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Seriously ill patients whose prioritized healthcare goals are understood by their clinicians are likely better positioned to receive goal-concordant care.To examine the proportion of seriously ill patients whose prioritized healthcare goal is accurately perceived by their clinician and identify factors associated with accurate perception.Secondary analysis of a multicenter cluster-randomized trial of outpatients with serious illness and their clinicians. Approximately two weeks after a clinic visit, patients reported their current prioritized healthcare goal- extending life over relief of pain and discomfort, or relief of pain and discomfort over extending life - and clinicians reported their perception of their patients' current prioritized healthcare goal; matching these items defined accurate perception.Of 252 patients with a prioritized healthcare goal, 60% had their goal accurately perceived by their clinician, 27% were cared for by clinicians who perceived prioritization of the alternative goal, and 13% had their clinician answer unsure. Patients who were older (OR 1.03 per year; 95%CI 1.01, 1.05), had stable goals (OR 2.52; 95%CI 1.26, 5.05), and had a recent goals-of-care discussion (OR 1.78, 95%CI 1.00, 3.16) were more likely to have their goals accurately perceived.A majority of seriously ill outpatients are cared for by clinicians who accurately perceive their patients' prioritized healthcare goals. However, a substantial portion are not and may be at higher risk for goal-discordant care. Interventions that facilitate goals-of-care discussions may help align care with goals, as recent discussions were associated with accurate perceptions of patients' prioritized goals.

ImportanceDiscussions about goals of care are important for high-quality palliative care yet are often lacking for hospitalized older patients with serious illness.ObjectiveTo evaluate a communication-priming intervention to promote goals-of-care discussions between clinicians and hospitalized older patients with serious illness.Design, Setting, and ParticipantsA pragmatic, randomized clinical trial of a clinician-facing communication-priming intervention vs usual care was conducted at 3 US hospitals within 1 health care system, including a university, county, and community hospital. Eligible hospitalized patients were aged 55 years or older with any of the chronic illnesses used by the Dartmouth Atlas project to study end-of-life care or were aged 80 years or older. Patients with documented goals-of-care discussions or a palliative care consultation between hospital admission and eligibility screening were excluded. Randomization occurred between April 2020 and March 2021 and was stratified by study site and history of dementia.InterventionPhysicians and advance practice clinicians who were treating the patients randomized to the intervention received a 1-page, patient-specific intervention (Jumpstart Guide) to prompt and guide goals-of-care discussions.Main Outcomes and MeasuresThe primary outcome was the proportion of patients with electronic health record–documented goals-of-care discussions within 30 days. There was also an evaluation of whether the effect of the intervention varied by age, sex, history of dementia, minoritized race or ethnicity, or study site.ResultsOf 3918 patients screened, 2512 were enrolled (mean age, 71.7 [SD, 10.8] years and 42% were women) and randomized (1255 to the intervention group and 1257 to the usual care group). The patients were American Indian or Alaska Native (1.8%), Asian (12%), Black (13%), Hispanic (6%), Native Hawaiian or Pacific Islander (0.5%), non-Hispanic (93%), and White (70%). The proportion of patients with electronic health record–documented goals-of-care discussions within 30 days was 34.5% (433 of 1255 patients) in the intervention group vs 30.4% (382 of 1257 patients) in the usual care group (hospital- and dementia-adjusted difference, 4.1% [95% CI, 0.4% to 7.8%]). The analyses of the treatment effect modifiers suggested that the intervention had a larger effect size among patients with minoritized race or ethnicity. Among 803 patients with minoritized race or ethnicity, the hospital- and dementia-adjusted proportion with goals-of-care discussions was 10.2% (95% CI, 4.0% to 16.5%) higher in the intervention group than in the usual care group. Among 1641 non-Hispanic White patients, the adjusted proportion with goals-of-care discussions was 1.6% (95% CI, −3.0% to 6.2%) higher in the intervention group than in the usual care group. There was no evidence of differential treatment effects of the intervention on the primary outcome by age, sex, history of dementia, or study site.Conclusions and RelevanceAmong hospitalized older adults with serious illness, a pragmatic clinician-facing communication-priming intervention significantly improved documentation of goals-of-care discussions in the electronic health record, with a greater effect size in racially or ethnically minoritized patients.Trial RegistrationClinicalTrials.gov Identifier: NCT04281784

CONTEXT: Documented goals-of-care discussions are an important quality metric for patients with serious illness. Natural language processing (NLP) is a promising approach for identifying goals-of-care discussions in the electronic health record (EHR). OBJECTIVES: To compare three NLP modeling approaches for identifying EHR documentation of goals-of-care discussions and generate hypotheses about differences in performance. METHODS: We conducted a mixed-methods study to evaluate performance and misclassification for three NLP featurization approaches modeled with regularized logistic regression: bag-of-words (BOW), rule-based, and a hybrid approach. From a prospective cohort of 150 patients hospitalized with serious illness over 2018–2020, we collected 4,391 inpatient EHR notes; 99 (2.3%) contained documented goals-of-care discussions. We used leave-one-out cross-validation to estimate performance by comparing pooled NLP predictions to human abstractors with receiver-operating-characteristic (ROC) and precision-recall (PR) analyses. We qualitatively examined a purposive sample of 70 NLP-misclassified notes using content analysis to identify linguistic features that allowed us to generate hypotheses underpinning misclassification. RESULTS: All three modeling approaches discriminated between notes with and without goals-of-care discussions (AUC(ROC): BOW, 0.907; rule-based, 0.948; hybrid, 0.965). Precision and recall were only moderate (precision at 70% recall: BOW, 16.2%; rule-based, 50.4%; hybrid, 49.3%; AUC(PR): BOW, 0.505; rule-based, 0.579; hybrid, 0.599). Qualitative analysis revealed patterns underlying performance differences between BOW and rule-based approaches. CONCLUSION: NLP holds promise for identifying EHR-documented goals-of-care discussions. However, the rarity of goals-of-care content in EHR data limits performance. Our findings highlight opportunities to optimize NLP modeling approaches, and support further exploration of different NLP approaches to identify goals-of-care discussions.

Background: Aortic stiffness promotes left ventricular (LV) remodeling and dysfunction. Thoracic aorta calcification (TAC) contributes to aortic stiffness, but it remains unclear how TAC presence, volume, and density impact LV structure and function. We tested the hypothesis that TAC presence and higher volume is associated with increased LV mass index, decreased LV end-diastolic volume (LVEDV) index, and impaired mid-wall circumferential strain (Ecc). Methods: We evaluated 1,693 participants from the MESA who underwent chest CT and cardiac MRI from 2010 to 2012. We used linear regression models to determine cross-sectional associations between the presence, volume, and density of TAC with LV mass index, LVEDV index, and Ecc. Each pair of predictor and outcome variables underwent three model adjustments: (1) age, gender, and race/ethnicity; (2) Model 1 plus education level, height, weight, physical activity, sedentary behavior, smoking status, eGFR, SBP, DBP, anti-HTN medication use, total cholesterol/HDL ratio, statin use, and diabetes; (3) Model 2 plus coronary artery calcium (CAC) presence and volume. TAC volume and density were evaluated separately, then jointly in the same models. Results: The mean age was 69 years (SD 9) and 53% were female, while 39% were White, 26% Black, 21% Hispanic/Latino, 15% Chinese. TAC was present in 1,518 (90%) participants. TAC volume and density were highly correlated (r=0.75) with respective median 213 (25%ile, 75%ile: 36, 800) mm 3 and mean 350 (SD 110) Hounsfield Units. LV mass index, LVEDV index, and Ecc had respective means of 65 g/m 2 (SD 14), 120 mL/m 2 (SD 31), and -18.2% (SD 2.8). After full adjustment (Model 3 without density), a 10% increase in TAC volume was associated with a 1.8% multiplicative higher Ecc (i.e., less negative Ecc) (95% CI 0.2-3.4%, p=0.04) reflecting reduced LV systolic and diastolic function. Higher TAC volume was marginally associated with higher LV mass index: a 10% increase in TAC volume was associated with a 5.6% increase (-0.6-11.7%, p=0.08) in Model 2 without density, 13.9% (2.1-25.7%, p=0.03) in Model 2 with density, 3.9% (-2.5-10.4%, p=0.23) in Model 3 without density, and 11.3% (-1.0-23.7%, p=0.08) in Model 3 with density. After adjustments in Models 2 or 3, there were no other significant associations between TAC presence, volume, or density with the outcomes. Conclusions: Higher TAC volume is associated with impaired Ecc independent of CAC and marginally associated with higher LV mass index. These results suggest that the extent of TAC may influence LV remodeling and thus reduced function.

