Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.

Promoting a research culture in family medicine: Five years of scholarly works and activities group.

BACKGROUND: The professional advancement of Family Medicine faculty requires contributions in the form of clinical service, teaching, and scholarly activity. While teaching and clinical work are part of the everyday routine of faculty members, a research culture can be challenging to build. METHODS: Our department started a Scholarly Works and Activities Group (SWAG). The group's aim is to promote a collegial, collaborative research culture in the department. Meetings occur monthly, and faculty have the opportunity to discuss scholarly projects with peers, as well as promotion/tenure goals. Minutes from each meeting are sent to all faculty members in the department. The aim of this retrospective study was to determine if SWAG meetings impacted faculty scholarly activity. Data were collected on presentations, publications, and collaborations from Curriculum Vitae (CVs), and were compared between 5 years prior to the intervention and the 5 years since. RESULTS: Results indicated increased scholarly activity in the time period during the SWAG group meetings. Faculty presentations increased by 34% while faculty publications more than doubled (221% increase), with publications constituting a small Cohen's d effect size. Interestingly, faculty collaboration did not increase. Two faculty members were promoted during the 5 years study period, and the total number of faculty who published went from three to eight. CONCLUSIONS: Implementation of a monthly SWAG meeting led to an increase in faculty peer reviewed publications. Furthermore, two faculty members were promoted during the time of the intervention. A monthly faculty meeting, even when brief, can help promote and build a research culture.

Clinical Quality Measure Exchange is Not Easy.

PURPOSE: The Trial of Aggregate Data Exchange for Maintenance of Certification and Raising Quality was a randomized controlled trial which first had to test whether quality reporting could be a by-product of clinical care. We report on the initial descriptive study of the capacity for and quality of exchange of whole-panel, standardized quality measures from health systems. METHODS: Family physicians were recruited from 4 health systems with mature quality measurement programs and agreed to submit standardized, physician-level quality measures for consenting physicians. Identified measure or transfer errors were captured and evaluated for root-cause problems. RESULTS: The health systems varied considerably by patient demographics and payer mix. From the 4 systems, 256 family physicians elected to participate. Of 19 measures negotiated for use, 5 were used by all systems. There were more than 15 types of identified errors including breaks in data delivery, changes in measures, and nonsensical measure results. Only 1 system had no identified errors. CONCLUSIONS: The secure transfer of standardized, physician-level quality measures from 4 health systems with mature measure processes proved difficult. There were many errors that required human intervention and manual repair, precluding full automation. This study reconfirms an important problem, namely, that despite widespread health information technology adoption and federal meaningful use policies, we remain far from goals to make clinical quality reporting a reliable by-product of care.

Contaminant metal concentrations in three species of aquatic macrophytes from the Coeur d'Alene Lake basin, USA.

The Coeur d'Alene Lake basin in Northwestern USA has extensive contamination from legacy mining waste, which overlaps with aquatic macrophyte habitat. We examined concentrations of arsenic (As), cadmium (Cd), copper (Cu), lead (Pb), and zinc (Zn) in three macrophytes: Elodea canadensis (submerged), Myriophyllum spicatum (submerged), and Sagittaria latifolia (emergent). We collected macrophyte tissues from five contaminated sites and one uncontaminated site. Tissue concentrations were compared to sediment quality guidelines to assess potential toxicity from metal(loid)s to macrophyte-associated biota. We used threshold and probable effect concentrations to screen for potential toxicity. For the submerged species, the highest site means ± SD (analyte mg/kg dry mass) were 96 ± 61 (As), 18 ± 1.7 (Cd), 24 ± 15 (Cu), 610 ± 392 (Pb), and 1425 ± 222 (Zn). For contaminated sites, the probable effect threshold was exceeded in 38% (As), 45% (Cd), 0% (Cu), 74% (Pb), and 67% (Zn) of submerged species concentrations. Metal concentrations in S. latifolia tubers were lower than the submerged species leaves and shoots. Tuber concentrations did not exceed the probable effect threshold for any metal. Spatial differences in concentrations were most distinct for the submerged species. Our work shows significant amounts of metals are accumulating in some macrophytes of the study area and that biota associated with this vegetation may experience toxicity based upon guideline exceedances. Additionally, managers of invasive plants (e.g., M. spicatum) should consider the ramifications of control efforts given the high metal content of some plants (e.g., disposal issue).

