Mobile Application-Based Communication Facilitation Platform for Family Members of Critically Ill Patients: A Randomized Clinical Trial.

Importance: Unmet and racially disparate palliative care needs are common in intensive care unit (ICU) settings. Objective: To test the effect of a primary palliative care intervention vs usual care control both overall and by family member race. Design, Setting, and Participants: This cluster randomized clinical trial was conducted at 6 adult medical and surgical ICUs in 2 academic and community hospitals in North Carolina between April 2019 and May 2022 with physician-level randomization and sequential clusters of 2 Black patient-family member dyads and 2 White patient-family member dyads enrolled under each physician. Eligible participants included consecutive patients receiving mechanical ventilation, their family members, and their attending ICU physicians. Data analysis was conducted from June 2022 to May 2023. Intervention: A mobile application (ICUconnect) that displayed family-reported needs over time and provided ICU attending physicians with automated timeline-driven communication advice on how to address individual needs. Main Outcomes and Measures: The primary outcome was change in the family-reported Needs at the End-of-Life Screening Tool (NEST; range 0-130, with higher scores reflecting greater need) score between study days 1 and 3. Secondary outcomes included family-reported quality of communication and symptoms of depression, anxiety, and posttraumatic stress disorder at 3 months. Results: A total of 111 (51% of those approached) family members (mean [SD] age, 51 [15] years; 96 women [86%]; 15 men [14%]; 47 Black family members [42%]; 64 White family members [58%]) and 111 patients (mean [SD] age, 55 [16] years; 66 male patients [59%]; 45 Black patients [41%]; 65 White patients [59%]; 1 American Indian or Alaska Native patient [1%]) were enrolled under 37 physicians randomized to intervention (19 physicians and 55 patient-family member dyads) or control (18 physicians and 56 patient-family member dyads). Compared with control, there was greater improvement in NEST scores among intervention recipients between baseline and both day 3 (estimated mean difference, -6.6 points; 95% CI, -11.9 to -1.3 points; P = .01) and day 7 (estimated mean difference, -5.4 points; 95% CI, -10.7 to 0.0 points; P = .05). There were no treatment group differences at 3 months in psychological distress symptoms. White family members experienced a greater reduction in NEST scores compared with Black family members at day 3 (estimated mean difference, -12.5 points; 95% CI, -18.9 to -6.1 points; P < .001 vs estimated mean difference, -0.3 points; 95% CI, -9.3 to 8.8 points; P = .96) and day 7 (estimated mean difference, -9.5 points; 95% CI, -16.1 to -3.0 points; P = .005 vs estimated mean difference, -1.4 points; 95% CI, -10.7 to 7.8; P = .76). Conclusions and Relevance: In this study of ICU patients and family members, a primary palliative care intervention using a mobile application reduced unmet palliative care needs compared with usual care without an effect on psychological distress symptoms at 3 months; there was a greater intervention effect among White family members compared with Black family members. These findings suggest that a mobile application-based intervention is a promising primary palliative care intervention for ICU clinicians that directly addresses the limited supply of palliative care specialists. Trial Registration: ClinicalTrials.gov Identifier: NCT03506438.

Impact of diagnostic guidelines on the diagnosis of hypersensitivity pneumonitis.

Introduction: Hypersensitivity pneumonitis (HP) is an immune-mediated interstitial lung disease from exposure to environmental antigens. Diagnosing HP could be challenging. The American College of Chest Physicians (CHEST) and American Thoracic Society/Japanese Respiratory Society/and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) have published diagnostic guidelines in 2021 and 2020 respectively. The CHEST guideline uses four grades of confidence: confident (>90%), provisional high (70-89%), provisional low (51-69%), and unlikely (≤50%). The ATS/JRS/ALAT guideline uses five grades of confidence: definite (>90%), high (80-89%), moderate (70-79%), low (51-69%) and not excluded (≤50%). In this study, we determined how these two guidelines could have affected the diagnosis of HP made before the guidelines. Methods: Two hundred and fifty-nine adult patients from a previous cohort with HP (ICD-9:495) made between Jan. 1, 2008, and Dec. 31, 2013, at Duke University Medical Center were included. We simplified the diagnostic confidence into three categories so we could compare the guidelines: high (≥90%), intermediate (51-89%), and low (≤50%). Results: There were 156 female and 103 male. Mean age was 58 (range: 20-90). 68.8% of the patients had restrictive defects (FVC < 80% pred) and 48.6% had lung biopsy. The CHEST guideline classified 33.6% of the patients into high, 59.5% into intermediate and 6.9% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.7% of the patients into high, 21.2% into intermediate and 49.0% into low confidence categories (p < 0.0001 vs. CHEST). Cohen's kappa was 0.331. In patients with identifiable inciting agents (IAs) (N = 168), the CHEST guideline classified 32.1% of the patients into high, 64.3% into intermediate and 3.6% into low confidence categories. The ATS/JRS/ALAT guideline classified 29.2% of the patients into high, 20.8% into intermediate, and 50.0% into low confidence categories. Cohen's kappa was 0.314. Discussion: In our HP cohort with two-thirds of the patients with restrictive defects, we found the two guidelines had fair agreement in diagnosing HP with or without identifiable IAs. They agreed more when the diagnostic confidence was high. When the diagnostic confidence was lower, however, the ATS/JRS/ALAT guideline was more stringent. Clinicians should be aware of the differences between the two guidelines when evaluating patients suspicious of HP.

