICT response was evaluated and independently validated through a statistical framework in bladder and lung cancer cohorts. All statistical tests were 2-sided., Results: DDR1 and DDR2 showed mutually exclusive gene expression patterns in human tumors. DDR2high BCa exhibited activation of immune pathways and a high immune score, indicative of a T-cell-inflamed phenotype, whereas DDR1high BCa exhibited a non-T-cell-inflamed phenotype. In IMvigor210 cohort, tumors with high DDR1 (hazard ratio [HR] = 1.53, 95% confidence interval [CI] = 1.16 to 2.06; P = .003) or DDR2 (HR = 1.42, 95% CI = 1.01 to 1.92; P = .04) scores had poor overall survival. Of note, DDR2high tumors from IMvigor210 and CheckMate 275 (n = 73) cohorts exhibited poorer overall survival (HR = 1.56, 95% CI = 1.20 to 2.06; P &lt; .001) and progression-free survival (HR = 1.77 95%, CI = 1.05 to 3.00; P = .047), respectively. This result was validated in independent cancer datasets., Conclusions: These findings implicate DDR1 and DDR2 driven signature scores in predicting ICT response., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: A clear and well-documented gender bias exists in the evaluation of sexual outcomes for women undergoing urologic surgery. Due to the anatomic template of anterior exenteration, women are commonly left with side effects that include sexual dysfunction and the perpetuated effects of surgical menopause., Objectives: To present evaluation and treatment recommendations for female sexual dysfunction treatment and evaluation, in addition to surgical templates during radical cystectomy (RC)., Methods: This article reviews current literature regarding sexual function and RC with urinary diversion in female bladder cancer patients. Furthermore, this review will provide a review of techniques for organ and neurovascular preservation, along with novel vaginal reconstruction templates. Our review will further focus on emerging technology, including minimally invasive surgery and organ and nerve preservation, directed at preservation of female sexual function., Results: Clinically, studies have demonstrated that females who have undergone genitalia-sparing and neurovascular preservation during RC regained sexual activity earlier than patients undergoing traditional RC. If organ and nerve preservation is not feasible due to involvement of trigone or bladder neck, vaginal reconstruction can mitigate the sexual dysfunction that results from a loss of the anterior vagina during a standard RC., Conclusion: Female sexual dysfunction is associated with high levels of patient distress and is best comanaged with a multidisciplinary treatment approach, including preoperative counseling, intraoperative nerve, and organ preservation, and postoperative interventions to mitigate sexual side effects. Davis L, Isali I, Prunty M, et al. Female Sexual Function Following Radical Cystectomy in Bladder Cancer. Sex Med Rev 2022;10:231-239., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Radical cystectomy (RC) is the historic gold standard treatment for muscle-invasive bladder cancer (MIBC), but trimodal therapy (TMT) has emerged as a valid therapeutic option for select patients. Given that prospective clinical trials have been difficult to perform in this area, our aim was to compare these two primary treatment strategies using decision analytic methods., Method: A two-dimensional Markov microsimulation model was constructed using TreeAge Pro to compare RC and TMT for patients with newly diagnosed MIBC. A comprehensive literature search was used to populate model probabilities and utilities. Our primary outcome was quality-adjusted life expectancy (QALE). Secondary outcomes included crude life expectancy (LE) and bladder cancer recurrences. The simulated patient for our model was an adult with MIBC (pT2-4 N0 M0) who was a candidate for either RC or TMT., Results: A total of 500 000 patients were simulated. TMT resulted in an estimated mean QALE of 7.48 vs. 7.41 for RC. However, the average LE for patients treated with TMT was lower compared with RC (10.20 vs. 10.74 years). A sensitivity analysis evaluating the impact of age showed that younger patients treated with RC had greater QALE and longer LE than those treated with TMT; inverse findings were observed for elderly patients. Overall, 39.4% of patients treated with TMT experienced a bladder recurrence., Conclusions: RC results in a longer LE compared to TMT (0.54 years), but with a lower QALE (-0.07 years). The preferred treatment strategy varied with patient age.

