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Background: Frailty is a state of decreased reserve affecting multiple organ systems, thereby increasing vulnerability to stressors. Several tools have been proposed to measure frailty in multiple myeloma (MM), such as the IMWG frailty index, and the Revised Myeloma Comorbidity Index. However, these are based on clinical trial datasets, and include chronological age as one of the indicators of frailty. A frailty index based on the principle of accumulation of health deficits (Rockwood doi:10.1093/gerona/62.7.738), provides a measure of physiologic age. This index can be readily calculated using various combinations of health deficits and has been shown to predict outcomes in several populations. Social support has been associated with improved outcomes in various populations, however its impact on survival in patients with MM has not been well studied. The objective of this study was to assess the impact of frailty measured by a deficit accumulation frailty index and the impact of relationship status on outcomes in patients with newly diagnosed MM. Methods: This is a retrospective study including patients diagnosed with MM between January 6 th, 2005, and September 19 th, 2018. We calculated a deficit accumulation frailty index using previously published methods (McNallan et. al doi.org/10.1016/j.ahj.2013.07.008, Searle et al. doi.org/10.1186/1471-2318-8-24). We used the electronic medical record system at Mayo Clinic in Rochester, MN, to extract data on activities of daily living (14 items) provided by patient-completed questionnaires, and data on comorbidities as recorded by treating providers (16 items), within 6 months prior to diagnosis. Each item was scored as 0, 0.5, or 1, with 1 indicating the presence of deficit (Table 1). The frailty index was defined as the sum of individual scores divided that by the total number of non-missing items. Patients who had N >2 missing items were excluded. Patients with a frailty index ≥0.15 were considered frail. We also extracted data on self-reported relationship status within 6 months prior to diagnosis. Variables were compared between groups using Fisher's exact test and Wilcoxon signed-rank test for categorical and continuous variables, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard models. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups using the Log-rank test. P values <0.05 were considered statistically significant. Results: We included 578 patients. Median age was 67 (interquartile range: 59-74) years, and 40% were female. Among all patients, 226 (39%) were frail. Compared to fit patients, patients who were frail were older (median age: 70 vs. 65 years, P<0.001) and more likely to have International Staging System (ISS) III (vs. I/II) disease (47% vs. 27%, P<0.001) and ECOG performance status ≥2 (vs. 0 or 1) (45% vs. 17%, P<0.001). There was no difference in R-ISS III disease or presence of high-risk cytogenetic abnormalities between fit and frail patients. Median OS was 7.6 and 4.1 years in fit and frail patient, respectively (P<0.001). Physician assessed ECOG performance status was available for 268 patients. Among patients with ECOG performance status 0 or 1 (193 patients), 136 (70%) were fit, and 57 (30%) were frail. The OS was 8.3 and 4.6 years in the 2 groups, respectively (P=0.006) (table 2). On multivariate analysis including age, frailty status, and R-ISS stage (III vs. I/II), all were associated with OS with frailty's hazard ratio (HR): 1.4 (95%CI [1.1-1.8]), P=0.004; the HR was 1.4 (95%CI [1.1-1.9]), P=0.02, when analysis was restricted to patients ≥60 years. Among all patients, those who were married or in a committed relationship (474 patients) had improved survival (median OS: 7.0 vs. 3.7 years, respectively, P<0.001) compared to patients who were divorced/separated, widowed, or single (96 patients). On multivariate analysis, which included age, R-ISS III, frailty status, and relationship status, all were associated with OS. The HR for relationship status was 1.4 (95%CI [1.0-1.8]), P=0.0465. Conclusion: Frailty, defined by the deficit accumulation frailty index, is independently associated with decreased survival in patients with newly diagnosed MM. Being married or in a committed relationship is associated with improved survival independent of age, disease stage, and frailty.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

