Serial Postoperative Circulating Tumor DNA Assessment Has Strong Prognostic Value During Long-Term Follow-Up in Patients With Breast Cancer.

PURPOSE: Here, we report the sensitivity of a personalized, tumor-informed circulating tumor DNA (ctDNA) assay (Signatera) for detection of molecular relapse during long-term follow-up of patients with breast cancer. METHODS: A total of 156 patients with primary breast cancer were monitored clinically for up to 12 years after surgery and adjuvant chemotherapy. Semiannual blood samples were prospectively collected, and analyzed retrospectively to detect residual disease by ultradeep sequencing using ctDNA assays, developed from primary tumor whole-exome sequencing data. RESULTS: Personalized Signatera assays detected ctDNA ahead of clinical or radiologic relapse in 30 of the 34 patients who relapsed (patient-level sensitivity of 88.2%). Relapse was predicted with a lead interval of up to 38 months (median, 10.5 months; range, 0-38 months), and ctDNA positivity was associated with shorter relapse-free survival (P < .0001) and overall survival (P < .0001). All relapsing triple-negative patients (n = 7/23) had a ctDNA-positive test within a median of 8 months (range, 0-19 months), while the 16 nonrelapsed patients with triple-negative breast cancer remained ctDNA-negative during a median follow-up of 58 months (range, 8-99 months). The four patients who had negative tests before relapse all had hormone receptor-positive (HR+) disease and conversely, five of the 122 nonrelapsed patients (all HR+) had an occasional positive test. CONCLUSION: Serial postoperative ctDNA assessment has strong prognostic value, provides a potential window for earlier therapeutic intervention, and may enable more effective monitoring than current clinical tests such as cancer antigen 15-3. Our study provides evidence that those with serially negative ctDNA tests have superior clinical outcomes, providing reassurance to patients with breast cancer. For select cases with HR+ disease, decisions about treatment management might require serial monitoring despite the ctDNA-positive result.

Does nurse use of a standardized flowsheet to document communication with advanced providers provide a mechanism to detect pulse oximetry failures? A retrospective study of electronic health record data.

BACKGROUND: Pulse oximetry guides clinical decisions, yet does not uniformly identify hypoxemia. We hypothesized that nursing documentation of notifying providers, facilitated by a standardized flowsheet for documenting communication to providers (physicians, nurse practitioners, and physician assistants), may increase when hypoxemia is present, but undetected by the pulse oximeter, in events termed "occult hypoxemia." OBJECTIVE: To compare nurse documentation of provider notification in the 4 h preceding cases of occult hypoxemia, normal oxygenation, and evident hypoxemia confirmed by an arterial blood gas reading. METHODS: We conducted a retrospective study using electronic health record data from patients with COVID-19 at five hospitals in a healthcare system with paired SpO2 and SaO2 readings (measurements within 10 min of oxygen saturation levels in arterial blood, SaO2, and by pulse oximetry, SpO2). We applied multivariate logistic regression to assess if having any nursing documentation of provider notification in the 4 h prior to a paired reading confirming occult hypoxemia was more likely compared to a paired reading confirming normal oxygen status, adjusting for characteristics significantly associated with nursing documentation. We applied conditional logistic regression to assess if having any nursing documentation of provider notification was more likely in the 4-hour window preceding a paired reading compared to the 4-hour window 24 h earlier separately for occult hypoxemia, visible hypoxemia, and normal oxygenation. RESULTS: There were data from 1910 patients hospitalized with COVID-19 who had 44,972 paired readings and an average of 26.5 (34.5) nursing documentation of provider notification events. The mean age was 63.4 (16.2). Almost half (866/1910, 45.3 %) were White, 701 (36.7 %) were Black, and 239 (12.5 %) were Hispanic. Having any nursing documentation of provider notification was 46 % more common in the 4 h before an occult hypoxemia paired reading compared to a normal oxygen status paired reading (OR 1.46, 95 % CI: 1.28-1.67). Comparing the 4 h immediately before the reading to the 4 h one day preceding the paired reading, there was a higher likelihood of having any nursing documentation of provider notification for both evident (OR 1.45, 95 % CI 1.24-1.68) and occult paired readings (OR 1.26, 95 % CI 1.04-1.53). CONCLUSION: This study finds that nursing documentation of provider notification significantly increases prior to confirmed occult hypoxemia, which has potential in proactively identifying occult hypoxemia and other clinical issues. There is potential value to encouraging standardized documentation of nurse concern, including communication to providers, to facilitate its inclusion in clinical decision-making.

