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Chronic end-organ complications result in morbidity and mortality in adults with sickle cell disease (SCD). In a retrospective-prospective cohort of 150 adults with SCD who received standard care screening for pulmonary function abnormalities, cardiac disease, and renal assessment from January 2003 to 2016, we tested the hypothesis that clustering of end-organ disease is common and multiple organ impairment predicts mortality. Any end-organ disease occurred in 59.3% of individuals, and 24.0% developed multiple organ (>1) end-organ disease. The number of end-organs affected was associated with mortality (P ≤ .001); 8.2% (5 of 61) of individuals with no affected end-organ, 9.4% (5 of 53) of those with 1 affected organ, 20.7% (6 of 29) of those with 2 affected end-organs, and 85.7% (6 of 7) with 3 affected end-organs died over a median follow up period of 8.7 (interquartile range 3.5-11.4) years. Of the 22 individuals who died, 77.3% had evidence of any SCD-related end-organ impairment, and this was the primary or secondary cause of death in 45.0%. SCD-related chronic impairment in multiple organs, and its association with mortality, highlights the need to understand the common mechanisms underlying chronic end-organ damage in SCD, and the urgent need to develop interventions to prevent irreversible end-organ complications in SCD.
© 2018 Wiley Periodicals, Inc.
The spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and provides insight into the functional importance of protein regions and the potential pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of human germline and somatic variation in 6,604 experimentally derived protein structures and 33,144 computationally derived homology models covering 77% of all human proteins. Using a systematic approach, we quantify differences in the spatial distributions of neutral germline variants, disease-causing germline variants, and recurrent somatic variants. Neutral missense variants exhibit a general trend toward spatial dispersion, which is driven by constraint on core residues. In contrast, germline disease-causing variants are generally clustered in protein structures and form clusters more frequently than recurrent somatic variants identified from tumor sequencing. In total, we identify 215 proteins with significant spatial constraints on the distribution of disease-causing missense variants in experimentally derived protein structures, only 65 (30%) of which have been previously reported. This analysis identifies many clusters not detectable from sequence information alone; only 12% of proteins with significant clustering in 3D were identified from similar analyses of linear protein sequence. Furthermore, spatial analyses of mutations in homology-based structural models are highly correlated with those from experimentally derived structures, supporting the use of computationally derived models. Our approach highlights significant differences in the spatial constraints on different classes of mutations in protein structure and identifies regions of potential function within individual proteins.
Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
EEG acquired simultaneously with fMRI (EEG-fMRI) is a multimodal method that has shown promise in mapping the seizure onset zone in patients with focal epilepsy. However, there are many instances when this method is unsuccessful or not applicable, and other data driven fMRI methods may be utilized. One such method is the two-dimensional temporal clustering analysis (2dTCA). In this study we compared the classic EEG-fMRI and 2dTCA performance in mapping regions related to the seizure onset region in 18 focal epilepsy patients (12 presenting interictal epileptiform discharges (IEDs), during EEG-fMRI acquisition) with Engel I or II surgical outcome. Activation maps of both 2dTCA timing outputs (positive and negative histograms) and EEG detected IEDs were computed and compared to the region of epilepsy surgical resection. Patients were evaluated in three categories based on frequency of EEG detected spiking during the MRI. EEG-fMRI maps were concordant to the epilepsy region in 5/12 subjects, four with frequent IEDs on EEG. The 2dTCA was successful in mapping 13/18 patients including 3/6 with no IEDs detected (10/12 with IEDs detected). The epilepsy-related activities were successfully mapped by both methods in only 4/12 patients. This work suggests that the epilepsy-related information detected by each method may be different: while EEG-fMRI is more accurate in patients with high rather than lower numbers of EEG detected IEDs; 2dTCA can be useful in evaluating patients even when no concurrent EEG spikes are detected or EEG-fMRI is not effective. Therefore, our results support that 2dTCA might be an alternative for mapping epilepsy-related BOLD activity in negative EEG-fMRI (6/7 patients) and spike-less patients.