The primary mediator of transforming growth factor β (TGFβ) responses are the Smad proteins. Here, we identify sorting nexin 9 (SNX9) as being required for Smad3 (but not Smad2) nuclear translocation and cell stimulation. SNX9 principally interacts with phosphorylated (p) Smad3 and promotes more rapid nuclear delivery from that observed independent of ligand. Although SNX9 does not bind Imp7, Impb, Nup153 or Nup214, it mediates the association of pSmad3 with Imp8 and the nuclear membrane. This facilitates recruitment of pSmad3/SNX9 to the nuclear pore, heterodimerization of Imp8 with Impb, and nuclear translocation of pSmad3, but not SNX9. The demonstration that Smad3 is regulated in a distinct manner from Smad2 provides the opportunity to develop intervention strategies to enhance or dampen specific aspects of the cellular response to TGFβ. Support or Funding Information This work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.

Background Inconsistent nomenclature and anatomical descriptions of regional anesthetic techniques hinder scientific communication and engender confusion; this in turn has implications for research, education and clinical implementation of regional anesthesia. Having produced standardized nomenclature for abdominal wall, paraspinal and chest wall regional anesthetic techniques, we aimed to similarly do so for upper and lower limb peripheral nerve blocks. Methods We performed a three-round Delphi international consensus study to generate standardized names and anatomical descriptions of upper and lower limb regional anesthetic techniques. A long list of names and anatomical description of blocks of upper and lower extremities was produced by the members of the steering committee. Subsequently, two rounds of anonymized voting and commenting were followed by a third virtual round table to secure consensus for items that remained outstanding after the first and second rounds. As with previous methodology, strong consensus was defined as ≥75% agreement and weak consensus as 50%–74% agreement. Results A total of 94, 91 and 65 collaborators participated in the first, second and third rounds, respectively. We achieved strong consensus for 38 names and 33 anatomical descriptions, and weak consensus for five anatomical descriptions. We agreed on a template for naming peripheral nerve blocks based on the name of the nerve and the anatomical location of the blockade and identified several areas for future research. Conclusions We achieved consensus on nomenclature and anatomical descriptions of regional anesthetic techniques for upper and lower limb nerve blocks, and recommend using this framework in clinical and academic practice. This should improve research, teaching and learning of regional anesthesia to eventually improve patient care.

AbstractIntroductionInpatient hyperglycemia is an established independent risk factor among several patient cohorts for hospital readmission. This has not been studied after kidney transplantation. Nearly one‐third of patients who have undergone a kidney transplant reportedly experience 30‐day readmission.MethodsData on first‐time solitary kidney transplantations were retrieved between September 2015 and December 2018. Information was linked to the electronic health records to determine diagnosis of diabetes mellitus and extract glucometric and insulin therapy data. Univariate logistic regression analysis and the XGBoost algorithm were used to predict 30‐day readmission. We report the average performance of the models on the testing set on bootstrapped partitions of the data to ensure statistical significance.ResultsThe cohort included 1036 patients who received kidney transplantation; 224 (22%) experienced 30‐day readmission. The machine learning algorithm was able to predict 30‐day readmission with an average area under the receiver operator curve (AUC) of 78% with (76.1%, 79.9%) 95% confidence interval (CI). We observed statistically significant differences in the presence of pretransplant diabetes, inpatient‐hyperglycemia, inpatient‐hypoglycemia, minimum and maximum glucose values among those with higher 30‐day readmission rates. The XGBoost model identified the index admission length of stay, presence of hyper‐ and hypoglycemia, the recipient and donor body mass index (BMI) values, presence of delayed graft function, and African American race as the most predictive risk factors of 30‐day readmission. Additionally, significant variations in the therapeutic management of blood glucose by providers were observed.ConclusionsSuboptimal glucose metrics during hospitalization after kidney transplantation are associated with an increased risk for 30‐day hospital readmission. Optimizing hospital blood glucose management, a modifiable factor, after kidney transplantation may reduce the risk of 30‐day readmission.