The Annual Wellness Visit Health Risk Assessment: Potential of Patient Portal-Based Completion and Patient-Oriented Education and Support.

Background and Objectives: Patient portals are secure online platforms that allow patients to perform electronic health management tasks and engage in bidirectional information exchange with their care team. Some health systems administer Medicare Annual Wellness Visit (AWV) health risk assessments through the patient portal. Scalable opportunities from portal-based administration of risk assessments are not well understood. Our objective is 2-fold-to understand who receives vs misses an AWV and health risk assessment and explore who might be missed with portal-based administration. Research Design and Methods: This is an observational study of electronic medical record and patient portal data (10/03/2021-10/02/2022) for 12 756 primary care patients 66+ years from a large academic health system. Results: Two-thirds (n = 8420) of older primary care patients incurred an AWV; 81.0% of whom were active portal users. Older adults who were active portal users were more likely to incur AWV than those who were not, though portal use was high in both groups (81.0% with AWV vs 76.8% without; p < .001). Frequently affirmative health risk assessment categories included falls/balance concerns (44.2%), lack of a documented advanced directive (42.3%), sedentary behaviors (39.9%), and incontinence (35.1%). Mean number of portal messages over the 12-month observation period varied from 7.2 among older adults affirmative responses to concerns about safety at home to 13.8 for older adults who reported difficulty completing activities of daily living. Portal messaging varied more than 2-fold across affirmative health risk categories and were marginally higher with greater number affirmative (mean = 13.8 messages/year no risks; 19.6 messages/year 10+ risks). Discussion and Implications: Most older adults were active portal users-a group more likely to have incurred a billed AWV. Efforts to integrate AWV risk assessments in the patient portal may streamline administration and scalability for dissemination of tailored electronically mediated preventive care but must attend to equity issues.

Patient portal messages to support an age-friendly health system for persons with dementia.

BACKGROUND: Patient portal secure messaging can support age-friendly dementia care, yet little is known about care partner use of the portal and how message concerns relate to age-friendly issues. METHODS: We conducted a two-part observational study. We first assessed the feasibility of automating care partner identification from patient portal messages by developing and testing a natural language processing (NLP) rule-based classification system from portal messages of 1973 unique patients 65 and older. Second, two independent reviewers manually coded a randomly selected sample of portal messages for 987 persons with dementia to identify the frequency of expressed needs from the 4M domains of an Age-Friendly Health System (medications, mentation, mobility, and what matters). RESULTS: A total of 267 (13.53%) of 1973 messages sent from older adults' portal accounts were identified through manual coding as sent by a nonpatient author. The NLP model performance to identify nonpatient authors demonstrated an AUC of 0.90. Most messages sent from the accounts of persons with dementia contained content relevant to the 4Ms (60%, 601/987), with the breakdown as follows: medications-36% (357/987), mobility-10% (101/987), mentation-16% (153/987), and what matters (aligning care with specific health goals and care preferences)-21%, 207/987. CONCLUSIONS: Patient portal messaging offers an avenue to identify care partners and meet the informational needs of persons with dementia and their care partners.

Tau seeding without tauopathy.

Neurodegenerative tauopathies such as Alzheimer's disease (AD) are caused by brain accumulation of tau assemblies. Evidence suggests tau functions as a prion, and cells and animals can efficiently propagate unique, transmissible tau pathologies. This suggests a dedicated cellular replication machinery, potentially reflecting a normal physiologic function for tau seeds. Consequently, we hypothesized that healthy control brains would contain seeding activity. We have recently developed a novel monoclonal antibody (MD3.1) specific for tau seeds. We used this antibody to immunopurify tau from the parietal and cerebellar cortices of 19 healthy subjects without any neuropathology, ranging 19 to 65 years. We detected seeding in lysates from the parietal cortex, but not in the cerebellum. We also detected no seeding in brain homogenates from wildtype or human tau knockin mice, suggesting that cellular/genetic context dictates development of seed-competent tau. Seeding did not correlate with subject age or brain tau levels. We confirmed our essential findings using an orthogonal assay, real-time quaking-induced conversion, which amplifies tau seeds in vitro. Dot blot analyses revealed no AT8 immunoreactivity above background levels in parietal and cerebellar extracts and ∼1/100 of that present in AD. Based on binding to a panel of antibodies, the conformational characteristics of control seeds differed from AD, suggesting a unique underlying assembly, or structural ensemble. Tau's ability to adopt self-replicating conformations under nonpathogenic conditions may reflect a normal function that goes awry in disease states.

