Statins Do Not Significantly Affect Oxidative Nitrosative Stress Biomarkers in the PREVENT Randomized Clinical Trial.

PURPOSE: Preventing Anthracycline Cardiovascular Toxicity with Statins (PREVENT) (NCT01988571) randomized breast cancer or lymphoma patients receiving anthracyclines to atorvastatin 40 mg daily or placebo. We evaluated the effects of atorvastatin on oxidative and nitrosative stress biomarkers, and explored whether these biomarkers could explain the lack of effect of atorvastatin on LVEF in PREVENT. PATIENTS AND METHODS: Blood samples were collected and cardiac magnetic resonance imaging was performed prior to doxorubicin initiation and at 6 and 24 months. Thirteen biomarkers (arginine-nitric oxide metabolites, paraoxonase-1 [PON-1] activity, and myeloperoxidase) were measured. Dimensionality reduction using principal component analysis was used to define biomarker clusters. Linear mixed-effects models determined the changes in biomarkers over time according to treatment group. Mediation analysis determined if biomarker clusters explained the lack of effect of atorvastatin on LVEF. RESULTS: Among 202 participants with available biomarkers, median age was 53 years; 86.6% had breast cancer; median LVEF was 62%. Cluster 1 levels, reflecting arginine methylation metabolites, were lower over time with atorvastatin, although this was not statistically significant (p=0.081); cluster 2 levels, reflecting PON-1 activity, were significantly lower with atorvastatin (p=0.024). There were no significant changes in other biomarker clusters (p>0.05). Biomarker clusters did not mediate an effect of atorvastatin on LVEF (p>0.05) Conclusions: Atorvastatin demonstrated very modest effects on oxidative/nitrosative stress biomarkers in this low cardiovascular risk population. Our findings provide potential mechanistic insight into the lack of effect of atorvastatin on LVEF in the PREVENT trial.

Comparison of Treatment Approaches and Subsequent Outcomes within a Pulmonary Embolism Response Team Registry.

Objectives: To characterize the association between pulmonary embolism (PE) severity and bleeding risk with treatment approaches, outcomes, and complications. Methods: Secondary analysis of an 11-hospital registry of adult ED patients treated by a PE response team (August 2016-November 2022). Predictors were PE severity and bleeding risk. The primary outcome was treatment approach: anticoagulation monotherapy vs. advanced intervention (categorized as "immediate" or "delayed" based on whether the intervention was received within 12 hours of PE diagnosis or not). Secondary outcomes were death, clinical deterioration, and major bleeding. Results: Of the 1832 patients, 139 (7.6%), 977 (53.3%), and 9 (0.5%) were classified as high-risk, intermediate-high, intermediate-low, and low-risk severity, respectively. There were 94 deaths (5.1%) and 218 patients (11.9%) had one or more clinical deterioration events. Advanced interventions were administered to 86 (61.9%), 195 (27.6%), and 109 (11.2%) patients with high-risk, intermediate-high, and intermediate-low severity, respectively.Major bleeding occurred in 61/1440 (4.2%) on ACm versus 169/392 (7.6%) with advanced interventions (p <0.001): bleeding withcatheter-directed thrombolysiswas 19/145 (13.1%) versus 33/154(21.4%) with systemic thrombolysis,p= 0.07. High risk was twice as strong as intermediate-high risk for association with advanced intervention (OR: 5.3 (4.2 and 6.9) vs. 1.9 (1.6 and 2.2)). High risk (OR: 56.3 (32.0 and 99.2) and intermediate-high risk (OR: 2.6 (1.7 and 4.0)) were strong predictors of clinical deterioration. Major bleeding was significantly associated with advanced interventions (OR: 5.2 (3.5 and 7.8) for immediate, 3.3 (1.8 and 6.2)) for delayed, and high-risk PE severity (OR: 3.4 (1.9 and 5.8)). Conclusions: Advanced intervention use was associated with high-acuity patients experiencing death, clinical deterioration, and major bleeding with a trend towards less bleeding with catheter-directed interventions versus systemic thrombolysis.

Hypertension Severity and Declines in Left Ventricular Ejection Fraction Among Women Receiving Adjuvant Chemotherapy for Breast Cancer (WF-97415 UPBEAT).

