Citations

Abstract Introduction There is increasing interest in plasma amyloid beta (Aβ) as an endophenotype of Alzheimer's disease (AD). Identifying the genetic determinants of plasma Aβ levels may elucidate important biological processes that determine plasma Aβ measures. Methods We included 12,369 non‐demented participants from eight population‐based studies. Imputed genetic data and measured plasma Aβ1‐40, Aβ1‐42 levels and Aβ1‐42/Aβ1‐40 ratio were used to perform genome‐wide association studies, and gene‐based and pathway analyses. Significant variants and genes were followed up for their association with brain positron emission tomography Aβ deposition and AD risk. Results Single‐variant analysis identified associations with apolipoprotein E ( APOE ) for Aβ1‐42 and Aβ1‐42/Aβ1‐40 ratio, and BACE1 for Aβ1‐40. Gene‐based analysis of Aβ1‐40 additionally identified associations for APP , PSEN2 , CCK , and ZNF397 . There was suggestive evidence for interaction between a BACE1 variant and APOE ε4 on brain Aβ deposition. Discussion Identification of variants near/in known major Aβ‐processing genes strengthens the relevance of plasma‐Aβ levels as an endophenotype of AD.

Introduction: Practice guidelines recommend use of subcutaneous implantable cardioverter-defibrillators (ICD) in patients (pts) at risk of sudden cardiac death and high risk for infection. This has prompted a need to better identify pts at high risk of infection to assist in de novo device selection. The objective of this study is to estimate infection incidence in de novo transvenous (TV) ICD implants and assess risk factors associated with infection in a large Medicare population. Methods: A retrospective cohort study was conducted using 100% Medicare administrative and claims data to identify pts who underwent de novo TV-ICD implantation between 7/2016 and 1/2018. Device-related infection within 2 years of implantation was identified using ICD-10 diagnosis and procedure codes. Baseline pt factors associated with infection were identified by univariable logistic regression analysis of all variables of interest, including factors in Charlson and Elixhauser comorbidity indices, followed by stepwise selection criteria with a p≤0.25 for inclusion in a multivariable model and a backwards, stepwise elimination process with p≤0.1 to remain in the model. A time-to-event analysis was also conducted. Results: Among 26,742 pts with de novo TV-ICD, 519 (1.9%) had a device-related infection over 2 years. The mean pt age with and without infection was 68 and 71 years, respectively. While more than half (54%) of infections occurred within 90 days post implant, infections continued to be diagnosed with 16% of infections occurring between years 1 and 2. Multivariable analysis revealed several significant predictors of infection (Figure) including age <70 years, end stage renal disease with chronic dialysis and diabetes with complications. Conclusion: The rate of de novo TV-ICD infection in a large real-world Medicare population is clinically significant. The factors associated with increased infection risk identified here can be used to help determine device selection.

Introduction: Hospitalization for acute decompensated heart failure (ADHF) remains a major source of morbidity and mortality. While previous studies have shown outpatient intravenous (IV) diuretic therapy to be safe and cost-effective, there have been no randomized controlled trials to evaluate the utilization of continued outpatient IV furosemide diuretic maintenance treatment in patients with HF following hospitalization for ADHF. Hypothesis: We hypothesized that 30-day hospital readmission from ADHF would be lower with routine, standardized outpatient IV diuretic treatment along with a comprehensive HF care approach vs standard treatment. Methods: In a single center, prospective, randomized, double-blind study, 100 patients were randomized to receive standard of care (Group 1), IV placebo infusion (Group 2), or IV furosemide infusion (Group 3) over 3 hours, biweekly for a one-month period following hospitalization for ADHF. Patients in Groups 2 and 3 also received a comprehensive HF care protocol including bi-weekly clinic visits for dose-adjusted IV-diuretics, medication adjustment, laboratory, weight, and blood pressure-monitoring, and education during infusion visits. Echocardiography, Kansas City Cardiomyopathy Questionnaire (KCCQ) and depression questionnaires were performed at baseline and 30-day follow-up. The primary outcome was 30-day re-hospitalization for ADHF. Results: Overall, a total of 94 patients were included in the study (mean age 64 years, 56% males, 69% African American, 70% HF reduced ejection fraction). There were a total of 14 (15%) readmissions for ADHF at 30 days, 6 (17.1%) in Group 1, 7 (22.6%) in Group 2, and 1 (3.7%) in Group 3 (overall p=0.11; p=0.037 comparing Group 2 and Group 3). Patients receiving IV furosemide infusion experienced significantly greater urine output and weight loss compared to those receiving placebo without any significant increase creatinine and no significant between group differences in echocardiography parameters, KCCQ or depression scores. Conclusions: The use of a standardized protocol of outpatient IV furosemide infusion for a one-month period following hospitalization for ADHF was found to be safe and efficacious in reducing 30-day re-hospitalization.