How do patients and care partners describe diagnostic uncertainty in an emergency department or urgent care setting?

OBJECTIVES: Little is known about how patients perceive diagnostic uncertainty. We sought to understand how patients and care partners perceive uncertainty in an emergency or urgent care setting, where making a final diagnosis is often not possible. METHODS: We administered a survey to a nationally representative panel on patient-reported diagnostic excellence in an emergency department or urgent care setting. The survey included items specific to perceived diagnostic excellence, visit characteristics, and demographics. We analyzed responses to two open-ended questions among those who reported uncertainty in the explanation they were given. Themes were identified using an inductive approach, and compared by whether respondents agreed or disagreed the explanation they were given was true. RESULTS: Of the 1,116 respondents, 106 (10 %) reported that the care team was not certain in the explanation of their health problem. Five themes were identified in the open-ended responses: poor communication (73 %), uncertainty made transparent (10 %), incorrect information provided (9 %), inadequate testing equipment (4 %), and unable to determine (4 %). Of the respondents who reported uncertainty, 21 % (n=22/106) reported the explanation of their problem given was not true. CONCLUSIONS: The findings of this analysis suggest that the majority of patients and their care partners do not equate uncertainty with a wrong explanation of their health problem, and that poor communication was the most commonly cited reason for perceived uncertainty.

Patient Portal Use during Home Health Care at an Academic Health System.

OBJECTIVES: To characterize patient portal use among older adults receiving skilled home health (HH) care. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: Older adults (aged ≥65 years) who received HH care from a large, academic health system between 2017 to 2022 (n = 8409 HH episodes provided to n = 4878 unique individuals). METHODS: We captured individual and HH episode characteristics from the electronic health record and identified specific types and dates of portal use for those with an active patient portal. We calculated the proportion of episodes in which patients engaged in specific patient portal activities (eg, viewing test results, managing appointments, sending messages). We used multivariable logistic regression to model the odds of engaging in each activity as a function of patient and episode characteristics, and charted the timing of patient portal activities across the 60-day HH episode. RESULTS: The patient portal was used by older adults in more than half (58%) of the episodes examined. Among those using their portal account during an HH episode, 84% viewed test results, 77% managed an existing appointment, 72% managed medications, and 55% sent a message to a provider. Adjusted odds of portal use were higher among HH patients who were married (aOR: 1.77, P < .001), receiving HH post-COVID pandemic (aOR: 2.73, P < .001), and accessing HH following a hospitalization (aOR: 1.30, P < .001) and lower among those who were Black compared with white (aOR: 0.52, P < .001). Portal use, particularly viewing test results and clinical notes and managing existing appointments, was highest during the first 10 days of an HH episode, especially among patients referred following a hospitalization. CONCLUSIONS AND IMPLICATIONS: HH patients use the patient portal to perform care management tasks and access clinical information. Study findings support opportunities to harness the patient portal to bridge information gaps and care coordination during HH care.

Patient Reasoning: Patients' and Care Partners' Perceptions of Diagnostic Accuracy in Emergency Care.