BACKGROUND: Hypertension is a risk factor for experiencing left ventricular ejection fraction (LVEF) declines during receipt of potentially cardiotoxic breast cancer (BC) treatment. We sought to determine whether the hypertension stage is associated with LVEF decline during BC treatment. METHODS: Across 24 centers, cardiac magnetic resonance measures of LVEF and brachial arterial blood pressure (BP) measurements were performed in women with stages I to III BC before and 3 months after initiating potentially cardiotoxic chemotherapy. Using multivariable analysis, we assessed in a blinded fashion the association between 3-month ΔLVEF and precancer treatment American Heart Association/American College of Cardiology stages of hypertension. RESULTS: Among 204 women, age averaged 56±1 years with 75% being White and 20% of Black race. Participants received anthracycline (45.6%), trastuzumab (22.5%), cyclophosphamide (52.9%), or paclitaxel (50%). After accounting for pretreatment LVEF, diabetes status, tobacco use, age, the number of antihypertensive medications, and body mass index, those with stage II hypertension experienced an LVEF decline of -2.89% ([95% CI, -0.69% to -5.19%]; P=0.01) relative to individuals with normal BP. Other stages saw nonsignificant declines relative to normal BP to elevated BP (-1.63% [95% CI, -0.62% to 3.88%]; P=0.16) and stage I hypertension (-0.94% [95% CI, -0.90% to 2.78%]; P=0.32). CONCLUSIONS: Compared with women receiving treatment for BC with normal BP, there is a stronger association of decline in LVEF in women with stage II hypertension relative to women with other hypertension stages. This raises the possibility that stage along with hypertension presence may be associated with an increased risk for the LVEF decline among women receiving potentially cardiotoxic chemotherapy for BC. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02791581 and NCT01719562.

Patient-Reported Adverse Events and Early Treatment Discontinuation Among Patients With Multiple Myeloma.

Importance: There is substantial interest in capturing cancer treatment tolerability from the patient's perspective using patient-reported outcomes (PROs). Objective: To examine whether a PRO question, item 5 from the Functional Assessment of Cancer Therapy-General General Physical Wellbeing Scale (GP5), was associated with early treatment discontinuation (ETD) due to adverse events. Design, Setting, and Participants: This prospective survey study was conducted from February to April 2023. Among participants in the ECOG-ACRIN E1A11 trial (a phase 3, parallel design trial conducted between 2013 and 2019), patients with newly diagnosed multiple myeloma were randomized to receive bortezomib (VRd) or carfilzomib (KRd) plus lenalidomide and dexamethasone as induction therapy. The GP5 item was administered at baseline (pretreatment) and at 1 month, 2.8 months, and 5.5 months postbaseline. Eligible participants included patients with newly diagnosed multiple myeloma treated at community oncology practices or academic medical centers in the US. Exposures: GP5 response options were "very much," "quite a bit," "somewhat," "a little bit," and "not at all." Responses at each assessment while undergoing treatment (1 month, 2.8 months, and 5.5 months) were categorized as high adverse event bother (ie, "very much," and "quite a bit") and low adverse event bother (ie, "somewhat," "a little bit," or "not at all"). In addition, change from baseline to each assessment while undergoing treatment was calculated and categorized as worsening by 1 response category and 2 or more response categories. Main Outcome and Measure: ETD due to adverse events (yes vs no) was analyzed using logistic regression adjusting for treatment group, performance status, gender, race, and disease stage. Results: Of the 1087 participants in the original trial, 1058 (mean [SD] age 64 [9] years; 531 receiving VrD [50.2%]; 527 receiving KRd [49.8%]) responded to item GP5 and were included in the secondary analysis. A small proportion (142 patients [13.4%]) discontinued treatment early due to AEs. For those with high adverse-effect bother, GP5 while undergoing treatment was associated with ETD at 1 month (adjusted odds ratio [aOR], 2.20; 95% CI, 1.25-3.89), 2.8 months (aOR, 3.41; 95% CI, 2.01-5.80), and 5.5 months (aOR, 4.66; 95% CI, 1.69-12.83). Worsening by 2 or more response categories on the GP5 was associated with ETD at 2.8 months (aOR, 3.02; 95% CI, 1.64-5.54) and 5.5 months (aOR, 5.49; 95% CI, 1.45-20.76). Conclusions and Relevance: In this survey study of the E1A11 trial, worse GP5 response was associated with ETD. These findings suggest that simple assessment of adverse-effect bother while receiving treatment is an efficient way to indicate treatment tolerability and ETD risk.