Despite the widespread availability of effective vaccines, new cases of infection with severe acute respiratory syndrome coronavirus-2, the cause of coronavirus disease 2019 (COVID-19), remain a concern in the settings of vaccine hesitancy and vaccine breakthrough. In this randomized, controlled, phase 2 trial, we hypothesized that high-dose ascorbic acid delivered intravenously to achieve pharmacologic concentrations may target the high viral phase of COVID-19 and thus improve early clinical outcomes. Sixty-six patients admitted with COVID-19 and requiring supplemental oxygen were randomized to receive either escalating doses of intravenous ascorbic acid plus standard of care or standard of care alone. The demographic and clinical characteristics were well-balanced between the two study arms. The primary outcome evaluated in this study was clinical improvement at 72 h after randomization. While the primary outcome was not achieved, point estimates for the composite outcome and its individual components of decreased use of supplemental oxygen, decreased use of bronchodilators, and the time to discharge were all favorable for the treatment arm. Possible favorable effects of ascorbic acid were most apparent during the first 72 h of hospitalization, although these effects disappeared over the course of the entire hospitalization. Future larger trials of intravenous ascorbic acid should be based on our current understanding of COVID-19 with a focus on the potential early benefits of ascorbic in hospitalized patients.

Loss-of-function alterations of Neurofibromin 1 (NF1) activate RAS, a driver of colorectal cancer. However, the clinical implications of NF1 alterations are largely unknown. We performed a comprehensive molecular profiling of NF1-mutant colorectal cancer using data from 8150 patients included in a dataset of commercial CLIA-certified laboratory (Caris Life Sciences). In addition, NF1 expression levels were tested for associations with clinical outcomes using data from 431 patients in the CALGB/SWOG 80405 trial. In the Caris dataset, 2.2% of patients had pathogenic or presumed pathogenic NF1 mutations. NF1-mutant tumors more frequently harbored PIK3CA (25.0% vs. 16.7%) and PTEN mutations (24.0% vs. 4.2%) than wild type tumors. Gene set enrichment analysis revealed that MAPK and PI3K pathway signatures were enriched in NF1-mutant tumors. In the CALGB/SWOG 80405 cohort, low NF1 expression was associated with poor prognosis, and high NF1 expression was associated with better efficacy of cetuximab than bevacizumab. Together, we revealed concurrent genetic alterations in the PI3K pathways in NF1-mutant tumors, suggesting the need to simultaneously block MAPK and PI3K pathways in treatment. The potential of NF1 alteration as a novel biomarker for targeted therapy was highlighted, warranting further investigations in clinical settings., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Coarse sediment transport in fluvial systems serves an important role in determining in-stream physical habitat, spawning potential and benthic community structure. However, despite more than a decade of pressure in Europe to restore stream continuity under the Water Framework Directive (WFD), there have been relatively few empirical studies on how low-head, run-of-river structures (i.e., weirs) disrupt the processes and dynamics of bedload conveyance. In this study we present an investigation into how coarse sediment is transferred through a low-head dam via the real-time monitoring of bedload transport over a weir in southeast Ireland. Critical discharge values for particle entrainment over the structure were derived from the novel use of a stationary RFID antenna, coupled with continuous recording of water levels and sediment captured downstream using pit-style sediment traps. The stationary RFID antenna was installed along a weir crest using both 'pass-under' and 'pass-over' configurations as a means of detecting the moment bedload tracers moved over the dam crest. Results show that 10% of tracers deployed upstream were detected passing over the weir, while a further 15% that were not detected were recovered downstream. These results indicate bedload material as large as the upstream D 70 (i.e., 90 mm) can move over the structure during infrequent high-flow events. However, thorough searches of the seeded area upstream of the dam also suggest that as many as 43% of the total number may have passed downstream, indicating that tracers moved over the weir after the antenna was damaged during a high-flow event, or were missed due to either particle velocity or signal collision. In addition, 30 of the tracers that remained upstream were shown to have either been buried due to the subsequent influx of sediment entering the reservoir, or were reworked though the surface material. Critical discharge values indicate size-selective transport patterns may dominate and a strong correlation between event peak discharge and total bedload captured downstream. These findings provide more evidence that low-head structures may eventually adopt a morphology that allows for the intermittent storage and later export of a channel's bedload downstream as hypothesized by other authors. Building upon these findings and those of other recent field studies, we present a set of possible schematic models that offer a basis for understanding the unique ways low-head dams can continue to disrupt sediment conveyance long after they have reached their functional storage capacity. The limitations of using a stationary RFID antenna and possible recommendations for future studies are discussed., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes., Methods: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate., Results: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival., Conclusions: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