Context Heart failure (HF) and chronic kidney disease (CKD) are associated with high morbidity and mortality, especially in combination, yet little is known about the impact of these conditions together on end-of-life care. Objectives Compare end-of-life care and advance care planning (ACP) documentation among patients with both HF and CKD to those with either condition. Methods We conducted a retrospective analysis of deceased patients (2010-2017) with HF and CKD (n = 1673), HF without CKD (n = 2671), and CKD without HF (n = 1706), excluding patients with cancer or dementia. We compared hospitalizations and intensive care unit (ICU) admissions in the last 30 days of life, hospital deaths, and ACP documentation >30 days before death. Results 39% of patients with HF and CKD were hospitalized and 33% were admitted to the ICU in the last 30 days vs. 30% and 28%, respectively, for HF, and 26% and 23% for CKD. Compared to patients with both conditions, those with only 1 were less likely to be admitted to the hospital [HF: adjusted odds ratio (aOR) 0.72, 95%CI 0.63-0.83; CKD: aOR 0.63, 95%CI 0.53-0.75] and ICU (HF: aOR 0.83, 95%CI 0.71-0.94; CKD: aOR 0.68, 95%CI 0.56-0.80) and less likely to have ACP documentation (aOR 0.53, 95%CI 0.47-0.61 and aOR 0.70, 95%CI 0.60-0.81). Conclusions Decedents with both HF and CKD had more ACP documentation and received more intensive end-of-life care than those with only 1 condition. These findings suggest that patients with co-existing HF and CKD may benefit from interventions to ensure care received aligns with their goals.

Background: Arterial stiffness (AS) is a robust risk factor for HTN and CVD. It remains unclear how thoracic aortic calcification (TAC) presence, volume, and density relate to AS in the aortic arch. Improved understanding of central AS may provide insight to future mechanistic approaches to prevent and control CVD. Methods: We evaluated 1,385 participants from MESA Exam 5 with TAC data throughout the thoracic aorta via Chest CT and pulse wave velocity (PWV) as a measure of AS across the aortic arch via MRI. We used linear regression models to assess cross-sectional associations of TAC presence, volume, and density with aortic arch PWV with adjustment for 1) age, sex, and race; and 2) age, sex, race, BMI, diabetes, estimated glomerular filtration rate, HTN-medication use, SBP, DBP, total cholesterol/high-density lipoprotein ratio, smoking status, CAC volume, CAC density, education, physical activity, and sedentary behavior. Results: Participants were a mean age of 69 years (SD 9) [717 (52%) female; 509 (37%) White, 359 (26%) Black, 285 (21%) Hispanic/Latino, and 232 (17%) Chinese]. Calcification was present in 1,263 (91%) and 1,228 (89%) participants in the entire thoracic aorta and aortic arch, respectively, compared to 848 (61%) and 138 (10%) in the descending and ascending aorta segments. Calcium volume in the entire thoracic aorta and aortic arch were highly correlated (r=0.94) with respective means of 866 (SD 1,724) and 564 (1,014) mm 3 . Mean PWV across the aortic arch was 9 m/sec (SD 4). After full adjustment, the presence of aortic arch calcification, compared to no aortic arch calcification, was associated with a 0.76 m/sec higher mean PWV (95% CI: 0.34 - 1.18; p3 increment in aortic arch calcium volume was associated with 0.36 m/sec higher mean PWV (95% CI: 0.08-0.64; p=0.01). Results were similar when calcification in the entire thoracic aorta was the primary predictor variable. Conversely, there were no significant associations between mean or maximum calcium density measures and aortic arch PWV. Conclusion: TAC is highly prevalent in the thoracic aorta, especially the aortic arch. Calcification presence and higher calcification volume in the thoracic aorta, as well as the aortic arch itself, are associated with greater aortic arch AS.

Goals-of-care discussions are important for patient-centered care among hospitalized patients with serious illness. However, there are little data on the occurrence, predictors, and timing of these discussions.To examine the occurrence, predictors, and timing of electronic health record (EHR)-documented goals-of-care discussions for hospitalized patients.This retrospective cohort study used natural language processing (NLP) to examine EHR-documented goals-of-care discussions for adults with chronic life-limiting illness or age ≥80 hospitalized 2015-2019. The primary outcome was NLP-identified documentation of a goals-of-care discussion during the index hospitalization. We used multivariable logistic regression to evaluate associations with baseline characteristics.Of 16,262 consecutive, eligible patients without missing data, 5,918 (36.4%) had a documented goals-of-care discussion during hospitalization; approximately 57% of these discussions occurred within 24 hours of admission. In multivariable analysis, documented goals-of-care discussions were more common for women (OR=1.26, 95%CI 1.18-1.36), older patients (OR=1.04 per year, 95%CI 1.03-1.04), and patients with more comorbidities (OR=1.11 per Deyo-Charlson point, 95%CI 1.10-1.13), cancer (OR=1.88, 95%CI 1.72-2.06), dementia (OR=2.60, 95%CI 2.29-2.94), higher acute illness severity (OR=1.12 per National Early Warning Score point, 95%CI 1.11-1.14), or prior advance care planning documents (OR=1.18, 95%CI 1.08-1.30). Documentation of these discussions was less common for racially or ethnically minoritized patients (OR=0.823, 95%CI 0.75-0.90).Among hospitalized patients with serious illness, documented goals-of-care discussions identified by NLP were more common among patients with older age and increased burden of acute or chronic illness, and less common among racially or ethnically minoritized patients. This suggests important disparities in goals-of-care discussions.

ImportanceFamily members of patients with severe acute brain injury (SABI) are at risk for poor psychological outcomes.ObjectiveTo explore the utility of the early use of a palliative care needs checklist in identifying care needs of patients with SABI and family members who are at risk of poor psychological outcomes.Design, Setting, and ParticipantsThis prospective cohort study included patients with SABI in an intensive care unit (ICU) for 2 days or more and a Glasgow Coma Scale score of 12 or lower and their family members. This single-center study was conducted at an academic hospital in Seattle, Washington, from January 2018 to June 2021. Data were analyzed from July 2021 to July 2022.ExposureAt enrollment, a 4-item palliative care needs checklist was completed separately by clinicians and family members.Main Outcomes and MeasuresA single family member for each enrolled patient completed questionnaires assessing symptoms of depression and anxiety, perception of goal-concordant care, and satisfaction in the ICU. Six months later, family members assessed their psychological symptoms, decisional regret, patient functional outcome, and patient quality of life (QOL).ResultsA total of 209 patient–family member pairs (family member mean [SD] age, 51 [16] years; 133 women [64%]; 18 Asian [9%], 21 Black [10%], 20 [10%] Hispanic, and 153 White [73%] participants) were included. Patients had experienced stroke (126 [60%]), traumatic brain injury (62 [30%]), and hypoxic-ischemic encephalopathy (21 [10%]). At least 1 need was identified for 185 patients or their families (88%) by family members and 110 (53%) by clinicians (κ = −0.007; 52% agreement). Symptoms of at least moderate anxiety or depression were present in 50% of family members at enrollment (87 with anxiety and 94 with depression) and 20% at follow-up (33 with anxiety and 29 with depression). After adjustment for patient age, diagnosis, and disease severity and family race and ethnicity, clinician identification of any need was associated with greater goal discordance (203 participants; relative risk = 1.7 [95% CI, 1.2 to 2.5]) and family decisional regret (144 participants; difference in means, 17 [95% CI, 5 to 29] points). Family member identification of any need was associated with greater symptoms of depression at follow-up (150 participants; difference in means of Patient Health Questionnaire–2, 0.8 [95% CI, 0.2 to 1.3] points) and worse perceived patient QOL (78 participants; difference in means, −17.1 [95% CI, −33.6 to −0.5] points).Conclusions and RelevanceIn this prospective cohort study of patients with SABI and their families, palliative care needs were common, although agreement on needs was poor between clinicians and family members. A palliative care needs checklist completed by clinicians and family members may improve communication and promote timely, targeted management of needs.