Trajectories of Palliative Care Needs in the ICU and Long-Term Psychological Distress Symptoms.

OBJECTIVES: While palliative care needs are assumed to improve during ICU care, few empiric data exist on need trajectories or their impact on long-term outcomes. We aimed to describe trajectories of palliative care needs during ICU care and to determine if changes in needs over 1 week was associated with similar changes in psychological distress symptoms at 3 months. DESIGN: Prospective cohort study. SETTING: Six adult medical and surgical ICUs. PARTICIPANTS: Patients receiving mechanical ventilation for greater than or equal to 2 days and their family members. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the 13-item Needs at the End-of-Life Screening Tool (NEST; total score range 0-130) completed by family members at baseline, 3, and 7 days. The Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and Post-Traumatic Stress Scale (PTSS) were completed at baseline and 3 months. General linear models were used to estimate differences in distress symptoms by change in need (NEST improvement ≥ 10 points or not). One-hundred fifty-nine family members participated (median age, 54.0 yr [interquartile range (IQR), 44.0-63.0 yr], 125 [78.6%] female, 54 [34.0%] African American). At 7 days, 53 (33%) a serious level of overall need and 35 (22%) ranked greater than or equal to 1 individual need at the highest severity level. NEST scores improved greater than or equal to 10 points in only 47 (30%). Median NEST scores were 22 (IQR, 12-40) at baseline and 19 (IQR, 9-37) at 7 days (change, -2.0; IQR, -11.0 to 5.0; p = 0.12). There were no differences in PHQ-9, GAD-7, or PTSS change scores by change in NEST score (all p > 0.15). CONCLUSIONS: Serious palliative care needs were common and persistent among families during ICU care. Improvement in needs was not associated with less psychological distress at 3 months. Serious needs may be commonly underrecognized in current practice.

A Study to Evaluate Relative Bioavailability, Food Effect, and Pharmacodynamics of Tropifexor, a Farnesoid X Receptor Agonist, in Healthy Participants.

This open-label, randomized, 3-treatment, 3-period, 6-sequence, crossover study in healthy subjects compared the pharmacokinetic and pharmacodynamic properties of a lipid-based (soft gelatin capsule) prototype final market image (pFMI) formulation of tropifexor (90-µg) to its clinical service form (CSF) and assessed the food effect for the pFMI formulation. In the fasted state, drug exposure was higher for the pFMI. The geometric mean ratios for pFMI versus CSF of peak concentration and area under the concentration-time curve were 2.0 and 1.5, respectively. No food effect was apparent for the pFMI formulation, and the geometric mean ratios for pFMI fed versus pFMI fasted of peak concentration and area under concentration-time curve were 1.0 and 1.0 respectively. Despite having lower systemic exposure, the CSF formulation provided a higher pharmacological response for the gut biomarker fibroblast growth factor 19. Under fasted conditions, fibroblast growth factor 19 maximum change from baseline serum concentration after drug administration and area under the change from baseline serum concentration-time curve from time 0 to 24 hours were 36% for CSF and 12% for FMI. For a second biomarker, serum 7-alpha hydroxy-4-cholest-3-one, the pharmacological activity was comparable between CSF (fasted) and pFMI (both fasted and fed states). The pFMI offers advantages over the CSF in terms of insensitivity to food effect, lower intersubject variability, and overcoming solubility limitations.