We performed a retrospective analysis of angiosarcoma (AS) genomic biomarkers and their associations with the site of origin in a cohort of 143 cases. Primary sites were head and neck (31%), breast (22%), extremity (11%), viscera (20%), skin at other locations (8%), and unknown (9%). All cases had Next Generation Sequencing (NGS) data with a 592 gene panel, and 53 cases had Whole Exome Sequencing (WES) data, which we used to study the microenvironment phenotype. The immunotherapy (IO) response biomarkers Tumor Mutation Burden (TMB), Microsatellite Instability (MSI), and PD-L1 status were the most frequently encountered alteration, present in 36.4% of the cohort and 65% of head and neck AS (H/N-AS) ( p < 0.0001). In H/N-AS, TMB-High was seen in 63.4% of cases ( p < 0.0001) and PDL-1 positivity in 33% of cases. The most common genetic alterations were TP53 (29%), MYC amplification (23%), ARID1A (17%), POT1 (16%), and ATRX (13%). H/N-AS cases had predominantly mutations in TP53 (50.0%, p = 0.0004), POT1 (40.5%, p < 0.0001), and ARID1A (33.3%, p = 0.5875). In breast AS, leading alterations were MYC amplification (63.3%, p < 0.0001), HRAS (16.1%, p = 0.0377), and PIK3CA (16.1%, p = 0.2352). At other sites, conclusions are difficult to generate due to the small number of cases. A microenvironment with a high immune signature, previously associated with IO response, was evenly distributed in 13% of the cases at different primary sites. Our findings can facilitate the design and optimization of therapeutic strategies for AS.

While focal therapy (FT) is increasingly endorsed for treating localized prostate cancer in the appropriately selected patient, management of recurrences following FT is not well-established in the literature. This case series describes three patients who received high-intensity focal ultrasound (HIFU) for primary treatment followed by focal laser interstitial thermal therapy (FLTT) for salvage therapy treated in the context of an ongoing clinical trial. Evaluation of these reported patients demonstrates that FLTT is feasible in the salvage setting with promising short-term oncologic outcomes and with the potential to preserve functional outcomes. Repeat focal therapy for previous failures is feasible however, it requires sophisticated imaging modalities for the accurate identification of recurrence and treatment of the tumor., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cancer of Unknown Primary (CUP) occurs in 3-5% of patients when standard histological diagnostic tests are unable to determine the origin of metastatic cancer. Typically, a CUP diagnosis is treated empirically and has very poor outcomes, with median overall survival less than one year. Gene expression profiling alone has been used to identify the tissue of origin but struggles with low neoplastic percentage in metastatic sites which is where identification is often most needed. MI GPSai, a Genomic Prevalence Score, uses DNA sequencing and whole transcriptome data coupled with machine learning to aid in the diagnosis of cancer. The algorithm trained on genomic data from 34,352 cases and genomic and transcriptomic data from 23,137 cases and was validated on 19,555 cases. MI GPSai predicted the tumor type in the labeled data set with an accuracy of over 94% on 93% of cases while deliberating amongst 21 possible categories of cancer. When also considering the second highest prediction, the accuracy increases to 97%. Additionally, MI GPSai rendered a prediction for 71.7% of CUP cases. Pathologist evaluation of discrepancies between submitted diagnosis and MI GPSai predictions resulted in change of diagnosis in 41.3% of the time. MI GPSai provides clinically meaningful information in a large proportion of CUP cases and inclusion of MI GPSai in clinical routine could improve diagnostic fidelity. Moreover, all genomic markers essential for therapy selection are assessed in this assay, maximizing the clinical utility for patients within a single test., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: FOLFOX, FOLFIRI, or FOLFOXIRI chemotherapy with bevacizumab is considered standard first-line treatment option for patients with metastatic colorectal cancer (mCRC). We developed and validated a molecular signature predictive of efficacy of oxaliplatin-based chemotherapy combined with bevacizumab in patients with mCRC., Experimental Design: A machine-learning approach was applied and tested on clinical and next-generation sequencing data from a real-world evidence (RWE) dataset and samples from the prospective TRIBE2 study resulting in identification of a molecular signature, FOLFOX ai . Algorithm training considered time-to-next treatment (TTNT). Validation studies used TTNT, progression-free survival, and overall survival (OS) as the primary endpoints., Results: A 67-gene signature was cross-validated in a training cohort ( N = 105) which demonstrated the ability of FOLFOX ai to distinguish FOLFOX-treated patients with mCRC with increased benefit from those with decreased benefit. The signature was predictive of TTNT and OS in an independent RWE dataset of 412 patients who had received FOLFOX/bevacizumab in first line and inversely predictive of survival in RWE data from 55 patients who had received first-line FOLFIRI. Blinded analysis of TRIBE2 samples confirmed that FOLFOX ai was predictive of OS in both oxaliplatin-containing arms (FOLFOX HR, 0.629; P = 0.04 and FOLFOXIRI HR, 0.483; P = 0.02). FOLFOX ai was also predictive of treatment benefit from oxaliplatin-containing regimens in advanced esophageal/gastro-esophageal junction cancers, as well as pancreatic ductal adenocarcinoma., Conclusions: Application of FOLFOX ai could lead to improvements of treatment outcomes for patients with mCRC and other cancers because patients predicted to have less benefit from oxaliplatin-containing regimens might benefit from alternative regimens., (©2020 American Association for Cancer Research.)

