Kremers, Walter K.

Abstract Background The timing of SCT for treatment of AML after first relapse is controversial, i.e.,whether to proceed to SCT at the time of relapse or to proceed to chemotherapy re-induction first in an attempt to reach a second remission. The purpose of this study is to determine the optimal time of allogeneic SCT in AML patients in first relapse by comparing outcomes of allogeneic SCT between patients untreated and patients post re-induction chemotherapy. Method This retrospective study was approved by the Mayo Foundation IRB. Between February 1983 and March 2003, 60 patients with AML in untreated first relapse (REL1) or post re-induction chemotherapy (CT) underwent allogeneic SCT in Mayo Clinic, Rochester. Study outcome included overall survival (OS), disease free survival (DFS), and transplant related mortality (TRM). The outcome was compared between the patients who underwent allogeneic SCT at REL1 and CT. Survival was analyzed using Kaplan-Meier (KM) and groups were compared statistically with the log-rank test. Result Of the 60 patients receiving allogeneic SCT , 25 patients and 35 patients underwent SCT at REL1 and CT, respectively. In the group of CT, 23 patients (66%) achieved CR2 while 12 patients (34%) had refractory disease. Forty-nine of 60 patients received cyclophosphamide and total body irradiation (Cy/TBI) as a conditioning regimen and the remainder received busulfan and cyclophosphamide( Bu/Cy). Patients in REL1 were older at SCT (median age 38 vs 31 years p= 0.024 ) and had lower percentage blast cells in bone marrow at first relapse (median 15% vs 50% p=0.00095) than in CT group. Difference in other baseline characteristics were not significant. KM analysis showed that the two groups did not show statistically differences in OS (p=0.43), DFS (p=0.68), and TRM (p=0.25). However, there were trends toward longer median OS (26.2 vs 5.4 months) and DFS (11.9 vs 3.3 months) with REL1 versus CT. OS at 1 year was 56 % for REL1 and 34.3 % for CT and at 5 year 32.1 % and 28.6 %, respectively. DFS at 1 year was 48 % for REL1 and 31.4 % for CT and at 5 years 22.9 % and 24.5 % respectively. TRM at 1 year was 25% for REL1 and 40 % for CT. A univariate Cox Proportional Hazard analysis for survival showed that unfavorable cytogenetics at diagnosis and relapse, antecedent MDS, and shorter duration of CR1 were significantly associated with a higher risk of death. Higher percentage of blast cells in bone marrow at first relapse was not significantly associated with a higher risk of death. In a multivariate model, unfavorable cytogenetics at first relapse and shorter duration of CR1 were both significantly associated with an increased risk of death. In this study, even after adjusting for other factors in a multivariate model, the difference between REL1 and CT groups was not statistically significant. Conclusion This study suggests that outcome of allogeneic SCT was comparable between REL1 and CT. Patients with AML in first relapse may proceed to allogeneic SCT because there appear to be no statistical differences in REL1 versus re-induction chemotherapy before SCT. REL1 patients tended to have a better outcome than CT patients.

Update This article was updated on December 6, 2019, because of a previous error. On page 1936, in Table VII, “Performance of the Bearing Surface Algorithm,” the row that had read “Bearing surface predicted by algorithm” now reads “Bearing surface predicted by algorithm*.” An erratum has been published: J Bone Joint Surg Am. 2020 Jan 2;102(1):e4. Update This article was updated on March 31, 2020, because of a previous error. On page 1934, in Table IV (“THA Bearing Surface-Related Keywords in Operative Notes”), the row that had read “Femoral stem; stem; HFx-stem; femoral component; femoral component/stem; permanent prosthesis; stem fem cemented” now reads “Femoral head; ball; delta head; delta ceramic head; ion treated; BIOLOX delta; ceramic head; ceramic femoral head; ceramic offset head; ceramic (size) head; alumina ceramic head; alumina prosthetic head; alumna ceramic head; BIOLOX ceramic head; BIOLOX delta head; BIOLOX femoral head; BIOLOX delta ceramic head.” An erratum has been published: J Bone Joint Surg Am. 2020 May 6;102(9):e43. Background: Manual chart review is labor-intensive and requires specialized knowledge possessed by highly trained medical professionals. Natural language processing (NLP) tools are distinctive in their ability to extract critical information from raw text in electronic health records (EHRs). As a proof of concept for the potential application of this technology, we examined the ability of NLP to correctly identify common elements described by surgeons in operative notes for total hip arthroplasty (THA). Methods: We evaluated primary THAs that had been performed at a single academic institution from 2000 to 2015. A training sample of operative reports was randomly selected to develop prototype NLP algorithms, and additional operative reports were randomly selected as the test sample. Three separate algorithms were created with rules aimed at capturing (1) the operative approach, (2) the fixation method, and (3) the bearing surface category. The algorithms were applied to operative notes to evaluate the language used by 29 different surgeons at our center and were applied to EHR data from outside facilities to determine external validity. Accuracy statistics were calculated with use of manual chart review as the gold standard. Results: The operative approach algorithm demonstrated an accuracy of 99.2% (95% confidence interval [CI], 97.1% to 99.9%). The fixation technique algorithm demonstrated an accuracy of 90.7% (95% CI, 86.8% to 93.8%). The bearing surface algorithm demonstrated an accuracy of 95.8% (95% CI, 92.7% to 97.8%). Additionally, the NLP algorithms applied to operative reports from other institutions yielded comparable performance, demonstrating external validity. Conclusions: NLP-enabled algorithms are a promising alternative to the current gold standard of manual chart review for identifying common data elements from orthopaedic operative notes. The present study provides a proof of concept for use of NLP techniques in clinical research studies and registry-development endeavors to reliably extract data of interest in an expeditious and cost-effective manner.