314 Background: In a recent trial, we observed no statistically significant increase in engagement after a web-based decision aid (DA) was delivered to breast cancer patients prior to a surgical consult. However, a minority of the intervention group (44%) reviewed the DA. The objective is to assess the effect of the DA on engagement for the cohort of patients who reviewed it. Methods: A stepped wedge trial was conducted with 10 NCI Community Oncology Research Program clinics that care for a high proportion of socioeconomically disadvantaged patients (6/2019-12/2021). Clinics were randomized to time of transition from usual care (UC) to delivery of a DA. Patients with stage 0-3 breast cancer eligible for surgery provided consent prior to a surgical consult. Engagement was measured from audio-recorded surgical consults (Active Patient Behaviors, Street protocol). For this analysis, we identified a cohort of treatment compliant (TC) patients who reviewed the DA. Intervention effects comparing TC and UC groups were tested with linear mixed-effects models, accounting for time, enrollment post-COVID, and patient age, race, education, and socioeconomic disadvantage (assessed with Area Deprivation Index and dichotomized). Exploratory models were generated using Active Patient Behavior subcomponents (asking questions, assertive responses, expressions of concern) as the outcome. Results: The cohort includes 407 patients (UC 264; TC 143). TC patients were more likely to be white (TC 73%, UC 64%, p=0.03), have a college degree (TC 65%, UC 55%, p=0.05), and not be disadvantaged (TC 89%, UC 72%, p=0.001). TC was associated with increased engagement (8.2 [0.08, 16.2], p=0.048, Table). A college degree was associated with higher, while black race and socioeconomic disadvantage lower, engagement. On exploratory analyses, TC had a stronger association with higher levels of assertive responses (2.9 [-0.3, 6.1], p=0.07) compared with asking questions (5.2 [-1.4, 11.9], p=0.12) or expressions of concern (0.08 [-0.60, 0.76], p=0.82). Conclusions: We observed increased engagement in breast cancer patients who reviewed a DA prior to a surgical consult. However, we also observed differences based on race, education, and socioeconomic disadvantage. Further research will identify adjunct interventions to combine with the DA to improve cancer care delivery for diverse populations. Support: UG1 CA189823; AHRQ R01HS025194; https://acknowledgments.alliancefound.org. Clinical trial information: NCT03766009 .[Table: see text]

SummaryMantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high‐risk call by a simplified MCL international prognostic index (s‐MIPI) (HR: 3.32, 95% CI: 1.65–6.68 compared to low risk), a high‐risk call by MCL35 (HR: 10.34, 95% CI: 2.37–45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92–9.22 compared to classic). Patients called high risk by both the s‐MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10–32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49–5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk‐stratify older MCL patients in future clinical trials.

Abstract The approach to patients with high-risk smoldering multiple myeloma (SMM) varies among clinicians; while some advocate early intervention, others reserve treatment at progression to multiple myeloma (MM). We aimed to describe the myeloma-defining events (MDEs) and clinical presentations leading to MM diagnosis among SMM patients seen at our institution. We included 406 patients diagnosed with SMM between 2013-2022, seen at Mayo Clinic, Rochester, MN. The 2018 Mayo 20/2/20 criteria were used for risk stratification. Median follow-up was 3.9 years. Among high-risk patients who did not receive treatment in the SMM phase (n=71), 51 progressed by last follow-up; the MDEs included: bone lesions(37%), anemia(35%), hypercalcemia(8%), and renal failure(6%); 24% met MM criteria based on marrow plasmacytosis (≥60%) and/or free light chain ratio (>100); 45% had clinically significant MDEs (hypercalcemia, renal insufficiency, and/or bone lesions). MM diagnosis was made based on surveillance labs/imaging(45%), testing obtained due to provider suspicion for progression(14%), bone pain(20%), and hospitalization/ED presentations due to MM complications/symptoms(4%). The presentation was undocumented in 14%. A high proportion (45%) of patients with high-risk SMM on active surveillance develop end-organ damage at progression. About a quarter of patients who progress to MM are not diagnosed based on routine interval surveillance testing.