Introduction: Radical cystectomy (RC) is a highly morbid procedure, with 30-day complication rates approaching 31%. Our objective was to determine risk factors for re-operation within 30 days following a RC for non-metastatic bladder cancer., Methods: We included all patients who underwent a RC for non-metastatic bladder cancer using The American College of Surgeons National Surgical Quality Improvement Program database between January 1, 2007 and December 31, 2014. Logistic regression analyses were used to evaluate predictors of re-operation., Results: A total of 2608 patients were included; 5.8% of patients underwent re-operation within 30 days. On multivariable analysis, increasing body mass index (BMI) (odds ratio [OR] 1.04, 95% confidence interval [CI] 1.01-1.07), African American race (vs. Caucasian OR 2.29, 95% CI 1.21-4.34), and history of chronic obstructive pulmonary disease (COPD) (OR 2.33, 95% CI 1.45-3.74) were significant predictors of re-operation within 30 days of RC. Urinary diversion type (ileal conduit vs. continent) and history of chemotherapy or radiotherapy within 30 days prior to RC were not. Patients who underwent re-operation within this timeframe had a significantly higher mortality rate (4.0% vs. 1.6%) and were more likely to experience cardiac (7.2% vs. 1.9%), pulmonary (23.0% vs. 3.0%), neurological (2.0% vs. 0.49%), and venous thromboembolic events (10.5% vs. 5.4%), as well as infectious complications (64.5% vs. 24.1%), with a significantly longer hospital length of stay (16.5 vs. 7.0 days)., Conclusions: Recognizing increasing BMI, COPD, and African American race as risk factors for re-operation within 30 days of RC will allow urologists to preoperatively identify such high-risk patients and prompt them to adopt more aggressive approaches to minimize postoperative surgical complications.

Regular menstrual shedding and repair of the endometrial functionalis is unique to humans and higher-order primates. The current consensus postulates endometrial glands to have a single-tubular architecture, where multi-potential stem cells reside in the blind-ending glandular-bases. Utilising fixed samples from patients, we have studied the three-dimensional (3D) micro-architecture of the human endometrium. We demonstrate that some non-branching, single, vertical functionalis glands originate from a complex horizontally interconnecting network of basalis glands. The existence of a multipotent endometrial epithelial stem cell capable of regenerating the entire complement of glandular lineages was demonstrated by in vivo lineage tracing, using naturally occurring somatic mitochondrial DNA mutations as clonal markers. Vertical tracking of mutated clones showed that at least one stem-cell population resides in the basalis glands. These novel findings provide insight into the efficient and scar-less regenerative potential of the human endometrium. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)