OBJECTIVES: The radial artery pulse waveform is a continuous measure of pressure throughout the cardiac cycle and thus can provide more information than just systolic and diastolic blood pressures. New indices based on a Windkessel model of the waveform, PTC1 and PTC2, are related to arterial compliance and add information for prediction of incident cardiovascular disease (coronary heart disease, stroke, myocardial infarction) but their association with heart failure is unknown. METHODS: Among 6229 adults (mean age 62 years) from 4 race/ethnic groups who were initially free of clinical cardiovascular disease and heart failure in 2000–2002, we evaluated the associations of baseline PTC1 and PTC2 with incident heart failure. RESULTS: Mean ± standard deviation PTC1 and PTC2 were 394 ± 334 and 94 ± 46 milliseconds, respectively. During a median of 15.7 years follow-up, there were 357 heart failure events (148 with reduced, 150 with preserved, and 59 with unknown ejection fraction). After adjustment for traditional risk factors, the hazard ratio for heart failure per 1 standard deviation higher PTC2 was 0.73 (95% confidence interval: 0.63, 0.85). Higher PTC2 was also significantly associated with lower risk of heart failure with reduced ejection fraction (hazard ratio = 0.67; 95% confidence interval: 0.56, 0.80). There was no evidence of a significant association between PTC2 and heart failure with preserved ejection fraction or between PTC1 and heart failure. CONCLUSIONS: The PTC2 measure of the radial artery pulse waveform may represent a novel phenotype related to heart failure, especially heart failure with reduced ejection fraction.

High-quality goals-of-care communication is critical to delivering goal-concordant, patient-centered care to hospitalized patients with chronic life-limiting illness. However, implementation and documentation of goals-of-care discussions remain important shortcomings in many health systems.To evaluate the efficacy, feasibility, and acceptability of a patient-facing and clinician-facing communication-priming intervention to promote goals-of-care communication for patients hospitalized with serious illness.This randomized clinical trial enrolled patients from November 6, 2018, to February 18, 2020. The setting was 2 hospitals in an academic health care system in Seattle, Washington. Participants included hospitalized adults with chronic life-limiting illness, aged 65 years or older and with markers of frailty, or aged 80 years or older. Data analysis was performed from August 2020 to August 2021.Patients were randomized to usual care with baseline questionnaires (control) vs the Jumpstart communication-priming intervention. Patients or surrogates in the intervention group and their clinicians received patient-specific Jumpstart Guides populated with data from questionnaires and the electronic health records (EHRs) that were designed to prompt and guide a goals-of-care discussion.The primary outcome was EHR documentation of a goals-of-care discussion between randomization and hospital discharge. Additional outcomes included patient-reported or surrogate-reported goals-of-care discussions, patient-reported or surrogate-reported quality of communication, and intervention feasibility and acceptability.Of 428 eligible patients, this study enrolled 150 patients (35% enrollment rate; mean [SD] age, 59.2 [13.6] years; 66 women [44%]; 132 [88%] by patient consent and 18 [12%] by surrogate consent). Seventy-five patients each were randomized to the intervention and control groups. Compared with the control group, the cumulative incidence of EHR-documented goals-of-care discussions between randomization and hospital discharge was higher in the intervention group (16 of 75 patients [21%] vs 6 of 75 patients [8%]; risk difference, 13% [95% CI, 2%-24%]; risk ratio, 2.67 [95% CI, 1.10-6.44]; P = .04). Patient-reported or surrogate-reported goals-of-care discussions did not differ significantly between groups (30 of 66 patients [45%] vs 36 of 66 patients [55%]), although the intrarater consistency of patient and surrogate reports was poor. Patient-rated or surrogate-rated quality of communication did not differ significantly between groups. The intervention was feasible and acceptable to patients, surrogates, and clinicians.In this randomized clinical trial, a patient-facing and clinician-facing communication priming intervention for seriously ill, hospitalized patients promoted EHR-documented goals-of-care discussions before discharge with good feasibility and acceptability. Communication-priming interventions should be reexamined in a larger randomized clinical trial to better understand their effectiveness in the inpatient setting.ClinicalTrials.gov Identifier: NCT03746392.

We investigated inter-arm systolic blood pressure (sIAD) difference, reproducibility, and incident cardiovascular disease (CVD). We hypothesized that higher sIAD values have low prevalence and nonpersistence over years, but that CVD risk is higher starting from the time of first high absolute sIAD. In Multi-Ethnic Study of Atherosclerosis participants (n = 6725, 53% female, 45-84 years old), Doppler systolic blood pressure (SBP) measurements were made in both arms (10-minute interval) thrice over 9.5 years. Proportional hazards for CVD (coronary heart disease, heart failure, stroke, peripheral arterial disease (PAD)) over 16.4 years were tested according to time-varying absolute inter-arm difference with covariates: (1) age, gender, race, and clinic; (2) model 1 plus height, heart rate, BP, antihypertensives, BMI, smoking status, lipids, lipid lowering medication, and diabetes. High sIAD was not persistent across exams. Maximum absolute sIAD ≥ 15 mmHg was found at least once in 815 persons. Maximum absolute sIAD had a graded relationship with incident stroke or PAD: 6.2% events; model 2 hazard ratio per 10 mmHg 1.34 (95% CI, 1.15-1.56) and this risk was approximately doubled for maximum absolute sIAD ≥ 15 mmHg vs 0-4 mmHg. Total CVD risk (18.4% events) was increased only for maximum absolute sIAD ≥25 mmHg. Associations with incident CVD did not differ for higher SBP in left vs right arm. A higher maximum absolute sIAD at any exam was associated with greater risk for stroke and PAD especially for values ≥ 15 mmHg, and ≥25 mmHg for other CVD. Measuring SBP between arms may help identify individuals at risk for CVD.

Key Points Question For patients with severe acute brain injury, how prevalent is prognosis discordance between physicians and families, and what factors are associated with it? Findings In this cross-sectional study of 193 patients with severe acute brain injury, prognosis discordance occurred for 61% of patients, with both misunderstanding and belief differences present; prognosis discordance was more likely for family members who were part of minoritized racial groups. Nurses seemed to accurately predict poor family understanding, whereas physicians perceived belief differences as poor family understanding. Meaning The results of this cross-sectional study suggest that prognosis discordance, which may hamper the shared decision-making process, is common between families and physicians for patients with severe acute brain injury., This cross-sectional study uses data from a single neuroscience center to assess for the presence of discordance between physicians and family members regarding prognosis in patients with severe acute brain injury., Importance Shared decision-making requires key stakeholders to align in perceptions of prognosis and likely treatment outcomes. Objective For patients with severe acute brain injury, the objective of this study was to better understand prognosis discordance between physicians and families by determining prevalence and associated factors. Design, Setting, and Participants This mixed-methods cross-sectional study analyzed a cohort collected from January 4, 2018, to July 22, 2020. This study was conducted in the medical and cardiac intensive care units of a single neuroscience center. Participants included families, physicians, and nurses of patients admitted with severe acute brain injury. Exposures Severe acute brain injury was defined as stroke, traumatic brain injury, or hypoxic ischemic encephalopathy with a Glasgow Coma Scale score less than or equal to 12 points after hospital day 2. Main Outcomes and Measures Prognosis discordance was defined as a 20% or greater difference between family and physician prognosis predictions; misunderstanding was defined as a 20% or greater difference between physician prediction and the family’s estimate of physician prediction; and optimistic belief difference was defined as any difference (>0%) between family prediction and their estimate of physician prediction. Logistic regression was used to identify associations with discordance. Optimistic belief differences were analyzed as a subgroup of prognosis discordance. Results Among 222 enrolled patients, prognostic predictions were available for 193 patients (mean [SD] age, 57 [19] years; 106 men [55%]). Prognosis discordance occurred for 118 patients (61%) and was significantly more common among families who identified with minoritized racial groups compared with White families (odds ratio [OR], 3.14; CI, 1.40-7.07, P = .006); among siblings (OR, 4.93; 95% CI, 1.35-17.93, P = .02) and adult children (OR, 2.43; 95% CI, 1.10-5.37; P = .03) compared with spouses; and when nurses perceived family understanding as poor compared with good (OR, 3.73; 95% CI, 1.88-7.40; P

