Publications

INTRODUCTION: Fear of cancer recurrence (FCR) is prevalent and distressing among survivors of cancer. Evidence-based mind-body and cognitive-behavioral skills lack integration and testing in scalable formats.

OBJECTIVE: This pilot randomized controlled trial (NCT04876599) tested a synchronous, virtual mind-body group resiliency intervention for FCR (IN FOCUS).

METHOD: Adults with elevated FCR (FCR Inventory severity ≥ 16; 16-21 = elevated, 22-36 = clinically elevated) after completing primary treatment for non-metastatic cancer were randomly assigned (1:1) to eight weekly sessions of IN FOCUS or usual care (UC; synchronous, virtual community group support referral). Feasibility metrics included ≥ 70% retention per arm (primary outcome), ≥ 75% attendance in ≥ 6 sessions, ≥ 75% adherence to relaxation skills practice ≥ 3 days per week and by delivery fidelity (% content covered in video-recorded sessions). Acceptability was assessed quantitatively via ratings of enjoyableness, convenience, helpfulness, odds of future use, and satisfaction (benchmark ≥ 80% of ratings ≥ 4 on 1-5 Likert scale) and qualitatively via individual exit interviews. Linear mixed models explicated slopes in FCR (secondary) and resiliency (exploratory; Current Experiences Scale) from baseline to 2 months (primary endpoint) and 5 months using intention-to-treat.

RESULTS: From July 2021 to March 2022, 64 survivors enrolled (25-73 years old, M = 7 years since diagnosis). IN FOCUS was feasible and acceptable (91% retention; attendance median = 7 sessions, 97% relaxation practice adherence, 95% content fully covered; 82% of acceptability ratings ≥ 4). Interviews (n = 59) revealed benefits in both arms. By 2 months, compared to UC, IN FOCUS reduced FCR to a medium-to-large effect (Mdiff = -2.4; 95% CI = -4.2, -0.7; d = 0.66). By 5 months, FCR effects had attenuated (Mdiff = -0.16, 95% CI -1.97, 1.65; d = -0.04), although levels of resiliency had increased with a medium-to-large effect (Mdiff = 10.0; 95% CI = 4.9, 15.1; d = 0.78).

CONCLUSIONS: For survivors of non-metastatic cancer, a synchronous, virtual mind-body resiliency program for FCR is feasible, acceptable, and seemingly beneficial compared to a community group referral.

INTRODUCTION: The prevalence of peripheral neuropathy (PN) in the lower limb increases with age and with the presence of diabetes. Studies show an association of PN with advanced cognitive impairment. Here we examine the association of PN with measures of early cognitive deficits in a cohort of older adults without apparent cognitive impairment, with or without diabetes.

METHODS: A total of 2,798 participants from the Cardiovascular Health Study were examined, mean age 80 years. All underwent tests of overall cognition (3MSE), executive function (DSST), and visual memory (BVRT). Impairment of vibration sensation in the toes, ankles, and tibial tuberosities was ascertained. Participants were graded according to the extent of impairment. Adjusted linear regression analyses of the extent of impaired vibration sensation with cognitive tests were performed. Results were further categorized by the presence or absence of diabetes.

RESULTS: 70% of participants had intact vibration sensation in the toes; 8% had no vibration sensation in the tibial tuberosities or below. Compared to participants with intact vibration sensation in the toes, those with no vibration sensation in the tibial tuberosities had lower 3MSE scores. Tests of executive function were lower in a stepwise manner with greater impaired vibration sensation. Visual memory was less strongly associated with impaired vibration sensation. Findings did not differ significantly by diabetes status.

CONCLUSION: In older adults, impaired vibration sensation in the lower limb is associated with impaired executive function and visual memory. These findings did not differ by diabetes status.

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; Padj&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; Padj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; Padj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

BACKGROUND: Although the pathogenesis of delirium is poorly understood, increasing evidence supports a role for inflammation. Previously, individual inflammatory biomarkers have been associated with delirium. Aggregating biomarkers into an index may provide more information than individual biomarkers in predicting certain health outcomes (e.g., mortality); however, inflammatory indices have not yet been examined in delirium.

