Citations

Introduction: Over 6 million people in the U.S. have heart failure (HF), less than half are expected to survive beyond 5 years. The need to better stratify mortality risk in HF is recognized. Frailty is associated with mortality in HF but not routinely measured clinically. As frailty is linked to inflammation and malnutrition, we hypothesized that the Metabolic Vulnerability Index (MVX) a multimarker score of systemic inflammation (small HDL particles, GlycA) and malnutrition (leucine, valine, isoleucine, citrate), could serve as a biomarker of frailty to predict mortality risk. Methods: Clinical data and plasma were collected from 1,389 patients from a HF community cohort between 2003-2012. We measured frailty using the Rockwood Index as the proportion of deficits present out of 32 physical limitations and comorbidities. MVX was calculated from the nuclear magnetic resonance LipoProfile® test. Patients were categorized by frailty (0-0.15; 0.16-0.27; 0.28-0.78) and MVX (33.4-50, 50-60, 60-70, 70-85.8) cutpoints. Cox models estimated the association of frailty and MVX assignment with mortality, adjusted for Meta-Analysis Global Group in Chronic HF (MAGGIC) score, a validated clinical risk score for HF mortality. Results: Frailty and MVX scores were available in 985 patients (median age 77, IQR: 67-84; 48% women). Higher frailty was associated with higher MVX (p-trend < 0.001). The highest frailty and MVX groups experienced large increases in risk of death, after adjustment for MAGGIC score (HR=3.3, 95% CI=2.6-4.2) and (HR=2.7, 95% CI=2.1-3.5), respectively. When adjusted for one another and MAGGIC score, MVX and frailty associations with death were only minimally attenuated: frailty (HR=3.2, 95% CI=2.5-4.0) and MVX (HR=2.4, 95% CI=1.9-3.2) (Figure 1). Conclusion: In this community cohort of patients with HF, frailty and MVX are positively associated with one another. However, both indicators are independently associated with an increased risk of death and can contribute to risk stratification.

Introduction: Heart Failure (HF) is a syndrome of high comorbidity and mortality. The impact of comorbidities on life expectancy in HF is well studied, but guideline-recommended disease-centric risk scores such as the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) score may not fully account for the effect of comorbidities. The Charlson Comorbidity Index (Charlson) is a validated measure that quantifies the prognostic impact of comorbidities. Objective: To examine the incremental value of Charlson over MAGGIC in predicting death in HF. Methods: In a population-based HF cohort, we computed MAGGIC and Charlson scores using electronically linked medical records. Patients were divided based on ejection fraction (EF) into reduced [EF <50%, HFrEF] or preserved [EF ≥50%, HFpEF]. Cox regression was performed to assess the association between the risk scores and mortality. The incremental value of Charlson over MAGGIC was tested by calculating the area under the ROC [receiver operating characteristic] curves (AUCs) with 95% confidence interval (CI). Results: We studied 1,388 patients with HF validated using the Framingham criteria (mean age, 75±13 years, 48% female, mean EF, 49±17%). The median Charlson was 7.0 (interquartile range 5.0-9.0) and was higher in HFpEF than HFrEF (7.0 [5.0-9.0] vs. 6.0 [4.0-8.3] respectively. Over a median follow-up of 13.9 years (13.3-14.2), mortality was 17.4% (95% CI, 15.4 -19.3%) and 36.8% (95% CI, 34.2-39.3%) at 1, and 3 years respectively. In regression analysis, increasing MAGGIC and Charlson were independently associated with death (HR 1.09, 95% CI 1.08-1.11 and HR,1.22, 95% CI 1.20-1.24, both p <0.001) irrespective of EF. Discrimination ability was improved by adding Charlson over MAGGIC (Table), reaching statistical significance at 3 years. Conclusion: In this HF cohort, the Charlson index provided an added value over MAGGIC in predicting the risk of death at 3 years. These findings emphasize the importance of accounting for comorbidities in mid-term risk stratification in HF.

Background: Heart failure (HF) is associated with metabolic alterations, including ketogenesis. However, determinants of ketogenesis and risk of mortality in HF is not defined. Total ketone bodies (KB) include β-hydroxybutyrate, acetoacetate, and acetone and can be measured in plasma by nuclear magnetic resonance (NMR). The aim of this study is to determine the relationship between KB and clinical characteristics in a community HF cohort and to assess the association between KB and all-cause mortality. Methods: A population-based cohort of 1,389 HF patients was prospectively enrolled between 2003 and 2012. Plasma KB was measured by LP4 NMR LipoProfile ® assay/test on the Vantera® NMR analyzer platform. A conditional inference tree method (ctree R Package) was used to determine optimal KB group cut points. Associations between clinical characteristics and KB were measured with Wilcoxon rank sum test and Pearson’s Chi-squared test. Kaplan-Meier method estimated survival. Cox regression analyses were used to estimate associations between KB concentrations and mortality. Results: Among the 1,382 HF patients with KB measurements, the median age was 78 years (IQR 68-84) and 52% were men. Median KB was 180 μM (IQR 134-308). Patients were divided into two groups with lower KB (≤471.5 μM) and higher KB (>471.5 μM). Patients with higher KB (N=210) had lower BMI, higher BNP, and were more likely to be in the New York Heart Association class III-IV; however, these patients were less likely to have hyperlipidemia, coronary disease, or diabetes mellitus (P < 0.05). Age, sex, creatinine, ejection fraction, or Meta-Analysis Global Group in Chronic HF (MAGGIC) score did not differ by KB group. Higher KB was associated with worse survival (figure). After adjustment for the MAGGIC score, higher KB was associated with increased risk of mortality (HR 1.3; 95% CI, 1.08-1.48). Conclusions: In this community HF cohort, higher KB was associated with increased mortality, independent of the MAGGIC score.