AbstractIntroductionBehavior/Comportment/Personality (BEHAV) and Language (LANG) domains were added to the Clinical Dementia Rating (CDR®) for improving evaluation of patients with frontotemporal lobar degeneration (FTLD) (CDR® plus NACC FTLD).MethodsWe analyzed the CDR® plus NACC FTLD among participants from the baseline visit of the Advancing Research and Treatment for Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects Consortium.ResultsThe CDR® plus NACC FTLD was able to detect early symptoms in the mildly impaired participants who were rated as CDR® sum of boxes (CDR®‐SB) = 0. The CDR®‐SB was not sensitive, particularly in participants with mild nonfluent/agrammatic primary progressive aphasia. Participants with familial and sporadic behavioral variant FTD exhibited similar CDR® plus NACC FTLD profiles except that language impairment was more frequent in participants with mild sporadic behavioral variant FTD. Adding the BEHAV and/or LANG domains to the CDR®‐SB significantly enhanced discriminatory power in differentiating among the FTLD spectrum disorders.DiscussionThe BEHAV and LANG domains enable the CDR® plus NACC FTLD to capture early symptomatology of FTLD.

Abstract Introduction The aim of this study was to investigate the rates of lobar atrophy in the asymptomatic microtubule‐associated protein tau ( MAPT ) mutation carriers. Methods MAPT mutation carriers (n = 14; 10 asymptomatic, 4 converters from asymptomatic to symptomatic) and noncarriers (n = 13) underwent structural magnetic resonance imaging and were followed annually with a median of 9.2 years. Longitudinal changes in lobar atrophy were analyzed using the tensor‐based morphometry with symmetric normalization algorithm. Results The rate of temporal lobe atrophy in asymptomatic MAPT mutation carriers was faster than that in noncarriers. Although the greatest rate of atrophy was observed in the temporal lobe in converters, they also had increased atrophy rates in the frontal and parietal lobes compared to noncarriers. Discussion Accelerated decline in temporal lobe volume occurs in asymptomatic MAPT mutation carriers followed by the frontal and parietal lobe in those who have become symptomatic. The findings have implications for monitoring the progression of neurodegeneration during clinical trials in asymptomatic MAPT mutation carriers.

AbstractBackground: hearing loss has been associated with mild cognitive impairment (MCI) and dementia. Studies have not assessed whether hearing difficulties (HD) that interfere with daily activities as reported by partners can be a marker for increased risk for cognitive decline and impairment.Objective: to assess the cross-sectional and longitudinal associations between informant-based HD, which interfere with daily activities and the risk for MCI and dementia.Methods: the study included 4812 participants without dementia, enrolled in the Mayo Clinic Study of Aging (mean age (SD) 73.7 (9.6) years) with cognitive evaluation and informant-based report on participant’s HD that interfere significantly with daily activities at baseline and for every 15 months. Cox proportional hazards models (utilising time-dependent HD status and age as the time scale) were used to examine HD and the risk for MCI or dementia, and mixed-effects models (allowing for random subject-specific intercepts and slopes) were used to examine the relationship between HD and cognitive decline.Results: about, 981 participants had HD and 612 (12.7%) had prevalent MCI at baseline; 759 participants developed incident MCI and 273 developed incident dementia. In cognitively unimpaired participants at baseline, those with HD had higher risk for MCI (hazard ratio [HR] = 1.29, 95% confidence interval [CI] (1.10, 1.51), P = 0.002; adjusting for sex, years of education). In participants without dementia, those with HD had higher risk for dementia (HR: 1.39, 95% CI, (1.08–1.79), P = 0.011; adjusting sex and education). In individuals with MCI, HD was associated with modestly greater cognitive decline.Conclusions: informant-based HD was associated with increased risk for MCI and dementia.