Aim: To explore how nurses, who are the principal character of zombie-focused feature films are portrayed., Design: A mixed methods study with a quantitative exploration of 44,000 feature film synopsis and additional online material for films made between 1900 and 2018 was used. Zombie-focused films (485) were reviewed for their genre, county, year of production, and plot-lines. Ten zombie films featuring nurses in key roles were analysed via an interpretive, qualitative thematic analysis. The study was undertaken between May 2018 - November 2018., Method: A quantitative review of film synopses and relevant movie specific web sites or key literature for the word, 'zombie' and/or 'zombie nurse' and an interpretive, qualitative thematic analysis of nurse specific zombie films., Results: Most of the 485 zombie-focused films located were produced or co-produced in the USA. Only 115 zombie-focused feature films were identified with health professionals, of these, 27 films featured nurses, 10 with nurses in the main role. Nurses were portrayed as romantic, sexualized, caring, self-sacrificial and strong or evil, however, the over-arching representation of nurses in zombie films was tied to the depravity from which zombie sub-culture is based., Conclusion: Few zombie films feature nurses in the main role. However, the negative, violent and deprived nature of this genre offers a poor reflection on nursing., Impact: How nurses are portrayed in films is important because it influences how the public, patients, and nurses themselves view their profession and role. Understanding the way nurses are portrayed may help professional bodies to better prepare recruitment material., (© 2019 John Wiley & Sons Ltd.)

Spliceosomal dysregulation dramatically affects many cellular processes, notably signal transduction, metabolism, and proliferation, and has led to the concept of targeting intracellular spliceosomal proteins to combat cancer. Here we show that a subset of lymphoma cells displays a spliceosomal complex on their surface, which we term surface spliceosomal complex (SSC). The SSC consists of at least 13 core components and was discovered as the binding target of the non-Hodgkin's lymphoma-specific aptamer C10.36. The aptamer triggers SSC internalization, causing global changes in alternative splicing patterns that eventually lead to necrotic cell death. Our study reveals an exceptional spatial arrangement of a spliceosomal complex and defines it not only as a potential target of anti-cancer drugs, but also suggests that its localization plays a fundamental role in cell survival., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Spotted-wing Drosophila, Drosophila suzukii (Matsumura) (Diptera: Drosophilidae) is a vinegar fly introduced unintentionally into the United States. Since 2008, D. suzukii has reduced annual berry yields from 6 to 100%. Effective control of D. suzukii during harvest requires weekly applications of low-residual, broad-spectrum insecticides that are unavailable for organic farming. A novel ingestible insecticide, a 4-carbon polyol, mesoerythritol (erythritol), was found to kill 75 to 100% of larval and adult D. suzukii. However, mesoerythritol, at effective concentrations (0.5-1.0M), may be cost-prohibitive. Therefore, we conducted laboratory tests to assess the effects of lower cost derivatives of erythritol, namely the pentaerythritol series of 1,3-diols on D. suzukii pupal production, adult production, adult mortality, brood output, and reproductive increase. We then selected the two most promising compounds for a field test on fruiting rabbiteye blueberry. From 90 to 100% of adults died when fed food moistened with 1M solutions of mesoerythritol and pentaerythritol. Mesoerythritol and dipentaerythritol at a concentration of 1M were ovicidal/larvicidal, killing ≥85% of immatures. Overall, 1M mesoerythritol killed 80% or more larvae and adults, thus bringing populations to near zero. The heaviest compound of this series, tripentaerythritol, at all concentrations, was largely benign to both adults and immatures. Thus, we cannot recommend tripentaerythritol for D. suzukii control. In a blueberry field, 0.5M mesoerythritol and 0.5M pentaerythritol, each by themselves, reduced egg infestation by 64% and larval infestation by 93%; their combination (0.25M mesoerythritol and 0.25M pentaerythritol) achieved even greater egg control with 82% fewer eggs infesting blueberry fruits.