Bipolar disorder: Managing the peaks and valleys.

Bipolar disorder is a psychiatric illness that is relatively common among patients presenting for treatment in primary care clinics. Physicians in primary care often face difficult decisions about how and when to intervene when a patient is experiencing depressive, manic, or hypomanic episodes consistent with bipolar disorder. This article reviews the literature on how to assess and diagnose bipolar disorder in primary care, and how to choose from the array of treatment options that exist. The psychotherapy and pharmacotherapy evidence base provides guidance on how to help patients effectively manage this ailment. Collaboration among health and mental health practitioners is key in helping manage the "peaks and valleys" of bipolar disorder. Special considerations need to be made to routinely assess for impulsivity, suicidality, and patient progress throughout the course of treatment.

Building Meaningful Patient Engagement in Research: Case Study From ADVANCE Clinical Data Research Network.

BACKGROUND: Strategies to engage patients to improve and enhance research and clinical care are increasingly being implemented in the United States, yet little is known about best practices for or the impacts of meaningful patient engagement. OBJECTIVE: We describe and reflect on our patient stakeholder groups, engagement framework, experiences, and lessons learned in engaging patients in research, from generating proposal ideas to disseminating findings. SETTING: The ADVANCE (Accelerating Data Value Across a National Community Health Center Network) clinical data research network is the nation's largest clinical dataset on the safety net, with outpatient clinical data from 122 health systems (1109 clinics) in 23 states. RESULTS: Patients stakeholders codeveloped the ADVANCE engagement framework and its implementation in partnership with network leaders. In phase I of ADVANCE, patients were involved with designing studies (input on primary outcome measures and methods) and usability testing (of the patient portal). In phase II, the network is prioritizing research training, dissemination opportunities, an "ambassador" program to pair more experienced patient stakeholders with those less experienced, and evaluation of engagement activities and impacts. DISCUSSION: The ADVANCE framework for patient engagement has successfully involved a diverse group of patients in the design, implementation, and interpretation of comparative effectiveness research. Our experience and framework can be used by other organizations and research networks to support patient engagement activities.

SR-2P vaginal microbicide gel provides protection against herpes simplex virus 2 when administered as a combined prophylactic and postexposure therapeutic.

Previously, we demonstrated that a single prophylactic dose of SR-2P, a novel dual-component microbicide gel comprising acyclovir and tenofovir, led to a modest increase in mouse survival following a lethal challenge of herpes simplex virus 2 (HSV-2). Here, we show that a dose of SR-2P administered 24 h prior to infection provides some protection against the virus, but to a lesser degree than SR-2P administered either once a day for 2 days or 1 h prior to infection. None of the prophylactic doses blocked infection by the virus, and all resulted in 80 to 100% lethality. However, given that a prophylactic dose still provided a significant reduction in overall clinical score, reduced rate of body weight loss, and increased median survival of the mice, we examined whether a repetitive dose regimen (postinfection) in addition to the prophylactic dose could prevent death and reduce the levels of virus in mice. Nearly all (9 of 10 in each group) of the mice that received SR-2P for 2 days prior to infection or that received SR-2P 1 h prior to infection and were administered SR-2P once a day for 10 days after infection showed no clinical symptoms of infection and no viral loads in vaginal swabs and survived for 28 days postinfection. Conversely, mice receiving no treatment or an identical vehicle treatment demonstrated advanced clinical signs and did not survive past day 9 postinfection. We conclude that SR-2P is an effective anti-HSV-2 agent in mice.

