Citations

AbstractObjectiveWhereas studies in adult epilepsy patients have shown higher rates of suicidal ideation and attempt, such studies in children are limited. Using the Rochester Epidemiology Project database, we compared the risk of self‐injurious behavior and suicidal ideation in a population‐based cohort of childhood epilepsy to controls.MethodsWe studied 339 cases with epilepsy and 678 age‐ and sex‐matched controls followed to a median age of 24.7 and 23.4 years, and identified 98 subjects with self‐injurious behavior or suicidal ideation (43 with epilepsy and 55 controls). All behaviors were categorized using the Columbia Suicide Severity Rating Scale.ResultsThose with epilepsy had a significantly higher rate of any self‐injurious behavior and suicidal ideation (hazard ratio [HR] = 1.56, 95% confidence interval [CI] = 1.04‐2.35) and tended to have an increased risk of suicidal ideation and attempt (HR = 1.48, 95% CI = 0.93‐2.37). The prevalence of preceding mood and substance abuse disorders was similarly high in both cases and controls with self‐injurious behavior or suicidal ideation; however, preceding attention‐deficit/hyperactivity disorder was more than twice as common in the epilepsy cases. Among cases with epilepsy, we did not identify any specific epilepsy‐related variable that was significantly correlated with risk of self‐injurious behavior or suicidal ideation.SignificanceChildren, teens, and young adults with a history of childhood epilepsy are at greater risk of self‐injurious behavior, highlighting the need for careful screening of mental health concerns as part of routine epilepsy care.

Abstract Structural grey matter covariance networks provide an individual quantification of morphological patterns in the brain. The network integrity is disrupted in sporadic Alzheimer’s disease, and network properties show associations with the level of amyloid pathology and cognitive decline. Therefore, these network properties might be disease progression markers. However, it remains unclear when and how grey matter network integrity changes with disease progression. We investigated these questions in autosomal dominant Alzheimer’s disease mutation carriers, whose conserved age at dementia onset allows individual staging based upon their estimated years to symptom onset. From the Dominantly Inherited Alzheimer Network observational cohort, we selected T1-weighted MRI scans from 269 mutation carriers and 170 non-carriers (mean age 38 ± 15 years, mean estimated years to symptom onset −9 ± 11), of whom 237 had longitudinal scans with a mean follow-up of 3.0 years. Single-subject grey matter networks were extracted, and we calculated for each individual the network properties which describe the network topology, including the size, clustering, path length and small worldness. We determined at which time point mutation carriers and non-carriers diverged for global and regional grey matter network metrics, both cross-sectionally and for rate of change over time. Based on cross-sectional data, the earliest difference was observed in normalized path length, which was decreased for mutation carriers in the precuneus area at 13 years and on a global level 12 years before estimated symptom onset. Based on longitudinal data, we found the earliest difference between groups on a global level 6 years before symptom onset, with a greater rate of decline of network size for mutation carriers. We further compared grey matter network small worldness with established biomarkers for Alzheimer disease (i.e. amyloid accumulation, cortical thickness, brain metabolism and cognitive function). We found that greater amyloid accumulation at baseline was associated with faster decline of small worldness over time, and decline in grey matter network measures over time was accompanied by decline in brain metabolism, cortical thinning and cognitive decline. In summary, network measures decline in autosomal dominant Alzheimer’s disease, which is alike sporadic Alzheimer’s disease, and the properties show decline over time prior to estimated symptom onset. These data suggest that single-subject networks properties obtained from structural MRI scans form an additional non-invasive tool for understanding the substrate of cognitive decline and measuring progression from preclinical to severe clinical stages of Alzheimer’s disease.

We identified a potentially novel homozygous duplication involving the promoter region and exons 1–4 of the gene encoding type 2 cardiac ryanodine receptor ( RYR2 ) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest RYR2- mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca 2+ handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca 2+ transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in RYR2 transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in RYR2- mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.

AbstractObjectiveThe Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects evaluates familial frontotemporal lobar degeneration (FTLD) kindreds with MAPT, GRN, or C9orf72 mutations. Objectives were to examine whether health‐related quality of life (HRQoL) correlates with clinical symptoms and caregiver burden, and whether self‐rated and informant‐rated HRQoL would correlate with each other.MethodsIndividuals were classified using the Clinical Dementia Rating (CDR®) Scale plus National Alzheimer's Coordinating Center (NACC) FTLD. HRQoL was measured with DEMQOL and DEMQOL‐proxy; caregiver burden with the Zarit Burden Interview (ZBI). For analysis, Pearson correlations and weighted kappa statistics were calculated.ResultsThe cohort of 312 individuals included symptomatic and asymptomatic individuals. CDR® plus NACC FTLD was negatively correlated with DEMQOL (r = −0.20, P = .001), as were ZBI and DEMQOL (r = −0.22, P = .0009). There was fair agreement between subject and informant DEMQOL (κ = 0.36, P <.0001).ConclusionLower HRQoL was associated with higher cognitive/behavior impairment and higher caregiver burden. These findings demonstrate the negative impact of FTLD on individuals and caregivers.