Increasing numbers of those living with and beyond cancer presents a clinical challenge for pain specialists. A large proportion of these patients experience pain secondary to their disease or its treatment, impeding rehabilitation and significantly impacting upon their quality of life. The successful management of this pain presents a considerable challenge. This review aims to outline current concepts and treatment options, while considering nuances within pain assessment and the use of large-scale data to help guide further advances.

Ten infrequently monitored antibiotics in biosolids were examined in archived American sewage sludges (n = 79) collected as part of the 2006/2007 U.S. Environmental Protection Agency (EPA) Targeted National Sewage Sludge Survey. This study inspected the occurrence of amoxicillin, ampicillin, erythromycin, furazolidone [proxy metabolite: 3-(2-nitrobenzylidenamino)-2-oxazolidinone (NP-AOZ)], nalidixic acid, oxolinic acid, oxytetracycline, spiramycin, sulfadimidine, and sulfadimethoxine in sewage sludges after nearly a decade in frozen storage. Six antibiotics were detected at the following average concentrations (ng/g dry weight): amoxicillin (1.0), nalidixic acid (19.1), oxolinic acid (2.7), erythromycin (0.6), oxytetracycline (4.5), and ampicillin (14.8). The remaining four were not detected in any samples (

Public health researchers are often tasked with accurately and quickly identifying the location and time when an epidemic originated from a representative sample of nucleotide sequences. In this paper, we investigate multiple approaches to subsampling the sequence set when employing a Bayesian phylogeographic generalized linear model. Our results indicate that near-categorical posterior MCC estimates on the root can be obtained with replicate runs using 25-50% of the sequence data, and that including 90% of sequences does not necessarily entail more accurate inferences. We present the first analysis of predictor signal suppression and show how the ability to detect the influence of predictor variables is limited when sample size predictors are included in the models., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Human ear reconstruction is recognized as the emblematic enterprise in tissue engineering. Up to now, it has failed to reach human applications requiring appropriate tissue complexity along with an accessible vascular tree. We hereby propose a new method to process human auricles in order to provide a poorly immunogenic, complex and vascularized ear graft scaffold., Methods: 12 human ears with their vascular pedicles were procured. Perfusion-decellularization was applied using a SDS/polar solvent protocol. Cell and antigen removal was examined by histology and DNA was quantified. Preservation of the extracellular matrix (ECM) was assessed by conventional and 3D-histology, proteins and cytokines quantifications. Biocompatibility was assessed by implantation in rats for up to 60 days. Adipose-derived stem cells seeding was conducted on scaffold samples and with human aortic endothelial cells whole graft seeding in a perfusion-bioreactor., Results: Histology confirmed cell and antigen clearance. DNA reduction was 97.3%. ECM structure and composition were preserved. Implanted scaffolds were tolerated in vivo, with acceptable inflammation, remodeling, and anti-donor antibody formation. Seeding experiments demonstrated cell engraftment and viability., Conclusions: Vascularized and complex auricular scaffolds can be obtained from human source to provide a platform for further functional auricular tissue engineered constructs, hence providing an ideal road to the vascularized composite tissue engineering approach., Statement of Significance: The ear is emblematic in the biofabrication of tissues and organs. Current regenerative medicine strategies, with matrix from donor tissues or 3D-printed, didn't reach any application for reconstruction, because critically missing a vascular tree for perfusion and transplantation. We previously described the production of vascularized and cell-compatible scaffolds, from porcine ear grafts. In this study, we ---- applied findings directly to human auricles harvested from postmortem donors, providing a perfusable matrix that retains the ear's original complexity and hosts new viable cells after seeding. This approach unlocks the ability to achieve an auricular tissue engineering approach, associated with possible clinical translation., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The use of generalized linear models in Bayesian phylogeography has enabled researchers to simultaneously reconstruct the spatiotemporal history of a virus and quantify the contribution of predictor variables to that process. However, little is known about the sensitivity of this method to the choice of the discrete state partition. Here we investigate this question by analyzing a data set containing 299 sequences of the West Nile virus envelope gene sampled in the United States and fifteen predictors aggregated at four spatial levels. We demonstrate that although the topology of the viral phylogenies was consistent across analyses, support for the predictors depended on the level of aggregation. In particular, we found that the variance of the predictor support metrics was minimized at the most precise level for several predictors and maximized at more sparse levels of aggregation. These results suggest that caution should be taken when partitioning a region into discrete locations to ensure that interpretable, reproducible posterior estimates are obtained. These results also demonstrate why researchers should use the most precise discrete states possible to minimize the posterior variance in such estimates and reveal what truly drives the diffusion of viruses.