Abstract Background In the 5 years that have passed since the publication of the 2018 International Consensus Statement on Allergy and Rhinology: Allergic Rhinitis (ICAR‐Allergic Rhinitis 2018), the literature has expanded substantially. The ICAR‐Allergic Rhinitis 2023 update presents 144 individual topics on allergic rhinitis (AR), expanded by over 40 topics from the 2018 document. Originally presented topics from 2018 have also been reviewed and updated. The executive summary highlights key evidence‐based findings and recommendation from the full document. Methods ICAR‐Allergic Rhinitis 2023 employed established evidence‐based review with recommendation (EBRR) methodology to individually evaluate each topic. Stepwise iterative peer review and consensus was performed for each topic. The final document was then collated and includes the results of this work. Results ICAR‐Allergic Rhinitis 2023 includes 10 major content areas and 144 individual topics related to AR. For a substantial proportion of topics included, an aggregate grade of evidence is presented, which is determined by collating the levels of evidence for each available study identified in the literature. For topics in which a diagnostic or therapeutic intervention is considered, a recommendation summary is presented, which considers the aggregate grade of evidence, benefit, harm, and cost. Conclusion The ICAR‐Allergic Rhinitis 2023 update provides a comprehensive evaluation of AR and the currently available evidence. It is this evidence that contributes to our current knowledge base and recommendations for patient evaluation and treatment.

Abstract Early detection of breast cancer through screening mammography saves lives. However, the sensitivity of mammography for breast cancer detection is reduced in women with dense breast tissue. Imaging modalities for supplemental breast cancer screening include MRI, whole breast US, contrast-enhanced mammography, and molecular breast imaging (MBI). Molecular breast imaging with 99mTc-sestamibi is a functional imaging test to identify metabolically active areas in the breast with positioning analogous to mammography. Since 2011, there have been six large, published studies of screening MBI as a supplement to mammography involving over 6000 women from four different institutions. A multicenter, prospective clinical trial of 3000 women comparing breast cancer detection using screening digital breast tomosynthesis alone or in combination with MBI recently completed enrollment. This review focuses on the current evidence of MBI use for supplemental breast cancer screening, the strengths and limitations of MBI, and recent technological advances.

Abstract Purpose To estimate the risk of contralateral breast cancer (CBC) among women in the general population with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. Methods Among 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer, a subset of 14,237 women were identified from population-based studies. The risk of CBC was estimated for PV carriers in each gene compared to women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor status. Results Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (Hazard ratio ≥ 1.9, p&lt; 0.05) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks. In contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 15-year cumulative incidence of CBC was &gt;20% for BRCA1, BRCA2 and CHEK2 PV carriers with breast cancer, and for PALB2 PV carriers with ER-negative breast cancer. The 15-year cumulative incidence of CBC among postmenopausal PV carriers was &lt; 20% for PV carriers in any of the 5 genes. Conclusions Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk-reduction strategies. Citation Format: Siddhartha Yadav, Nicholas J. Boddicker, Jie Na, Eric C. Polley, Chunling Hu, Steven N. Hart, Rohan D. Gnanaolivu, Nicole Larson, Carolyn Dunn, Susan Holtegaard, Huaizhi Huang, Lauren R. Teras, Alpa V. Patel, James V. Lacey Jr., Susan Neuhausen, Leslie Bernstein, Elena Martinez, Christopher Haiman, Fei Chen, Kathryn Ruddy, Janet Olson, Esther John, Allison W. Kurian, Dale P. Sandler, Katie M. O’Brien, Jack A. Taylor, Clarice R. Weinberg, Hoda Anton-Culver, Argyrios Ziogas, Gary R. Zirpoli, David E. Goldgar, Katherine L. Nathanson, Susan Domchek, Julie R. Palmer, Jeffrey Weitzel, Peter Kraft, Fergus J. Couch. Population-based Estimates of contralateral Breast Cancer Risk among Carriers of Germline Pathogenic Variants in ATM, BRCA1, BRCA2, CHEK2, and PALB2 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-04.