Although goals-of-care discussions are important for high-quality palliative care, this communication is often lacking for hospitalized older patients with serious illness. Electronic health records (EHR) provide an opportunity to identify patients who might benefit from these discussions and promote their occurrence, yet prior interventions using the EHR for this purpose are limited. We designed two complementary yet independent randomized trials to examine effectiveness of a communication-priming intervention (Jumpstart) for hospitalized older adults with serious illness.We report the protocol for these 2 randomized trials. Trial 1 has two arms, usual care and a clinician-facing Jumpstart, and is a pragmatic trial assessing outcomes with the EHR only (n = 2000). Trial 2 has three arms: usual care, clinician-facing Jumpstart, and clinician- and patient-facing (bi-directional) Jumpstart (n = 600). We hypothesize the clinician-facing Jumpstart will improve outcomes over usual care and the bi-directional Jumpstart will improve outcomes over the clinician-facing Jumpstart and usual care. We use a hybrid effectiveness-implementation design to examine implementation barriers and facilitators.For both trials, the primary outcome is EHR documentation of a goals-of-care discussion within 30 days of randomization; additional outcomes include intensity of end-of-life care. Trial 2 also examines patient- or family-reported outcomes assessed by surveys targeting 3-5 days and 4-8 weeks after randomization including quality of goals-of-care communication, receipt of goal-concordant care, and psychological symptoms.This novel study incorporates two complementary randomized trials and a hybrid effectiveness-implementation approach to improve the quality and value of care for hospitalized older adults with serious illness.STUDY00007031-A and STUDY00007031-B.

Aims Traditional atherosclerotic cardiovascular disease (ASCVD) risk factors fail to address the full spectrum of the complex interplay of atherosclerotic and atherothrombotic factors integral to ASCVD events. This study sought to examine the association between atherothrombotic biomarkers and ASCVD events. Methods and results The association between atherothrombotic biomarkers and 877 ASCVD events with and without adjustment for traditional risk factors was evaluated via Cox proportional hazards models and factor analysis in 5789 Multi-Ethnic Study of Atherosclerosis participants over a median follow-up of 14.7 years. Factor analysis accounted for multidimensional relationship and shared variance among study biomarkers, which identified two new variables: a thrombotic factor (Factor 1), principally defined by shared variance in fibrinogen, plasmin–antiplasmin complex, factor VIII, D-dimer, and lipoprotein(a), and a fibrinolytic factor (Factor 2), principally defined by shared variance of plasminogen and oxidized phospholipids on plasminogen. In a model including both factors, the thrombotic factor was associated with the higher risk of ASCVD events [hazard ratio (HR) 1.57, 95% confidence interval (CI) 1.45, 1.70], while the fibrinolytic factor was associated with the lower risk of ASCVD events (HR 0.76, 95% CI 0.70, 0.82), with estimated ASCVD free survival highest for low atherothrombotic Factor 1 and high atherothrombotic Factor 2. Conclusion Two atherothrombotic factors, one representative of thrombotic propensity and the other representative of fibrinolytic propensity, were significantly and complementarily associated with incident ASCVD events, remained significantly associated with incident ASCVD after controlling for traditional risk factors, and have promise for identifying patients at high ASCVD event risk specifically due to their atherothrombotic profile.

Background Critically-ill patients and their families suffer a high burden of psychological symptoms due, in part, to many transitions among clinicians and settings during and after critical illness, resulting in fragmented care. Communication facilitators may help. Design and intervention We are conducting two cluster-randomized trials, one in the U.S. and one in France, with the goal of evaluating a nurse facilitator trained to support, model, and teach communication strategies enabling patients and families to secure care consistent with patients' goals, beginning in ICU and continuing for 3 months. Participants We will randomize 376 critically-ill patients in the US and 400 in France to intervention or usual care. Eligible patients have a risk of hospital mortality of greater than15% or a chronic illness with a median survival of approximately 2 years or less. Outcomes We assess effectiveness with patient- and family-centered outcomes, including symptoms of depression, anxiety, and post-traumatic stress, as well as assessments of goal-concordant care, at 1-, 3-, and 6-months post-randomization. The primary outcome is family symptoms of depression over 6 months. We also evaluate whether the intervention improves value by reducing utilization while improving outcomes. Finally, we use mixed methods to explore implementation factors associated with implementation outcomes (acceptability, fidelity, acceptability, penetration) to inform dissemination. Conducting the trial in U.S. and France will provide insights into differences and similarities between countries. Conclusions We describe the design of two randomized trials of a communication facilitator for improving outcomes for critically ill patients and their families in two countries.

Context Goals-of-care discussions are an important quality metric in palliative care. However, goals-of-care discussions are often documented as free text in diverse locations. It is difficult to identify these discussions in the electronic health record (EHR) efficiently. Objectives To develop, train, and test an automated approach to identifying goals-of-care discussions in the EHR, using natural language processing (NLP) and machine learning (ML). Methods From the electronic health records of an academic health system, we collected a purposive sample of 3183 EHR notes (1435 inpatient notes and 1748 outpatient notes) from 1426 patients with serious illness over 2008–2016, and manually reviewed each note for documentation of goals-of-care discussions. Separately, we developed a program to identify notes containing documentation of goals-of-care discussions using NLP and supervised ML. We estimated the performance characteristics of the NLP/ML program across 100 pairs of randomly partitioned training and test sets. We repeated these methods for inpatient-only and outpatient-only subsets. Results Of 3183 notes, 689 contained documentation of goals-of-care discussions. The mean sensitivity of the NLP/ML program was 82.3% (SD 3.2%), and the mean specificity was 97.4% (SD 0.7%). NLP/ML results had a median positive likelihood ratio of 32.2 (IQR 27.5–39.2) and a median negative likelihood ratio of 0.18 (IQR 0.16–0.20). Performance was better in inpatient-only samples than outpatient-only samples. Conclusion Using NLP and ML techniques, we developed a novel approach to identifying goals-of-care discussions in the EHR. NLP and ML represent a potential approach toward measuring goals-of-care discussions as a research outcome and quality metric.

Systolic and diastolic blood pressures provide information about cardiovascular disease (CVD) but are only extremes of the pressure waveform during the cardiac cycle. We developed summaries of the pressure decay, called PTC1 and PTC2, that are related to arterial compliance and to an existing proprietary summary that has been shown to predict CVD. We derived the summaries from a Windkessel model (consisting of a decaying exponential plus a dampened cosine, with an intercept so they are independent of calibration with blood pressure, unlike the proprietary measures), and we estimated them using nonlinear least squares with standard, free software. Among 6,228 adults from the Multi-Ethnic Study of Atherosclerosis, initially free of CVD in 2000–2002, mean PTC2 was 94 (standard deviation, 46) milliseconds. During median 15-year follow-up, there were 911 CVD events (including 609 incidents of coronary heart disease and 270 strokes). One-standard-deviation higher PTC2 was associated with 17% (95% confidence interval: 10, 24) lower CVD risk, after adjustment for traditional risk factors. Results were similar for PTC1. PTC1 and PTC2 are relatively straightforward to compute and add information beyond traditional risk factors for prediction of CVD. Our work enables others to replicate and extend our results with waveforms from any suitable device.