Assessing the phenotypic diversity underlying tumour progression requires the identification of variations in the respective molecular interaction networks. Here we report proof-of-concept for a platform called poly-ligand profiling (PLP) that surveys these system states and distinguishes breast cancer patients who did or did not derive benefit from trastuzumab. We perform tissue-SELEX on breast cancer specimens to enrich single-stranded DNA (ssDNA) libraries that preferentially interact with molecular components associated with the two clinical phenotypes. Testing of independent sample sets verifies the ability of PLP to classify trastuzumab-treated patients according to their clinical outcomes with ROC-AUC of 0.78. Standard HER2 testing of the same patients gives a ROC-AUC of 0.47. Kaplan-Meier analysis reveals a median increase in benefit from trastuzumab-containing treatments of 300 days for PLP-positive compared to PLP-negative patients. If prospectively validated, PLP may increase success rates in precision oncology and clinical trials, thus improving both patient care and drug development.

Topical prevention of HIV and other STIs is a global health priority. To provide options for users, developers have worked to design safe, effective and acceptable vaginal dissolving film formulations. We aimed to characterize user experiences of vaginal film size, texture and color, and their role in product-elicited sensory perceptions (i.e. perceptibility), acceptability and willingness to use. In the context of a user-centered product evaluation study, we elicited users' 'first impressions' of various vaginal film formulation designs via visual and tactile prototype inspection during a qualitative user evaluation interview. Twenty-four women evaluated prototypes. Participants considered size and texture to be important for easy insertion. Color was more important following dissolution than prior to insertion. When asked to combine and balance all properties to arrive at an ideal film, previously stated priorities for individual characteristics sometimes shifted, with the salience of some individual characteristics lessening when multiple characteristics were weighted in combination. While first impressions alone may not drive product uptake, users' willingness to initially try a product is likely impacted by such impressions. Developers should consider potential users' experiences and preferences in vaginal film design. This user-focused approach is useful for characterizing user sensory perceptions and experiences relevant to early design of prevention technologies.

Aim: To investigate if the early treatment effects of radiofrequency ablation (RFA) on renal cell carcinoma (RCC) can be detected with dynamic contrast enhanced (DCE)-MRI and to correlate RCC perfusion with RFA treatment time., Materials and Methods: 20 patients undergoing RFA of their 21 RCCs were evaluated with DCE-MRI before and at one month after RFA treatment. Perfusion was estimated using the maximum slope technique at two independent sittings. Total RCC blood flow was correlated with total RFA treatment time, tumour location, size and histology., Results: DCE-MRI examinations were successfully evaluated for 21 RCCs (size from 1.3 to 4 cm). Perfusion of the RCCs decreased significantly ( p < 0.0001) from a mean of 203 (±80) mL/min/100 mL before RFA to 8.1 (±3.1) mL/min/100 mL after RFA with low intra-observer variability ( r ≥ 0.99, p < 0.0001). There was an excellent correlation ( r = 0.95) between time to complete ablation and pre-treatment total RCC blood flow. Tumours with an exophytic location exhibit the lowest mean RFA treatment time., Conclusion: DCE-MRI can detect early treatment effects by measuring RCC perfusion before and after RFA. Perfusion significantly decreases in the zone of ablation, suggesting that it may be useful for the assessment of treatment efficacy. Pre-RFA RCC blood flow may be used to predict RFA treatment time., Competing Interests: The authors declare no conflicts of interest.