Palliative care phenotypes among critically ill patients and family members: intensive care unit prospective cohort study.

OBJECTIVE: Because the heterogeneity of patients in intensive care units (ICUs) and family members represents a challenge to palliative care delivery, we aimed to determine if distinct phenotypes of palliative care needs exist. METHODS: Prospective cohort study conducted among family members of adult patients undergoing mechanical ventilation in six medical and surgical ICUs. The primary outcome was palliative care need measured by the Needs at the End-of-Life Screening Tool (NEST, range from 0 (no need) to 130 (highest need)) completed 3 days after ICU admission. We also assessed quality of communication, clinician-family relationship and patient centredness of care. Latent class analysis of the NEST's 13 items was used to identify groups with similar patterns of serious palliative care needs. RESULTS: Among 257 family members, latent class analysis yielded a four-class model including complex communication needs (n=26, 10%; median NEST score 68.0), family spiritual and cultural needs (n=21, 8%; 40.0) and patient and family stress needs (n=43, 31%; 31.0), as well as a fourth group with fewer serious needs (n=167, 65%; 14.0). Interclass differences existed in quality of communication (median range 4.0-10.0, p<0.001), favourable clinician-family relationship (range 34.6%-98.2%, p<0.001) and both the patient centredness of care Eliciting Concerns (median range 4.0-5.0, p<0.001) and Decision-Making (median range 2.3-4.5, p<0.001) scales. CONCLUSIONS: Four novel phenotypes of palliative care need were identified among ICU family members with distinct differences in the severity of needs and perceived quality of the clinician-family interaction. Knowledge of need class may help to inform the development of more person-centred models of ICU-based palliative care.

Drug-Drug Interaction Studies to Evaluate the Effect of Inhibition of UGT1A1 and CYP3A4 and Induction of CYP3A4 on the Pharmacokinetics of Tropifexor in Healthy Subjects.

Tropifexor, a farnesoid X receptor agonist, is currently under clinical development for the treatment of nonalcoholic steatohepatitis. Tropifexor undergoes glucuronidation by uridine 5'-diphosphoglucuronosyltransferase (UGT) 1A1 and oxidation by cytochrome P450 (CYP) 3A4, as reported in in vitro studies. Here, we report the results from 2 drug-drug interaction studies. Study 1 enrolled 20 healthy subjects to investigate the effect of the UGT1A1 inhibitor atazanavir (ATZ) on tropifexor pharmacokinetics (PK). Study 2 had 2 cohorts with 16 healthy subjects each to investigate the effect of the strong CYP3A4 inhibitor itraconazole and strong CYP3A4 inducer rifampin on the PK of tropifexor. Coadministration of ATZ reduced the maximum plasma concentration (Cmax ) of tropifexor by 40%; however, it did not lead to increased exposure of tropifexor (both area under the plasma concentration-time curve [AUC] from time 0 to the last quantifiable concentration [AUClast ] and AUC from time 0 to infinity [AUCinf ] reduced by only 10%), suggesting minor relevance of the UGT1A1 pathway for clearance of tropifexor and no expected drug-drug interactions based on UGT1A1 inhibition. Inhibition of CYP3A4 by itraconazole increased the Cmax of tropifexor by only 9% and exposure (both AUClast and AUCinf ) by 47%, suggesting a weak effect of strong CYP3A4 inhibitors on tropifexor PK. Inducing CYP3A4 with rifampin decreased Cmax (55%) and AUC (AUClast by 79% and AUCinf by 77%). Coadministration of tropifexor with either ATZ, itraconazole, or rifampin was well tolerated.

Assessment of Clinical Palliative Care Trigger Status vs Actual Needs Among Critically Ill Patients and Their Family Members.