Introduction: Atrial Fibrillation (AF) has been associated with various behavioral risk factors such as tobacco, alcohol, and/or substance abuse. Hypothesis: The main objective is to describe the national trends and burden of tobacco and substance abuse in AF hospitalizations. Methods: The National Inpatient Sample database from 2007 to 2015 was utilized and the hospitalizations with AF were identified using the international classification of disease, Ninth Revision, Clinical Modification (ICD-9-CM) code 427.31 in the primary diagnosis column. They were stratified into without abuse, tobacco use disorder (TUD), substance use disorder (SUD), alcohol use disorder (AUD), and drug use disorder (DUD). We used the Jonckheere-Terpstra trend test to analyze the trend in this study. Results: Out of 3,631,507 AF hospitalizations, 852,110 (23.46%) had TUD, 1851,170 (5.1%) had SUD, 155,681 (4.29%) had AUD and 42,667 (1.17%) had DUD. The trends of all increased substantially during the study period (Figure) . The prevalence of TUD, SUD, AUD, and DUD was substantially increased across all age groups, races, and gender during the study period. Female sex was associated with lower odds TUD (0.57 (0.56-0.57), P-value <0.001), SUD (0.27 (0.26-0.27), P-value <0.001), AUD (0.22 (0.22-0.22), P-value <0.001), and DUD (0.51 (0.5-0.52), P-value <0.001). Among AF hospitalizations, the black race was associated with higher odds of SUD (1.12 (1.1-1.14), P-value <0.001), and DUD(1.42 (1.38-1.47), P-value <0.001). The younger age group (18-35 years), male, Medicare/Medicaid as primary insurance, and lower socioeconomic status were associated with increased risk of both TUD and SUDs. Conclusions: Tobacco and substance use disorder among hospitalized AF patients in the US mainly affects males, younger individuals, white more than black, and those of lower socioeconomic status which demands the development of preventive strategies to address multilevel influences.

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disease with diverse etiologies. Obstructive sleep apnea (OSA) is known to increase the risk of diastolic dysfunction and heart failure. OSA also increases the risk and severity of type 2 diabetes (DM2) independent of age and obesity. However, its role in patients with HFpEF and concomitant DM2 is unclear. Hypothesis: Our aim was to study the role of OSA in hospitalizations in patients with HFpEF and concomitant DM2. Methods: We did a retrospective chart analysis of 142 patients age (72 ± 11, 54.9% women) with HFpEF and known DM2 for five years after the initial diagnosis of HFpEF. Presence of OSA at the time of initial HFpEF diagnosis was noted based on the results of a documented sleep study. A multivariable cox-proportional hazard model was used to assess whether the presence of OSA had any significant impact on the risk of future HFpEF hospitalization. Kaplan-Meier analysis was used to calculate if OSA predicted time to future HFpEF hospitalization. Results: After a five year follow up, 63 (44.3%) participants developed HFpEF exacerbation. Patients were dichotomized based on presence (n=40, 28.1%) or absence (n=102, 71.8%) of OSA. In a multivariable model adjusted for baseline demographics, risk factors and medications, presence of OSA did not predict risk for a future HFpEF hospitalization (p=0.57, Table). Additionally, on Kaplan-Meier analysis, presence of OSA was not a significant predictor for HFpEF hospitalization (p=0.77, Figure). Conclusion: In patients with HFpEF and concomitant DM2, presence of OSA was not a predictor for future heart failure hospitalizations.

Objective “Pain interference” and “headache impact” refer to negative consequences that pain and headache have on one’s life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse. Methods Six hundred and eleven adults were enrolled from 34 headache, neurology, and primary care clinics. Negative consequences of chronic migraine with medication overuse were determined using the Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Interference 6b questionnaire and the Headache Impact Test 6. Relationships between PROMIS-6b and Headache Impact Test 6 scores with demographics, headache characteristics, medication use, anxiety symptoms, and depression symptoms were assessed with linear regression. Elastic Net regression was used to develop a multiple regression model. Results PROMIS-6b T-Scores averaged 65.2 (SD 5.4) and Headache Impact Test 6 scores averaged 65.0 (SD 5.3), indicating severe negative consequences of chronic migraine with medication overuse. Chronic migraine with medication overuse interfered with enjoyment of life, concentration, daily activities, doing tasks away from home, and socializing. Depression symptom severity had the strongest relationship with pain interference and headache impact. Moderate-to-severe headache frequency, headache intensity, and anxiety symptoms were also associated with pain interference and headache impact. Conclusions Chronic migraine with medication overuse is associated with substantial negative consequences, the extent of which is most strongly related to depression symptoms.