s Background Electrocardiography R-wave to radial artery pulse delay (RRD) represents pulse transit time inclusive of pre-ejection period (PEP) and arterial pulse propagation time. RRD is proposed to largely reflect arterial stiffness when PEP is accounted for (shorter RRD = higher arterial stiffness). Sleep disordered breathing (SDB) causes intermittent hypoxemia and sympathetic activation, which negatively influences vascular function. We aimed to examine the association of measures of SDB with RRD. Methods Our sample consisted of participants in the Multi-Ethnic Study of Atherosclerosis without prevalent cardiovascular disease who underwent a daytime arterial elasticity exam, cardiac magnetic resonance imaging (MRI), and overnight polysomnography. SDB measures of interest included apnea hypopnea index (AHI) and oxygen desaturation index (ODI) (N = 1173). RRD was regressed on each measure of SDB separately, with adjustment for other cardiovascular risk factors as well as for correlates of the PEP, another component of RRD, by including cardiac MRI measures of contractility and preload. Results In multivariate analysis, among measures of SDB, ODI, a marker of intermittent hypoxemia, was inversely associated with RRD (β = −60.2 msec per SD [15.5/hr], p = 0.04). No significant association was found with AHI. In gender stratified analyses, ODI and AHI were predictive of RRD in men only (β = −111.3 msec per SD [15.5/hr], p = 0.01 and β = −100.3 msec per SD [16.1/hr], p = 0.02 respectively). Conclusion Severity of SDB as measured by ODI was associated with RRD, a marker of arterial stiffness. Thus, association of RRD with measures of SDB appears to be gender-dependent.

Purpose of report: Understanding the impact of palliative care interventions on intensive care unit (ICU) costs and utilization is critical for demonstrating the value of palliative care. Performing these economic assessments, however, can be challenging. The purpose of this special report is to highlight and discuss important considerations when assessing ICU utilization and costs from the hospital perspective, with the goal of providing recommendations on methods to consider for future analyses.ICU length of stay (LOS) and associated costs of care are common and important outcome measures, but must be analyzed properly to yield valid conclusions. There is significant variation in costs by day of stay in the ICU with only modest differences between an ICU day at the end of a stay and the first day on the acute care floor; this variation must be appropriately accounted for analytically. Furthermore, reporting direct variable costs, in addition to total ICU costs, is needed to understand short-term and long-term impact of a reduction in LOS. Importantly, incentives for the hospital to realize savings vary depending on reimbursement policies.ICU utilization and costs are common outcomes in studies evaluating palliative care interventions. Accurate estimation and interpretation are key to understanding the economic implications of palliative care interventions.

Objective: To evaluate the association between the number of chronic conditions and hospital utilization at the end of life. Background: An understanding of the association of multimorbidi...

Objectives To develop an enhanced understanding of factors that influence providers' views about end-of-life care, we examined the contributions of provider, hospital, and country to variability in agreement with consensus statements about end-of-life care. Design and setting Data were drawn from a survey of providers' views on principles of end-of-life care obtained during the consensus process for the Worldwide End-of-Life Practice for Patients in ICUs study. Subjects Participants in Worldwide End-of-Life Practice for Patients in ICUs included physicians, nurses, and other providers. Our sample included 1,068 providers from 178 hospitals and 31 countries. Interventions None. Measurements and main results We examined views on cardiopulmonary resuscitation and withholding/withdrawing life-sustaining treatments, using a three-level linear mixed model of responses from providers within hospitals within countries. Of 1,068 providers from 178 hospitals and 31 countries, 1% strongly disagreed, 7% disagreed, 11% were neutral, 44% agreed, and 36% strongly agreed with declining to offer cardiopulmonary resuscitation when not indicated. Of the total variability in those responses, 98%, 0%, and 2% were explained by differences among providers, hospitals, and countries, respectively. After accounting for provider characteristics and hospital size, the variance partition was similar. Results were similar for withholding/withdrawing life-sustaining treatments. Conclusions Variability in agreement with consensus statements about end-of-life care is related primarily to differences among providers. Acknowledging the primary source of variability may facilitate efforts to achieve consensus and improve decision-making for critically ill patients and their family members at the end of life.

Whether the cardiopulmonary resuscitation (CPR) preferences of patients receiving dialysis align with their values and other aspects of end-of-life care is not known.To describe the CPR preferences of patients receiving dialysis and how these preferences are associated with their responses to questions about other aspects of end-of-life care.Cross-sectional survey study of a consecutive sample of patients receiving dialysis at 31 nonprofit dialysis facilities in 2 US metropolitan areas (Seattle, Washington, and Nashville, Tennessee) between April 22, 2015, and October 2, 2018. Analyses for this article were conducted between December 2018 and April 2020.Participants were asked to respond to the question "If you had to decide right now, would you want CPR if your heart were to stop beating?" Those who indicated they would probably or definitely want CPR were categorized as preferring CPR.This study examined the association between preference for CPR and other treatment preferences, engagement in advance care planning, values, desired place of death, expectations about prognosis, symptoms, and palliative care needs.Of the 1434 individuals invited to complete the survey, 1009 agreed to participate, and 876 were included in the analytic cohort (61.1%). The final cohort had a mean (SD) age of 62.6 (14.0) years; 492 (56.2%) were men, and 528 (60.3%) were White individuals. Among 738 of 876 participants (84.2%) who indicated that they would definitely or probably want CPR (CPR group), 555 (75.2%) wanted mechanical ventilation vs 13 of 138 (9.4%) of those who did not want CPR (do not resuscitate [DNR] group) (P .001). A total of 249 of 738 participants (33.7%) in the CPR group vs 84 of 138 (60.9%) in the DNR group had documented treatment preferences (P .001). In terms of values about future care, 171 participants (23.2%) in the CPR group vs 5 of 138 (3.6%) in the DNR group valued life prolongation (P .001); 320 in the CPR group (43.4%) vs 109 of 138 in the DNR group (79.0%) valued comfort (P .001); and 247 participants (33.5%) in the CPR group vs 24 of 138 (17.4%) in the DNR group were unsure about their wishes for future care (P .001). In the CPR group, 207 (28.0%) had thought about stopping dialysis vs 62 of 138 (44.9%) in the DNR group (P .001), and 181 (24.5%) vs 58 of 138 (42.0%) had discussed stopping dialysis (P = .001). No statistically significant associations were observed between CPR preference and documentation of a surrogate decision maker, thoughts or discussion of hospice, preferred place of death, expectations about prognosis, reported symptoms, or palliative care needs.The CPR preferences of patients receiving dialysis were associated with some, but not all, other aspects of end-of-life care. How participants responded to questions about these other aspects of end-of-life care were not always aligned with their CPR preference. More work is needed to integrate discussions about code status with bigger picture conversations about patients' values, goals, and preferences for end-of-life care.