Importance: Palliative care consultations in intensive care units (ICUs) are increasingly prompted by clinical characteristics associated with mortality or resource utilization. However, it is not known whether these triggers reflect actual palliative care needs. Objective: To compare unmet needs by clinical palliative care trigger status (present vs absent). Design, Setting, and Participants: This prospective cohort study was conducted in 6 adult medical and surgical ICUs in academic and community hospitals in North Carolina between January 2019 and September 2020. Participants were consecutive patients receiving mechanical ventilation and their family members. Exposure: Presence of any of 9 common clinical palliative care triggers. Main Outcomes and Measures: The primary outcome was the Needs at the End-of-Life Screening Tool (NEST) score (range, 0-130, with higher scores reflecting greater need), which was completed after 3 days of ICU care. Trigger status performance in identifying serious need (NEST score ≥30) was assessed using sensitivity, specificity, positive and negative likelihood ratios, and C statistics. Results: Surveys were completed by 257 of 360 family members of patients (71.4% of the potentially eligible patient-family member dyads approached) with a median age of 54.0 years (IQR, 44-62 years); 197 family members (76.7%) were female, and 83 (32.3%) were Black. The median age of patients was 58.0 years (IQR, 46-68 years); 126 patients (49.0%) were female, and 88 (33.5%) were Black. There was no difference in median NEST score between participants with a trigger present (45%) and those with a trigger absent (55%) (21.0; IQR, 12.0-37.0 vs 22.5; IQR, 12.0-39.0; P = .52). Trigger presence was associated with poor sensitivity (45%; 95% CI, 34%-55%), specificity (55%; 95% CI, 48%-63%), positive likelihood ratio (1.0; 95% CI, 0.7-1.3), negative likelihood ratio (1.0; 95% CI, 0.8-1.2), and C statistic (0.50; 95% CI, 0.44-0.57). Conclusions and Relevance: In this cohort study, clinical palliative care trigger status was not associated with palliative care needs and no better than chance at identifying the most serious needs, which raises questions about an increasingly common clinical practice. Focusing care delivery on directly measured needs may represent a more person-centered alternative.

Pharmacokinetics of Tropifexor, a Potent Farnesoid X Receptor Agonist, in Participants With Varying Degrees of Hepatic Impairment.

Tropifexor, a non-bile acid farnesoid X receptor (FXR) agonist, has dose-proportional pharmacokinetics and no obvious major enterohepatic circulation. This open-label study investigated the effect of hepatic impairment (HI), as determined by Child-Pugh grade, on tropifexor's pharmacokinetics, safety, and tolerability following a 200-µg dose in the fasted state. Blood samples were collected through 168 hours after dosing for quantification and plasma protein-binding determination. Total tropifexor exposure was comparable across participants with HI vs those with normal hepatic function. Tropifexor was highly protein bound (>99%) in human plasma across participants of all groups. The average unbound fractions (percentage free) were 0.14% in participants with normal hepatic function and mild HI, which increased to 0.17% and 0.24% in participants with moderate and severe HI, respectively. Similar unbound drug exposure was noted in participants with mild HI and normal hepatic function. Participants with moderate HI (N = 8) had a 1.6-fold increase in unbound exposure (area under the plasma concentration-time curve from time 0 to infinity [AUCinf,u ]) and a 1.3-fold increase in maximal exposure (Cmax,u ) vs those with normal hepatic function (geometric mean ratio: AUCinf,u , 1.64 [90%CI, 1.25-2.16]; Cmax,u , 1.30 [90%CI, 0.96-1.76]). Participants with severe HI (N = 8) had a 1.6-fold increase in AUCinf,u (1.61 [90%CI, 1.04-2.49]) and comparable Cmax,u (1.02 [90%CI, 0.60-1.72]) compared to participants with normal hepatic function. Tropifexor was well tolerated. The relative insensitivity of tropifexor to HI offers the potential to treat patients with severe liver disease without dose adjustment.

Evaluation of the Absorption, Metabolism, and Excretion of a Single Oral 1-mg Dose of Tropifexor in Healthy Male Subjects and the Concentration Dependence of Tropifexor Metabolism.