OBJECTIVES: In the context of validating a measure of patient report specific to diagnostic accuracy in emergency department or urgent care, this study investigates patients' and care partners' perceptions of diagnoses as accurate and explores variations in how they reason while they assess accuracy. METHODS: In February 2022, we surveyed a national panel of adults who had an emergency department or urgent care visit in the past month to test a patient-reported measure. As part of the survey validation, we asked for free-text responses about why the respondents indicated their (dis)agreement with 2 statements comprising patient-reported diagnostic accuracy: 1) the explanation they received of the health problem was true and 2) the explanation described what to expect of the health problem. Those paired free-text responses were qualitatively analyzed according to themes created inductively. RESULTS: A total of 1,116 patients and care partners provided 982 responses coded into 10 themes, which were further grouped into 3 reasoning types. Almost one-third (32%) of respondents used only corroborative reasoning in assessing the accuracy of the health problem explanation (alignment of the explanation with either test results, patients' subsequent health trajectory, their medical knowledge, symptoms, or another doctor's opinion), 26% used only perception-based reasoning (perceptions of diagnostic process, uncertainty around the explanation received, or clinical team's attitudes), and 27% used both types of reasoning. The remaining 15% used general beliefs or nonexplicated logic (used only about accurate diagnoses) and combinations of general reasoning with perception-based and corroborative. CONCLUSIONS: Patients and care partners used multifaceted reasoning in their assessment of diagnostic accuracy. IMPLICATIONS: As health care shifts toward meaningful diagnostic co-production and shared decision making, in-depth understanding of variations in patient reasoning and mental models informs use in clinical practice. HIGHLIGHTS: An analysis of 982 responses examined how patients and care partners reason about the accuracy of diagnoses they received in emergency or urgent care.In reasoning, people used their perception of the process and whether the diagnosis matched other factual information they have.We introduce "patient reasoning" in the diagnostic measurement context as an area of further research to inform diagnostic shared decision making and co-production of health.

The associations between rapid response systems and their components with patient outcomes: A scoping review.

Background: While rapid response systems have been widely implemented, their impact on patient outcomes remains unclear. Further understanding of their components-including medical emergency team triggers, medical emergency team member composition, additional roles in patient care beyond responding to medical emergency team events, and their involvement in "Do-Not-Resuscitate" order placement-may elucidate the relationship between rapid response systems and outcomes. Objective: To explore how recent studies have examined rapid response system components in the context of relevant adverse patient outcomes, such as in-hospital cardiac arrests and hospital mortality. Design: Scoping review. Methods: PubMed, CINAHL, and Embase were searched for articles published between November 2014 and June 2022. Studies mainly focused on rapid response systems and associations with in-hospital cardiac arrests were considered. The following were extracted for analysis: study design, location, sample size, participant characteristics, system characteristics (including medical emergency team member composition, additional system roles outside of medical emergency team events), medical emergency team triggers, in-hospital cardiac arrests, and hospital mortality. Results: Thirty-four studies met inclusion criteria. While most studies described triggers used, few analyzed medical emergency team trigger associations with outcomes. Of those, medical emergency team triggers relating to respiratory abnormalities and use of multiple triggers to activate the medical emergency team were associated with adverse patient outcomes. Many studies described medical emergency team member composition, but the way composition was reported varied across studies. Of the seven studies with dedicated medical emergency team members, six found their systems were associated with decreased incidence of in-hospital cardiac arrests. Six of seven studies that described additional medical emergency team roles in educating staff in rapid response system use found their systems were associated with significant decreases in adverse patient outcomes. Four of five studies that described proactive rounding responsibilities reported found their systems were associated with significant decreases in adverse patient outcomes. Reporting of rapid response system involvement in "Do-Not-Resuscitate" order placement was variable across studies. Conclusions: Inconsistencies in describing rapid response system components and related data and outcomes highlights how these systems are complex to a degree not fully captured in existing literature. Further large-scale examination of these components across institutions is warranted. Development and use of robust and standardized metrics to track data related to rapid response system components and related outcomes are needed to optimize these systems and improve patient outcomes.

Circulating neutrophils from patients with early breast cancer have distinct subtype-dependent phenotypes.

PURPOSE: An elevated number of circulating neutrophils is a poor prognostic factor for breast cancer, where evidence of bone marrow cancer-dependent priming is found. However, how early this priming is detectable remains unclear. PATIENTS AND METHODS: Here, we investigate changes in circulating neutrophils from newly diagnosed breast cancer patients before any therapeutic interventions. To do this, we assessed their lifespan and their broader intracellular kinase network activation states by using the Pamgene Kinome assay which measures the activity of neutrophil kinases. RESULTS: We found sub-type specific L-selectin (CD62L) changes in circulating neutrophils as well as perturbations in their overall global kinase activity. Strikingly, breast cancer patients of different subtypes (HR+, HER2+, triple negative) exhibited distinct neutrophil kinase activity patterns indicating that quantifiable perturbations can be detected in circulating neutrophils from early breast cancer patients, that are sensitive to both hormonal and HER-2 status. We also detected an increase in neutrophils lifespan in cancer patients, independently of tumour subtype. CONCLUSIONS: Our results suggest that the tumour-specific kinase activation patterns in circulating neutrophils may be used in conjunction with other markers to identify patients with cancer from those harbouring only benign lesions of the breast. Given the important role neutrophil in breast cancer progression, the significance of this sub-type of specific priming warrants further investigation.