Objectives: Margin status and invasion pattern are prognostic factors for oral tongue squamous cell carcinoma (OTSCC). Current methods to identify these factors are limited to 2D observation; it is necessary to explore 3D reconstruction with whole-mount sample to improve the accuracy of analysis. This study aimed to study the tissue preparation, section generation, and 3D reconstruction with whole-mount OTSCC specimen., Study Design: Two OTSCC samples were retrieved from Nanjing Stomatological Hospital, Medical School of Nanjing University. One sample was sliced into 3 equal-sized pieces and subjected to different processing schedules to determine the best method. The second sample was processed accordingly. Serial whole-mount sections of the second sample were generated, stained with HE/anticytokine antibody in intersection manner, and scanned into digital images. Digital images were aligned and reconstructed into 3D images with Hetero Genius Medical Image Manager 3D Pathology Add-On [HGMIM3D]., Results: Successful serial whole-mount sections of comparable quality to traditional sections were generated. Three-dimensional images with serial whole-mount sections were successfully generated., Conclusions: Whole-mount histopathological 3D reconstruction of OTSCC was successfully generated, providing a solid foundation for comprehensive margin and invasion analysis. Although future study and improvement were needed, whole-mount histopathological 3D reconstruction proved to be a promising method in OTSCC study., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

After decades on the margins of primary health care, surgical and anaesthesia care is gaining increasing priority within the global development arena. The 2015 publications of the Disease Control Priorities third edition on Essential Surgery and the Lancet Commission on Global Surgery created a compelling evidenced-based argument for the fundamental role of surgery and anaesthesia within cost-effective health systems strengthening global strategy. The launch of the Global Alliance for Surgical, Obstetric, Trauma, and Anaesthesia Care in 2015 has further coordinated efforts to build priority for surgical care and anaesthesia. These combined efforts culminated in the approval of a World Health Assembly resolution recognizing the role of surgical care and anaesthesia as part of universal health coverage. Momentum gained from these milestones highlights the need to identify consensus goals, targets and indicators to guide policy implementation and track progress at the national level. Through an open consultative process that incorporated input from stakeholders from around the globe, a global target calling for safe surgical and anaesthesia care for 80% of the world by 2030 was proposed. In order to achieve this target, we also propose 15 consensus indicators that build on existing surgical systems metrics and expand the ability to prioritize surgical systems strengthening around the world.

Purpose: The aim of this work was to quantify the extent of lipid-rich necrotic core (LRNC) and intraplaque hemorrhage (IPH) in atherosclerotic plaques., Methods: Patients scheduled for carotid endarterectomy underwent four-point Dixon and T1-weighted magnetic resonance imaging (MRI) at 3 Tesla. Fat and R2* maps were generated from the Dixon sequence at the acquired spatial resolution of 0.60 × 0.60 × 0.70 mm voxel size. MRI and three-dimensional (3D) histology volumes of plaques were registered. The registration matrix was applied to segmentations denoting LRNC and IPH in 3D histology to split plaque volumes in regions with and without LRNC and IPH., Results: Five patients were included. Regarding volumes of LRNC identified by 3D histology, the average fat fraction by MRI was significantly higher inside LRNC than outside: 12.64 ± 0.2737% versus 9.294 ± 0.1762% (mean ± standard error of the mean [SEM]; P < 0.001). The same was true for IPH identified by 3D histology, R2* inside versus outside IPH was: 71.81 ± 1.276 s -1 versus 56.94 ± 0.9095 s -1 (mean ± SEM; P < 0.001). There was a strong correlation between the cumulative fat and the volume of LRNC from 3D histology (R 2  = 0.92) as well as between cumulative R2* and IPH (R 2  = 0.94)., Conclusion: Quantitative mapping of fat and R2* from Dixon MRI reliably quantifies the extent of LRNC and IPH. Magn Reson Med 78:285-296, 2017. © 2016 International Society for Magnetic Resonance in Medicine., (© 2016 International Society for Magnetic Resonance in Medicine.)

The risk and benefits of gain-of-function studies on influenza A have been widely debated since 2012 when the methods to create two respiratory transmissible H5N1 mutant isolates were published. Opponents of gain-of-function studies argue the biosecurity risk is unacceptable, while proponents cite potential uses for pandemic surveillance, preparedness and mitigation. In this commentary, we provide an overview of the background and applications of gain-of-function research and argue that the anticipated benefits have yet to materialize while the significant risks remain., (© 2017 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)