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PurposeSomatic activating variants in the PI3K-AKT pathway cause vascular malformations with and without overgrowth. We previously reported an individual with capillary and lymphatic malformation harboring a pathogenic somatic variant in PIK3R1, which encodes three PI3K complex regulatory subunits. Here, we investigate PIK3R1 in a large cohort with vascular anomalies and identify an additional 16 individuals with somatic mosaic variants in PIK3R1.MethodsAffected tissue from individuals with vascular lesions and overgrowth recruited from a multisite collaborative network was studied. Next-generation sequencing targeting coding regions of cell-signaling and cancer-associated genes was performed followed by assessment of variant pathogenicity.ResultsThe phenotypic and variant spectrum associated with somatic variation in PIK3R1 is reported herein. Variants occurred in the inter-SH2 or N-terminal SH2 domains of all three PIK3R1 protein products. Phenotypic features overlapped those of the PIK3CA-related overgrowth spectrum (PROS). These overlapping features included mixed vascular malformations, sandal toe gap deformity with macrodactyly, lymphatic malformations, venous ectasias, and overgrowth of soft tissue or bone.ConclusionSomatic PIK3R1 variants sharing attributes with cancer-associated variants cause complex vascular malformations and overgrowth. The PIK3R1-associated phenotypic spectrum overlaps with PROS. These data extend understanding of the diverse phenotypic spectrum attributable to genetic variation in the PI3K-AKT pathway.

Reactive angioendotheliomatosis (RAE) is an uncommon, benign, antiproliferative condition associated with systemic diseases that may cause occlusion or inflammation of the vascular lumina. A link between antiphospholipid syndrome (APS) and RAE has been reported a few times in the literature. Herein, we present a unique case of RAE diagnosed in a patient with primary APS who was well-managed on warfarin and rituximab with no recent thrombotic events. As RAE can precede or follow a diagnosis of APS, the presence of the condition indicates a need to workup for APS and to ensure those with the condition are adequately anticoagulated. However, as demonstrated in this case, the condition can still occur in patients who are adequately anticoagulated.

IntroductionHeterogeneity of segmentation protocols for medial temporal lobe regions and hippocampal subfields on in vivo magnetic resonance imaging hinders the ability to integrate findings across studies. We aim to develop a harmonized protocol based on expert consensus and histological evidence.MethodsOur international working group, funded by the EU Joint Programme-Neurodegenerative Disease Research (JPND), is working toward the production of a reliable, validated, harmonized protocol for segmentation of medial temporal lobe regions. The working group uses a novel postmortem data set and online consensus procedures to ensure validity and facilitate adoption.ResultsThis progress report describes the initial results and milestones that we have achieved to date, including the development of a draft protocol and results from the initial reliability tests and consensus procedures.DiscussionA harmonized protocol will enable the standardization of segmentation methods across laboratories interested in medial temporal lobe research worldwide.

BackgroundMulti-omic profiling of pancreatic neuroendocrine tumors (PanNETs) was performed to correlate genomic, proteomic, and molecular pathway alterations with clinicopathologic factors and identify novel co-occurring pathogenic alterations of potential clinical relevance to PanNET management.MethodsPanNETs referred to Perthera, Inc. having undergone molecular profiling for precision matched therapeutic purposes were screened. Correlative analyses were performed using Fisher's exact test across individual pathogenic alterations or altered molecular pathways and clinicopathologic variables. Associations were visualized by hierarchical clustering. Prognostic associations with overall survival (OS) were identified using Cox regression for pathogenic alterations and pathway-level alterations. Hazard ratios (HR) and odds ratios (OR) were reported with 95% confidence intervals (CI).ResultsFrom 12/2014-1/2019, 46 patients with predominantly locally advanced and metastatic PanNETs were included. MEN1 alterations by next-generation sequencing (NGS) were less associated with having high-grade PanNETs and metastatic disease at diagnosis (p ≤ 0.05). Genomic alterations associated with increased replicative stress (primarily driven by RB1 and TP53) correlated with higher grade (OR 6.87 [95% CI: 1.57-35.18], p = 0.0043) and worse OS (HR 13.62 [95% CI: 1.51-122.5], p = 0.0198). Other significant associations included: ERCC1 protein expression with DAXX or MEN1 alterations (NGS), PTEN (NGS) with ARID1A or TP53 alterations (NGS), and history of diabetes coincided with cell cycle pathway alterations but was mutually exclusive with replicative stress pathway alterations.ConclusionsWe identified several molecular signatures of potential clinical significance for therapeutic targeting and prognostication in PanNETs warranting prospective validation. Our findings are hypothesis generating and can inform larger molecular profiling efforts in PanNETs.

Introduction: Identifying the associations between rural-living or neighborhood disadvantage and neurobiology may clarify rural–urban disparities in older adults with cognitive impairment related to Alzheimer’s disease. Methods: We examined rural–urban differences and neighborhood disadvantages in brain cortical thickness (CT) measures among 71 rural and 87 urban-dwelling older adults. Analysis of covariance was used to test each FreeSurfer-derived CT measures’ associations with rural–urban living, clinical impairment status, and their interactions. Post-hoc linear regressions were used to test the association between CT measures and neighborhood disadvantage index. Results: Rural-dwelling older adults had thinner cortices in temporal and inferior frontal regions compared to urban participants, especially among clinically normal participants, where the thinner temporal cortex further correlated with higher neighborhood disadvantage. Conversely, rural participants had thicker cortices in superior frontal, parietal and occipital regions. Discussion: Our results suggest a complex interplay between community contexts and neurobiology. For memory-related regions, rural-living and neighborhood disadvantage might be negatively associated with subjects’ brain structures. [ABSTRACT FROM AUTHOR]

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc.