Tropifexor (NVP-LJN452) is a highly potent, selective, nonsteroidal, non-bile acid farnesoid X receptor agonist for the treatment of nonalcoholic steatohepatitis. Its absorption, metabolism, and excretion were studied after a 1-mg oral dose of [14C]tropifexor was given to four healthy male subjects. Mass balance was achieved with ∼94% of the administered dose recovered in excreta through a 312-hour collection period. Fecal excretion of tropifexor-related radioactivity played a major role (∼65% of the total dose). Tropifexor reached a maximum blood concentration (Cmax) of 33.5 ng/ml with a median time to reach Cmax of 4 hours and was eliminated with a plasma elimination half-life of 13.5 hours. Unchanged tropifexor was the principal drug-related component found in plasma (∼92% of total radioactivity). Two minor oxidative metabolites, M11.6 and M22.4, were observed in circulation. Tropifexor was eliminated predominantly via metabolism with >68% of the dose recovered as metabolites in excreta. Oxidative metabolism appeared to be the major clearance pathway of tropifexor. Metabolites containing multiple oxidative modifications and combined oxidation and glucuronidation were also observed in human excreta. The involvement of direct glucuronidation could not be ruled out based on previous in vitro and nonclinical in vivo studies indicating its contribution to tropifexor clearance. The relative contribution of the oxidation and glucuronidation pathways appeared to be dose-dependent upon further in vitro investigation. Because of these complexities and the instability of glucuronide metabolites in the gastrointestinal tract, the contribution of glucuronidation remained undefined in this study. SIGNIFICANCE STATEMENT: Tropifexor was found to be primarily cleared from the human body via oxidative metabolism. In vitro metabolism experiments revealed that the relative contribution of oxidation and glucuronidation was concentration-dependent, with glucuronidation as the predominant pathway at higher concentrations and the oxidative process becoming more important at lower concentrations near clinical exposure range. The body of work demonstrated the importance of carefully designed in vivo and in vitro experiments for better understanding of disposition processes during drug development.

Improving racial disparities in unmet palliative care needs among intensive care unit family members with a needs-targeted app intervention: The ICUconnect randomized clinical trial.

INTRODUCTION: The technologies used to treat the millions who receive care in intensive care unit (ICUs) each year have steadily advanced. However, the quality of ICU-based communication has remained suboptimal, particularly concerning for Black patients and their family members. Therefore we developed a mobile app intervention for ICU clinicians and family members called ICUconnect that assists with delivering need-based care. OBJECTIVE: To describe the methods and early experiences of a clustered randomized clinical trial (RCT) being conducted to compare ICUconnect vs. usual care. METHODS AND ANALYSIS: The goal of this two-arm, parallel group clustered RCT is to determine the clinical impact of the ICUconnect intervention in improving outcomes overall and for each racial subgroup on reducing racial disparities in core palliative care outcomes over a 3-month follow up period. ICU attending physicians are randomized to either ICUconnect or usual care, with outcomes obtained from family members of ICU patients. The primary outcome is change in unmet palliative care needs measured by the NEST instrument between baseline and 3 days post-randomization. Secondary outcomes include goal concordance of care and interpersonal processes of care at 3 days post-randomization; length of stay; as well as symptoms of depression, anxiety, and post-traumatic stress disorder at 3 months post-randomization. We will use hierarchical linear models to compare outcomes between the ICUconnect and usual care arms within all participants and assess for differential intervention effects in Blacks and Whites by adding a patient-race interaction term. We hypothesize that both compared to usual care as well as among Blacks compared to Whites, ICUconnect will reduce unmet palliative care needs, psychological distress and healthcare resource utilization while improving goal concordance and interpersonal processes of care. In this manuscript, we also describe steps taken to adapt the ICUconnect intervention to the COVID-19 pandemic healthcare setting. ENROLLMENT STATUS: A total of 36 (90%) of 40 ICU physicians have been randomized and 83 (52%) of 160 patient-family dyads have been enrolled to date. Enrollment will continue until the end of 2021.

Operationalizing needs-focused palliative care for older adults in intensive care units: Design of and rationale for the PCplanner randomized clinical trial.

INTRODUCTION: The number of older adults who receive life support in an intensive care unit (ICU), now 2 million per year, is increasing while survival remains unchanged. Because the quality of ICU-based palliative care is highly variable, we developed a mobile app intervention that integrates into the electronic health records (EHR) system called PCplanner (Palliative Care planner) with the goal of improving collaborative primary and specialist palliative care delivery in ICU settings. OBJECTIVE: To describe the methods of a randomized clinical trial (RCT) being conducted to compare PCplanner vs. usual care. METHODS AND ANALYSIS: The goal of this two-arm, parallel group mixed methods RCT is to determine the clinical impact of the PCplanner intervention on outcomes of interest to patients, family members, clinicians, and policymakers over a 3-month follow up period. The primary outcome is change in unmet palliative care needs measured by the NEST instrument between baseline and 1 week post-randomization. Secondary outcomes include goal concordance of care, patient-centeredness of care, and quality of communication at 1 week post-randomization; length of stay; as well as symptoms of depression, anxiety, and post-traumatic stress disorder at 3 months post-randomization. We will use general linear models for repeated measures to compare outcomes across the main effects and interactions of the factors. We hypothesize that compared to usual care, PCplanner will have a greater impact on the quality of ICU-based palliative care delivery across domains of core palliative care needs, psychological distress, patient-centeredness, and healthcare resource utilization.