Quantitative measurement of alterations in DNA damage repair (DDR) pathways using single cell network profiling (SCNP).

BACKGROUND: Homologous recombination repair (HRR) pathway deficiencies have significant implications for cancer predisposition and treatment strategies. Improved quantitative methods for functionally characterizing these deficiencies are required to accurately identify patients at risk of developing cancer and to identify mechanisms of drug resistance or sensitivity. METHODS: Flow cytometry-based single cell network profiling (SCNP) was used to measure drug-induced activation of DNA damage response (DDR) proteins in cell lines with defined HRR pathway mutations (including ATM-/-, ATM+/-, BRCA1+/-, BRCA2-/-) and in primary acute myeloid leukemia (AML) samples. Both non-homologous end joining (NHEJ) and HRR pathways were examined by measuring changes in intracellular readouts (including p-H2AX, p-ATM, p-DNA-PKcs, p-53BP1, p-RPA2/32, p-BRCA1, p-p53, and p21) in response to exposure to mechanistically distinct genotoxins. The cell cycle S/G2/M phase CyclinA2 marker was used to normalize for proliferation rates. RESULTS: Etoposide induced proliferation-independent DNA damage and activation of multiple DDR proteins in primary AML cells and ATM +/+but not ATM -/- cell lines. Treatment with the PARPi AZD2281 +/- temozolomide induced DNA damage in CyclinA2+ cells in both primary AML cells and cell lines and distngiushed cell lines deficient (BRCA2-/-) or impaired (BRCA1+/-) in HRR activity from BRCA1+/+ cell lines based on p-H2AX induction. Application of this assay to primary AML samples identified heterogeneous patterns of repair activity including muted or proficient activation of NHEJ and HRR pathways and predominant activation of NHEJ in a subset of samples. CONCLUSIONS: SCNP identified functional DDR readouts in both NHEJ and HRR pathways, which can be applied to identify cells with BRCA1+/- haploinsuffiency and characterize differential DDR pathway functionality in primary clinical samples.

Single cell network profiling assay in bladder cancer.

The aim of this study was to assess the feasibility of applying the single cell network profiling (SCNP) assay to the examination of signaling networks in epithelial cancer cells, using bladder washings from 29 bladder cancer (BC) and 15 nonbladder cancer (NC) subjects. This report describes the methods we developed to detect rare epithelial cells (within the cells we collected from bladder washings), distinguish cancer cells from normal epithelial cells, and reproducibly quantify signaling within these low frequency cancer cells. Specifically, antibodies against CD45, cytokeratin, EpCAM, and cleaved-PARP (cPARP) were used to differentiate nonapoptotic epithelial cells from leukocytes, while measurements of DNA content to determine aneuploidy (DAPI stain) allowed for distinction between tumor and normal epithelial cells. Signaling activity in the PI3K and MAPK pathways was assessed by measuring intracellular levels of p-AKT and p-ERK at baseline and in response to pathway modulation; 66% (N = 19) of BC samples and 27% (N = 4) of NC samples met the "evaluable" criteria, i.e., at least 400,000 total cells available upon sample receipt with >2% of cells showing an epithelial phenotype. The majority of epithelial cells detected in BC samples were nonapoptotic and all signaling data were generated from identified cPARP negative cells. In four of 19 BC samples but in none of the NC specimens, SCNP assay identified epithelial cancer cells with a quantifiable increase in epidermal growth factor-induced p-AKT and p-ERK levels. Furthermore, preincubation with the PI3K inhibitor GDC-0941 reduced or completely inhibited basal and epidermal growth factor-induced p-AKT but, as expected, had no effect on p-ERK levels. This study demonstrates the feasibility of applying SCNP assay using multiparametric flow cytometry to the functional characterization of rare, bladder cancer cells collected from bladder washing. Following assay standardization, this method could potentially serve as a tool for disease characterization and drug development in bladder cancer and other solid tumors.