Risk of Obesity and Unhealthy Central Adiposity in Adolescents Born Preterm With Very Low Birthweight Compared to Term-Born Peers.

Background: Early-life factors such as preterm birth or very low birthweight (VLBW) are associated with increased cardiovascular disease risk. However, it remains unknown whether this is due to an increased risk of obesity (unhealthy central adiposity) because studies have predominantly defined obesity based on BMI, an imprecise adiposity measure. Objective: Investigate if adolescents born preterm with VLBW have a higher risk of unhealthy central adiposity compared to term-born peers. Study Design: Cross-sectional analysis of data from a prospective cohort study of 177 individuals born preterm with VLBW (<1500 g) and 51 term-born peers (birthweight ≥2500 g). Individuals with congenital anomalies, genetic syndromes, or major health conditions were excluded. Height, weight, waist circumference, skin fold thickness, and dual energy X-ray absorptiometry body composition were measured at age 14 years. We calculated BMI percentiles and defined overweight/obesity as BMI ≥85th percentile for age and sex. We estimated the preterm-term differences in overweight/obesity prevalence and adiposity distribution with multivariable generalized linear models. Results: There was no difference in small for gestational age status or overweight/obesity prevalence. Compared to term, youth born preterm with VLBW had lower BMI z-score [ß -0.38, 95% confidence limits (CL) -0.75 to -0.02] but no differences in adiposity apart from subscapular-to-triceps ratio (STR; ß 0.18, 95% CL 0.08 to 0.28). Conclusions: Adolescents born preterm with VLBW had smaller body size than their term-born peers and had no differences in central adiposity except greater STR.

Importance of Low- and Moderate-Grade Adverse Events in Patients' Treatment Experience and Treatment Discontinuation: An Analysis of the E1912 Trial.

PURPOSE: Despite defined grades of 1 to 5 for adverse events (AEs) on the basis of Common Terminology Criteria for Adverse Events criteria, mild (G1) and moderate (G2) AEs are often not reported in phase III trials. This under-reporting may inhibit our ability to understand patient toxicity burden. We analyze the relationship between the grades of AEs experienced with patient side-effect bother and treatment discontinuation. METHODS: We analyzed a phase III Eastern Cooperative Oncology Group-American College of Radiology Imaging Network trial with comprehensive AE data. The Likert response Functional Assessment of Cancer Therapy-GP5 item, "I am bothered by side effects of treatment" was used to define side-effect bother. Bayesian mixed models were used to assess the impact of G1 and G2 AE counts on patient side-effect bother and treatment discontinuation. AEs were further analyzed on the basis of symptomatology (symptomatic or asymptomatic). The results are given as odds ratios (ORs) and 95% credible interval (CrI). RESULTS: Each additional G1 and G2 AEs experienced during a treatment cycle increased the odds of increased self-reported patient side-effect bother by 13% (95% CrI, 1.06 to 1.21) and 35% (95% CrI, 1.19 to 1.54), respectively. Furthermore, only AEs defined as symptomatic were associated with increased side-effect bother, with asymptomatic AEs showing no association regardless of grade. Count of G2 AEs increased the odds of treatment discontinuation by 59% (95% CrI, 1.32 to 1.95), with symptomatic G2 AEs showing a stronger association (OR, 1.75; 95% CrI, 1.28 to 2.39) relative to asymptomatic G2 AEs (OR, 1.45; 95% CrI, 1.12 to 1.89). CONCLUSION: Low- and moderate-grade AEs are related to increased odds of increased patient side-effect bother and treatment discontinuation, with symptomatic AEs demonstrating greater magnitude of association than asymptomatic. Our findings suggest that limiting AE capture to grade 3+ misses important contributors to treatment side-effect bother and discontinuation.