Chronic hypersensitivity pneumonitis in the southeastern United States: an assessment of how clinicians reached the diagnosis.

BACKGROUND: Chronic hypersensitivity pneumonitis (cHP) is a disease caused by exposure to inhaled environmental antigens. Diagnosis of cHP is influenced by the awareness of the disease prevalence, which varies significantly in different regions, and how clinicians utilize relevant clinical information. We conducted a retrospective study to evaluate how clinicians in the Southeast United States, where the climate is humid favoring mold growth, diagnosed cHP using items identified in the international modified Delphi survey of experts, i.e., environmental exposure, CT imaging and lung pathology, METHODS: We searched Duke University Medical Center database for patients over the age of 18 with a diagnosis of cHP (ICD-9 code: 495) between Jan. 1, 2008 to Dec. 31, 2013 using a query tool, Duke Enterprise Data Unified Content Explorer (DEDUCE). RESULTS: Five hundred patients were identified and 261 patients had cHP confirmed in clinic notes by a pulmonologist or an allergist. About half of the patients lived in the Research Triangle area where our medical center is located, giving an estimated prevalence rate of 6.5 per 100,000 persons. An exposure source was mentioned in 69.3% of the patient. The most common exposure sources were environmental molds (43.1%) and birds (26.0%). We used Venn diagram to evaluate how the patients met the three most common cHP diagnostic criteria: evidence of environmental exposures (history or precipitin) (E), chest CT imaging (C) and pathology from lung biopsies (P). Eighteen patients (6.9%) met none of three criteria. Of the remaining 243 patients, 135 patients (55.6%) had one (E 35.0%, C 3.3%, P 17.3%), 81 patients (33.3%) had two (E + C 12.3%, E + P 17.3%, C + P 4.9%), and 27 patients (11.1%) had all three criteria (E + C + P). Overall, 49.4% of patients had pathology from lung biopsy compared to 31.6% with CT scan. CONCLUSIONS: Environmental mold was the most common exposure for cHP in the Southeast United States. Lung pathology was available in more than half of cHP cases in our tertiary care center, perhaps reflecting the complexity of referrals. Differences in exposure sources and referral patterns should be considered in devising future diagnostic pathways or guidelines for cHP.

Knowledge and Perceptions Regarding Palliative Care Among Religious Leaders in Uasin Gishu County, Kenya: Survey and Focus Group Analysis.

Spirituality and religion are at the core of Kenyan life. Pastoral leaders play a key role in shaping the individual and community's response to living with chronic and life-threatening illnesses. Involvement of religious leaders would therefore be critical in advocacy and education efforts in palliative care (PC) to address the needs of this population. The goal of this study was to evaluate the knowledge and perceptions of religious leaders in Western Kenya regarding PC. This was a mixed-methods study with 86 religious leaders utilizing a 25-question survey followed by 5-person focus group discussions. Eighty-one percent of participants agreed that pastors should encourage members with life-threatening illnesses to talk about death and dying. However, almost a third of participants (29%) also agreed with the statement that full use of PC can hasten death. The pastors underscored challenges in end-of-life spiritual preparation as well as the importance of traditional beliefs in shaping cultural norms. Pastors supported the need for community-based PC education and additional training in PC for religious leaders. The results of this study confirm the dominant role of religion and spirituality in PC in Kenya. This dominant role in shaping PC is tied closely to Kenyan attitudes and norms surrounding death and dying.

Oncotargets GD2 and GD3 are highly expressed in sarcomas of children, adolescents, and young adults.