Patient portal interventions: a scoping review of functionality, automation used, and therapeutic elements of patient portal interventions.

Objectives: We sought to understand the objectives, targeted populations, therapeutic elements, and delivery characteristics of patient portal interventions. Materials and Methods: Following Arksey and O-Malley's methodological framework, we conducted a scoping review of manuscripts published through June 2022 by hand and systematically searching PubMed, PSYCHInfo, Embase, and Web of Science. The search yielded 5403 manuscripts; 248 were selected for full-text review; 81 met the eligibility criteria for examining outcomes of a patient portal intervention. Results: The 81 articles described: trials involving comparison groups (n = 37; 45.7%), quality improvement initiatives (n = 15; 18.5%), pilot studies (n = 7; 8.6%), and single-arm studies (n = 22; 27.2%). Studies were conducted in primary care (n = 33, 40.7%), specialty outpatient (n = 24, 29.6%), or inpatient settings (n = 4, 4.9%)-or they were deployed system wide (n = 9, 11.1%). Interventions targeted specific health conditions (n = 35, 43.2%), promoted preventive services (n = 19, 23.5%), or addressed communication (n = 19, 23.4%); few specifically sought to improve the patient experience (n = 3, 3.7%). About half of the studies (n = 40, 49.4%) relied on human involvement, and about half involved personalized (vs exclusively standardized) elements (n = 42, 51.8%). Interventions commonly collected patient-reported information (n = 36, 44.4%), provided education (n = 35, 43.2%), or deployed preventive service reminders (n = 14, 17.3%). Discussion: This scoping review finds that most patient portal interventions have delivered education or facilitated collection of patient-reported information. Few interventions have involved pragmatic designs or been deployed system wide. Conclusion: The patient portal is an important tool in real-world efforts to more effectively support patients, but interventions to date rely largely on evidence from consented participants rather than pragmatically implemented systems-level initiatives.

Palliative Care Utilization in Patients Requiring Extracorporeal Membrane Oxygenation: An Observational Study.

Palliative care (PC) is a model of care centered around improving the quality of life for individuals with life-limiting illnesses. Few studies have examined its impact in patients on extracorporeal membrane oxygenation (ECMO). We aimed to describe demographics, clinical characteristics, and complications associated with PC consultation in adult patients requiring ECMO support. We analyzed data from an ECMO registry, including patients aged 18 years and older who have received either venoarterial (VA)- or venovenous (VV)-ECMO support between July 2016 and September 2021. We used analysis of variance and Fisher exact tests to identify factors associated with PC consultation. Of 256, 177 patients (69.1%) received VA-ECMO support and 79 (30.9%) received VV-ECMO support. Overall, 115 patients (44.9%) received PC consultation while on ECMO. Patients receiving PC consultation were more likely to be non-white (47% vs. 53%, p = 0.016), have an attending physician from a medical versus surgical specialty (65.3% vs. 39.6%), have VV-ECMO (77.2% vs. 30.5%, p < 0.001), and have longer ECMO duration (6.2 vs. 23.0, p < 0.001). Patients were seen by the PC team on an average of 7.6 times (range, 1-35), with those who died having significantly more visits (11.2 vs. 5.6, p < 0.001) despite the shorter hospital stay. The average time from cannulation to the first PC visit was 5.3 ± 5 days. Congestive heart failure in VA-ECMO, coronavirus disease 2019 infection in VV-ECMO, and non-white race and longer ECMO duration for all patients were associated with PC consultation. We found that despite the benefits of PC, it is underused in this population.

Participatory evaluation of the process of co-producing resources for the public on data science and artificial intelligence.