Patient Characteristics Associated with Telemedicine Use for Diabetes Mellitus Care: Experience of a University Health System.

OBJECTIVES: The objective was to understand the characteristics of patients who used telemedicine for diabetes management to inform future implementation of telemedicine. METHODS: We examined patient characteristics associated with telemedicine use for diabetes mellitus (DM) care between March 1, 2020 and April 1, 2021 (the coronavirus disease 2019 pandemic period) in a large university health system when telemedicine visits increased rapidly. Logistic regression models assessed patient characteristics associated with telemedicine visits and delays in DM process measures (hemoglobin A1c checks, nephropathy, and retinopathy evaluations) during the pandemic period after adjusting for potential confounders and corresponding values before the pandemic period (March 1, 2019-February 29, 2020). RESULTS: A total of 45,159 patients were seen from 987,791 visits during the pandemic period. The number of visits averaged one visit less during the pandemic period than before the pandemic period. Approximately 5.4% of patients used telemedicine during the pandemic period from 42,750 visits. The mean (standard deviation) telemedicine visit was 1.28 (0.91). Men, Asian, Black, and other race (vs White), having Medicare or uninsured (vs private insurance), were less likely to use telemedicine. Patients with more visits before the pandemic period were more likely to use telemedicine and less likely to experience a delay in DM process measures during the pandemic period. Telemedicine users were 18% less likely to experience a delay in nephropathy visits than nonusers, but without difference for other process measures. CONCLUSIONS: Race, sex, insurance, and prepandemic in-person visits were associated with telemedicine use for DM management in a large health system. Telemedicine use was not associated with delays in hemoglobin A1c testing, nephropathy, and retinopathy assessments. Understanding reasons for not using telemedicine is important to be able to deliver equitable DM care.

Duration of Simultaneous Exposure to High-Risk and Lower-Risk Nephrotoxic Antimicrobials in the Neonatal Intensive Care Unit (NICU) and Future Adolescent Kidney Health.

OBJECTIVE: To determine whether greater duration of simultaneous exposure to antimicrobials with high nephrotoxicity risk combined with lower-risk antimicrobials (simultaneous exposure) in the neonatal intensive care unit (NICU) is associated with worse later kidney health in adolescents born preterm with very low birth weight (VLBW). STUDY DESIGN: Prospective cohort study of participants born preterm with VLBW (<1500 g) as singletons between January 1, 1992, and June 30, 1996. We defined simultaneous exposure as a high-risk antimicrobial, such as vancomycin, administered with a lower-risk antimicrobial on the same date in the NICU. Outcomes were serum creatinine, estimated glomerular filtration rate (eGFR), and first-morning urine albumin-creatinine ratio (ACR) at age 14 years. We fit multivariable linear regression models with days of simultaneous exposure and days of nonsimultaneous exposure as main effects, adjusting for gestational age, birth weight, and birth weight z-score. RESULTS: Of the 147 out of 177 participants who had exposure data, 97% received simultaneous antimicrobials for mean duration 7.2 days (SD 5.6). No participant had eGFR <90 ml/min/1.73 m2. The mean ACR was 15.2 mg/g (SD 38.7) and 7% had albuminuria (ACR >30 mg/g). Each day of simultaneous exposure was associated only with a 1.04-mg/g higher ACR (95% CI 1.01 to 1.06). CONCLUSIONS: Despite frequent simultaneous exposure to high-risk combined with lower-risk nephrotoxic antimicrobials in the NICU, there were no clinically relevant associations with worse kidney health identified in adolescence. Although future studies are needed, these findings may provide reassurance in a population thought to be at increased risk of chronic kidney disease.

Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

A single-center survey on physical activity barriers, behaviors and preferences in adults with epilepsy.