Background: Computer-aided machine learning models are being actively developed with clinically available biomarkers to diagnose Alzheimer's disease (AD) in living persons. Despite considerable work with cross-sectional in vivo data, many models lack validation against postmortem AD neuropathological data. Objective: Train machine learning models to classify the presence or absence of autopsy-confirmed severe AD neuropathology using clinically available features. Methods: AD neuropathological status are assessed at postmortem for participants from the National Alzheimer's Coordinating Center (NACC). Clinically available features are utilized, including demographics, Apolipoprotein E(APOE) genotype, and cortical thicknesses derived from ante-mortem MRI scans encompassing AD meta regions of interest (meta-ROI). Both logistic regression and random forest models are trained to identify linearly and nonlinearly separable features between participants with the presence (N = 91, age-at-MRI = 73.6±9.24, 38 women) or absence (N = 53, age-at-MRI = 68.93±19.69, 24 women) of severe AD neuropathology. The trained models are further validated in an external data set against in vivo amyloid biomarkers derived from PET imaging (amyloid-positive: N = 71, age-at-MRI = 74.17±6.37, 26 women; amyloid-negative: N = 73, age-at-MRI = 71.59±6.80, 41 women). Results: Our models achieve a cross-validation accuracy of 84.03% in classifying the presence or absence of severe AD neuropathology, and an external-validation accuracy of 70.14% in classifying in vivo amyloid positivity status. Conclusions: Our models show that clinically accessible features, including APOE genotype and cortical thinning encompassing AD meta-ROIs, are able to classify both postmortem confirmed AD neuropathological status and in vivo amyloid status with reasonable accuracies. These results suggest the potential utility of AD meta-ROIs in determining AD neuropathological status in living persons. [ABSTRACT FROM AUTHOR]

ObjectiveAn increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol.MethodMRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement.ResultsThe differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail.ConclusionsThe combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Objective This study aimed to determine the impact of pregnancy weight gain above National Academy of Medicine (NAM) guidelines on cesarean delivery rates following induction. Study Design This is a secondary analysis of a prospective cohort study of patients who underwent induction at a single tertiary care center between July 2017 and July 2019. Included in the primary study were patients undergoing term (≥37 weeks) labor induction with a singleton gestation, intact membranes, and unfavorable cervical examination (Bishop score of ≤6 and cervical dilation ≤ 2 cm). Eligibility for this analysis was limited to patients with a documented prenatal body mass index (BMI) < 20 weeks' gestation. The primary exposure was gestational weight gain greater than NAM guidelines (WGGG) for a patient's initial BMI category. The primary outcome was cesarean delivery for any indication. Results Of 1,610 patients included in the original cohort, 1,174 (72.9%) met inclusion criteria for this analysis and 517 (44.0%) of these had weight gain above NAM guidelines. Of the entire cohort, 60.0% were Black and 52.7% had private insurance. In total, 160 patients (31%) with WGGG underwent cesarean compared with 127 patients (19.3%) without WGGG (p < 0.001), which equates to a 59% increased odds of cesarean when controlling for initial BMI category, parity, gestational diabetes, and indication for induction (Adjusted Odds Ratio [aOR] 1.58, 95% confidence interval [CI] 1.17–2.12). Among only nulliparous patients, WGGG was associated with an increased odds of cesarean (26.4 vs. 38.2%, aOR 1.50, 95% CI 1.07–2.10). In multiparous patients, however, there was no difference in cesarean between those with and without WGGG (8.8 vs. 14.1%, aOR 1.85, 95% CI 0.96–3.58). Conclusion This study demonstrates that weight gain above NAM guidelines is associated with more than a 50% increased odds of cesarean. Patients should be informed of this association as gestational weight gain may be a modifiable risk factor for cesarean delivery. Key Points Weight gain above NAM guidelines was associated with a 59% increased odds of cesarean delivery. Nulliparous patients with weight gain above NAM guidelines are at higher risk of cesarean delivery. No difference in cesarean delivery among multiparous patients regardless of gestational weight gain. [ABSTRACT FROM AUTHOR]

In cardiovascular research, sex and gender have not typically been considered in research design and reporting until recently. This has resulted in clinical research findings from which not only all women, but also gender-diverse individuals have been excluded. The resulting dearth of data has led to a lack of sex- and gender-specific clinical guidelines and raises serious questions about evidence-based care. Basic research has also excluded considerations of sex. Including sex and/or gender as research variables not only has the potential to improve the health of society overall now, but it also provides a foundation of knowledge on which to build future advances. The goal of this guidelines article is to provide advice on best practices to include sex and gender considerations in study design, as well as data collection, analysis, and interpretation to optimally establish rigor and reproducibility needed to inform clinical decision-making and improve outcomes. In cardiovascular physiology, incorporating sex and gender is a necessary component when optimally designing and executing research plans. The guidelines serve as the first guidance on how to include sex and gender in cardiovascular research. We provide here a beginning path toward achieving this goal and improve the ability of the research community to interpret results through a sex and gender lens to enable comparison across studies and laboratories, resulting in better health for all. [ABSTRACT FROM AUTHOR]