Importance Patients with chronic illness frequently use Physician Orders for Life-Sustaining Treatment (POLST) to document treatment limitations. Objectives To evaluate the association between POLST order for medical interventions and intensive care unit (ICU) admission for patients hospitalized near the end of life. Design, Setting, and Participants Retrospective cohort study of patients with POLSTs and with chronic illness who died between January 1, 2010, and December 31, 2017, and were hospitalized 6 months or less before death in a 2-hospital academic health care system. Exposures POLST order for medical interventions (“comfort measures only” vs “limited additional interventions” vs “full treatment”), age, race/ethnicity, education, days from POLST completion to admission, histories of cancer or dementia, and admission for traumatic injury. Main Outcomes and Measures The primary outcome was the association between POLST order and ICU admission during the last hospitalization of life; the secondary outcome was receipt of a composite of 4 life-sustaining treatments: mechanical ventilation, vasopressors, dialysis, and cardiopulmonary resuscitation. For evaluating factors associated with POLST-discordant care, the outcome was ICU admission contrary to POLST order for medical interventions during the last hospitalization of life. Results Among 1818 decedents (mean age, 70.8 [SD, 14.7] years; 41% women), 401 (22%) had POLST orders for comfort measures only, 761 (42%) had orders for limited additional interventions, and 656 (36%) had orders for full treatment. ICU admissions occurred in 31% (95% CI, 26%-35%) of patients with comfort-only orders, 46% (95% CI, 42%-49%) with limited-interventions orders, and 62% (95% CI, 58%-66%) with full-treatment orders. One or more life-sustaining treatments were delivered to 14% (95% CI, 11%-17%) of patients with comfort-only orders and to 20% (95% CI, 17%-23%) of patients with limited-interventions orders. Compared with patients with full-treatment POLSTs, those with comfort-only and limited-interventions orders were significantly less likely to receive ICU admission (comfort only: 123/401 [31%] vs 406/656 [62%], aRR, 0.53 [95% CI, 0.45-0.62]; limited interventions: 349/761 [46%] vs 406/656 [62%], aRR, 0.79 [95% CI, 0.71-0.87]). Across patients with comfort-only and limited-interventions POLSTs, 38% (95% CI, 35%-40%) received POLST-discordant care. Patients with cancer were significantly less likely to receive POLST-discordant care than those without cancer (comfort only: 41/181 [23%] vs 80/220 [36%], aRR, 0.60 [95% CI, 0.43-0.85]; limited interventions: 100/321 [31%] vs 215/440 [49%], aRR, 0.63 [95% CI, 0.51-0.78]). Patients with dementia and comfort-only orders were significantly less likely to receive POLST-discordant care than those without dementia (23/111 [21%] vs 98/290 [34%], aRR, 0.44 [95% CI, 0.29-0.67]). Patients admitted for traumatic injury were significantly more likely to receive POLST-discordant care (comfort only: 29/64 [45%] vs 92/337 [27%], aRR, 1.52 [95% CI, 1.08-2.14]; limited interventions: 51/91 [56%] vs 264/670 [39%], aRR, 1.36 [95% CI, 1.09-1.68]). In patients with limited-interventions orders, older age was significantly associated with less POLST-discordant care (aRR, 0.93 per 10 years [95% CI, 0.88-1.00]). Conclusions and Relevance Among patients with POLSTs and with chronic life-limiting illness who were hospitalized within 6 months of death, treatment-limiting POLSTs were significantly associated with lower rates of ICU admission compared with full-treatment POLSTs. However, 38% of patients with treatment-limiting POLSTs received intensive care that was potentially discordant with their POLST.

Pulmonary exacerbations (PEs) are used as clinical endpoints in infants and preschool children with cystic fibrosis (CF); however, their characteristics and impact in this age range are poorly understood. We used data from the Infant Study of Inhaled Saline, a multicenter trial of inhaled hypertonic versus isotonic saline, to describe PEs in children with CF

Systolic blood pressure (SBP) differs between the brachial artery and aorta. Prospective data suggest that central pressure predicts future cardiovascular events, but it is unclear if it is superior to brachial pressure. Methods and Results: A systematic review and individual participant data meta-analysis from 15 studies was undertaken. Study-specific associations of central and brachial pressure with cardiovascular outcomes, with and without mutual adjustment, were determined using Cox proportional hazard models, and random effect models to estimate pooled estimates. Of 22,433 participants, 908 had a myocardial infarction (MI) and 641 a stroke. The pooled age, sex, height and heart rate adjusted hazard ratio (HR) [95% CI] per SD increase in brachial SBP was 1.17 [1.03, 1.32] for MI and 1.28 [1.13, 1.46] for stroke and 1.16 [1.02, 1.33] and 1.33 [1.15, 1.53] for central SBP, respectively. Mutual adjustment attenuated the HRs for MI: brachial SBP (1.16 [0.90, 1.48]), central SBP (1.09 [0.87, 1.38]) and stroke: brachial SBP (1.18 [0.97, 1.42]), central SBP (1.19 [0.99, 1.44]). However, associations between central SBP and stroke, after adjustment for brachial SBP, were higher in those aged

The optimal strategy for monitoring cystic fibrosis lung disease in infancy remains unclear. Our objective was to describe longitudinal associations between infant pulmonary function tests, chest radiograph scores and other characteristics. Cystic fibrosis patients aged ≤24 months were enrolled in a 10-centre study evaluating infant pulmonary function tests four times over a year. Chest radiographs ∼1 year apart were scored using the Wisconsin and Brasfield systems. Associations of infant pulmonary function tests with clinical characteristics were evaluated with mixed effects models. The 100 participants contributed 246 acceptable flow/volume (forced expiratory volume in 0.5 s (FEV0.5) and forced expiratory flow at 75% of the forced vital capacity (FEF75%)), 303 functional residual capacity measurements and 171 chest radiographs. Both Brasfield and Wisconsin chest radiograph scores worsened significantly over the 1-year interval. Worse Wisconsin chest radiograph scores and Staphylococcus aureus were both associated with hyperinflation (significantly increased functional residual capacity), but not with diminished FEV0.5 or FEF75%. Parent-reported cough was associated with significantly diminished forced expiratory flow at 75% but not with hyperinflation. In this infant cohort in whom we previously reported worsening in average lung function, chest radiograph scores also worsened over a year. The significant associations detected between both Wisconsin chest radiograph score and S. aureus and hyperinflation, as well as between cough and diminished flows, reinforce the ability of infant pulmonary function tests and chest radiographs to detect early cystic fibrosis lung disease.

Objectives This study sought to assess the relationship between central pressure profiles and cardiovascular events (CVEs) in a large community-based sample. Background Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear. Methods Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 5,960 participants in the Multiethnic Study of Atherosclerosis. The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM = [Reflected/Forward wave amplitude] × 100), augmentation index ([Second/First systolic peak] × 100) and pulse pressure amplification ([Radial/aortic pulse pressure] × 100) were assessed as predictors of CVEs and congestive heart failure (CHF) during a median follow-up of 7.61 years. Results After adjustment for established risk factors, aortic AIx independently predicted hard CVEs (hazard ratio [HR] per 10% increase: 1.08; 95% confidence interval [CI]: 1.01 to 1.14; p = 0.016), whereas PPA independently predicted all CVEs (HR per 10% increase: 0.82; 95% CI: 0.70 to 0.96; p = 0.012). RM was independently predictive of all CVEs (HR per 10% increase: 1.34; 95% CI: 1.08 to 1.67; p = 0.009) and hard CVEs (HR per 10% increase: 1.46; 95% CI: 1.12 to 1.90; p = 0.006) and was strongly predictive of new-onset CHF (HR per 10% increase: 2.69; 95% CI: 1.79 to 4.04; p Conclusions Arterial wave reflections represent a novel strong risk factor for CHF in the general population.

This study aimed to describe lung function in a cohort of children with cystic fibrosis (CF) who underwent infant pulmonary function tests (IPFTs) and preschool spirometry. Children performed up to four IPFTs (raised volume rapid thoracic compression technique) over 1 yr and five preschool spirometry tests over up to 2 yrs during participation in prospective, multicentre studies of infant and preschool lung function. All lung function data were reviewed centrally for measurement acceptability. 45 children had 252 acceptable measurements (137 IPFTs and 115 preschool spirometries) at ages 0.3-6.5 yrs. The median number of measurements per participant was 6 (range 3-9). Recent Pseudomonas aeruginosa infection was associated with 5.1% (95% CI 0.01-9.9%) lower forced expiratory volume in 0.5 s (FEV(0.5)) and 16.4% (95% CI 7.0-24.9%) lower forced expiratory flow at 25-25% of forced vital capacity (FEF(25-75%)), after adjustment for length, test type and centre. Recent cough was associated with 5.7% (95% CI 1.1-10.1%) lower FEV(0.5) and 10.1% (95% CI 0.6-18.7%) lower FEF(25-75%). Even after accounting for infection status, cough, sex, length, test type and centre, there was significant inter-individual variability in lung function (p0.01 for each of FEV(0.5), FEF(25-75%) and forced vital capacity). Recent P. aeruginosa infection and cough are associated with lower lung function in children with CF. Significant inter-individual variability in lung function remains to be explained.