Illumina genotyping arrays have powered thousands of large-scale genome-wide association studies over the past decade. Yet, because of the tremendous volume and complicated genetic assumptions of Illumina genotyping data, processing and quality control (QC) of these data remain a challenge. Thorough QC ensures the accurate identification of single-nucleotide polymorphisms and is required for the correct interpretation of genetic association results. By processing genotyping data on > 100 000 subjects from >10 major Illumina genotyping arrays, we have accumulated extensive experience in handling some of the most peculiar scenarios related to the processing and QC of Illumina genotyping data. Here, we describe strategies for processing Illumina genotyping data from the raw data to an analysis ready format, and we elaborate on the necessary QC procedures required at each processing step. High-quality Illumina genotyping data sets can be obtained by following our detailed QC strategies.
Understanding brain volumetry is essential to understand neurodevelopment and disease. Historically, age-related changes have been studied in detail for specific age ranges (e.g., early childhood, teen, young adults, elderly, etc.) or more sparsely sampled for wider considerations of lifetime aging. Recent advancements in data sharing and robust processing have made available considerable quantities of brain images from normal, healthy volunteers. However, existing analysis approaches have had difficulty addressing (1) complex volumetric developments on the large cohort across the life time (e.g., beyond cubic age trends), (2) accounting for confound effects, and (3) maintaining an analysis framework consistent with the general linear model (GLM) approach pervasive in neuroscience. To address these challenges, we propose to use covariate-adjusted restricted cubic spline (C-RCS) regression within a multi-site cross-sectional framework. This model allows for flexible consideration of non-linear age-associated patterns while accounting for traditional covariates and interaction effects. As a demonstration of this approach on lifetime brain aging, we derive normative volumetric trajectories and 95% confidence intervals from 5111 healthy patients from 64 sites while accounting for confounding sex, intracranial volume and field strength effects. The volumetric results are shown to be consistent with traditional studies that have explored more limited age ranges using single-site analyses. This work represents the first integration of C-RCS with neuroimaging and the derivation of structural covariance networks (SCNs) from a large study of multi-site, cross-sectional data.
BACKGROUND - Human papillomavirus (HPV) infection has been causally linked to six cancers, and many disproportionately affect minorties. This study reports on the development and effectiveness of an intervention aimed at increasing HPV vaccine uptake among African American and Hispanic pediatric patients in safety-net clinics.
METHODS - Formative research, community engagement, and theory guided development of the intervention. A clustered, non-randomized controlled pragmatic trial was conducted in four clinics providing healthcare for the underserved in Tennessee, U.S., with two intervention sites and two usual care sites. Patients aged 9-18 years (N = 408) and their mothers (N = 305) enrolled, with children clustered within families. The intervention consisted of two provider/staff training sessions and provision of patient education materials, consisting of a video/flyer promoting HPV vaccine. Medical records were reviewed before/after the initial visit and after 12 months.
RESULTS - At the initial visit, provision of patient education materials and provider recommendation were higher at intervention sites versus usual care sites, and receipt of HPV vaccine was higher at intervention sites (45.4% versus 32.9%) but not significantly after adjusting for patient's age and mother's education. Provider recommendation, but not education materials, increased the likelihood of vaccine receipt at the initial visit, although over one-third of intervention mothers cited the flyer/video as motivating vaccination. Completion of the 3-dose series at follow-up was lower in the intervention arm.
CONCLUSIONS - Future interventions should combine patient education, intensive provider/staff education, and patient reminders. Research should compare patient education focusing on HPV vaccine only versus all adolescent vaccines.
TRIAL REGISTRATION - Retrospectively registered with ClinicalTrials.gov NCT02808832 , 9/12/16.