Compound haploinsufficiencies of Ebf1 and Runx1 genes impede B cell lineage progression.

Early B cell factor (EBF)1 is essential for B lineage specification. Previously, we demonstrated the synergistic activation of Cd79a (mb-1) genes by EBF1 and its functional partner, RUNX1. Here, we identified consequences of Ebf1 haploinsufficiency together with haploinsufficiency of Runx1 genes in mice. Although numbers of "committed" pro-B cells were maintained in Ebf1(+/-)Runx1(+/-) (ER(het)) mice, activation of B cell-specific gene transcription was depressed in these cells. Expression of genes encoding Aiolos, kappa0 sterile transcripts, CD2 and CD25 were reduced and delayed in ER(het) pro-B cells, whereas surface expression of BP-1 was increased on late pro-B cells in ER(het) mice. Late pre-B and immature and mature B cells were decreased in the bone marrow of Ebf1(+/-) (E(het)) mice and were nearly absent in ER(het) mice. Although we did not observe significant effects of haploinsuficiencies on IgH or Igkappa rearrangements, a relative lack of Iglambda rearrangements was detected in E(het) and ER(het) pre-B cells. Together, these observations suggest that B cell lineage progression is impaired at multiple stages in the bone marrow of E(het) and ER(het) mice. Furthermore, enforced expression of EBF1 and RUNX1 in terminally differentiated plasmacytoma cells activated multiple early B cell-specific genes synergistically. Collectively, these studies illuminate the effects of reduced Ebf1 dosage and the compounding effects of reduced Runx1 dosage. Our data confirm and extend the importance of EBF1 in regulating target genes and Ig gene rearrangements necessary for B cell lineage specification, developmental progression, and homeostasis.

Appalachian women and heart health: current prevention strategies and future directions.

BACKGROUND: Heart disease claims the lives of 25% of women in the United States. Only about half of women recognize it as the number one cause of adult female mortality, indicating a gap in the public's knowledge base. In West Virginia, women often face barriers such as social isolation, lack of healthy lifestyle options and fewer physician visits. METHODS: Literature review focused on successful efforts to remedy barriers in Appalachian women with strategies such as community outreach, group, and individual education. RESULTS: Primary care doctors can get involved by providing personalized information on heart health risk and utilizing appointments as opportunities for preventative heart health treatment. CONCLUSIONS: Future initiatives should highlight the need for brief, accurate risk assessments and continued encouragement to decrease cardiac risk factors. An ongoing West Virginia Rural Scholars project is aimed at achieving those two aforementioned goals: increasing awareness and reducing risk factors for women's heart health.

Aquatic macrophytes show distinct spatial trends in contaminant metal and nutrient concentrations in Coeur d'Alene Lake, USA.

Coeur d'Alene Lake (the Lake) has received significant contamination from legacy mining. Aquatic macrophytes provide important ecosystem services, such as food or habitat, but also have the ability to accumulate contaminants. We examined contaminants (arsenic, cadmium, copper, lead, and zinc) and other analytes (e.g., iron, phosphorus, and total Kjeldahl nitrogen (TKN)) in macrophytes from the Lake. Macrophytes were collected in the Lake from the uncontaminated southern end to the outlet of the Coeur d'Alene River (main contaminant source) located northward and mid lake. Most analytes showed significant north to south trends (Kendall's tau p ≤ 0.015). Concentrations of cadmium (18.2 ± 12.1), copper (13.0 ± 6.6), lead (195 ± 193), and zinc (1128 ± 523) were highest in macrophytes near the Coeur d'Alene River outlet (mean ± standard deviation in mg/kg dry biomass). Conversely, aluminum, iron, phosphorus, and TKN were highest in macrophytes from the south, potentially related to the Lake's trophic gradient. Generalized additive modelling confirmed latitudinal trends, but revealed that longitude and depth were also important predictors of analyte concentration (40-95% deviance explained for contaminants). We used sediment and soil screening benchmarks to calculate toxicity quotients. Quotients were used to assess potential toxicity to macrophyte associated biota and delineate where macrophyte concentrations exceeded local background concentrations. Exceedances (toxicity quotient > one) of background levels by macrophyte concentrations were highest for zinc (86%), followed by cadmium (84%), lead (23%), and arsenic (5%).