BACKGROUND: Improved understanding of physical activity barriersand preferences in people with epilepsyis needed to successfully design and perform larger, more robust effectivenesstrials. METHODS: Adult patients at a single tertiary epilepsy center between January and April 2020 were surveyed. The survey included a validated physical activity questionnaire (Physical Activity Scale for the Elderly) plus 15 items aimed to address 1) perceptions and beliefs regarding physical activity, 2) barriers to routine physical activity, and 3) willingness and ability to participate in a physical activity intervention and 4) current physical abilities, activities, and preferences. RESULTS: 95 participants with epilepsy (age 42 ± 16.2, 59 % female) completed the survey. Sixty-five participants (68.4 %) reported that they believe that physical activity could improve their seizure frequency. However, 40 % of those surveyed said their neurologist had never talked to them about physical activity. The most commonly reported barriers to physical activity were lack of time (24.7 %) and fear of having a seizure (19.7 %), while barriers to intervention participation included being unable to come to in-person sessions (53 % of those willing to participate),living far away (39.3 %), time constraints (28.6 %), and lack of transportation (21.4 %). CONCLUSION: Future physical activity studies in people with epilepsy should focus on using tailored interventions that accommodate their unique beliefs and barriers.

Incidence, severity and detection of blood pressure and heart rate perturbations in postoperative ward patients after noncardiac surgery.

STUDY OBJECTIVE: We sought to determine changes in continuous mean and systolic blood pressure and heart rate in a cohort of non-cardiac surgical patients recovering on the postoperative ward. Furthermore, we estimated the proportion of vital signs changes that would remain undetected with intermittent vital signs checks. DESIGN: Retrospective cohort. SETTING: Post-operative general ward. PATIENTS: 14,623 adults recovering from non-cardiac surgical procedures. INTERVENTIONS & MEASUREMENTS: Using a wireless, noninvasive monitor, we recorded postoperative blood pressure and heart rate at 15-s intervals and encouraged nursing intervention as clinically indicated. MAIN RESULTS: 7% of our cohort of 14,623 patients spent >15 sustained minutes with a MAP <65 mmHg, and 23% had MAP <75 mmHg for 15 sustained minutes. Hypertension was more common, with 67% of patients spending at least 60 sustained minutes with MAP >110 mmHg. Systolic pressures <90 mmHg were present for 15 sustained minutes in about a fifth of all patients, and 40% of patients had pressures >160 mmHg sustained for 30 min. 40% of patients were tachycardic with heart rates >100 beats/min for at least continuous 15 min and 15% of patients were bradycardic at a threshold of <50 beats/min for 5 sustained minutes. Conventional vital sign assessments at 4-h intervals would have missed 54% of mean pressure episodes <65 mmHg sustained >15 min, 20% of episodes of mean pressures >130 mmHg sustained >30 min, 36% of episodes of heart rate > 120 beats/min sustained <10 min, and 68% of episodes of heart rate sustained <40 beats per minute for >3 min. CONCLUSIONS: Substantial hemodynamic disturbances persisted despite implementing continuous portable ward monitoring coupled with nursing alarms and interventions. A significant proportion of these changes would have gone undetected using traditional intermittent monitoring. Better understanding of effective responses to alarms and appropriate interventions on hospital wards remains necessary.

Comparing predictive performance of pulmonary embolism risk stratification tools for acute clinical deterioration.

Objectives: Existing pulmonary embolism (PE) risk scores were developed to predict death within weeks, but not more proximate adverse events. We determined the ability of 3 PE risk stratification tools (simplified pulmonary embolism severity index [sPESI], 2019 European Society of Cardiology guidelines [ESC], and PE short-term clinical outcomes risk estimation [PE-SCORE]) to predict 5-day clinical deterioration after emergency department (ED) diagnosis of PE. Methods: We analyzed data from six EDs on ED patients with confirmed PE. Clinical deterioration was defined as death, respiratory failure, cardiac arrest, new dysrhythmia, sustained hypotension requiring vasopressors or volume resuscitation, or escalated intervention within 5 days of PE diagnosis. We determined sensitivity and specificity of sPESI, ESC, and PE-SCORE for predicting clinical deterioration. Results: Of 1569 patients, 24.5% had clinical deterioration within 5 days. sPESI, ESC, and PE-SCORE classifications were low-risk in 558 (35.6%), 167 (10.6%), and 309 (19.6%), respectively. Sensitivities of sPESI, ESC, and PE-SCORE for clinical deterioration were 81.8 (78, 85.7), 98.7 (97.6, 99.8), and 96.1 (94.2, 98), respectively. Specificities of sPESI, ESC, and PE-SCORE for clinical deterioration were 41.2 (38.4, 44), 13.7 (11.7, 15.6), and 24.8 (22.4, 27.3). Areas under the curve were 61.5 (59.1, 63.9), 56.2 (55.1, 57.3), and 60.5 (58.9, 62.0). Negative predictive values were 87.5 (84.7, 90.2), 97 (94.4, 99.6), and 95.1 (92.7, 97.5). Conclusions: ESC and PE-SCORE were better than sPESI for detecting clinical deterioration within 5 days after PE diagnosis.