METHODS: Four inflammatory markers, C-reactive protein, Interleukin-6, Soluble Tumor Necrosis Factor Alpha Receptor-1, and Chitinase-3 Like Protein-1 (CHI3L1), were measured preoperatively (PREOP) and on postoperative day 2 (POD2) in 548 adults aged 70+ undergoing major noncardiac surgery (mean age 76.7 [standard deviation 5.2], 58% female, 24% delirium). From these markers, four inflammatory indices were considered: 1) quartile summary score, 2) weighted summary score (WSS), 3) principal component score, 4) a well-established inflammatory (LASSO-derived) index associated with mortality. Delirium was assessed using the Confusion Assessment Method (CAM), supplemented by chart review. Generalized linear models (GLM) with a log-link term were used to determine the association between each inflammatory index and delirium incidence.

RESULTS: Among the inflammatory indices, WSS demonstrated the strongest association with delirium: participants in WSS quartile (Q)4 had a higher risk of delirium vs. participants in Q1, after clinical variable adjustment (relative risk [RR], 95% confidence interval [CI] for PREOP: 3.07, 1.80-5.22; and POD2: 2.65, 1.63-4.30). WSS was more strongly associated with delirium than the strongest associated individual inflammatory marker (PREOP CHI3L1 [RR 2.45, 95% CI 1.53-3.92]; POD2 interleukin-6 [RR 2.39, 95% CI 1.50-3.82]).

CONCLUSIONS: A multi-protein inflammatory index using WSS provides a slight advantage over individual inflammatory markers in their association with delirium.

OBJECTIVE: Acute hyperglycemia following intracerebral hemorrhage (ICH) is associated with poor functional outcomes and may result from a neuroendocrine stress response. Given the proximity of neuroendocrine structures to the cerebral ventricles, we tested the hypothesis that intraventricular hemorrhage (IVH) is associated with hyperglycemia.

MATERIALS AND METHODS: A post-hoc analysis of the ICH Deferoxamine (i-DEF) trial was conducted to determine predictors of IVH. Variables with significant differences (p < 0.1) in univariable tests between patients with and without IVH were entered into a logistic regression model along with age, sex, diabetes, hyperglycemia (admission glucose ≥140 mg/dL), and baseline intraparenchymal hemorrhage (IPH) volume. This model was then applied to an independent cohort of consecutive non-traumatic ICH patients admitted to a single referral center (2007 to 2018).

RESULTS: Among 294 patients in the i-DEF cohort with mean age 60 ± 12 years (IVH in 41 %), hyperglycemia (aOR 1.90, 95 % CI [1.06-3.38]), smoking history (aOR 1.90, 95 % CI [1.11-3.27]), and non-lobar ICH location (aOR 3.38, 95 % CI [1.49-7.69]) were independently associated with IVH. In the independent cohort consisting of 856 patients with mean age 71 ± 12 years (IVH in 37 %), hyperglycemia (aOR 2.23, 95 % CI [1.55-3.20]), non-lobar ICH location (aOR 2.50, 95 % CI [1.75-3.59]), and IPH volume (aOR 1.02, 95 % CI [1.01-1.02]) were associated with IVH.

CONCLUSIONS: Hyperglycemia is associated with IVH and may be a peripheral marker for the inflammatory response to hemorrhage within the ventricles. Further translational studies are needed to elucidate the pathophysiological basis for this phenomenon.

BACKGROUND: Reliable, noninvasive tools to diagnose at-risk metabolic dysfunction-associated steatohepatitis (MASH) are urgently needed to improve management. We developed a risk stratification score incorporating proteomics-derived serum markers with clinical variables to identify high-risk patients with MASH (NAFLD activity score >4 and fibrosis score >2).

METHODS: In this 3-phase proteomic study of biopsy-proven metabolic dysfunction-associated steatotic fatty liver disease, we first developed a multi-protein predictor for discriminating NAFLD activity score >4 based on SOMAscan proteomics quantifying 1305 serum proteins from 57 US patients. Four key predictor proteins were verified by ELISA in the expanded US cohort (N = 168) and enhanced by adding clinical variables to create the 9-feature MASH Dx score, which predicted MASH and also high-risk MASH (F2+). The MASH Dx score was validated in 2 independent, external cohorts from Germany (N = 139) and Brazil (N = 177).