BACKGROUND: The growth of data science and artificial intelligence offers novel healthcare applications and research possibilities. Patients should be able to make informed choices about using healthcare. Therefore, they must be provided with lay information about new technology. A team consisting of academic researchers, health professionals, and public contributors collaboratively co-designed and co-developed the new resource offering that information. In this paper, we evaluate this novel approach to co-production. METHODS: We used participatory evaluation to understand the co-production process. This consisted of creative approaches and reflexivity over three stages. Firstly, everyone had an opportunity to participate in three online training sessions. The first one focused on the aims of evaluation, the second on photovoice (that included practical training on using photos as metaphors), and the third on being reflective (recognising one's biases and perspectives during analysis). During the second stage, using photovoice, everyone took photos that symbolised their experiences of being involved in the project. This included a session with a professional photographer. At the last stage, we met in person and, using data collected from photovoice, built the mandala as a representation of a joint experience of the project. This stage was supported by professional artists who summarised the mandala in the illustration. RESULTS: The mandala is the artistic presentation of the findings from the evaluation. It is a shared journey between everyone involved. We divided it into six related layers. Starting from inside layers present the following experiences (1) public contributors had space to build confidence in a new topic, (2) relationships between individuals and within the project, (3) working remotely during the COVID-19 pandemic, (4) motivation that influenced people to become involved in this particular piece of work, (5) requirements that co-production needs to be inclusive and accessible to everyone, (6) expectations towards data science and artificial intelligence that researchers should follow to establish public support. CONCLUSIONS: The participatory evaluation suggests that co-production around data science and artificial intelligence can be a meaningful process that is co-owned by everyone involved.

Modern technology offers new treatment options for patients and novel avenues of research. However, there is limited available information in easily understandable language for the public explaining how technology relates to them and could influence their healthcare. The researchers, healthcare professionals and public members worked together collaboratively to address this problem by creating new materials for the public. Our paper explores that project through creative methods. Firstly, everyone involved was offered an opportunity to attend training sessions. Then, people took photos and described them to illustrate to others what is their experience of working together. Finally, we all met to use included photos as building blocks to present a shared experience in the project. Afterwards, the professional artist included it as one circular illustration with six interlinked layers. These layers present everyone's experiences (from inside) (1) is about the opportunity to build confidence in a new topic, (2) relationships with others, (3) working remotely during the pandemic, (4) motivation that influenced people to become involved in this particular piece of work, (5) expectation that the project needs be inclusive and accessible, (6) ethical principles that researchers using new technology should follow. We showed that it is possible for researchers, healthcare professionals and members of the public to feel joint ownership of the project and that working together can be meaningful to everyone.

Patient Portal Use Among Older Adults With Dementia Diagnosis.

This cohort study assesses the level of engagement with an electronic health management system among patients with recently diagnosed dementia and their caregivers.

Use of the patient portal among older adults with diagnosed dementia and their care partners.

INTRODUCTION: Care partners are at the forefront of dementia care, yet little is known about patient portal use in the context of dementia diagnosis. METHODS: We conducted an observational cohort study of date/time-stamped patient portal use for a 5-year period (October 3, 2017-October 2, 2022) at an academic health system. The cohort consisted of 3170 patients ages 65+ with diagnosed dementia with 2+ visits within 24 months. Message authorship was determined by manual review of 970 threads involving 3065 messages for 279 patients. RESULTS: Most (71.20%) older adults with diagnosed dementia were registered portal users but far fewer (10.41%) had a registered care partner with shared access. Care partners authored most (612/970, 63.09%) message threads, overwhelmingly using patient identity credentials (271/279, 97.13%). DISCUSSION: The patient portal is used by persons with dementia and their care partners. Organizational efforts that facilitate shared access may benefit the support of persons with dementia and their care partners. Highlights Patient portal registration and use has been increasing among persons with diagnosed dementia. Two thirds of secure messages from portal accounts of patients with diagnosed dementia were identified as being authored by care partners, primarily using patient login credentials. Care partners who accessed the patient portal using their own identity credentials through shared access demonstrate similar levels of activity to patients without dementia. Organizational initiatives should recognize and support the needs of persons with dementia and their care partners by encouraging awareness, registration, and use of proper identity credentials, including shared, or proxy, portal access.

The consequences of emotionally evocative patient behaviors on emergency nurses' patient assessments and handoffs: An experimental study using simulated patient cases.