Objective To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF). Methods Longitudinal eight-center observational study of children with CF aged 36–60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites). Results Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF25–75) (−1.3 vs. −0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed. Conclusions Prior Pa infection is associated with a greater rate of decline in FEF25–75 z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected. Pediatr Pulmonol. 2012; 47:574–581. © 2011 Wiley Periodicals, Inc.

Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.

Background Inhaled hypertonic saline (HS) is an attractive agent for chronic maintenance therapy in infants and toddlers with cystic fibrosis (CF) because it improves defective mucociliary clearance. Prior to undertaking a clinical trial of HS efficacy in young children with CF, tolerability, adherence and safety must be established.

The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures.To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF.Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit.A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes.In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

We show how to use generalized linear mixed models to adjust for confounding by cluster of the effect of a within-cluster covariate. We derive estimators for both a cluster-specific causal effect and a population-averaged causal effect.

In social epidemiology, one often considers neighborhood or contextual effects on health outcomes, in addition to effects of individual exposures. This paper is concerned with the estimation of an individual exposure effect in the presence of confounding by neighborhood effects, motivated by an analysis of National Health Interview Survey (NHIS) data. In the analysis, we operationalize neighborhood as the secondary sampling unit of the survey, which consists of small groups of neighboring census blocks. Thus the neighborhoods are sampled with unequal probabilities, as are individuals within neighborhoods. We develop and compare several approaches for the analysis of the effect of dichotomized individual-level education on the receipt of adequate mammography screening. In the analysis, neighborhood effects are likely to confound the individual effects, due to such factors as differential availability of health services and differential neighborhood culture. The approaches can be grouped into three broad classes: ordinary logistic regression for survey data, with either no effect or a fixed effect for each cluster; conditional logistic regression extended for survey data; and generalized linear mixed model (GLMM) regression for survey data. Standard use of GLMMs with small clusters fails to adjust for confounding by cluster (e.g. neighborhood); this motivated us to develop an adaptation. We use theory, simulation, and analyses of the NHIS data to compare and contrast all of these methods. One conclusion is that all of the methods perform poorly when the sampling bias is strong; more research and new methods are clearly needed.

The availability of sensitive, reproducible, and feasible outcome measures for quantifying lung disease in children with cystic fibrosis (CF) younger than 6 years is critical to the conduct of clinical trials in this important population. Historically, identifying and quantifying the presence of lung disease in very young children with CF was hampered by a lack of reproducible measures of lung function or lung pathology. Over the past 10 years, significant progress has led to physiologic, anatomic, and bronchoscopic measures that may serve as endpoints for future intervention trials. These endpoints include infant and preschool lung function testing, computed tomography of the chest, and bronchoalveolar lavage markers of inflammation and infection. Much progress has occurred in standardizing lung function testing, which is essential for multicenter collaboration. Pulmonary exacerbation has the potential to serve as a clinical endpoint; however, there is currently no standardized definition in children with CF younger than 6 years. Further development of these outcomes measures will enable clinical trials in the youngest CF population with the objective of improving long-term prognosis.

Arterial dysfunction has been linked to decline in cardiac function and increased risk of cardiovascular disease events. We calculated the value of arterial function, measured at baseline (2000-2002), in predicting time to first coronary heart disease (CHD) event (median follow-up, 10.2 years) among participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Measures included the following: C1 and C2, derived from diastolic pulse contour analysis from the radial artery blood pressure waveform obtained by tonometry (n = 6,336); carotid distensibility and Young's elastic modulus at the carotid artery, derived from carotid artery ultrasonography (n = 6,531 and 6,528); and aortic distensibility, measured using cardiac magnetic resonance imaging (n = 3,677). After adjustment, the hazard ratio for a CHD event per standard-deviation increment in arterial function was 0.97 (95% confidence interval (CI): 0.86, 1.10) for C1, 0.73 (95% CI: 0.63, 0.86) for C2, 0.98 (95% CI: 0.86, 1.11) for carotid distensibility, 0.99 (95% CI: 0.90, 1.09) for Young's modulus, and 0.90 (95% CI: 0.74, 1.10) for aortic distensibility. We examined the area under the receiver operating characteristic curve for the model with full adjustment plus the addition of each measure individually. C2 provided additional discrimination for the prediction of CHD (area under the curve = 0.736 vs. 0.743; P = 0.04). Lower C2 was associated with a higher risk of future CHD events.

Background The Infant Study of Inhaled Saline (ISIS) in CF was the first multicenter clinical trial to utilize infant pulmonary function tests (iPFTs) as an endpoint. Methods Secondary analysis of ISIS data was conducted in order to assess feasibility of iPFT measures and their associations with respiratory symptoms. Standard deviations were calculated to aid in power calculations for future clinical trials. Results Seventy-three participants enrolled, 70 returned for the final visit; 62 (89%) and 45 (64%) had acceptable paired functional residual capacity (FRC) and raised volume measurements, respectively. Mean baseline FEV 0.5 , FEF 75 and FRC z -scores were 0.3 (SD: 1.2), −0.2 (SD: 2.0), and 1.8 (SD: 2.0). Conclusions iPFTs are not appropriate primary endpoints for multicenter clinical trials due to challenges of obtaining acceptable data and near-normal average raised volume measurements. Raised volume measures have potential to serve as secondary endpoints in future clinical CF trials.

Background Experimental studies demonstrate that high aortic pressure in late systole relative to early systole causes greater myocardial remodeling and dysfunction, for any given absolute peak systolic pressure. Methods and Results We tested the hypothesis that late systolic hypertension, defined as the ratio of late (last one third of systole) to early (first two thirds of systole) pressure–time integrals ( PTI ) of the aortic pressure waveform, independently predicts incident heart failure ( HF ) in the general population. Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 6124 adults. The late/early systolic PTI ratio (L/ E SPTI ) was assessed as a predictor of incident HF during median 8.5 years of follow‐up. The L/ E SPTI was predictive of incident HF (hazard ratio per 1% increase=1.22; 95% CI =1.15 to 1.29; P HF ( HR =1.23; 95% CI =1.14 to 1.32: P HF , L/ E SPTI was the modifiable factor associated with the greatest improvements in model performance. A high L/ E SPTI (>58.38%) was more predictive of HF than the presence of hypertension. After adjustment for each other and various predictors of HF , the HR associated with hypertension was 1.39 (95% CI =0.86 to 2.23; P =0.18), whereas the HR associated with a high L/E was 2.31 (95% CI =1.52 to 3.49; P Conclusions Independently of the absolute level of peak pressure, late systolic hypertension is strongly associated with incident HF in the general population.

Background: Arterial stiffness is a well-recognized predictor of cardiovascular disease (CVD). ECG R-wave to Radial artery pulse delay (RRD) is a novel hemodynamic index in which arterial stiffness is an important component (shorter delay = Higher arterial stiffness) and is obtainable from a single tonometric measurement at the radial artery with simultaneous ECG. Sleep disordered breathing (SDB) has emerged as a risk factor for CVD. The aim of the study was to determine the association of SDB with RRD. Methods: Multi-Ethnic Study of Atherosclerosis participants in 2010-2012 without overt CVD who underwent a sleep study, radial artery tonometry and cardiac MRI were eligible for this cross-sectional analysis (N = 1173, Mean [SD] age: 67.8 ± 8.8, Women: 55.4%). Independent associations between SDB indices including apnea hypopnea index (AHI) and oxygen (O2) desaturation index (ODI: events with more than 4% O2 desaturation), and RRD (transit time in msec) were examined. Model was constructed to adjust for isovolumetric contraction time, another component of RRD, by including measures of contractility and preload (left ventricular ejection fraction (LVEF) and left ventricular end diastolic volume (LVEDV) respectively). Results: Median [IQR] of AHI and ODI were 7.9/hr [2.9- 18.0] and 7.5/hr [3.0- 17.5] respectively. Adjusting for transit path length, demographic factors, BMI and CVD risk factors, both AHI and ODI were inversely associated with RRD (β= -50.3 msec per SD, p = 0.09 and β= -0.60.2 msec per SD, p = 0.04 respectively). In gender stratified analyses given presence of significant interaction, measures of SDB were predictive of RRD only in men. No significant associations were found with key nocturnal hypoxemia indices including mean O2 saturation (SpO2), percent time with SpO2less than 90 % and minimum SpO2. Men, older age, Asian race, high blood pressure, LVEF and LVEDV were also inversely associated with RRD. Conclusion: SDB was associated with shorter RRD implying higher arterial stiffness in men only. These findings suggest the importance of apnea related dynamic change in SpO2 (intermittent hypoxia and reoxygenation) in its potential link to arterial stiffness and also highlights effect modification by gender in the association between the two.

