Diagnosis of superficial endometriosis on transvaginal ultrasound by visualization of peritoneum of pouch of Douglas.

OBJECTIVE: Around 80% of women with endometriosis have superficial endometriosis (SE) rather than ovarian or deep endometriosis (DE). However, to date, advances in non-invasive, imaging-based diagnosis have been limited to DE or ovarian disease. The objective of this study was to determine whether we can detect SE on transvaginal ultrasound scan (TVS) by assessing the peritoneum of the pouch of Douglas (POD). METHODS: This was a retrospective diagnostic test study following a change in practice to include POD peritoneum assessment for SE during TVS at a tertiary London hospital. Eligible patients underwent TVS by a single clinician trained in endometriosis scanning and a subsequent surgical procedure (laparoscopy) between April 2018 and September 2021. Participants formed a consecutive series. The TVS findings were compared with those of laparoscopy as the gold standard. Comparison of TVS findings with intraoperative findings was performed by calculating the diagnostic test performance measures (sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and positive and negative likelihood ratios). RESULTS: The study included a total of 100 patients. We found that 43/100 (43.0%) patients had no endometriosis, 33/100 (33.0%) had SE and 24/100 (24.0%) had DE on laparoscopy. SE was correctly detected on TVS in 17/33 patients, with a sensitivity of 51.5% (95% CI, 33.5-69.2%), specificity of 94.0% (95% CI, 85.4-98.4%), PPV of 81.0% (95% CI, 60.8-92.1%) and NPV of 79.7% (95% CI, 73.4-84.9%). DE was correctly diagnosed in 20/24 cases, including all ovarian cases, with a sensitivity of 83.3% (95% CI, 62.3-95.3%), specificity of 97.4% (95% CI, 90.8-99.7%), PPV of 90.9% (95% CI, 71.6-97.5%) and NPV of 94.9% (95% CI, 88.3-97.8%). The detection of SE on TVS was most accurate in the POD (sensitivity, 50.0%; specificity, 96.4%; PPV, 76.9%; NPV, 88.9%). CONCLUSIONS: This study shows that the detection of SE in the POD is possible using routine TVS. While negative TVS does not reliably confirm the absence of disease or replace diagnostic laparoscopy, positive TVS facilitates non-invasive diagnosis for a much larger group of women than was previously possible. This should help to reduce the time from the onset of symptoms to diagnosis and enable initiation of medical treatment without the risk, cost and delay associated with a surgical diagnosis. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Microfluidic Digital Quantitative PCR to Measure Internal Cargo of Individual Liposomes.

Lipid nanoparticles serve as drug delivery vehicles for biopharmaceutical products. The lipid membrane shields internal nucleic-acid drug cargo from enzymatic degradation and facilitates cellular uptake of the drug. However, existing methods to assess drug loading within liposomes are limited to averaged bulk measurements, which obscures heterogeneity of the biopharmaceutical formulation. This report describes the development of a single-liposome analysis method to measure copy numbers of DNA within liposomes and assess population heterogeneity. This novel measurement was achieved by integrating two orthogonal polymerase chain reaction (PCR) techniques─digital PCR (dPCR) and quantitative PCR (qPCR)─within a single microfluidic assay. The dPCR dimension quantified liposomes to validate their capture in the single-liposome analysis regime. The qPCR dimension quantified DNA copy numbers packaged within each liposome. The ability of digital quantitative PCR (dqPCR) to analyze large numbers of individual liposomes in parallel revealed significant population heterogeneity, which could not be obtained from standard bulk analysis methods. Our innovative measurement of internal DNA cargo from single liposomes has the potential to inform liposome synthesis procedures and create more uniform liposomal biopharmaceutical formulations to enhance drug safety and efficacy.

Mycobacterium avium subsp. hominissuis (MAH) Microaggregate induction of host innate immunity is linked to biofilm formation.

Bacterial aggregation is a strategy employed by many pathogens to establish infection. Mycobacterium avium subsp. hominissuis (MAH) undergoes a phenotypic change, microaggregation, when exposed to the respiratory epithelium. We therefore compared how non-aggregated bacteria, or planktonic, and microaggregated MAH can establish lung infections by evaluating mucosal epithelial cell and phagocytic cell responses. It was determined that human mucosal lung epithelial cells recognition of MAH occurs through toll-like receptors 1 and 2. MAPK 1/3 is phosphorylated at 30 min post infection, and active at the transcriptional level 2 h post infection for both phenotypes. Microaggregate infected BEAS-2B cells up-regulated CCL5, IL-1ß, and TNF-α cDNA, while planktonic infected cells only up-regulated IL-1ß cDNA at 2 h post infection. Microaggregates are associated with increased uptake by macrophages after 1 h compared to planktonic bacteria (8.83% vs. 5.00%, P < 0.05). In addition, the microaggregate phenotype, when internalized by macrophages, had reduced growth compared to planktonic bacteria, which increased when the host cells were exposed to microaggregate supernatant, obtained from the incubation of MAH with HEp-2 cells. Moreover, microaggregate supernatant stimulated biofilm formation by planktonic and microaggregated bacteria. Microaggregate supernatant also induces the production of both pro- and anti-inflammatory cytokines, which was suppressed following MAH infection. The results suggest that epithelial recognition occurs during MAH infection, and the microaggregate phenotype stimulates an inflammatory response. The initial bacterial interaction with the mucosal epithelium and development of the microaggregate phenotype has a role in pathogenesis, allowing for more robust biofilm formation and infection establishment.

Comparison of Two Methods for Implementing Comfort Care Order Sets in the Inpatient Setting: a Cluster Randomized Trial.

BACKGROUND: There is an ongoing need for interventions to improve quality of end-of-life care for patients in inpatient settings. OBJECTIVE: To compare two methods for implementing a Comfort Care Education Intervention for Palliative Care Consultation Teams (PCCT) in Veterans Affairs Medical Centers (VAMCs). DESIGN: Cluster randomized implementation trial conducted March 2015-April 2019. PCCTs were assigned to a traditional implementation approach using a teleconference or to an in-person, train-the-champion workshop to prepare PCCTs to be clinical champions at their home sites. PARTICIPANTS: One hundred thirty-two providers from PCCTs at 47 VAMCs. INTERVENTIONS: Both training modalities involved review of educational materials, instruction on using an electronic Comfort Care Order Set, and coaching to deliver the intervention to other providers. MAIN MEASUREMENTS: Several processes of care were identified a priori as quality endpoints for end-of-life care (last 7 days) and abstracted from medical records of veterans who died within 9 months before or after implementation (n = 6,491). The primary endpoint was the presence of an active order for opioid medication at time of death. Secondary endpoints were orders/administration of antipsychotics, benzodiazepines, and scopolamine, do-not-resuscitate orders, advance directives, locations of death, palliative care consultations, nasogastric tubes, intravenous lines, physical restraints, pastoral care visits, and family presence at/near time of death. Generalized estimating equations were conducted adjusting for potential covariates. KEY RESULTS: Eighty-eight providers from 23 VAMCs received teleconference training; 44 providers from 23 VAMCs received in-person workshop training. Analyses found no significant differences between intervention groups in any process-of-care endpoints (primary endpoint AOR (CI) = 1.18 (0.74, 1.89). Furthermore, pre-post changes were not significant for any endpoints (primary endpoint AOR (CI) = 1.16 (0.92, 1.46). Analyses may have been limited by high baseline values on key endpoints with little room for improvement. CONCLUSION: Findings suggest the clinical effectiveness of palliative care educational intervention was not dependent on which of the two implementation methods was used. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02383173.

The Relationship of Post-traumatic Stress Disorder to End-of-life Care Received by Dying Veterans: a Secondary Data Analysis.

BACKGROUND: Post-traumatic stress disorder (PTSD) can be exacerbated by subsequent trauma, but it is unclear if symptoms are worsened by impending death. PTSD symptoms, including hyperarousal, negative mood and thoughts, and traumatic re-experiencing, can impact end-of-life symptoms, including pain, mood, and poor sleep. Thus, increased symptoms may lead to increased end-of-life healthcare utilization. OBJECTIVES: To determine if veterans with PTSD have increased end-of-life healthcare utilization or medication use and to examine predictors of medication administration. DESIGN: Secondary analysis of a stepped-wedge design implementation trial to improve end-of-life care for Veterans Affairs (VA) inpatients. Outcome variables were collected via direct chart review. Analyses included hierarchical, generalized estimating equation models, clustered by medical center. SUBJECTS: Veterans, inpatient at one of six VA facilities, dying between 2005 and 2011. MAIN MEASURES: Emergency room (ER) visits, hospitalizations, and medication administration in the last 7 days of life. KEY RESULTS: Of 5341 veterans, 468 (8.76%) had PTSD. Of those, 21.4% (100/468) had major depression and 36.5% (171/468) had anxiety. Veterans with PTSD were younger (mean age 65.4 PTSD, 70.5 no PTSD, p < 0.0001) and had more VA hospitalizations and ER visits in the last 12 months of life (admissions: PTSD 2.8, no PTSD 2.4, p < 0.0001; ER visits: 3.2 vs 2.5, p < 0.0001). PTSD was associated with antipsychotic administration (OR 1.52, 95% CI 1.06-2.18). Major depression (333/5341, 6.2%) was associated with opioid administration (OR 1.348, 95% CI 1.129-1.609) and benzodiazepines (OR 1.489, 95% CI 1.141-1.943). Anxiety disorders (778/5341, 14.6%) were only associated with benzodiazepines (OR 1.598, 95% CI 1.194-2.138). CONCLUSIONS: PTSD's association with increased end-of-life healthcare utilization and increased antipsychotic administration in the final days of life suggests increased symptom burden and potential for terminal delirium in individuals with PTSD. Understanding the burden of psychiatric illness and potential risks for delirium may facilitate the end-of-life care for these patients. TRIAL REGISTRATION: NCT00234286.

Influence of microfabrication on digital PCR performance in bead-based microwell array assays.

Digital PCR (dPCR) is a highly sensitive analytical technique used to quantify DNA targets. Detection sensitivity can be further enhanced by capturing target sequences onto beads for preconcentration and sample cleanup prior to analysis in microfluidic microwell arrays. However, robust digital analysis requires individual beads to be interrogated within individual wells. Fabricating microwells with dimensions ≤ 3 µm is challenging, and the high surface area-to-volume ratio of the wells leaves PCR susceptible to inhibition stemming from materials used during device processing. This report describes the development of a microfabrication procedure to create ultralow-volume wells (100 fL) for bead-based dPCR and characterize the effects of microprocessing materials on assay performance. Standard microfabrication protocols used for creating microelectronics resulted in devices with nanoscopic debris originating from photoresists used during processing. A model dPCR assay was developed to characterize the effects of this debris, which revealed variable PCR inhibition. Debris within microwells attenuated digital and analog assay signals to a greater extent than debris on the device surface. Spatial heterogeneity of debris across devices was quantified to characterize regional PCR inhibition and intra- and inter-device variability. Ultimately, a fabrication procedure was developed to create pristine microfluidic arrays using dual processes to remove positive resist and forgoing use of negative resist entirely, which enabled robust amplification with digital signals matching theoretical predictions. Results from this work catalog the unique performance artifacts from device microfabrication and provide a guide for future studies seeking to conduct robust, high-sensitivity bead-based dPCR assays. Graphical abstract.

"They Said on the Death Certificate But Really What I Think Happened": Characterizing Cause of Death in VA Medical Centers.

Cause of death information is a vital resource for family and public health, yet significant issues persist regarding its determination, documentation and communication. In this study, we aim to characterize cause of death attribution process from the perspective of next-of-kin of Veterans who died in Veterans Affairs (VA) Medical Centers. Using a semi-structured guide, we explored next-of-kin's experiences of the Veteran's terminal hospitalization and conducted a content analysis of interview texts. In over two-third of cases next-of-kin's understanding was not consistent with their recollection of physicians' determination of cause of death. Discrepancies between official cause of death and lay understanding engendered confusion and distress. Findings have relevance for shaping the context of post-death patient/family-centered clinical practice and serve as a means for improving efficacy of cause of death communication and reducing potential for misunderstandings.

"He's on his dying bed": Next-of-kin's experiences of the dying body.

For family members of dying patients who have grown accustomed to providing daily body care, the transition from home to hospital is stressful. The authors used the experiences surrounding death for 78 U.S. veterans who died in a Veterans Affairs hospital. The research is based on interviews conducted with the decedent's next-of-kin. Secondary qualitative analysis of previously-coded transcribed interviews was used. Themes of social disorganization and a loss of control over the body emerged. Next-of-kin experienced the physical and functional breakdown of their loved one's body. Understanding the nature of the loss of control may help alleviate the loss of control may help alleviate the strain on families.

"I was ready to take him home": next-of-kin's accounts of loved one's death during hospice and palliative care discussions in Veterans Affairs Medical Centers.

This study explored next-of-kin's retrospective accounts of hospice and palliative care discussions for hospitalized veterans. In-depth, face-to-face interviews were used to generate narrative accounts of 78 next-of-kin's experience of their loved one's hospital care during the last days of the patient's life. One-third of participants reported taking part in a hospice or palliative care discussion during the patient's final hospitalization. In over one-half of those cases, the patients died before discharge or transfer to hospice or palliative care was accomplished. Hospice and palliative care discussions in the hospital setting shaped family perceptions of the patients' care, directed family efforts in the days prior to death, and engendered anticipation of remaining quality time with the patient. Discussions about hospice or palliative care have meaning, emotional impact, practical effects, and unintended consequences for next-of-kin. Social workers in hospital settings can play a critical role in supporting family members through the hospice and palliative care discussion process and facilitate timely care transitions. They also can attend to the psychosocial concerns of family members, particularly when death occurs prior to discharge to hospice or transfer to an inpatient palliative care service.

Intervention to improve care at life's end in inpatient settings: the BEACON trial.

BACKGROUND: Widespread implementation of palliative care treatment plans could reduce suffering in the last days of life by adopting best practices of traditionally home-based hospice care in inpatient settings. OBJECTIVE: To evaluate the effectiveness of a multi-modal intervention strategy to improve processes of end-of-life care in inpatient settings. DESIGN: Implementation trial with an intervention staggered across hospitals using a multiple-baseline, stepped wedge design. PARTICIPANTS: Six Veterans Affairs Medical Centers (VAMCs). INTERVENTION: Staff training was targeted to all hospital providers and focused on identifying actively dying patients and implementing best practices from home-based hospice care, supported with an electronic order set and paper-based educational tools. MAIN MEASURES: Several processes of care were identified as quality endpoints for end-of-life care (last 7 days) and abstracted from electronic medical records of veterans who died before or after intervention (n = 6,066). Primary endpoints were proportion with an order for opioid pain medication at time of death, do-not-resuscitate order, location of death, nasogastric tube, intravenous line infusing, and physical restraints. Secondary endpoints were administration of opioids, order/administration of antipsychotics, benzodiazepines, and scopolamine (for death rattle); sublingual administration; advance directives; palliative care consultations; and pastoral care services. Generalized estimating equations were conducted adjusting for longitudinal trends. KEY RESULTS: Significant intervention effects were observed for orders for opioid pain medication (OR: 1.39), antipsychotic medications (OR: 1.98), benzodiazepines (OR: 1.39), death rattle medications (OR: 2.77), sublingual administration (OR: 4.12), nasogastric tubes (OR: 0.71), and advance directives (OR: 1.47). Intervention effects were not significant for location of death, do-not-resuscitate orders, intravenous lines, or restraints. CONCLUSIONS: This broadly targeted intervention strategy led to modest but statistically significant changes in several processes of care, indicating its potential for widespread dissemination to improve end-of-life care for thousands of patients who die each year in inpatient settings.

Formative evaluation of a multi-component, education-based intervention to improve processes of end-of-life care.

A multicomponent, palliative care, education-based intervention was implemented in six Veterans Affairs Medical Centers in the southeast United States. The intervention comprised onsite staff training plus supporting written materials, installation of an electronic order set, and follow-up consultations. Training included large-group didactic presentations, small-group clinical demonstrations, and one-on-one consultations. The intervention strategy was targeted broadly to hundreds of hospital providers, including physician, nursing, and ancillary staff. The purpose was to train staff in identifying actively dying patients and implementing best practices of home-based hospice care. A formative evaluation was conducted utilizing semistructured telephone interviews with key informants from each site. Qualitative data analysis revealed processes that facilitated or impeded uptake of the intervention. Results will be used to inform ongoing and future clinical initiatives and optimize future implementation of education-based interventions to improve adoption of best practices for end-of-life care within acute care settings.

A Report on the Innovative University of Colorado Community Hospice and Palliative Medicine Fellowship.

Background: Predictive health services modeling signals a shortage of board-certified Hospice and Palliative Medicine (HPM) physicians. Methods: This article introduces the Community Hospice and Palliative Medicine (CHPM) Fellowship, an Accreditation Council for Graduate Medical Education (ACGME) Advancing Innovation in Residency Education (AIRE) project designed to enable mid-career physicians (at least five years out from residency or fellowship) to achieve eligibility for board certification in HPM. Results: From 2020 to 2023, 24 fellows have completed or are currently participating in the CHPM fellowship which is evaluated using the Kirkpatrick model. Conclusion: This program shows promise in addressing the impending HPM workforce shortage by allowing physicians to complete a fellowship in their local communities.

Tumor Subtype Classification Tool for HPV-associated Head and Neck Cancers.

Importance: Molecular subtypes of HPV-associated Head and Neck Squamous Cell Carcinoma (HNSCC), named IMU (immune strong) and KRT (highly keratinized), are well-recognized and have been shown to have distinct mechanisms of carcinogenesis, clinical outcomes, and potentially differing optimal treatment strategies. Currently, no standardized method exists to subtype a new HPV+ HNSCC tumor. Our paper introduces a machine learning-based classifier and webtool to reliably subtype HPV+ HNSCC tumors using the IMU/KRT paradigm and highlights the importance of subtype in HPV+ HNSCC. Objective: To develop a robust, accurate machine learning-based classification tool that standardizes the process of subtyping HPV+ HNSCC, and to investigate the clinical, demographic, and molecular features associated with subtype in a meta-analysis of four patient cohorts. Data Sources: We conducted RNA-seq on 67 HNSCC FFPE blocks from University of Michigan hospital. Combining this with three publicly available datasets, we utilized a total of 229 HPV+ HNSCC RNA-seq samples. All participants were HPV+ according to RNA expression. An ensemble machine learning approach with five algorithms and three different input training gene sets were developed, with final subtype determined by majority vote. Several additional steps were taken to ensure rigor and reproducibility throughout. Study Selection: The classifier was trained and tested using 84 subtype-labeled HPV+ RNA-seq samples from two cohorts: University of Michigan (UM; n=18) and TCGA-HNC (n=66). The classifier robustness was validated with two independent cohorts: 83 samples from the HPV Virome Consortium and 62 additional samples from UM. We revealed 24 of 39 tested clinicodemographic and molecular variables significantly associated with subtype. Results: The classifier achieved 100% accuracy in the test set. Validation on two additional cohorts demonstrated successful separation by known features of the subtypes. Investigating the relationship between subtype and 39 molecular and clinicodemographic variables revealed IMU is associated with epithelial-mesenchymal transition (p=2.25×10-4), various immune cell types, and lower radiation resistance (p=0.0050), while KRT is more highly keratinized (p=2.53×10-8), and more likely female than IMU (p=0.0082). Conclusions and Relevance: This study provides a reliable classifier for subtyping HPV+ HNSCC tumors as either IMU or KRT based on bulk RNA-seq data, and additionally, improves our understanding of the HPV+ HNSCC subtypes.

Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization.

Tumor-associated macrophages (TAMs) and other myelomonocytic cells are implicated in regulating responsiveness to immunotherapies, including immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis. We have developed an ex vivo high-throughput approach to discover modulators of macrophage-mediated T cell suppression, which can improve clinical outcomes of ICIs. We screened 1,430 Food and Drug Administration (FDA)-approved small-molecule drugs using a co-culture assay employing bone-marrow-derived macrophages (BMDMs) and splenic-derived T cells. This identified 57 compounds that disrupted macrophage-mediated T cell suppression. Seven compounds exerted prominent synergistic T cell expansion activity when combined with αPD-L1. These include four COX1/2 inhibitors and two myeloid cell signaling inhibitors. We demonstrate that the use of cyclooxygenase (COX)1/2 inhibitors in combination with αPD-L1 decreases tumor growth kinetics and enhances overall survival in triple-negative breast cancer (TNBC) tumor models in a CD8+ T cell-dependent manner. Altogether, we present a rationalized approach for identifying compounds that synergize with ICI to potentially enhance therapeutic outcomes for patients with solid tumors.

"He got his last wishes": ways of knowing a loved one's end-of-life preferences and whether those preferences were honored.

As a patient approaches death, family members often are asked about their loved one's preferences regarding treatment at the end of life. Advance care directives may provide information for families and surrogate decision makers; however, less than one-third of Americans have completed such documents. As the U.S. population continues to age, many surrogate decision makers likely will rely on other means to discern or interpret a loved one's preferences. While many surrogates indicate that they have some knowledge of their loved one's preferences, how surrogates obtain such knowledge is not well understood. Additionally, although research indicates that the emotional burden of end-of-life decision making is diminished when surrogates have knowledge that a loved one's preferences are honored, it remains unclear how surrogates come to know these preferences were carried out. The current study examined the ways that next of kin knew veterans' end-of-life preferences, and their ways of knowing whether those preferences were honored in Veteran Affairs Medical Center (VAMC) inpatient settings.

Understanding the Relationships Between Health Care Providers' Moral Distress and Patients' Quality of Death.

Introduction: Moral distress is a commonly recognized phenomenon among health care providers; however, the experience of moral distress by staff caring for patients who die during an acute care hospital stay has not been previously examined. It also remains unclear how the quality of a death may impact moral distress among these providers. Objectives: We sought to understand levels of moral distress experienced by intern physicians and nurses who provided care during a patient's final 48 hours of life, and how the perceived quality of death impacted moral distress. Materials and Methods: We utilized a mixed-method prospective cohort design, surveying nurses and interns following inpatient hospital deaths at an academic safety-net hospital in the United States. Participants completed surveys and answered open-ended questions to evaluate moral distress and the quality of the patient's death. Results: A total of 126 surveys were sent to nurses and interns caring for 35 patients who died, with 46 surveys completed. Overall moderate-to-high levels of moral distress were identified among participants, and we found that higher levels of moral distress correlated with lower perceived quality of death. We identified five themes in our qualitative analysis highlighting the challenges nurses and interns face in end-of-life care, including the following: poor communication, unexpected deaths, patient suffering, resource limitations, and failure to prioritize a patient's wishes or best interests. Conclusions: Nurses and interns experience moderate-to-high levels of moral distress when caring for dying patients. Lower quality of end-of-life care is associated with higher levels of moral distress.

Whole-genome CpG-resolution DNA Methylation Profiling of HNSCC Reveals Distinct Mechanisms of Carcinogenesis for Fine-scale HPV+ Cancer Subtypes.

DNA methylation is a vital early step in carcinogenesis. Most findings of aberrant DNA methylation in head and neck squamous cell carcinomas (HNSCC) are array based with limited coverage and resolution, and mainly explored by human papillomavirus (HPV) status, ignoring the high heterogeneity of this disease. In this study, we performed whole-genome bisulfite sequencing on a well-studied HNSCC cohort (n = 36) and investigated the methylation changes between fine-scaled HNSCC subtypes in relation to genomic instability, repetitive elements, gene expression, and key carcinogenic pathways. The previously observed hypermethylation phenotype in HPV-positive (HPV+) tumors compared with HPV-negative tumors was robustly present in the immune-strong (IMU) HPV+ subtype but absent in the highly keratinized (KRT) HPV+ subtype. Methylation levels of IMU tumors were significantly higher in repetitive elements, and methylation showed a significant correlation with genomic stability, consistent with the IMU subtype having more genomic stability and better prognosis. Expression quantitative trait methylation (cis-eQTM) analysis revealed extensive functionally-relevant differences, and differential methylation pathway analysis recapitulated gene expression pathway differences between subtypes. Consistent with their characteristics, KRT and HPV-negative tumors had high regulatory potential for multiple regulators of keratinocyte differentiation, which positively correlated with an expression-based keratinization score. Together, our findings revealed distinct mechanisms of carcinogenesis between subtypes in HPV+ HNSCC and uncovered previously ignored epigenomic differences and clinical implications, illustrating the importance of fine-scale subtype analysis in cancer. Significance: This study revealed that the previously observed hypermethylation of HPV(+) HNSCC is due solely to the IMU subtype, illustrating the importance of fine-scale subtype analysis in such a heterogeneous disease. Particularly, IMU has significantly higher methylation of transposable elements, which can be tested as a prognosis biomarker in future translational studies.

Mid-Career Training to Advance Palliative Care.

The demand for specialist palliative medicine physicians, advanced practice providers, and other team members outstrips supply. Traditional paths to specialty practice will not meet projected need. Therefore, innovation and research are required. One innovation is the training of midcareer professionals; those who have been in practice and want to change to palliative care. Barriers to leaving practice and returning to traditional training are high; not the least of which is the opportunity cost. In this roundtable, experts discuss what they have learned from current research, and point the way to additional needed research.