Abstract Comparative data guiding initial therapy for Waldenström macroglobulinemia (WM), an infrequently encountered non‐Hodgkin lymphoma, are sparse. We evaluated three commonly used rituximab‐based frontline regimens: rituximab‐bendamustine (R‐Benda); dexamethasone, rituximab, cyclophosphamide (DRC); and bortezomib, dexamethasone, rituximab (BDR) in 220 treatment‐naïve patients with WM, seen at Mayo Clinic between November 1, 2000 and October 31, 2019. The median follow‐up was 4.5 (95%CI: 4–5) years. The R‐Benda cohort (n = 83) demonstrated superior overall response rate (ORR: 98%), in comparison to DRC (n = 92, ORR: 78%) or BDR (n = 45, ORR: 84%) cohorts, p = 0.003. Similarly, longer progression‐free survival (PFS) was evident with R‐Benda use [median 5.2 vs. 4.3 (DRC) and 1.8 years (BDR), p < 0.001]. The time‐to‐next therapy (TTNT) favored R‐Benda [median, not‐reached, 4.4 (DRC) and 2.6 years (BDR), p < 0.001). These endpoints were comparable between the DRC and BDR cohorts. Overall survival (OS) was similar across the three cohorts, p = 0.77. In a subset analysis of 142 patients genotyped for MYD88 L265P mutation, the ORR, PFS and TTNT were unaffected by the patients' MYD88 signature within each cohort. In conclusion, ORR, PFS and TTNT with R‐Benda are superior compared to DRC or BDR in treatment‐naïve patients with active WM. The patient outcomes with any one of these three regimens are unaffected by the MYD88 L265P mutation status.

OBJECTIVE The ideal surgical management of grade I lumbar spondylolisthesis has not been determined despite extensive prior investigations. In this cohort study, the authors used data from the large, multicenter, prospectively collected Quality Outcomes Database to bridge the gap between the findings in previous randomized trials and those in a more heterogeneous population treated in a typical practice. The objective was to assess the difference in patient-reported outcomes among patients undergoing decompression alone or decompression plus fusion. METHODS The primary outcome measure was change in 24-month Oswestry Disability Index (ODI) scores. The minimal clinically important difference (MCID) in ODI score change and 30% change in ODI score at 24 months were also evaluated. After adjusting for patient-specific and clinical factors, multivariable linear and logistic regressions were employed to evaluate the impact of fusion on outcomes. To account for differences in age, sex, body mass index, and baseline listhesis, a sensitivity analysis was performed using propensity score analysis to match patients undergoing decompression only with those undergoing decompression and fusion. RESULTS In total, 608 patients who had grade I lumbar spondylolisthesis were identified (85.5% with at least 24 months of follow-up); 140 (23.0%) underwent decompression alone and 468 (77.0%) underwent decompression and fusion. The 24-month change in ODI score was significantly greater in the fusion plus decompression group than in the decompression-only group (−25.8 ± 20.0 vs −15.2 ± 19.8, p < 0.001). Fusion remained independently associated with 24-month ODI score change (B = −7.05, 95% CI −10.70 to −3.39, p ≤ 0.001) in multivariable regression analysis, as well as with achieving the MCID for the ODI score (OR 1.767, 95% CI 1.058–2.944, p = 0.029) and 30% change in ODI score (OR 2.371, 95% CI 1.286–4.371, p = 0.005). Propensity score analysis resulted in 94 patients in the decompression-only group matched 1 to 1 with 94 patients in the fusion group. The addition of fusion to decompression remained a significant predictor of 24-month change in the ODI score (B = 2.796, 95% CI 2.228–13.275, p = 0.006) and of achieving the 24-month MCID ODI score (OR 2.898, 95% CI 1.214–6.914, p = 0.016) and 24-month 30% change in ODI score (OR 2.300, 95% CI 1.014–5.216, p = 0.046). CONCLUSIONS These results suggest that decompression plus fusion in patients with grade I lumbar spondylolisthesis may be associated with superior outcomes at 24 months compared with decompression alone, both in reduction of disability and in achieving clinically meaningful improvement. Longer-term follow-up is warranted to assess whether this effect is sustained.