Statistical Modeling of Extracellular Vesicle Cargo to Predict Clinical Trial Outcomes For Hypoplastic Left Heart Syndrome

Cardiac-derived c-kit+ progenitor cells (CPCs) are under investigation in the CHILD phase I clinical trial (NCT03406884) for the treatment of hypoplastic left heart syndrome (HLHS). The therapeutic efficacy of CPCs can be attributed to the release of extracellular vesicles (EVs). to understand sources of cell therapy variability we took a machine learning approach: combining bulk CPC-derived EV (CPC-EV) RNA sequencing and cardiac-relevan

Modality-Dependent Impact of Hallucinations on Low-Frequency Fluctuations in Schizophrenia

Prior resting-state functional magnetic resonance imaging (fMRI) analyses have identified patterns of functional connectivity associated with hallucinations in schizophrenia (Sz). In this study, we performed an analysis of the mean amplitude of low-frequency fluctuations (ALFF) to compare resting state spontaneous low-frequency fluctuations in patients with Sz who report experiencing hallucinations impacting different sensory modalities. By exploring dynamics across 2 low-frequency passbands (slow-4 and slow-5), we assessed the impact of hallucination modality and frequency range on spatial ALFF variation. Drawing from a sample of Sz and healthy controls studied as part of the Functional Imaging Biomedical Informatics Research Network (FBIRN), we replicated prior findings showing that patients with Sz have decreased ALFF in the posterior brain in comparison to controls. Remarkably, we found that patients that endorsed visual hallucinations did not show this pattern of reduced ALFF in the back of the brain. These patients also had elevated ALFF in the left hippocampus in comparison to patients that endorsed auditory (but not visual) hallucinations. Moreover, left hippocampal ALFF across all the cases was related to reported hallucination severity in both the auditory and visual domains, and not overall positive symptoms. This supports the hypothesis that dynamic changes in the ALFF in the hippocampus underlie severity of hallucinations that impact different sensory modalities

Social Attention in Children with Epilepsy

Children with epilepsy may be vulnerable to impaired social attention given the increased risk of neu- robehavioural comorbidities. Social attentional orienting and the potential modulatory role of attentional control on the perceptual processing of gaze and emotion cues have not been examined in childhood onset epilepsies. Social attention mechanisms were investigated in patients with epilepsy (n = 25) aged 8–18 years old and performance compared to healthy controls (n = 30). Dynamic gaze and emotion facial stimuli were integrated into an antisaccade eye-tracking paradigm. The time to orient attention and exe- cute a horizontal saccade toward (prosaccade) or away (antisaccade) from a peripheral target measured processing speed of social signals under conditions of low or high attentional control. Patients with epi- lepsy had impaired processing speed compared to healthy controls under conditions of high attentional control only when gaze and emotions were combined meaningfully to signal motivational intent of approach (happy or anger with a direct gaze) or avoidance (fear or sad with an averted gaze). Group dif- ferences were larger in older adolescent patients. Analyses of the discrete gaze emotion combinations found independent effects of epilepsy-related, cognitive and behavioural problems. A delayed disengage- ment from fearful gaze was also found under low attentional control that was linked to epilepsy devel- opmental factors and was similarly observed in patients with higher reported anxiety problems. Overall, findings indicate increased perceptual processing of developmentally relevant social motivations during increased cognitive control, and the possibility of a persistent fear-related attentional bias. This was not limited to patients with chronic epilepsy, lower IQ or reported behavioural problems and has implica- tions for social and emotional development in individuals with childhood onset epilepsies beyond remission

Early ultrasound surveillance of newly-created haemodialysis arteriovenous fistula

IntroductionWe assess if ultrasound surveillance of newly-created arteriovenous fistulas (AVFs) can predict nonmaturation sufficiently reliably to justify randomized controlled trial (RCT) evaluation of ultrasound-directed salvage intervention.MethodsConsenting adults underwent blinded fortnightly ultrasound scanning of their AVF after creation, with scan characteristics that predicted AVF nonmaturation identified by logistic regression modeling.ResultsOf 333 AVFs created, 65.8% matured by 10 weeks. Serial scanning revealed that maturation occurred rapidly, whereas consistently lower fistula flow rates and venous diameters were observed in those that did not mature. Wrist and elbow AVF nonmaturation could be optimally modeled from week 4 ultrasound parameters alone, but with only moderate positive predictive values (PPVs) (wrist, 60.6% [95% confidence interval, CI: 43.9–77.3]; elbow, 66.7% [48.9–84.4]). Moreover, 40 (70.2%) of the 57 AVFs that thrombosed by week 10 had already failed by the week 4 scan, thus limiting the potential of salvage procedures initiated by that scan’s findings to alter overall maturation rates. Modeling of the early ultrasound characteristics could also predict primary patency failure at 6 months; however, that model performed poorly at predicting assisted primary failure (those AVFs that failed despite a salvage attempt), partly because patency of at-risk AVFs was maintained by successful salvage performed without recourse to the early scan data.ConclusionEarly ultrasound surveillance may predict fistula maturation, but is likely, at best, to result in only very modest improvements in fistula patency. Power calculations suggest that an impractically large number of participants (>1700) would be required for formal RCT evaluation

Restrictive or Liberal Red-Cell Transfusion for Cardiac Surgery.