RESULTS: The discovery phase identified a 6-protein classifier that achieved an AUC of 0.93 for identifying MASH. Significant elevation of 4 proteins (THBS2, GDF15, SELE, and IGFBP7) was verified by ELISA in the expanded discovery and independently in the 2 external cohorts. MASH Dx score incorporated these proteins with established MASH risk factors (age, body mass index, ALT, diabetes, and hypertension) to achieve good discrimination between MASH and metabolic dysfunction-associated steatotic fatty liver disease without MASH (AUC: 0.87-discovery; 0.83-pooled external validation cohorts), with similar performance when evaluating high-risk MASH F2-4 (vs. MASH F0-1 and metabolic dysfunction-associated steatotic fatty liver disease without MASH).

CONCLUSIONS: The MASH Dx score offers the first reliable noninvasive approach combining novel, biologically plausible ELISA-based fibrosis markers and clinical parameters to detect high-risk MASH in patient cohorts from the United States, Brazil, and Europe.

BACKGROUND: Patients undergoing colectomy are at risk of numerous major complications. However, existing binary risk stratification models do not predict when a patient may be at highest risks of each complication. Accurate prediction of the timing of complications facilitates targeted, resource-efficient monitoring. We sought to develop and internally validate Cox proportional hazards models to predict time-to-complication of major complications within 30 days after elective colectomy.

METHODS: We studied a retrospective cohort from the multicentered American College of Surgeons National Surgical Quality Improvement Program procedure-targeted colectomy dataset. Patients aged 18 years or above, who underwent elective colectomy between January 1, 2014 and December 31, 2019 were included. A priori candidate predictors were selected based on variable availability, literature review, and multidisciplinary team consensus. Outcomes were mortality, hospital readmission, myocardial infarction, cerebral vascular events, pneumonia, venous thromboembolism, acute renal failure, and sepsis or septic shock within 30 days after surgery.

RESULTS: The cohort consisted of 132145 patients (mean ± SD age, 61 ± 15 years; 52% females). Complication rates ranged between 0.3% (n = 383) for cardiac arrest and acute renal failure to 5.3% (n = 6986) for bleeding requiring transfusion, with readmission rate of 8.6% (n = 11415). We observed distinct temporal patterns for each complication: the median [quartiles] postoperative day of complication diagnosis ranged from 1 [0, 2] days for bleeding requiring transfusion to 12 [6, 18] days for venous thromboembolism. Models for mortality, myocardial infarction, pneumonia, and renal failure showed good discrimination with a concordance > 0.8, while models for readmission, venous thromboembolism, and sepsis performed poorly with a concordance of 0.6 to 0.7. Models exhibited good calibration but ranges were limited to low probability areas.

CONCLUSIONS: We developed and internally validated time-to-event prediction models for complications after elective colectomy. Once further validated, the models can facilitate tailored monitoring of high risk patients during high risk periods.

TRIAL REGISTRATION: Clinicaltrials.gov (NCT05150548; Principal Investigator: Janny Xue Chen Ke, M.D., M.Sc., F.R.C.P.C.; initial posting: November 25, 2021).

BACKGROUND: Diagnostic scope is the range of diagnoses found in a clinical setting. Although the diagnostic scope is an essential feature of training and evaluating artificial intelligence (AI) systems to promote diagnostic excellence, its impact on AI systems and the diagnostic process remains under-explored.

CONTENT: We define the concept of diagnostic scope, discuss its nuanced role in building safe and effective AI-based diagnostic decision support systems, review current challenges to measurement and use, and highlight knowledge gaps for future research.

SUMMARY: The diagnostic scope parallels the differential diagnosis although the latter is at the level of an encounter and the former is at the level of a clinical setting. Therefore, diagnostic scope will vary by local characteristics including geography, population, and resources. The true, observed, and considered scope in each setting may also diverge, both posing challenges for clinicians, patients, and AI developers, while also highlighting opportunities to improve safety. Further work is needed to systematically define and measure diagnostic scope in terms that are accurate, equitable, and meaningful at the bedside. AI tools tailored to a particular setting, such as a primary care clinic or intensive care unit, will each require specifying and measuring the appropriate diagnostic scope.