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [P b ] to that of the forward wave [P f ]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. P b was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in P b =2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and P b (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.

Background: There is an urgent need to evaluate treatments for young children with cystic fibrosis (CF); however, efforts have been hampered by a lack of reliable, practical endpoints. To examine whether a patient-reported outcome could be reliable in children 4 to 60 months of age, we assessed the psychometric properties of the modified Parent Cystic Fibrosis Questionnaire—Revised (CFQ-R) using data from the Infant Study of Inhaled Saline (ISIS). We also characterized patterns of symptom presentation and daily functioning in children in this age range to inform future measure development. Methods: Parents (N = 314) completed the CFQ-R and Treatment Adherence Questionnaire (TAQ) at five quarterly visits, as well as a weekly Parent Symptom Diary. Results: The Parent CFQ-R demonstrated good construct validity and adequate internal consistency (α's .58–.75). Associations with age, TAQ, and Parent Symptom Diary were observed. The Treatment Burden scale demonstrated responsiveness to change. Conclusions: Parents were reliable observers of young children's symptoms and daily functioning, and PROs show promise for this age group. Research is needed to identify key symptoms in infants and young children with CF, and to develop a parent proxy PRO according to FDA/EMA guidelines.

Pulmonary exacerbations (PEs) are used as clinical endpoints in infants and preschool children with cystic fibrosis (CF); however, their characteristics and impact in this age range are poorly understood. We used data from the Infant Study of Inhaled Saline, a multicenter trial of inhaled hypertonic versus isotonic saline, to describe PEs in children with CF6 years and evaluate associations between PEs and parent-reported outcomes assessed by a weekly parent questionnaire (10 items) and three scales of the Cystic Fibrosis Questionnaire-Revised (CFQ-R), and other participant characteristics. There were 659 PEs among 253 of the 321 ISIS participants (mean age 2.3 years) during 287 participant-years follow-up. Of the 659 PEs, 636 (97%) were treated with oral and 45 (7%) with IV antibiotics (not mutually exclusive). Among 222 participants with PEs who had completed parent questionnaires during a PE and at baseline, 9 of the 10 symptoms were each present in a statistically significantly higher proportion of participants during a PE than at baseline. Lower (worse) baseline Respiratory Symptom and Physical Functioning CFQ-R scores were significantly associated with higher PE rate: rate ratio 1.08 (95%CI: 1.02, 1.14) and 1.21 (1.07, 1.36) per 10 point lower score in respective scale. A higher PE rate was also significantly associated with worse CFQ-R Respiratory Symptom and Physical Functioning scores at the end of the study, adjusted for baseline scores. Though most PEs did not require IV antibiotics, PEs appeared to have a negative impact on parent-reported health outcomes in infants and preschoolers with CF. Pediatr Pulmonol. 2015; 50:236-243. © 2014 Wiley Periodicals, Inc.

Background: Left ventricular mass (LVM) and hypertrophy (LVH) are important parameters, but their use is surrounded by controversies. We compare LVM by echocardiography and cardiac magnetic resonance (CMR), investigating reproducibility aspects and the effect of echocardiography image quality. We also compare indexing methods within and between imaging modalities for classification of LVH and cardiovascular risk. Methods: Multi-Ethnic Study of Atherosclerosis enrolled 880 participants in Baltimore city, 146 had echocardiograms and CMR on the same day. LVM was then assessed using standard techniques. Echocardiography image quality was rated (good/limited) according to the parasternal view. LVH was defined after indexing LVM to body surface area, height 1.7 , height 2.7 , or by the predicted LVM from a reference group. Participants were classified for cardiovascular risk according to Framingham score. Pearson’s correlation, Bland–Altman plots, percent agreement, and kappa coefficient assessed agreement within and between modalities. Results: Left ventricular mass by echocardiography (140 40 g) and by CMR were correlated (r = 0.8, P < 0.001) regardless of the echocardiography image quality. The reproducibility profile had strong correlations and agreement for both modalities. Image quality groups had similar characteristics; those with good images compared to CMR slightly superiorly. The prevalence of LVH tended to be higher with higher cardiovascular risk. The agreement for LVH between imaging modalities ranged from 77% to 98% and the kappa coefficient from 0.10 to 0.76. Conclusions: Echocardiography has a reliable performance for LVM assessment and classification of LVH, with limited influence of image quality. Echocardiography and CMR differ in the assessment of LVH, and additional differences rise from the indexing methods. (Echocardiography 2013;00:1‐9)

ECG R-wave to Radial Artery Pulse Delay (RRD) is a novel hemodynamic index obtainable from a single tonometric measurement with simultaneous ECG to assess the timing of an electrical marker (ECG R-wave peak) until a corresponding mechanical feature (end diastole at the radial pulse). We studied the

Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45–84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.

To analyze cross-sectional and longitudinal associations between lung function measures and clinical features in a cohort of preschool children with cystic fibrosis (CF).Longitudinal eight-center observational study of children with CF aged 36-60 months at enrollment, who underwent semiannual pulmonary function tests (PFTs) for up to 2 years consisting of spirometry (all 8 sites), forced oscillometry (FO, 5 sites), and measures of thoracoabdominal asynchrony using respiratory inductive plethysmography (IP, 5 sites).Ninety-three subjects were enrolled; 181 acceptable spirometry measurements from 71 subjects, 128 FO from 47 subjects, and 142 IP from 50 subjects were available for analysis. Cross sectional analyses did not detect an association between any PFT parameter at enrollment and Pseudomonas aeruginosa (Pa) status, CF gene mutation class, Wisconsin cough score, Shwachman score, environmental tobacco smoke exposure, family history of asthma, or nutritional indices. In longitudinal analyses, Pa infection within 6 months preceding enrollment was associated with a significantly greater rate of decline in z-scores for forced expiratory flow between 25 and 75% of forced vital capacity (FEF(25-75) ) (-1.3 vs. -0.4 Z scores/year, P = 0.024) and greater thoracoabdominal asynchrony measured by IP (mean phase angle difference 4.6°, P = 0.004). No other significant longitudinal associations were observed.Prior Pa infection is associated with a greater rate of decline in FEF(25-75) z-score and mild thoracoabdominal asynchrony in preschool children with CF. In this multicenter US study, significant associations between other lung function measures and clinical features were not detected.

The aim of this report was to describe the reproducibility of arterial elasticity parameters derived from radial artery diastolic pulse contour analysis.Two measurements were taken on the same day by the same technician with the HDI/Pulsewave CR-2000 System on each of a subset of participants selected randomly from the Multi-Ethnic Study of Atherosclerosis. Large and small artery elasticities (C1 and C2), C1 and C2 each multiplied by systemic vascular resistance (C1xR and C2xR, which are functions of the radial artery pulse waveform only), and systolic and diastolic blood pressures (SBP and DBP) were evaluated.Two measurements were taken of each of the 131 participants. The mean difference±standard deviation of the difference was -0.13±3.5 mmHg ×10 for C1, -0.03±1.5 mmHg ×100 for C2, 0.10±4.6 s ×10 for C1xR, 0.05±1.8 s ×100 for C2xR, 2.8±8.2 mmHg for SBP, and 1.5±5.0 mmHg for DBP. The between-measure correlation was 0.74 for C1, 0.84 for C2, 0.58 for C1xR, 0.74 for C2xR, 0.90 for SBP, and 0.86 for DBP.The reproducibility of arterial elasticity measurements is less than that of SBP and DBP . Multiple measurements of arterial elasticity of a participant are recommended.