Sensing and responding to environmental cues is critical to the lifestyle of filamentous fungi. How environmental variation influences fungi to produce a wide diversity of ecologically important secondary metabolites (SMs) is not well understood. To address this question, we first examined changes in global gene expression of the opportunistic human pathogen, Aspergillus fumigatus, after exposure to different temperature conditions. We found that 11 of the 37 SM gene clusters in A. fumigatus were expressed at higher levels at 30° than at 37°. We next investigated the role of the light-responsive Velvet complex in environment-dependent gene expression by examining temperature-dependent transcription profiles in the absence of two key members of the Velvet protein complex, VeA and LaeA We found that the 11 temperature-regulated SM gene clusters required VeA at 37° and LaeA at both 30 and 37° for wild-type levels of expression. Interestingly, four SM gene clusters were regulated by VeA at 37° but not at 30°, and two additional ones were regulated by VeA at both temperatures but were substantially less so at 30°, indicating that the role of VeA and, more generally of the Velvet complex, in the regulation of certain SM gene clusters is temperature-dependent. Our findings support the hypothesis that fungal secondary metabolism is regulated by an intertwined network of transcriptional regulators responsive to multiple environmental factors.
Copyright © 2016 Lind et al.
BACKGROUND - Soy food intake may have protective effects against the risk for breast cancer, including estrogen receptor (ER)-negative breast cancer. However, the underlying molecular mechanisms remain unclear.
METHODS - To evaluate the association of soy intake with the expression of microRNAs (miRNAs) and genes in the tumor tissue of patients with triple-negative breast cancer (TNBC; ie, breast cancer lacking expression of ER, progesterone receptor, and human epidermal growth factor receptor 2), the expression of 800 miRNAs and 302 genes were measured with NanoString nCounter assays in formalin-fixed, paraffin-embedded tumor tissue from 272 TNBC patients. Soy intake during the 1-year period before the cancer diagnosis was assessed with a validated food-frequency questionnaire. The association of soy intake with the expression of miRNAs and genes was evaluated via linear regression analysis with adjustments for patient age and TNM stage.
RESULTS - A total of 14 miRNAs and 24 genes were significantly associated with soy food intake (P < .05): Thirteen of the 14 miRNAs (92.9%) and 9 of the 24 genes (37.5%), including tumor suppressors miR-29a-3p and IGF1R, showed overexpression for those women with high soy intake, whereas the remaining miRNAs and genes, including oncogenes KRAS and FGFR4, showed underexpression. Furthermore, cell growth-related genes showed a predominantly underexpression pattern according to a comparison of tumor samples from women with high soy food intake and samples from women with lower soy food intake.
CONCLUSIONS - This study suggests that long-term prediagnosis soy intake may lead to increased expression of tumor suppressors and decreased expression of oncogenes, especially cell growth-related genes, in breast tumor tissues. Cancer 2016;122:2544-51. © 2016 American Cancer Society.
© 2016 American Cancer Society.
Structural restrictions are present even in the most sequence diverse portions of antibodies, the complementary determining region (CDR) loops. Previous studies identified robust rules that define canonical structures for five of the six CDR loops, however the heavy chain CDR 3 (HCDR3) defies standard classification attempts. The HCDR3 loop can be subdivided into two domains referred to as the "torso" and the "head" domains and two major families of canonical torso structures have been identified; the more prevalent "bulged" and less frequent "non-bulged" torsos. In the present study, we found that Rosetta loop modeling of 28 benchmark bulged HCDR3 loops is improved with knowledge-based structural restraints developed from available antibody crystal structures in the PDB. These restraints restrict the sampling space Rosetta searches in the torso domain, limiting the φ and ψ angles of these residues to conformations that have been experimentally observed. The application of these restraints in Rosetta result in more native-like structure sampling and improved score-based differentiation of native-like HCDR3 models, significantly improving our ability to model antibody HCDR3 loops.
Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.
Copyright © 2016 Elsevier Inc. All rights reserved.