OUTLOOK: AI tools will promote diagnostic excellence if they are aligned with patient and clinician needs and trained on an accurately measured diagnostic scope. A careful understanding and rigorous evaluation of the diagnostic scope in each clinical setting will promote optimal care through human-AI collaborations in the diagnostic process.

BACKGROUND: Dietary guidelines recommend substituting animal protein with plant protein, however, the ideal ratio of plant-to-animal protein (P:A) remains unknown.

OBJECTIVES: We aimed to evaluate associations between the P:A ratio and incident cardiovascular disease (CVD), coronary artery disease (CAD), and stroke in 3 cohorts.

METHODS: Multivariable-adjusted Cox proportional hazard models were used to estimate hazard ratios (HRs) for CVD outcomes among 70,918 females in the Nurses' Health Study (NHS) (1984-2016), 89,205 females in the NHSII (1991-2017) and 42,740 males from the Health Professionals Follow-up Study (1986-2016). The P:A ratio was based on percent energy from plant and animal protein and assessed using food frequency questionnaires every 4 y.

RESULTS: During 30 y of follow-up, 16,118 incident CVD cases occurred. In the pooled multivariable-adjusted models, participants had a lower risk of total CVD [HR: 0.81; 95% confidence interval (CI): 0.76, 0.87; P trend < 0.001], CAD (HR: 0.73; 95% CI: 0.67, 0.79; P trend < 0.001), but not stroke (HR: 0.98; 95% CI: 0.88, 1.09; P trend = 0.71), when comparing highest to lowest deciles of the P:A ratio (ratio: ∼0.76 compared with ∼0.24). Dose-response analyses showed evidence of linear and nonlinear relationships for CVD and CAD, with more marked risk reductions early in the dose-response curve. Lower risk of CVD (HR: 0.72; 95% CI: 0.64, 0.82) and CAD (HR: 0.64; 95% CI: 0.55, 0.75) were also observed with higher ratios and protein density (20.8% energy) combined. Substitution analyses indicated that replacing red and processed meat with several plant protein sources showed the greatest cardiovascular benefit.

CONCLUSIONS: In cohort studies of United States adults, a higher plant-to-animal protein ratio is associated with lower risks of CVD and CAD, but not stroke. Furthermore, a higher ratio combined with higher protein density showed the most cardiovascular benefit.

BACKGROUND: Orthostatic hypertension is an emerging risk factor for adverse events. Recent consensus statements combine an increase in blood pressure upon standing with standing hypertension, but whether these 2 components have similar risk associations with cardiovascular disease (CVD) is unknown.

METHODS: The ARIC study (Atherosclerosis Risk in Communities) measured supine and standing blood pressure during visit 1 (1987-1989). We defined systolic orthostatic increase (a rise in systolic blood pressure [SBP] ≥20 mm Hg, standing minus supine blood pressure) and elevated standing SBP (standing SBP ≥140 mm Hg) to examine the new consensus statement definition (rise in SBP ≥20 mm Hg and standing SBP ≥140 mm Hg). We used Cox regression to examine associations with incident coronary heart disease, heart failure, stroke, fatal coronary heart disease, and all-cause mortality.

RESULTS: Of 11 369 participants (56% female; 25% Black adults; mean age, 54 years) without CVD at baseline, 1.8% had systolic orthostatic increases, 20.1% had standing SBP ≥140 mm Hg, and 1.3% had systolic orthostatic increases with standing SBP ≥140 mm Hg. During up to 30 years of follow-up, orthostatic increases were not significantly associated with any of the adverse outcomes of interest, while standing SBP ≥140 mm Hg was significantly associated with all end points. In joint models comparing systolic orthostatic increases and standing SBP ≥140 mm Hg, standing SBP ≥140 mm Hg was significantly associated with a higher risk of CVD, and associations differed significantly from systolic orthostatic increases.

CONCLUSIONS: Unlike systolic orthostatic increases, standing SBP ≥140 mm Hg was strongly associated with CVD outcomes and death. These differences in CVD risk raise important concerns about combining systolic orthostatic increases and standing SBP ≥140 mm Hg in a consensus definition for orthostatic hypertension.