AbstractPurposeTo assess differences in Patient Aligned Care Team (PACT) performance between rural and urban primary care clinics within the Veterans Health Administration (VHA).MethodsAn Explanatory Sequential Mixed Methods design was conducted using VHA administrative data to assess performance of a national sample of 891 VHA primary care clinics. Generalized Estimating Equations with repeated measures were used to estimate associations between rurality and process‐oriented endpoints including: chronic disease management through telehealth; use of telephone visits, group visits or secured messaging; same‐day access; continuity with primary care provider; and postdischarge follow‐up. Qualitative data collected during on‐site visits with 5 clinics were used to provide insights into PACT processes from the perspectives of staff in rural and urban clinics.FindingsAfter adjusting for patient‐ and practice‐level characteristics, clinics located in large rural or small/isolated rural areas demonstrated difficulty enhancing access through use of telephone visits, group visits, or secured messaging and completing postdischarge follow‐up calls, compared to urban clinics. Qualitative analysis indicated that staff from both rural and urban clinics reported similar barriers implementing these PACT processes. Both patient and staff behaviors and preferences impact implementation of these processes. Distance to care and access to high‐speed Internet were also reported as barriers.ConclusionsThis study contributes to the understanding of PACT performance in rural settings by highlighting ways contextual and behavioral factors relate to performance. Increasing implementation of patient‐centered medical home (PCMH) models, such as PACT, will require additional attention to the complex relationships between the practice and surrounding context.

Characterizing the release profile for materials-directed local delivery of bioactive molecules and its effect on bone regeneration is an important step to improve our understanding of, and ability to optimize, the bone healing response. This study examined the local delivery of parathyroid hormone (PTH) using a thiol-ene hydrogel embedded in a porous poly(propylene fumarate) (PPF) scaffold for bone regeneration applications. The aim of this study was to characterize the degradation-controlled in vitro release kinetics of PTH from the thiol-ene hydrogels, in vivo hydrogel degradation in a subcutaneous implant model, and bone healing in a rat critical size bone defect. Tethering PTH to the hydrogel matrix eliminated the early timepoint burst release that was observed in previous in vitro work where PTH was free to diffuse out of the matrix. Only 8% of the tethered PTH was released from the hydrogel during the first 2 weeks, but by day 21, 80% of the PTH was released, and complete release was achieved by day 28. In vivo implantation revealed that complete degradation of the hydrogel alone occurred by day 21; however, when incorporated in a three-dimensional printed osteoconductive PPF scaffold, the hydrogel persisted for >56 days. Treatment of bone defects with the composite thiol-ene hydrogel–PPF scaffold, delivering either 3 or 10 μg of tethered PTH 1-84, was found to increase bridging of critical size bone defects, whereas treatment with 30 μg of tethered PTH resulted in less bone ingrowth into the defect area. Continued development of this biomaterial delivery system for PTH could lead to improved therapies for treatment of nonunion fractures and critical size bone defects.

Abstract Purpose: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with &gt;95% accuracy that was maintained in all analytic and biological validations. Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271

AbstractObjectiveWe describe the clinical characteristics and genetic etiology of several new cases within the ACO2‐related disease spectrum. Mitochondrial aconitase (ACO2) is a nuclear‐encoded tricarboxylic acid cycle enzyme. Homozygous pathogenic missense variants in the ACO2 gene were initially associated with infantile degeneration of the cerebrum, cerebellum, and retina, resulting in profound intellectual and developmental disability and early death. Subsequent studies have identified a range of homozygous and compound heterozygous pathogenic missense, nonsense, frameshift, and splice‐site ACO2 variants in patients with a spectrum of clinical manifestations and disease severities.MethodsWe describe a cohort of five novel patients with biallelic pathogenic variants in ACO2. We review the clinical histories of these patients as well as the molecular and functional characterization of the associated ACO2 variants and compare with those described previously in the literature.ResultsTwo siblings with relatively mild symptoms presented with episodic ataxia, mild developmental delays, severe dysarthria, and behavioral abnormalities including hyperactivity and depressive symptoms with generalized anxiety. One patient presented with the classic form with cerebellar hypoplasia, ataxia, seizures, optic atrophy, and retinitis pigmentosa. Another unrelated patient presented with ataxia but developed severe progressive spastic quadriplegia. Another patient demonstrated a spinal muscular atrophy‐like presentation with severe neonatal hypotonia, diminished reflexes, and poor respiratory drive, leading to ventilator dependence until death at the age of 9 months.InterpretationIn this study, we highlight the importance of recognizing milder forms of the disorder, which may escape detection due to atypical disease presentation.