A Pragmatic Pilot Trial Comparing Patient-Triggered Adaptive Pressure Control to Patient-Triggered Volume Control Ventilation in Critically Ill Adults.

BACKGROUND: Patient-triggered adaptive pressure control (APC) continuous mandatory ventilation (CMV) (APC-CMV) has been widely adopted as an alternative ventilator mode to patient-triggered volume control (VC) CMV (VC-CMV). However, the comparative effectiveness of the 2 ventilator modes remains uncertain. We sought to explore clinical and implementation factors pertinent to a future definitive randomized controlled trial assessing APC-CMV versus VC-CMV as an initial ventilator mode strategy. The research objectives in our pilot trial tested clinician adherence and explored clinical outcomes. METHODS: In a single-center pragmatic sequential cluster crossover pilot trial, we enrolled all eligible adults with acute respiratory failure requiring mechanical ventilation admitted during a 9-week period to the medical ICU. Two-week time epochs were assigned a priori in which subjects received either APC-CMV or VC-CMV The primary outcome of the trial was feasibility, defined as 80% of subjects receiving the assigned mode within 1 h of initiation of ICU ventilation. The secondary outcome was proportion of the first 24 h on the assigned mode. Finally, we surveyed clinician stakeholders to understand potential facilitators and barriers to conducting a definitive randomized trial. RESULTS: We enrolled 137 subjects who received 152 discreet episodes of mechanical ventilation during time epochs assigned to APC-CMV (n = 61) and VC-CMV (n = 91). One hundred and thirty-one episodes were included in the prespecified primary outcome. One hundred and twenty-six (96%) received the assigned mode within the first hour of ICU admission (60 of 61 subjects assigned APC-CMV and 66 of 70 assigned VC-CMV). VC-CMV subjects spent a lower proportion of first 24 h (84% [95% CI 78-89]) on the assigned mode than APC-CMV recipients (95% [95% CI 91-100]). Mixed-methods analyses identified preconceived perceptions of subject comfort by clinicians and need for real-time education to address this concern. CONCLUSIONS: In this pilot pragmatic, sequential crossover trial, unit-wide allocation to a ventilator mode was feasible and acceptable to clinicians.

Mechanisms of mindfulness in patients with migraine: Results of a qualitative study.

OBJECTIVE: To understand the mechanisms of mindfulness' impact on migraine. BACKGROUND: Promising mindfulness research demonstrates potential benefit in migraine, but no data-driven model exists from the lived experiences of patients that explains the mechanisms of mindfulness in migraine. METHODS: Semi-structured qualitative interviews were conducted with adults with migraine who participated in two mindfulness-based stress reduction (MBSR) clinical trials (n = 43). Interviews were audio-recorded, transcribed, and summarized into a framework matrix with development of a master codebook. Constructivist grounded theory approach was used to identify themes/subthemes. RESULTS: Participants who learned mindfulness techniques through MBSR experienced altered pain perception, altered response to migraine attacks and disease, increased awareness of external and internal experiences, improved overall well-being, and group benefits. Mindfulness resulted in earlier stress-body awareness and increased interoceptive awareness resulting in earlier attack recognition, leading to earlier and more effective management. Interictal factors of self-blame, guilt, and stigma decreased while migraine acceptance, hope, empowerment, self-efficacy, and self-compassion increased. Improved emotion regulation resulted in decreased fear of migraine, pain catastrophizing, anticipatory anxiety, and pain reactivity. Although taught as prevention, mindfulness was used both acutely and prophylactically. We created a conceptual model hypothesizing that MBSR skills led to an infusion of mindfulness in daily life, resulting in altered pain perception and experience, ultimately leading to improvement in overall well-being, which may positively feed back to the infusion of mindfulness in daily life. The therapeutic benefit of learning mindfulness in a group setting may moderate these effects. CONCLUSIONS: This study identified several new potential mechanisms of mindfulness' effect on migraine. After learning MBSR skills, participants reported altered pain and migraine perception and experiences. Increased stress-body and interoceptive awareness resulted in earlier migraine awareness and treatment. Mindfulness may target important interictal factors that affect disease burden such as fear of migraine, pain catastrophizing, and anticipatory anxiety. This is the first data-driven study to help elucidate the mechanisms of mindfulness on migraine from patient voices and can help direct future research endeavors.