Significance Statement Research investigating glomerular morphology in different cortical regions has been limited to animal models and a small number of human autopsy kidneys. In this study, the authors used tissue from living patients who underwent a radical nephrectomy (for a renal tumor) to characterize glomerular morphology and glomerulosclerosis by cortical depth. They found that glomerular volume and glomerulosclerosis differed by depth across three cortical regions (superficial, middle, and deep). Although most clinical associations with glomerulosclerosis and glomerulomegaly did not differ by cortical depth, there were important exceptions. Age-related glomerulosclerosis appeared to be an ischemic process and was more evident in the superficial (subcapsular) region. Diabetes-related glomerulosclerosis was more evident in the deep (juxtamedullary) region. Obesity more strongly associated with larger glomeruli in the superficial region. Background Age, CKD risk factors, and kidney function are associated with larger glomerular volume and a higher percentage of globally sclerotic glomeruli. Knowledge of how these associations may differ by cortical depth is limited. Methods To investigate glomerular volume and glomerulosclerosis across different depths of cortex, we studied wedge sections of the renal parenchyma from 812 patients who underwent a radical nephrectomy (for a tumor), separately characterizing glomeruli in the superficial (subcapsular), middle, and deep (juxtamedullary) regions. We compared the association of mean nonsclerotic glomerular volume and of glomerulosclerosis (measured as the percentage of globally sclerotic glomeruli) with age, obesity, diabetes, smoking, kidney function, and structural pathology in the superficial, middle, and deep regions. Results The superficial, middle, and deep regions showed significant differences in glomerular volume (0.0025, 0.0031, and 0.0028 µ m 3 , respectively) and in glomerulosclerosis (18%, 7%, and 11%, respectively). There was a marked increase in glomerulosclerosis with age in the superficial region, but larger glomerular volume was not associated with age at any cortical depth. Glomerulosclerosis associated more strongly with arteriosclerosis and ischemic-appearing glomeruli in the superficial region. Hypertension, lower eGFR, and interstitial fibrosis associated with glomerulosclerosis and glomerular volume to a similar extent at any depth. Diabetes and proteinuria more strongly associated with glomerulosclerosis in the deep and middle regions, respectively, but neither associated with glomerular volume differently by depth. Obesity associated more strongly with glomerular volume in the superficial cortex. Conclusions Most clinical characteristic show similar associations with glomerulosclerosis and glomerulomegaly at different cortical depths. Exceptions include age-related glomerulosclerosis, which appears to be an ischemic process and is more predominant in the superficial region.

Abstract Although white matter hyperintensities have traditionally been viewed as a marker of vascular disease, recent pathology studies have found an association between white matter hyperintensities and Alzheimer’s disease pathologies. The objectives of this study were to investigate the topographic patterns of white matter hyperintensities associated with Alzheimer’s disease biomarkers measured using PET. From the population-based Mayo Clinic Study of Aging, 434 participants without dementia (55% male) with FLAIR and gradient recall echo MRI, tau-PET (AV-1451) and amyloid-PET scans were identified. A subset had cerebral microbleeds detected on T2* gradient recall echo scans. White matter hyperintensities were semi-automatically segmented using FLAIR MRI in participant space and normalized to a custom template. We used statistical parametric mapping 12-based, voxel-wise, multiple-regression analyses to detect white matter hyperintense regions associated with Alzheimer’s biomarkers (global amyloid from amyloid-PET and meta-regions of interest tau uptake from tau-PET) after adjusting for age, sex and hypertension. For amyloid associations, we additionally adjusted for tau and vice versa. Topographic patterns of amyloid-associated white matter hyperintensities included periventricular white matter hyperintensities (frontal and parietal lobes). White matter hyperintense volumes in the detected topographic pattern correlated strongly with lobar cerebral microbleeds (P < 0.001, age and sex adjusted Cohen’s d = 0.703). In contrast, there were no white matter hyperintense regions significantly associated with increased tau burden using voxel-based analysis or region-specific analysis. Among non-demented elderly, amyloid load correlated with a topographic pattern of white matter hyperintensities. Further, the amyloid-associated, white matter hyperintense regions strongly correlated with lobar cerebral microbleeds suggesting that cerebral amyloid angiopathy contributes to the relationship between amyloid and white matter hyperintensities. The study did not support an association between increased tau burden and white matter hyperintense burden.