Angiotensin II in liver transplantation (AngLT-1): protocol of a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Catecholamine vasopressors such as norepinephrine are the standard drugs used to maintain mean arterial pressure during liver transplantation. At high doses, catecholamines may impair organ perfusion. Angiotensin II is a peptide vasoconstrictor that may improve renal perfusion pressure and glomerular filtration rate, a haemodynamic profile that could reduce acute kidney injury. Angiotensin II is approved for vasodilatory shock but has not been rigorously evaluated for treatment of hypotension during liver transplantation. The objective is to assess the efficacy of angiotensin II as a second-line vasopressor infusion during liver transplantation. This trial will establish the efficacy of angiotensin II in decreasing the dose of norepinephrine to maintain adequate blood pressure. Completion of this study will allow design of a follow-up, multicentre trial powered to detect a reduction of organ injury in liver transplantation. METHODS AND ANALYSIS: This is a double-blind, randomised clinical trial. Eligible subjects are adults with a Model for End-Stage Liver Disease Sodium Score ≥25 undergoing deceased donor liver transplantation. Subjects are randomised 1:1 to receive angiotensin II or saline placebo as the second-line vasopressor infusion. The study drug infusion is initiated on reaching a norepinephrine dose of 0.05 µg kg-1 min-1 and titrated per protocol. The primary outcome is the dose of norepinephrine required to maintain a mean arterial pressure ≥65 mm Hg. Secondary outcomes include vasopressin or epinephrine requirement and duration of hypotension. Safety outcomes include incidence of thromboembolism within 48 hours of the end of surgery and severe hypertension. An intention-to-treat analysis will be performed for all randomised subjects receiving the study drug. The total dose of norepinephrine will be compared between the two arms by a one-tailed Mann-Whitney U test. ETHICS AND DISSEMINATION: The trial protocol was approved by the local Institutional Review Board (#20-30948). Results will be posted on ClinicalTrials.gov and published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ClinicalTrials.govNCT04901169.

A dose-dependent role for EBF1 in repressing non-B-cell-specific genes.

In the absence of early B-cell factor 1 (EBF1), B-cell development is arrested at an uncommitted progenitor stage that exhibits increased lineage potentials. Previously, we investigated the roles of EBF1 and its DNA-binding partner Runx1 by evaluating B lymphopoiesis in single (EBF1(het) and Runx1(het)) and compound haploinsufficent (Ebf1(+/-) Runx1(+/-), ER(het)) mice. Here, we demonstrate that decreased Ebf1 gene dosage results in the inappropriate expression of NK-cell lineage-specific genes in B-cell progenitors. Moreover, prolonged expression of Ly6a/Sca-1 suggested the maintenance of a relatively undifferentiated phenotype. These effects were exacerbated by reduced expression of Runx1 and occurred despite expression of Pax5. Repression of inappropriately expressed genes was restored in most pre-B and all immature B cells of ER(het) mice. Enforced EBF1 expression repressed promiscuous transcription in pro-B cells of ER(het) mice and in Ebf1(-/-) Pax5(-/-) fetal liver cells. Together, our studies suggest that normal levels of EBF1 are critical for maintaining B-cell identity by directing repression of non-B-cell-specific genes.

Opposing effects of SWI/SNF and Mi-2/NuRD chromatin remodeling complexes on epigenetic reprogramming by EBF and Pax5.