Quality of life 1 month after acute pulmonary embolism in emergency department patients.

OBJECTIVE: The Pulmonary Embolism Quality-of-Life (PEmb-QoL) questionnaire assesses quality of life (QoL) after pulmonary embolism (PE). We aimed to determine whether any clinical or pathophysiologic features of PE were associated with worse PEmb-QoL scores 1 month after PE. METHODS: In this prospective multicenter registry, we conducted PEmb-QoL questionnaires. We determined differences in QoL domain scores for four primary variables: clinical deterioration (death, cardiac arrest, respiratory failure, hypotension requiring fluid bolus, catecholamine support, or new dysrhythmia), right ventricular dysfunction (RVD), PE risk stratification, and subsequent rehospitalization. For overall QoL score, we fit a multivariable regression model that included these four primary variables as independent variables. RESULTS: Of 788 PE patients participating in QoL assessments, 156 (19.8%) had a clinical deterioration event, 236 (30.7%) had RVD of which 38 (16.1%) had escalated interventions. For those without and with clinical deterioration, social limitations had mean (±SD) scores of 2.07 (±1.27) and 2.36 (±1.47), respectively (p = 0.027). For intensity of complaints, mean (±SD) scores for patients without RVD (4.32 ± 2.69) were significantly higher than for those with RVD with or without reperfusion interventions (3.82 ± 1.81 and 3.83 ± 2.11, respectively; p = 0.043). There were no domain score differences between PE risk stratification groups. All domain scores were worse for patients with rehospitalization versus without. By multivariable analysis, worse total PEmb-QoL scores with effect sizes were subsequent rehospitalization 11.29 (6.68-15.89), chronic obstructive pulmonary disease (COPD) 8.17 (3.91-12.43), and longer index hospital length of stay 0.06 (0.03-0.08). CONCLUSIONS: Acute clinical deterioration, RVD, and PE severity were not predictors of QoL at 1 month post-PE. Independent predictors of worsened QoL were rehospitalization, COPD, and index hospital length of stay.

Quasi-partial order continual reassessment method: Applying toxicity scores to cancer dose-finding drug combination trials.

The primary endpoint of most dose-finding cancer trials is patient toxicity, and the primary goal is to identify the maximum tolerated dose (MTD), that is, the highest dose that falls below or within a pre-specified toxicity tolerability threshold. Conventionally, dose-finding methods have utilized a binary toxicity endpoint based on whether or not a patient experiences a dose limiting-toxicity (DLT). Improving upon this, in recent years several methods have been developed for modeling toxicity scores, a novel continuous endpoint designed to more precisely estimate patient toxicity burden. Separately, drug-combination trials have become increasingly prevalent, and due to added complexities regarding estimating 'true' dose ordering and potential for more complex patient toxicity profiles, provide an ideal setting which may benefit from the improved precision of toxicity scores. In this paper, we merge two frameworks based on the Continual Reassessment Method (CRM) - the Quasi-CRM and the Partial Order CRM (POCRM) - to propose a novel approach for modeling toxicity scores in a combination-trial setting. We demonstrate that utilizing toxicity scores has the potential to greatly improve correct dose-selection over a variety of trial scenarios. We further present a simple adaptation to the toxicity-score model to control for potential over-dosing issues such that it adheres to the conventional DLT definition and will, at worst, perform equivalently to that of the traditional binary DLT framework. We demonstrate that extending toxicity scores to the combination-trial setting offers potential for improvement over the conventional binary endpoint models.