BACKGROUND: GD2 and GD3 are the tumor-associated glycolipid antigens found in a broad spectrum of human cancers. GD2-specific antibody is currently a standard of care for high-risk neuroblastoma therapy. In this study, the pattern of GD2 and GD3 expression among pediatric/adolescent or young adult tumors was determined, providing companion diagnostics for targeted therapy. METHODS: Ninety-two specimens of human osteosarcoma (OS), rhabdomyosarcoma (RMS), Ewing family of tumors, desmoplastic small round cell tumor (DSRCT), and melanoma were analyzed for GD2/GD3 expression by immunohistochemistry. Murine monoclonal antibody 3F8 was used for GD2 staining, and R24 for GD3. Staining was scored according to both intensity and percentage of positive tumor cells from 0 to 4. RESULTS: Both gangliosides were highly prevalent in OS and melanoma. Among other tumors, GD3 expression was higher than GD2 expression. Most OS samples demonstrated strong staining for GD2 and GD3, whereas expression for other tumors was highly variable. Mean intensity of GD2 expression was significantly more heterogeneous (P < 0.001) when compared to GD3 across tumor types. When assessing the difference between GD2 and GD3 expression in all tumor types combined, GD3 expression had a significantly higher score (P = 0.049). When analyzed within each cancer, GD3 expression was significantly higher only in DSRCT (P = 0.002). There was no statistical difference in either GD2 or GD3 expression between primary and recurrent sarcomas. CONCLUSION: GD2/GD3 expression among pediatric solid tumors is common, albeit with variable level of expression. Especially for patients with sarcoma, these gangliosides can be potential targets for antibody-based therapies.

A strategy for improving comparability across sites for ligand binding assays measuring therapeutic proteins.

Outsourcing and multi-site testing has increased for ligand binding assays supporting protein therapeutic measurement. It is common to combine and compare data across studies with data from multiple bioanalytical sites. We designed a prospective study to determine the benefits of increasing control over the transfer process to improve ruggedness. The experiment involved the testing of 30 incurred samples at 3 stages with incremental laboratory harmonization in standard/quality controls and assay components: Stage I represented a transfer of a detailed protocol and critical reagents. Stage II, a single source of standards and quality controls were provided to each site. Stage III, standards and quality controls plus a ready-to-use kit were provided. The results indicated that all testing facilities failed agreement testing using the stage I procedure. The introduction of standards from a single source improved the agreement. The modification reduced variation by 33% compared to the stage I approach. There was no additional benefit when a packaged kit was provided. In conclusion, introduction of a single source of standards and quality controls reduced the inter-site component of variation and should allow for combinability of data.

The potential of genes and other markers to inform about risk.

BACKGROUND: Advances in biotechnology have raised expectations that biomarkers, including genetic profiles, will yield information to accurately predict outcomes for individuals. However, results to date have been disappointing. In addition, statistical methods to quantify the predictive information in markers have not been standardized. METHODS: We discuss statistical techniques to summarize predictive information, including risk distribution curves and measures derived from them, that relate to decision making. Attributes of these measures are contrasted with alternatives such as receiver operating characteristic curves, R(2), percent reclassification, and net reclassification index. Data are generated from simple models of risk conferred by genetic profiles for individuals in a population. Statistical techniques are illustrated, and the risk prediction capacities of different risk models are quantified. RESULTS: Risk distribution curves are most informative and relevant to clinical practice. They show proportions of subjects classified into clinically relevant risk categories. In a population in which 10% have the outcome event and subjects are categorized as high risk if their risk exceeds 20%, we identified some settings where more than half of those destined to have an event were classified as high risk by the risk model. Either 150 genes each with odds ratio of 1.5 or 250 genes each with odds ratio of 1.25 were required when the minor allele frequencies are 10%. We show that conclusions based on receiver operating characteristic curves may not be the same as conclusions based on risk distribution curves. CONCLUSIONS: Many highly predictive genes will be required to identify substantial numbers of subjects at high risk.

Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi).

Angiotensin receptor blockade and neprilysin (NEP) inhibition together offer potential benefits for the treatment of hypertension and heart failure. LCZ696 is a novel single molecule comprising molecular moieties of valsartan and NEP inhibitor prodrug AHU377 (1:1 ratio). Oral administration of LCZ696 caused dose-dependent increases in atrial natriuretic peptide immunoreactivity (due to NEP inhibition) in Sprague-Dawley rats and provided sustained, dose-dependent blood pressure reductions in hypertensive double-transgenic rats. In healthy participants, a randomized, double-blind, placebo-controlled study (n = 80) of single-dose (200-1200 mg) and multiple-dose (50-900 mg once daily for 14 days) oral administration of LCZ696 showed that peak plasma concentrations were reached rapidly for valsartan (1.6-4.9 hours), AHU377 (0.5-1.1 hours), and its active moiety, LBQ657 (1.8-3.5 hours). LCZ696 treatment was associated with increases in plasma cGMP, renin concentration and activity, and angiotensin II, providing evidence for NEP inhibition and angiotensin receptor blockade. In a randomized, open-label crossover study in healthy participants (n = 56), oral LCZ696 400 mg and valsartan 320 mg were shown to provide similar exposure to valsartan (geometric mean ratio [90% confidence interval]: AUC(0-infinity) 0.90 [0.82-0.99]). LCZ696 was safe and well tolerated. These data support further clinical development of LCZ696, a novel, orally bioavailable, dual-acting angiotensin receptor-NEP inhibitor (ARNi) for hypertension and heart failure.

Performance of a single assay for both type III and type VI TMPRSS2:ERG fusions in noninvasive prediction of prostate biopsy outcome.

BACKGROUND: TMPRSS2:ERG fusions are promising prostate cancer biomarkers. Because they can occur in multiple forms in a single cancer specimen, we developed a quantitative PCR test that detects both type III and type VI TMPRSS2:ERG fusions. The assay is quantified from a standard curve determined with a plasmid-cloned type III TMPRSS2:ERG fusion target. METHODS: We collected expressed prostatic secretion (EPS) under an institutional review board-approved, blinded, prospective study from 74 patients undergoing transrectal ultrasound-guided biopsy for prostate cancer. We compared the characteristic performance of the test for type III and type VI TMPRSS2:ERG fusions in predicting biopsy outcome and distinguishing between high and low Gleason scores with similar tests for the expression of PCA3 and DNA methylation levels of the APC, RARB, RASSF1, and GSTP1 genes. We used logistic regression to analyze the effects of multiple biomarkers in linear combinations. RESULTS: Each test provided a significant improvement in characteristic performance over baseline digital rectal examination (DRE) plus serum prostate-specific antigen (PSA); however, the test for type III and type VI TMPRSS2:ERG fusions yielded the best performance in predicting biopsy outcome [area under the curve (AUC) 0.823, 95% CI 0.728-0.919, P < 0.001] and Gleason grade >7 (AUC 0.844, 95% CI 0.740-0.948, P < 0.001). CONCLUSIONS: Although each test appears to have diagnostic value, PSA plus DRE plus type III and type VI TMPRSS2:ERG provided the best diagnostic performance in EPS specimens.

Association between a frequent allele of the gene encoding OATP1B1 and enhanced LDL-lowering response to fluvastatin therapy.

INTRODUCTION: Marked lowering of low-density-lipoprotein cholesterol (LDL-C) levels (< or =50%) with intensive statin therapy is associated with major reduction in cardiovascular risk, but is limited by a potential increase in adverse effects, thereby justifying optimization of LDL-C reduction with minimal risk. The organic anion transporting polypeptide-1B1 encoded by the SLCO1B1 gene is implicated as a major transporter in cellular uptake of statins, and notably fluvastatin. We postulated that genetic variation in SLCO1B1 might affect statin bioavailability, and might therefore influence drug response and potential adverse effects. MATERIALS & METHODS: Elderly hypercholesterolemic subjects (n = 724), whose plasma lipid profile was determined before and 2 months after fluvastatin extended-release treatment (80 mg/day, n = 420), or placebo (n = 304), were genotyped for the most frequent nonsynonymous polymorphisms (SNP) in the SLCO1B1 gene (c.388A>G, c.463C>A and c.521T>C). RESULTS: Due to linkage disequilibrium, only four alleles (*1b, *5, *14 and *15) of SLCO1B1 were detected in addition to the wild-type allele (*1a). The c.463A genotype, which was systematically associated with the c.388G SNP corresponding to the *14 allele was significantly associated with percentage LDL-C reduction from baseline (p = 0.005) and with mean post-treatment LDL-C values (p = 0.0005). Subjects homozygous for the c.463C genotype (n = 294) exhibited significantly less LDL-C reduction and higher post-treatment LDL-C levels (-31.5%, 138 mg/dl) relative to heterozygous C/A patients (-36.2%, 126 mg/dl; n = 111), and to homozygous A/A subjects (-41%, 115 mg/dl; n = 15). CONCLUSIONS: These results reveal that OATP1B1 is implicated in the pharmacological action and efficacy of fluvastatin. Indeed, the common *14 allele, which is distinguished by the presence of the c.463C>A polymorphism, was associated with enhanced lipid-lowering efficacy in this study.