BACKGROUND The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .)

The evolution of self-control

This work was supported by the National Evolutionary Synthesis Center (NESCent) through support of a working group led by C.L.N. and B.H. NESCent is supported by the National Science Foundation (NSF) EF-0905606. For training in phylogenetic comparative methods, we thank the AnthroTree Workshop (supported by NSF BCS-0923791). Y.S. thanks the National Natural Science Foundation of China (Project 31170995) and National Basic Research Program (973 Program: 2010CB833904). E.E.B. thanks the Duke Vertical Integration Program and the Duke Undergraduate Research Support Office. J.M.P. was supported by a Newton International Fellowship from the Royal Society and the British Academy. L.R.S. thanks the James S. McDonnell Foundation for Award 220020242. L.J.N.B. and M.L.P. acknowledge the National Institutes of Mental Health (R01-MH096875 and R01-MH089484), a Duke Institute for Brain Sciences Incubator Award (to M.L.P.), and a Duke Center for Interdisciplinary Decision Sciences Fellowship (to L.J.N.B.). E.V. and E.A. thank the Programma Nazionale per la Ricerca–Consiglio Nazionale delle Ricerche (CNR) Aging Program 2012–2014 for financial support, Roma Capitale–Museo Civico di Zoologia and Fondazione Bioparco for hosting the Istituto di Scienze e Tecnologie della Cognizione–CNR Unit of Cognitive Primatology and Primate Centre, and Massimiliano Bianchi and Simone Catarinacci for assistance with capuchin monkeys. K.F. thanks the Japan Society for the Promotion of Science (JSPS) for Grant-in-Aid for Scientific Research 20220004. F. Aureli thanks the Stages in the Evolution and Development of Sign Use project (Contract 012-984 NESTPathfinder) and the Integrating Cooperation Research Across Europe project (Contract 043318), both funded by the European Community’s Sixth Framework Programme (FP6/2002–2006). F. Amici was supported by Humboldt Research Fellowship for Postdoctoral Researchers (Humboldt ID 1138999). L.F.J. and M.M.D. acknowledge NSF Electrical, Communications, and Cyber Systems Grant 1028319 (to L.F.J.) and an NSF Graduate Fellowship (to M.M.D.). C.H. thanks Grant-in-Aid for JSPS Fellows (10J04395). A.T. thanks Research Fellowships of the JSPS for Young Scientists (21264). F.R. and Z.V. acknowledge Austrian Science Fund (FWF) Project P21244-B17, the European Research Council (ERC) under the European Union’s Seventh Framework Programme (FP/2007–2013)/ERC Grant Agreement 311870 (to F.R.), Vienna Science and Technology Fund Project CS11-026 (to Z.V.), and many private sponsors, including Royal Canin for financial support and the Game Park Ernstbrunn for hosting the Wolf Science Center. S.M.R. thanks the Natural Sciences and Engineering Research Council (Canada). J.K.Y. thanks the US Department of Agriculture–Wildlife Services–National Wildlife Research Center. J.F.C. thanks the James S. McDonnell Foundation and Alfred P. Sloan Foundation. E.L.M. and B.H. thank the Duke Lemur Center and acknowledge National Institutes of Health Grant 5 R03 HD070649-02 and NSF Grants DGE-1106401, NSF-BCS-27552, and NSF-BCS-25172. This is Publication 1265 of the Duke Lemur Center.Cognition presents evolutionary research with one of its greatest challenges. Cognitive evolution has been explained at the proximate level by shifts in absolute and relative brain volume and at the ultimate level by differences in social and dietary complexity. However, no study has integrated the experimental and phylogenetic approach at the scale required to rigorously test these explanations. Instead, previous research has largely relied on various measures of brain size as proxies for cognitive abilities. We experimentally evaluated these major evolutionary explanations by quantitatively comparing the cognitive performance of 567 individuals representing 36 species on two problem-solving tasks measuring self-control. Phylogenetic analysis revealed that absolute brain volume best predicted performance across species and accounted for considerably more variance than brain volume controlling for body mass. This result corroborates recent advances in evolutionary neurobiology and illustrates the cognitive consequences of cortical reorganization through increases in brain volume. Within primates, dietary breadth but not social group size was a strong predictor of species differences in self-control. Our results implicate robust evolutionary relationships between dietary breadth, absolute brain volume, and self-control. These findings provide a significant first step toward quantifying the primate cognitive phenome and explaining the process of cognitive evolution.PostprintPeer reviewe

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation