Virus-induced genetics revealed by multidimensional precision medicine transcriptional workflow applicable to COVID-19.

Precision medicine requires the translation of basic biological understanding to medical insights, mainly applied to characterization of each unique patient. In many clinical settings, this requires tools that can be broadly used to identify pathology and risks. Patients often present to the intensive care unit with broad phenotypes, including multiple organ dysfunction syndrome (MODS) resulting from infection, trauma, or other disease processes. Etiology and outcomes are unique to individuals, making it difficult to cohort patients with MODS, but presenting a prime target for testing/developing tools for precision medicine. Using multitime point whole blood (cellular/acellular) total transcriptomics in 27 patients, we highlight the promise of simultaneously mapping viral/bacterial load, cell composition, tissue damage biomarkers, balance between syndromic biology versus environmental response, and unique biological insights in each patient using a single platform measurement. Integration of a transcriptome workflow yielded unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms, highlighted by a unique case of virally induced genetics (VIG) within one of these 27 patients. The power of RNA-Seq to study unique patient biology while investigating environmental contributions can be a critical tool moving forward for translational sciences applied to precision medicine.

Pregnancy Interventions to Improve Birth Outcomes: What Are the Effects on Maternal Outcomes? A Scoping Review.

Objectives: Interventions in pregnancy are commonly evaluated for their effects on birth outcomes because maternal infection and poor nutrition are the primary contributors to adverse pregnancy outcomes, especially in low- and middle-income countries (LMICs). However, the extent to which such interventions directly impact maternal health and nutrition has not been succinctly characterized. Methods: We conducted a scoping review of systematic reviews and meta-analyses of 27 pregnancy interventions to summarize the evidence of impact on maternal outcomes. Results: Overall, these were reported incompletely, and we failed to find any evidence for eight interventions. Influenza vaccination, insecticide-treated bed nets, intermittent preventive treatment for malaria, anthelmintic therapy, and treatment of bacterial vaginosis, asymptomatic bacteriuria, and periodontal disease during pregnancy provided direct benefit to women, with reductions in infection risk. Nutritional interventions such as micronutrient supplementation and balanced energy and protein improved outcomes of maternal anemia and gestational weight gain, particularly in deficient populations. Calcium and low dose aspirin significantly reduced the risk of pre-eclampsia. Conclusion: These findings highlight antenatal interventions benefitting maternal health and provide insights into pathways for impacting birth and infant outcomes.

Spanish Medical Interpreters' Management of Challenges in End of Life Discussions.

OBJECTIVE: Professional medical interpreters facilitate patient understanding of illness, prognosis, and treatment options. Facilitating end of life discussions can be challenging. Our objective was to better understand the challenges professional medical interpreters face and how they affect the accuracy of provider-patient communication during discussions of end of life. METHODS: We conducted semi-structured interviews with professional Spanish medical interpreters. We asked about their experiences interpreting end of life discussions, including questions about values, professional and emotional challenges interpreting these conversations, and how those challenges might impact accuracy. We used a grounded theory, constant comparative method to analyze the data. Participants completed a short demographic questionnaire. RESULTS: Seventeen Spanish language interpreters participated. Participants described intensive attention to communication accuracy during end of life discussions, even when discussions caused emotional or professional distress. Professional strains such as rapid discussion tempo contributed to unintentional alterations in discussion content. Perceived non-empathic behaviors of providers contributed to rare, intentional alterations in discussion flow and content. CONCLUSION: We found that despite challenges, Spanish language interpreters focus intensively on accurate interpretation in discussions of end of life. PRACTICE IMPLICATIONS: Provider training on how to best work with interpreters in these important conversations could support accurate and empathetic interpretation.

Intensive Care Unit Nurse: Could We Call a Palliative Care Consult? Intensive Care Unit Provider: It's Too Early. Palliative Care Integration in the Intensive Care Unit: The Struggle to Translate Evidence Into Practice.

Despite evidence regarding the value of palliative care, there remains a translation-to-practice gap in the intensive care setting. The purpose of this article is to describe challenges and propose solutions to palliative care integration through the presentation and discussion of a critical care patient scenario. We also present recommendations for a collaborative palliative care practice framework that holds the potential to improve quality of life for patients and families. Collaborative palliative care is characterized by close working relationships with families, interprofessional intensive care unit healthcare teams, and palliative care specialists. The shortage of palliative care specialists has become a pressing policy and practice issue and highlights the importance of increasing primary palliative care delivery by the intensive care team. Underexplored aspects of collaborative palliative care delivery include the interprofessional communication required, identification of key skills, and expected outcomes. Increased recognition of intensive care unit palliative care as a process of engagement among nurses, providers, patients, and their family members heralds a vital culture shift toward collaborative palliative care. The interprofessional palliative specialist team has the expertise to support intensive care teams in developing their primary palliative skills and recognizing when specialist palliative care support is required. Promotion of strategic palliative care delivery through this collaborative framework has the potential to decrease suffering among patients and families and reduce moral distress among healthcare professionals.

ARID1A Mutations Promote P300-Dependent Endometrial Invasion through Super-Enhancer Hyperacetylation.

Endometriosis affects 1 in 10 women and is characterized by the presence of abnormal endometrium at ectopic sites. ARID1A mutations are observed in deeply invasive forms of the disease, often correlating with malignancy. To identify epigenetic dependencies driving invasion, we use an unbiased approach to map chromatin state transitions accompanying ARID1A loss in the endometrium. We show that super-enhancers marked by high H3K27 acetylation are strongly associated with ARID1A binding. ARID1A loss leads to H3K27 hyperacetylation and increased chromatin accessibility and enhancer RNA transcription at super-enhancers, but not typical enhancers, indicating that ARID1A normally prevents super-enhancer hyperactivation. ARID1A co-localizes with P300 at super-enhancers, and genetic or pharmacological inhibition of P300 in ARID1A mutant endometrial epithelia suppresses invasion and induces anoikis through the rescue of super-enhancer hyperacetylation. Among hyperactivated super-enhancers, SERPINE1 (PAI-1) is identified as an essential target gene driving ARID1A mutant endometrial invasion. Broadly, our findings provide rationale for therapeutic strategies targeting super-enhancers in ARID1A mutant endometrium.

Attitudes of Liver and Palliative Care Clinicians toward Specialist Palliative Care Consultation for Patients with End-Stage Liver Disease.

Objective: Delays in specialized palliative care (PC) consultation in end-stage liver disease (ESLD) patients may be explained by clinician attitudes toward PC. Our aim is to assess the attitudes of hepatology and liver transplant (HLT) and PC clinicians toward PC consultation and consultant roles in ESLD patient care. Methods: Clinician members of HLT and PC professional societies were surveyed. Using a five-point Likert scale, they rated their comfort level toward various PC consultant roles and their agreement with triggers for and reasons to defer PC consultation. Change in attitudes toward PC consultation resulting from liver transplant (LT) eligibility was evaluated. Results: A total of 311 HLT (6.2%) and 379 PC (8.1%) clinicians completed the survey. The vast majority of HLT clinicians (>80%) were comfortable if PC consultants palliate symptoms, provide support, or facilitate advance care planning in LT-ineligible patients. LT eligibility reduced HLT clinician comfort toward all PC consultant roles, except supportive care. A vast majority of PC clinicians (>90%) were comfortable assuming all PC roles, except pain management without opioids (43-51%). About 80% of HLT clinicians agree with PC consultation in LT-ineligible patients with decompensated cirrhosis or hepatocellular carcinoma (HCC), compared to 20-30% if LT ineligible. Common justifications for deferring PC consultation included mild disease, LT eligibility, unavailability of PC specialists, and lack of addressable palliative issues. Conclusions: Barriers to specialized PC consultation in ESLD include HLT clinician discomfort with PC consultant roles, patients' LT eligibility, perception that PC is end-of-life care, unclear triggers for PC consultation, and concern about opioid-based pain palliation.

ARID1A and PI3-kinase pathway mutations in the endometrium drive epithelial transdifferentiation and collective invasion.

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. Here we show that monoallelic loss of ARID1A in the mouse endometrial epithelium is sufficient for vaginal bleeding when combined with PI3K activation. Sorted mutant epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT). We further show that ARID1A is bound to promoters with open chromatin, but ARID1A loss leads to increased promoter chromatin accessibility and the expression of EMT genes. PI3K activation partially rescues the mesenchymal phenotypes driven by ARID1A loss through antagonism of ARID1A target gene expression, resulting in partial EMT and invasion. We propose that ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates, and that coexistent ARID1A and PI3K mutations promote epithelial transdifferentiation and collective invasion. Broadly, our findings support a role for collective epithelial invasion in the spread of abnormal endometrial tissue.

ARL1 and membrane traffic in Saccharomyces cerevisiae.

To examine the functions of the Arf-like protein, Arl1p, in Saccharomyces cerevisiae, a null allele, arl1delta::HIS3, was constructed in two strains. In one background only, loss of ARL1 resulted in temperature-sensitive (ts) growth (suppressed on high-osmolarity media). Allelic variation at the SSD1 locus accounted for differences between strains. Strains lacking ARL1 exhibited several defects in membrane traffic. First, arl1delta strains secreted less protein as measured by TCA-precipitable radioactivity found in the media of [(35)S]-labelled cells. A portion of newly synthesized carboxypeptidase Y (CPY) was secreted rather than correctly targeted to the vacuole. Uptake of the fluid-phase marker, lucifer yellow, was reduced. All these phenotypes were exacerbated in an ssd1 background. The ts phenotype of the arl1deltassd1 strain was suppressed by YPT1, the yeast Rab1a homologue, suggesting that ARL1 and YPT1 have partially overlapping functions. These findings demonstrate that ARL1 encodes a regulator of membrane traffic.