Circuits between infected macrophages and T cells in SARS-CoV-2 pneumonia.

Some patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop severe pneumonia and acute respiratory distress syndrome1 (ARDS). Distinct clinical features in these patients have led to speculation that the immune response to virus in the SARS-CoV-2-infected alveolus differs from that in other types of pneumonia2. Here we investigate SARS-CoV-2 pathobiology by characterizing the immune response in the alveoli of patients infected with the virus. We collected bronchoalveolar lavage fluid samples from 88 patients with SARS-CoV-2-induced respiratory failure and 211 patients with known or suspected pneumonia from other pathogens, and analysed them using flow cytometry and bulk transcriptomic profiling. We performed single-cell RNA sequencing on 10 bronchoalveolar lavage fluid samples collected from patients with severe coronavirus disease 2019 (COVID-19) within 48 h of intubation. In the majority of patients with SARS-CoV-2 infection, the alveolar space was persistently enriched in T cells and monocytes. Bulk and single-cell transcriptomic profiling suggested that SARS-CoV-2 infects alveolar macrophages, which in turn respond by producing T cell chemoattractants. These T cells produce interferon-γ to induce inflammatory cytokine release from alveolar macrophages and further promote T cell activation. Collectively, our results suggest that SARS-CoV-2 causes a slowly unfolding, spatially limited alveolitis in which alveolar macrophages containing SARS-CoV-2 and T cells form a positive feedback loop that drives persistent alveolar inflammation.

"The Equipoise Ruler:" A National Survey on Surgeon Judgment about the Value of Surgery.

OBJECTIVE: The objective of this study was to understand professional norms regarding the value of surgery. SUMMARY BACKGROUND DATA: Agreed-upon professional norms may improve surgical decision making by contextualizing the nature of surgical treatment for patients. However, the extent to which these norms exist among surgeons practicing in the US is not known. METHODS: We administered a survey with 30 exemplar cases asking surgeons to use their best judgement to place each case on a scale ranging from "Definitely would do this surgery" to "Definitely would not do this surgery." We then asked surgeons to repeat their assessments after providing responses from the first survey. We interviewed respondents to characterize their rationale. RESULTS: We received 580 responses, a response rate of 28.5%. For 19 of 30 cases there was consensus (≥60% agreement) about the value of surgery (range 63% - 99%). There was little within-case variation when the mode was for surgery and more variation when the mode was against surgery or equipoise. Exposure to peer response increased the number of cases with consensus. Women were more likely to endorse a non-operative approach when treatment had high mortality. Specialists were less likely to operate for salvage procedures. Surgeons noted their clinical practice was to withhold judgment and let patients decide despite their assessment. CONCLUSIONS: Professional judgment about the value of surgery exists along a continuum. While there is less variation in judgment for cases that are highly beneficial, consensus can be improved by exposure to the assessments of peers.

Barriers and Facilitators to End-of-Life Care Delivery in ICUs: A Qualitative Study.

OBJECTIVES: To understand frontline ICU clinician's perceptions of end-of-life care delivery in the ICU. DESIGN: Qualitative observational cross-sectional study. SETTING: Seven ICUs across three hospitals in an integrated academic health system. SUBJECTS: ICU clinicians (physicians [critical care, palliative care], advanced practice providers, nurses, social workers, chaplains). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: In total, 27 semi-structured interviews were conducted, recorded, and transcribed. The research team reviewed all transcripts inductively to develop a codebook. Thematic analysis was conducted through coding, category formulation, and sorting for data reduction to identify central themes. Deductive reasoning facilitated data category formulation and thematic structuring anchored on the Systems Engineering Initiative for Patient Safety model identified that work systems (people, environment, tools, tasks) lead to processes and outcomes. Four themes were barriers or facilitators to end-of-life care. First, work system barriers delayed end-of-life care communication among clinicians as well as between clinicians and families. For example, over-reliance on palliative care people in handling end-of-life discussions prevented timely end-of-life care discussions with families. Second, clinician-level variability existed in end-of-life communication tasks. For example, end-of-life care discussions varied greatly in process and outcomes depending on the clinician leading the conversation. Third, clinician-family-patient priorities or treatment goals were misaligned. Conversely, regular discussion and joint decisions facilitated higher familial confidence in end-of-life care delivery process. These detailed discussions between care teams aligned priorities and led to fewer situations where patients/families received conflicting information. Fourth, clinician moral distress occurred from providing nonbeneficial care. Interviewees reported standardized end-of-life care discussion process incorporated by the people in the work system including patient, family, and clinicians were foundational to delivering end-of-life care that reduced both patient and family suffering, as well as clinician moral distress. CONCLUSIONS: Standardized work system communication tasks may improve end-of life discussion processes between clinicians and families.