OBJECTIVE Limited information is available about glycemic outcomes with a closed-loop control (CLC) system compared with a predictive low-glucose suspend (PLGS) system. RESEARCH DESIGN AND METHODS After 6 months of use of a CLC system in a randomized trial, 109 participants with type 1 diabetes (age range, 14–72 years; mean HbA1c, 7.1% [54 mmol/mol]) were randomly assigned to CLC (N = 54, Control-IQ) or PLGS (N = 55, Basal-IQ) groups for 3 months. The primary outcome was continuous glucose monitor (CGM)-measured time in range (TIR) for 70–180 mg/dL. Baseline CGM metrics were computed from the last 3 months of the preceding study. RESULTS All 109 participants completed the study. Mean ± SD TIR was 71.1 ± 11.2% at baseline and 67.6 ± 12.6% using intention-to-treat analysis (69.1 ± 12.2% using per-protocol analysis excluding periods of study-wide suspension of device use) over 13 weeks on CLC vs. 70.0 ± 13.6% and 60.4 ± 17.1% on PLGS (difference = 5.9%; 95% CI 3.6%, 8.3%; P &lt; 0.001). Time &gt;180 mg/dL was lower in the CLC group than PLGS group (difference = −6.0%; 95% CI −8.4%, −3.7%; P &lt; 0.001) while time &lt;54 mg/dL was similar (0.04%; 95% CI −0.05%, 0.13%; P = 0.41). HbA1c after 13 weeks was lower on CLC than PLGS (7.2% [55 mmol/mol] vs. 7.5% [56 mmol/mol], difference −0.34% [−3.7 mmol/mol]; 95% CI −0.57% [−6.2 mmol/mol], −0.11% [1.2 mmol/mol]; P = 0.0035). CONCLUSIONS Following 6 months of CLC, switching to PLGS reduced TIR and increased HbA1c toward their pre-CLC values, while hypoglycemia remained similarly reduced with both CLC and PLGS.

4500 Background: Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2). The primary objective of RTOG 1010 was to determine if trastuzumab increases disease-free survival (DFS) when combined with trimodality treatment for patients with HER2 overexpressing esophageal adenocarcinoma. Methods: This open label, randomized phase III trial included patients with newly diagnosed stage T1N1-2, T2-3N0-2 adenocarcinoma of the esophagus involving the mid, distal, or esophagogastric junction and up to 5cm of the stomach. All patients received chemotherapy (C) of paclitaxel, 50mg/m2 and carboplatin AUC = 2, weekly for 6 weeks, with radiation (XRT: 3D-CRT or IMRT, 50.4 Gy in 28 fractions) followed by surgery. Patients were randomized 1:1 to receive weekly trastuzumab 4mg/kg week 1 then 2mg/kg/weekly x 5 during CXRT then 6 mg/kg for 1 dose prior to surgery and 6mg/kg every 3 weeks for 13 treatments after surgery. HER2 status was determined by IHC and gene amplification by FISH. With a 2-sided alpha of 0.05, 162 DFS events provide 90% power to detect a signal for an increase in median DFS from 15 to 25 months. DFS and overall survival (OS) were estimated by the Kaplan-Meier method. and arms were compared using the log rank test. The Cox proportional hazards model was used to analyze treatment effect. Results: 571 patients were entered for assessment of HER2 expression, 203 HER2+ patients randomized. The median follow-up for alive patients is 5.0 years. The estimated 2, 3, and 4-year DFS (95% CI) for the CXRT +trastuzumab arm were 41.8% (31.8%, 51.7%), 34.3% (24.7%, 43.9%), and 33.1% (23.6%, 42.7%), respectively, and for the CXRT arm were 40.0% (30.0%, 49.9%), 33.4% (23.8%, 43.0%), and 30.1% (20.7%, 39.4%), respectively; log-rank p = 0.85. The median DFS time is 19.6 months (13.5-26.2) for the CXRT +trastuzumab arm compared to 14.2 months (10.5-23.0) for the CXRT arm. The hazard ratio (95% CI) comparing the DFS of CXRT+trastuzumab arm to the CXRT arm was 0.97 (0.69, 1.36). The median OS time was 38.5 months (26.2-70.4) for the CXRT+trastuzumab arm compared to 38.9 months (29.0-64.5) for the CXRT arm, hazard ratio (95% CI): 1.01 (0.69, 1.47). There was no statistically significant increase in treatment-related toxicities with the addition of trastuzumab including no increase in cardiac events. Conclusions: The addition of trastuzumab to trimodality treatment did not improve DFS for patients with HER2 overexpressing esophageal adenocarcinoma. Supported by NCI grants U10CA180868, UG1CA189867, U10CA180822 and Genentech. Clinical trial information: NCT01196390 .