Objectives:We sought to evaluate the safety and effectiveness of fecal microbiota transplantation (FMT) for recurrent Clostridioides difficile infection (CDI) in pediatric immunocompromised (IC) patients.Methods:This is a multicenter retrospective cohort study of pediatric participants who underwent FMT between March 2013 and April 2020 with 12‐week follow‐up. Pediatric patients were included if they met the definition of IC and were treated with FMT for an indication of recurrent CDI. We excluded patients over 18 years of age, those with incomplete records, insufficient follow‐up, or not meeting study definition of IC. We also excluded those treated for Clostridioides difficile recurrence without meeting the study definition and those with inflammatory bowel disease without another immunocompromising condition.Results:Of 59 pediatric patients identified at 9 centers, there were 42 who met inclusion and no exclusion criteria. Included patients had a median age of 6.7 years. Etiology of IC included: solid organ transplantation (18, 43%), malignancy (12, 28%), primary immunodeficiency (10, 24%), or other chronic conditions (2, 5%). Success rate was 79% after first FMT and 86% after 1 or more FMT. There were no statistically significant differences in patient characteristics or procedural components when patients with a failed FMT were compared to those with a successful FMT. There were 15 total serious adverse events (SAEs) in 13 out of 42 (31%) patients that occurred during the follow‐up period; 4 (9.5%) of which were likely treatment‐related. There were no deaths or infections with multidrug resistant organisms during follow‐up and all patients with a SAE fully recovered.Conclusions:The success rate of FMT for recurrent CDI in this pediatric IC cohort is high and mirrors data for IC adults and immunocompetent children. FMT‐related SAEs do occur (9.5%) and highlight the need for careful consideration of risk and benefit.

Abstract Neurofilament light chain, a putative measure of neuronal damage, is measurable in blood and CSF and is predictive of cognitive function in individuals with Alzheimer’s disease. There has been limited prior work linking neurofilament light and functional connectivity, and no prior work has investigated neurofilament light associations with functional connectivity in autosomal dominant Alzheimer’s disease. Here, we assessed relationships between blood neurofilament light, cognition, and functional connectivity in a cross-sectional sample of 106 autosomal dominant Alzheimer’s disease mutation carriers and 76 non-carriers. We employed an innovative network-level enrichment analysis approach to assess connectome-wide associations with neurofilament light. Neurofilament light was positively correlated with deterioration of functional connectivity within the default mode network and negatively correlated with connectivity between default mode network and executive control networks, including the cingulo-opercular, salience, and dorsal attention networks. Further, reduced connectivity within the default mode network and between the default mode network and executive control networks was associated with reduced cognitive function. Hierarchical regression analysis revealed that neurofilament levels and functional connectivity within the default mode network and between the default mode network and the dorsal attention network explained significant variance in cognitive composite scores when controlling for age, sex, and education. A mediation analysis demonstrated that functional connectivity within the default mode network and between the default mode network and dorsal attention network partially mediated the relationship between blood neurofilament light levels and cognitive function. Our novel results indicate that blood estimates of neurofilament levels correspond to direct measurements of brain dysfunction, shedding new light on the underlying biological processes of Alzheimer’s disease. Further, we demonstrate how variation within key brain systems can partially mediate the negative effects of heightened total serum neurofilament levels, suggesting potential regions for targeted interventions. Finally, our results lend further evidence that low-cost and minimally invasive blood measurements of neurofilament may be a useful marker of brain functional connectivity and cognitive decline in Alzheimer’s disease.

PURPOSE To estimate the risk of contralateral breast cancer (CBC) among women with germline pathogenic variants (PVs) in ATM, BRCA1, BRCA2, CHEK2, and PALB2. METHODS The study population included 15,104 prospectively followed women within the CARRIERS study treated with ipsilateral surgery for invasive breast cancer. The risk of CBC was estimated for PV carriers in each gene compared with women without PVs in a multivariate proportional hazard regression analysis accounting for the competing risk of death and adjusting for patient and tumor characteristics. The primary analyses focused on the overall cohort and on women from the general population. Secondary analyses examined associations by race/ethnicity, age at primary breast cancer diagnosis, menopausal status, and tumor estrogen receptor (ER) status. RESULTS Germline BRCA1, BRCA2, and CHEK2 PV carriers with breast cancer were at significantly elevated risk (hazard ratio > 1.9) of CBC, whereas only the PALB2 PV carriers with ER-negative breast cancer had elevated risks (hazard ratio, 2.9). By contrast, ATM PV carriers did not have significantly increased CBC risks. African American PV carriers had similarly elevated risks of CBC as non-Hispanic White PV carriers. Among premenopausal women, the 10-year cumulative incidence of CBC was estimated to be 33% for BRCA1, 27% for BRCA2, and 13% for CHEK2 PV carriers with breast cancer and 35% for PALB2 PV carriers with ER-negative breast cancer. The 10-year cumulative incidence of CBC among postmenopausal PV carriers was 12% for BRCA1, 9% for BRCA2, and 4% for CHEK2. CONCLUSION Women diagnosed with breast cancer and known to carry germline PVs in BRCA1, BRCA2, CHEK2, or PALB2 are at substantially increased risk of CBC and may benefit from enhanced surveillance and risk reduction strategies.