Urea cycle disorders in critically Ill adults.

PURPOSE OF REVIEW: Urea cycle disorders (UCDs) cause elevations in ammonia which, when severe, cause irreversible neurologic injury. Most patients with UCDs are diagnosed as neonates, though mild UCDs can present later - even into adulthood - during windows of high physiologic stress, like critical illness. It is crucial for clinicians to understand when to screen for UCDs and appreciate how to manage these disorders in order to prevent devastating neurologic injury or death. RECENT FINDINGS: Hyperammonemia, particularly if severe, causes time- and concentration-dependent neurologic injury. Mild UCDs presenting in adulthood are increasingly recognized, so broader screening in adults is recommended. For patients with UCDs, a comprehensive, multitiered approach to management is needed to prevent progression and irreversible injury. Earlier exogenous clearance is increasingly recognized as an important complement to other therapies. SUMMARY: UCDs alter the core pathway for ammonia metabolism. Screening for mild UCDs in adults with unexplained neurologic symptoms can direct care and prevent deterioration. Management of UCDs emphasizes decreasing ongoing ammonia production, avoiding catabolism, and supporting endogenous and exogenous ammonia clearance. Core neuroprotective and supportive critical care supplements this focused therapy.

Language in Bioethics: Beyond the Representational View.

Though assumptions about language underlie all bioethical work, the field has rarely partaken of theories of language. This article encourages a more linguistically engaged bioethics. We describe the tacit conception of language that is frequently upheld in bioethics-what we call the representational view, which sees language essentially as a means of description. We examine how this view has routed the field's theories and interventions down certain paths. We present an alternative model of language-the pragmatic view-and explore how it expands and clarifies traditional bioethical concerns. To lend concreteness, we apply the pragmatic view to a pervasive concept in bioethics and adjacent fields: decision making. We suggest that problems of the decision-making approach to bioethical issues are grounded in adherence to the representational view. Drawing on empirical work in surgery and critical care, we show how the pragmatic view productively reframes bioethical questions about how medical treatments are pursued.

Derivation and performance of an end-of-life practice score aimed at interpreting worldwide treatment-limiting decisions in the critically ill.

BACKGROUND: Limitations of life-sustaining interventions in intensive care units (ICUs) exhibit substantial changes over time, and large, contemporary variation across world regions. We sought to determine whether a weighted end-of-life practice score can explain a large, contemporary, worldwide variation in limitation decisions. METHODS: The 2015-2016 (Ethicus-2) vs. 1999-2000 (Ethicus-1) comparison study was a two-period, prospective observational study assessing the frequency of limitation decisions in 4952 patients from 22 European ICUs. The worldwide Ethicus-2 study was a single-period prospective observational study assessing the frequency of limitation decisions in 12,200 patients from 199 ICUs situated in 8 world regions. Binary end-of-life practice variable data (1 = presence; 0 = absence) were collected post hoc (comparison study, 22/22 ICUs, n = 4592; worldwide study, 186/199 ICUs, n = 11,574) for family meetings, daily deliberation for appropriate level of care, end-of-life discussions during weekly meetings, written triggers for limitations, written ICU end-of-life guidelines and protocols, palliative care and ethics consultations, ICU-staff taking communication or bioethics courses, and national end-of-life guidelines and legislation. Regarding the comparison study, generalized estimating equations (GEE) analysis was used to determine associations between the 12 end-of-life practice variables and treatment limitations. The weighted end-of-life practice score was then calculated using GEE-derived coefficients of the end-of-life practice variables. Subsequently, the weighted end-of-life practice score was validated in GEE analysis using the worldwide study dataset. RESULTS: In comparison study GEE analyses, end-of-life discussions during weekly meetings [odds ratio (OR) 0.55, 95% confidence interval (CI) 0.30-0.99], end-of-life guidelines [OR 0.52, (0.31-0.87)] and protocols [OR 15.08, (3.88-58.59)], palliative care consultations [OR 2.63, (1.23-5.60)] and end-of-life legislation [OR 3.24, 1.60-6.55)] were significantly associated with limitation decisions (all P < 0.05). In worldwide GEE analyses, the weighted end-of-life practice score was significantly associated with limitation decisions [OR 1.12 (1.03-1.22); P = 0.008]. CONCLUSIONS: Comparison study-derived, weighted end-of-life practice score partly explained the worldwide study's variation in treatment limitations. The most important components of the weighted end-of-life practice score were ICU end-of-life protocols, palliative care consultations, and country end-of-life legislation.