BACKGROUND: Engaging with human emotions is an integral but poorly understood part of the work of emergency healthcare providers. Patient factors (e.g., irritable behavior; mental illness) can evoke strong emotions, and evidence suggests that these emotions can impact care quality and patient safety. Given that nurses play a critical role in providing high quality care, efforts to identify and remedy factors that may compromise care are needed. Yet to date, few experiments have been conducted. OBJECTIVE: To examine the effects of emotionally evocative patient behavior as well as the presence of mental illness on emergency nurses' emotions, patient assessments, testing advocacy, and written handoffs. DESIGN: Experimental vignette research. SETTING: Online experiment distributed via email between October and December 2020. PARTICIPANTS: Convenience sample of 130 emergency nurses from seven hospitals in the Northeastern United States and one hospital in the mid-Atlantic region in the United States. METHODS: Nurses completed four multimedia computer-simulated patient encounters in which patient behavior (irritable vs. calm) and mental illness (present vs. absent) were experimentally varied. Nurses reported their emotions and clinical assessments, recommended diagnostic tests, and provided written handoffs. Tests were coded for whether the test would result in a correct diagnosis, and handoffs were coded for negative and positive patient descriptions and the presence of specific clinical information. RESULTS: Nurses experienced more negative emotions (anger, unease) and reported less engagement when assessing patients exhibiting irritable (vs. calm) behavior. Nurses also judged patients with irritable (vs. calm) behavior as more likely to exaggerate their pain and as poorer historians, and as less likely to cooperate, return to work, and recover. Nurses' handoffs were more likely to communicate negative descriptions of patients with irritable (vs. calm) behavior and omit specific clinical information (e.g., whether tests were ordered, personal information). The presence of mental illness increased unease and sadness and resulted in nurses being less likely to recommend a necessary test for a correct diagnosis. CONCLUSIONS: Emergency nurses' assessments and handoffs were impacted by patient factors, particularly irritable patient behavior. As nurses are central to the clinical team and experience regular, close contact with patients, the effects of irritable patient behavior on nursing assessments and care practices have important implications. We discuss potential approaches to address these ill effects, including reflexive practice, teamwork, and standardization of handoffs. TWEETABLE ABSTRACT: Simulated experimental study found that despite having received identical clinical information, emergency nurses believed that patients displaying irritable behaviours were less likely to return to work soon and were less likely to recover than patients who displayed calm behaviour.

ZBTB7A regulates MDD-specific chromatin signatures and astrocyte-mediated stress vulnerability in orbitofrontal cortex.

Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A - a transcriptional regulator of astrocyte reactivity - as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress - a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability.

Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior.

Background: Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods: We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results: We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions: These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.

A Rapid, Shallow Whole Genome Sequencing Workflow Applicable to Limiting Amounts of Cell-Free DNA.

BACKGROUND: Somatic copy number alterations (sCNAs) acquired during the evolution of breast cancer provide valuable prognostic and therapeutic information. Here we present a workflow for screening sCNAs using picogram amounts of cell-free DNA (cfDNA) and single circulating tumor cells (CTCs). METHODS: We repurposed the Ion ReproSeq PGS™ preimplantation genetic testing kit to perform shallow whole genome sequencing on 178 cfDNA samples (300 pg) and individual CTCs from 10 MBC patients with metastatic breast cancer (MBC) recovered by CellSearch®/DEPArray™. Results were analyzed using a tailored ichorCNA workflow. RESULTS: sCNAs were detected in cfDNA of 41/105 (39%) patients with MBC and 3/23 (13%) primary breast cancers on follow-up (PBC FU), all of whom subsequently relapsed. In 8 of 10 MBCs, individual CTCs had a higher copy number count than matched cfDNA. The median tumor fraction detected by ichorCNA was 0.34 (range 0.17-0.58) for MBC and 0.36 (range 0.31-0.37) for PBC FU. Patients with detectable tumor fraction (≥ 0.1) and TFx and OncomineTM variants had significantly lower overall survival rates (P values P = 0.002 and P < 0.0001 for the log-rank test, respectively). CONCLUSIONS: The ReproSeq PGS assay is rapid, at approximately $120 per sample, providing both a sCNA profile and estimation of the tumor DNA fraction from limiting cfDNA template (300pg) and individual CTCs. The approach could be used to examine the copy number landscape over time to guide treatment decisions, support future trial designs, and be applied to low volume blood spot samples enabling remote monitoring.