Transcriptionally silent genes are maintained in inaccessible chromatin. Accessibility of these genes requires their modification by chromatin remodeling complexes (CRCs), which are recruited to promoters by sequence-specific DNA-binding proteins. Early B-cell factor (EBF), which is crucial for B-cell lineage specification, reprograms mb-1 (Ig-alpha) promoters by increasing chromatin accessibility and initiating the loss of DNA methylation. In turn, this facilitates promoter activation by Pax5. Here, we investigated the roles of ATP-dependent CRCs in these mechanisms. Fusion of EBF and Pax5 with the ligand-binding domain of ERalpha allowed for 4-hydroxytamoxifen-dependent, synergistic activation of mb-1 transcription in plasmacytoma cells. Knock-down of the SWI/SNF ATPases Brg1 and Brm inhibited transcriptional activation by EBF:ER and Pax5:ER. In contrast, knock-down of the Mi-2/NuRD complex subunit Mi-2beta greatly enhanced chromatin accessibility and mb-1 transcription in response to the activators. The reduction of Mi-2beta also propagated DNA demethylation in response to EBF:ER and Pax5:ER, resulting in fully unmethylated mb-1 promoters. In EBF- or EBF/Pax5-deficient fetal liver cells, both EBF and Pax5 were required for efficient demethylation of mb-1 promoters. Together, our data suggest that Mi-2/NuRD is important for the maintenance of hypermethylated chromatin in B cells. We conclude that SWI/SNF and Mi-2/NuRD function in opposition to enable or limit the reprogramming of genes by EBF and Pax5 during B-cell development.

Diagnosis of childhood pneumonia: clinical assessment without radiological confirmation may lead to overtreatment.

OBJECTIVES: Consensus guidelines discourage the use of routine radiologic confirmation of clinically diagnosed pneumonia in children. The goal of the present study was to assess the degree of antibiotic overtreatment resulting from this approach. DESIGN: This was a prospective data collection. SETTING: This was performed in 5 urgent care clinics in Jerusalem, Israel. PARTICIPANTS: This study was composed of previously healthy children between 2 months and 18 years of age who presented with a chief complaint of fever, cough, or dyspnea between August 1, 2007, and March 15, 2008, by for whom chest x-rays were obtained because of clinical suspicion of pneumonia. OUTCOME MEASURES: Outcome measure was percentage of children with clinical findings associated with pneumonia (hypoxia, tachypnea, rales, dyspnea) who did not have radiological findings of pneumonia. RESULTS: With the exception of wheezing, 55% to 65% of children with specific signs and symptoms did not have radiologic pneumonia. A similar range of children with a combination of the signs did not have radiologic pneumonia. For wheezing, alone or in combination, the percentages were higher. On multivariate analysis, only fever was found to be predictive of pneumonia. Wheezing was found to be negatively predictive. CONCLUSIONS: Treatment of childhood pneumonia on the basis of clinical parameters alone with no chest x-ray confirmation may lead to a large portion of children receiving unnecessary antibiotic therapy. In an era when the emphasis is to decrease antibiotic resistance, radiological confirmation of pneumonia should be obtained when possible.

Physician-patient communication: breaking bad news.

Physicians often struggle with how to manage the task of breaking bad news with patients. Moreover, the arduous nature of the task can contribute to physician detachment from the patient or an avoidance of breaking the news in a timely manner. A plan of action can only improve physician confidence in breaking bad news, and also make the task more manageable. Over a decade ago, Rabow and McPhee offered a strategy; the ABCDE plan, which provided a patient centered framework from which to deliver troubling news to patients and families. At the heart of this plan was the creation of a safe environment, the demonstration of timely communication skills, and the display of empathy on the physician's part. Careful consideration of the doctor's own reactions to death and dying also played an important role. A close review of the five tenets of this plan indicates the relevance of Rabow and McPhee's strategy today. The patient base in our nation and state continues to be older, on average, and physicians are faced with numerous patients who have terminal illness. A constructive plan with specific ideas for breaking bad news can help physicians effectively navigate this difficult task.