Use and Meaning of "Goals of Care" in the Healthcare Literature: a Systematic Review and Qualitative Discourse Analysis.

BACKGROUND: The specific phrase "goals of care" (GOC) is pervasive in the discourse about serious illness care. Yet, the meaning of this phrase is ambiguous. We sought to characterize the use and meaning of the phrase GOC within the healthcare literature to improve communication among patients, families, clinicians, and researchers. METHODS: A systematic review of the English language healthcare literature indexed in MEDLINE/PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and Scopus was performed in October of 2018. We searched for all publications with the exact phrase "goals of care" within the title or abstract; no limitations on publication date or format were applied; conference abstracts were excluded. We used qualitative, discourse analysis to identify key themes and generate an operational definition and conceptual model of GOC. RESULTS: A total of 214 texts were included in the final analysis. Use of GOC increased over time with 87% of included texts published in the last decade (2009-2018). An operational definition emerged from consensus within the published literature: the overarching aims of medical care for a patient that are informed by patients' underlying values and priorities, established within the existing clinical context, and used to guide decisions about the use of or limitation(s) on specific medical interventions. Application of the GOC concept was described as important to the care of patients with serious illness, in order to (1) promote patient autonomy and patient-centered care, (2) avoid unwanted care and identify valued care, and (3) provide psychological and emotional support for patients and their families. DISCUSSION: The use of the phrase "goals of care" within the healthcare literature is increasingly common. We identified a consensus, operational definition that can facilitate communication about serious illness among patients, families, and clinicians and provide a framework for researchers developing interventions to improve goal-concordant care.

Patient and Family Engagement During Treatment Decisions in an ICU: A Discourse Analysis of the Electronic Health Record.

OBJECTIVES: Shared decision-making is recommended for critically ill adults who face major, preference-sensitive treatment decisions. Yet, little is known about when and how patients and families are engaged in treatment decision-making over the longitudinal course of a critical illness. We sought to characterize patterns of treatment decision-making by evaluating clinician discourse in the electronic health record of critically ill adults who develop chronic critical illness or die in an ICU. DESIGN, SETTING, AND PATIENTS: We conducted qualitative content analysis of the electronic health record of 52 adult patients, admitted to a medical ICU in a tertiary medical center from January 1, 2016, to December 31, 2016. We included patients who met a consensus definition of chronic critical illness (26 patients) and a matched sample who died or transitioned to hospice care in the ICU before developing chronic critical illness (26 patients). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Characterization of clinician decision-making discourse documented during the course of an ICU stay. Clinician decision-making discourse in the electronic health record followed a single, consistent pattern across both groups. Initial decisions about admission to the ICU focused on specific interventions that can only be provided in an ICU environment (intervention-focused decisions). Following admission, the documented rationale for additional treatments was guided by physiologic abnormalities (physiology-centered decisions). Clinician discourse transitioned to documented engagement of patients and families in decision-making when treatments failed to achieve specified physiologic goals. The phrase "goals of care" is common in the electronic health record and is used to indicate poor prognosis, to describe conflict with families, and to provide rationale for treatment limitations. CONCLUSIONS: Clinician discourse in the electronic health record reveals that patient physiology strongly guides treatment decision-making throughout the longitudinal course of critical illness. Documentation of patient and family engagement in treatment decision-making is limited until available medical treatments fail to achieve physiologic goals.

Time-Limited Trials in the Intensive Care Unit to Promote Goal-Concordant Patient Care.

Consider the hypothetical case of a 75-year-old patient admitted to the intensive care unit (ICU) for acute hypoxic respiratory failure due to pneumonia and systolic heart failure. Although she suffers from a potentially treatable infection, her advanced age and chronic illness increase her risk of experiencing a poor outcome. Her family feels conflicted about whether the use of mechanical ventilation would be acceptable given what they understand about her values and preferences. In the ICU setting, clinicians, patients, and surrogate decision-makers frequently face challenges of prognostic uncertainty as well as uncertainty regarding patients' goals and values. Time-limited trials (TLTs) of life-sustaining treatments in the ICU have been proposed as one strategy to help facilitate goal-concordant care in the midst of a complex and high-stakes decision-making environment. TLTs represent an agreement between clinicians and patients or surrogate decision-makers to employ a therapy for an agreed-upon time period, with a plan for subsequent reassessment of the patient's progress according to previously-established criteria for improvement or decline. Herein, we review the concept of TLTs in intensive care, and explore their potential benefits, barriers, and challenges. Research demonstrates that, in practice, TLTs are conducted infrequently and often incompletely, and are challenged by system-level factors that diminish their effectiveness. The promise of TLTs in intensive care warrants continued research efforts, including implementation studies to improve adoption and fidelity, observational research to determine optimal timeframes for TLTs, and interventional trials to determine if TLTs ultimately improve the delivery of goal-concordant care in the ICU.

Reconsidering the Language of Serious Illness.

This Viewpoint expresses how use of certain language complicates decision-making for critically ill patients, and it highlights alternative phrasing for effective communication.

High-quality genetic mapping with ddRADseq in the non-model tree Quercus rubra.

BACKGROUND: Restriction site associated DNA sequencing (RADseq) has the potential to be a broadly applicable, low-cost approach for high-quality genetic linkage mapping in forest trees lacking a reference genome. The statistical inference of linear order must be as accurate as possible for the correct ordering of sequence scaffolds and contigs to chromosomal locations. Accurate maps also facilitate the discovery of chromosome segments containing allelic variants conferring resistance to the biotic and abiotic stresses that threaten forest trees worldwide. We used ddRADseq for genetic mapping in the tree Quercus rubra, with an approach optimized to produce a high-quality map. Our study design also enabled us to model the results we would have obtained with less depth of coverage. RESULTS: Our sequencing design produced a high sequencing depth in the parents (248×) and a moderate sequencing depth (15×) in the progeny. The digital normalization method of generating a de novo reference and the SAMtools SNP variant caller yielded the most SNP calls (78,725). The major drivers of map inflation were multiple SNPs located within the same sequence (77% of SNPs called). The highest quality map was generated with a low level of missing data (5%) and a genome-wide threshold of 0.025 for deviation from Mendelian expectation. The final map included 849 SNP markers (1.8% of the 78,725 SNPs called). Downsampling the individual FASTQ files to model lower depth of coverage revealed that sequencing the progeny using 96 samples per lane would have yielded too few SNP markers to generate a map, even if we had sequenced the parents at depth 248×. CONCLUSIONS: The ddRADseq technology produced enough high-quality SNP markers to make a moderately dense, high-quality map. The success of this project was due to high depth of coverage of the parents, moderate depth of coverage of the progeny, a good framework map, an optimized bioinformatics pipeline, and rigorous premapping filters. The ddRADseq approach is useful for the construction of high-quality genetic maps in organisms lacking a reference genome if the parents and progeny are sequenced at sufficient depth. Technical improvements in reduced representation sequencing (RRS) approaches are needed to reduce the amount of missing data.

Patient-reported Limitations to Surgical Buy-in: A Qualitative Study of Patients Facing High-risk Surgery.

OBJECTIVE: To characterize how patients buy-in to treatments beyond the operating room and what limits they would place on additional life-supporting treatments. BACKGROUND: During a high-risk operation, surgeons generally assume that patients buy-in to life-supporting interventions that might be necessary postoperatively. How patients understand this agreement and their willingness to participate in additional treatment is unknown. METHODS: We purposively sampled surgeons in Toronto, Ontario, Boston, Massachusetts, and Madison, Wisconsin, who are good communicators and routinely perform high-risk operations. We audio-recorded their conversations with patients considering high-risk surgery. For patients who were then scheduled for surgery, we performed open-ended preoperative and postoperative interviews. We used directed qualitative content analysis to analyze the interviews and surgeon visits, specifically evaluating the content about the use of postoperative life support. RESULTS: We recorded 43 patients' conversations with surgeons, 34 preoperative, and 27 postoperative interviews. Patients expressed trust in their surgeon to make decisions about additional treatments if a serious complication occurred, yet expressed a preference for significant treatment limitations that were not discussed with their surgeon preoperatively. Patients valued the existence or creation of an advance directive preoperatively, but they did not discuss this directive with their surgeon. Instead they assumed it would be effective if needed and that family members knew their wishes. CONCLUSIONS: Patients implicitly trust their surgeons to treat postoperative complications as they arise. Although patients may buy-in to some additional postoperative interventions, they hold a broad range of preferences for treatment limitations that were not discussed with the surgeon preoperatively.

Constructing High-stakes Surgical Decisions: It's Better to Die Trying.

OBJECTIVE: To explore high-stakes surgical decision making from the perspective of seniors and surgeons. BACKGROUND: A majority of older chronically ill patients would decline a low-risk procedure if the outcome was severe functional impairment. However, 25% of Medicare beneficiaries have surgery in their last 3 months of life, which may be inconsistent with their preferences. How patients make decisions to have surgery may contribute to this problem of unwanted care. METHODS: We convened 4 focus groups at senior centers and 2 groups of surgeons in Madison and Milwaukee, Wisconsin, where we showed a video about a decision regarding a choice between surgery and palliative care. We used qualitative content analysis to identify themes about communication and explanatory models for end-of-life treatment decisions. RESULTS: Seniors (n = 37) and surgeons (n = 17) agreed that maximizing quality of life should guide treatment decisions for older patients. However, when faced with an acute choice between surgery and palliative care, seniors viewed this either as a choice between life and death or a decision about how to die. Although surgeons agreed that very frail patients should not have surgery, they held conflicting views about presenting treatment options. CONCLUSIONS: Seniors and surgeons highly value quality of life, but this notion is difficult to incorporate in acute surgical decisions. Some seniors use these values to consider a choice between surgery and palliative care, whereas others view this as a simple choice between life and death. Surgeons acknowledge challenges framing decisions and describe a clinical momentum that promotes surgical intervention.

"And I think that we can fix it": mental models used in high-risk surgical decision making.

OBJECTIVE: To examine how surgeons use the "fix-it" model to communicate with patients before high-risk operations. BACKGROUND: The "fix-it" model characterizes disease as an isolated abnormality that can be restored to normal form and function through medical intervention. This mental model is familiar to patients and physicians, but it is ineffective for chronic conditions and treatments that cannot achieve normalcy. Overuse may lead to permissive decision making favoring intervention. Efforts to improve surgical decision making will need to consider how mental models function in clinical practice, including "fix-it." METHODS: We observed surgeons who routinely perform high-risk surgery during preoperative discussions with patients. We used qualitative content analysis to explore the use of "fix-it" in 48 audio-recorded conversations. RESULTS: Surgeons used the "fix-it" model for 2 separate purposes during preoperative conversations: (1) as an explanatory tool to facilitate patient understanding of disease and surgery, and (2) as a deliberation framework to assist in decision making. Although surgeons commonly used "fix-it" as an explanatory model, surgeons explicitly discussed limitations of the "fix-it" model as an independent rationale for operating as they deliberated about the value of surgery. CONCLUSIONS: Although the use of "fix-it" is familiar for explaining medical information to patients, surgeons recognize that the model can be problematic for determining the value of an operation. Whether patients can transition between understanding how their disease is fixed with surgery to a subsequent deliberation about whether they should have surgery is unclear and may have broader implications for surgical decision making.

Better Conversations for Better Informed Consent: Talking with Surgical Patients.

For more than sixty years, surgeons have used bioethical strategies to promote patient self-determination, many of these now collectively described as "informed consent." Yet the core framework-understanding, risks, benefits, and alternatives-fails to support patients in deliberation about treatment. We find that surgeons translate this framework into an overly complicated technical explanation of disease and treatment and an overly simplified narrative that surgery will "fix" the problem. They omit critical information about the goals and downsides of surgery and present untenable options as a matter of patient choice. We propose a novel framework called "better conversations." Herein, surgeons provide context about clinical norms, establish the goals of surgery, and comprehensively delineate the downsides of surgery to generate a deliberative space for patients to consider whether surgery is right for them. This paradigm shift meets the standards for informed consent, supports deliberation, and allows patients to anticipate and prepare for the experience of treatment.

Mapping the process of ICU care delivery to improve treatment decisions in acute respiratory failure.

Evidence suggests system-level norms and care processes influence individual patients' medical decisions, including end-of-life decisions for patients with critical illnesses like acute respiratory failure. Yet, little is known about how these processes unfold over the course of a patient's critical illness in the intensive care unit (ICU). Our objective was to map current-state ICU care delivery processes for patients with acute respiratory failure and to identify opportunities to improve the process. We conducted a process mapping study at two academic medical centers, using focus groups and semi-structured interviews. The 70 participants represented 17 distinct roles in ICU care, including interprofessional medical ICU and palliative care clinicians, surrogate decision makers, and patient survivors. Participants refined and endorsed a process map of current-state care delivery for all patients admitted to the ICU with acute respiratory failure requiring mechanical ventilation. The process contains four critical periods for active deliberation about the use of life-sustaining treatments. However, active deliberation steps are inconsistently performed and frequently disrupted, leading to prolongation of life-sustaining treatment by default, without consideration of patients' individual goals and priorities. Interventions to standardize active deliberation in the ICU may improve treatment decisions for ICU patients with acute respiratory failure.

Time-Limited Trials for Patients With Critical Illness: A Review of the Literature.

TOPIC IMPORTANCE: Since the 1990s, time-limited trials have been described as an approach to navigate uncertain benefits and limits of life-sustaining therapies in patients with critical illness. In this review, we aim to synthesize the evidence on time-limited trials in critical care, establish what is known, and highlight important knowledge gaps. REVIEW FINDINGS: We identified 18 empirical studies and 15 ethical analyses about time-limited trials in patients with critical illness. Observational studies suggest time-limited trials are part of current practice in ICUs in the United States, but their use varies according to unit and physician factors. Some ICU physicians are familiar with, endorse, and have participated in time-limited trials, and some older adults appear to favor time-limited trial strategies over indefinite life-sustaining therapy or care immediately focused on comfort. When time-limited trials are used, they are often implemented incompletely and challenged by systematic barriers (eg, continually rotating ICU staff). Predictive modeling studies support prevailing clinical wisdom that prognostic uncertainty decreases over time in the ICU for some patients. One study prospectively comparing usual ICU care with an intervention designed to support time-limited trials yielded promising preliminary results. Ethical analyses describe time-limited trials as a pragmatic approach within the longstanding discussion about withholding and withdrawing life-sustaining therapies. SUMMARY: Time-limited trials are endorsed by physicians, align with the priorities of some older adults, and are part of current practice. Substantial efforts are needed to test their impact on patient-centered outcomes, improve their implementation, and maximize their potential benefit.