Do dental nonmetric traits actually work as proxies for neutral genomic data? Some answers from continental- and global-level analyses

Objectives: Crown and root traits, like those in the Arizona State University Dental Anthropology System (ASUDAS), are seemingly useful as genetic proxies. However, recent studies report mixed results concerning their heritability, and ability to assess variation to the level of genomic data. The aim is to test further if such traits can approximate genetic relatedness, among continental and global samples. Materials and Methods: First, for 12 African populations, Mantel correlations were calculated between mean measure of divergence (MMD) distances from up to 36 ASUDAS traits, and FST distances from >350,000 single nucleotide polymorphisms (SNPs) among matched dental and genetic samples. Second, among 32 global samples, MMD and FST distances were again compared. Correlations were also calculated between them and inter-sample geographic distances to further evaluate correspondence. Results: A close ASUDAS/SNP association, based on MMD and FST correlations, is evident, with rm-values between .72 globally and .84 in Africa. The same is true concerning their association with geographic distances, from .68 for a 36-trait African MMD to .77 for FST globally; one exception is FST and African geographic distances, rm = 0.49. Partial MMD/FST correlations controlling for geographic distances are strong for Africa (.78) and moderate globally (.4). Discussion: Relative to prior studies, MMD/FST correlations imply greater dental and genetic correspondence; for studies allowing direct comparison, the present correlations are markedly stronger. The implication is that ASUDAS traits are reliable proxies for genetic data—a positive conclusion, meaning they can be used with or instead of genomic markers when the latter are unavailable

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Highly-parallelized simulation of a pixelated LArTPC on a GPU

The rapid development of general-purpose computing on graphics processing units (GPGPU) is allowing the implementation of highly-parallelized Monte Carlo simulation chains for particle physics experiments. This technique is particularly suitable for the simulation of a pixelated charge readout for time projection chambers, given the large number of channels that this technology employs. Here we present the first implementation of a full microphysical simulator of a liquid argon time projection chamber (LArTPC) equipped with light readout and pixelated charge readout, developed for the DUNE Near Detector. The software is implemented with an end-to-end set of GPU-optimized algorithms. The algorithms have been written in Python and translated into CUDA kernels using Numba, a just-in-time compiler for a subset of Python and NumPy instructions. The GPU implementation achieves a speed up of four orders of magnitude compared with the equivalent CPU version. The simulation of the current induced on 10^3 pixels takes around 1 ms on the GPU, compared with approximately 10 s on the CPU. The results of the simulation are compared against data from a pixel-readout LArTPC prototype

The DUNE far detector vertical drift technology. Technical design report

DUNE is an international experiment dedicated to addressing some of the questions at the forefront of particle physics and astrophysics, including the mystifying preponderance of matter over antimatter in the early universe. The dual-site experiment will employ an intense neutrino beam focused on a near and a far detector as it aims to determine the neutrino mass hierarchy and to make high-precision measurements of the PMNS matrix parameters, including the CP-violating phase. It will also stand ready to observe supernova neutrino bursts, and seeks to observe nucleon decay as a signature of a grand unified theory underlying the standard model. The DUNE far detector implements liquid argon time-projection chamber (LArTPC) technology, and combines the many tens-of-kiloton fiducial mass necessary for rare event searches with the sub-centimeter spatial resolution required to image those events with high precision. The addition of a photon detection system enhances physics capabilities for all DUNE physics drivers and opens prospects for further physics explorations. Given its size, the far detector will be implemented as a set of modules, with LArTPC designs that differ from one another as newer technologies arise. In the vertical drift LArTPC design, a horizontal cathode bisects the detector, creating two stacked drift volumes in which ionization charges drift towards anodes at either the top or bottom. The anodes are composed of perforated PCB layers with conductive strips, enabling reconstruction in 3D. Light-trap-style photon detection modules are placed both on the cryostat's side walls and on the central cathode where they are optically powered. This Technical Design Report describes in detail the technical implementations of each subsystem of this LArTPC that, together with the other far detector modules and the near detector, will enable DUNE to achieve its physics goals

A learner-centered diabetes management curriculum: Reducing resident errors on an inpatient diabetes pathway

OBJECTIVE: Diabetes errors, particularly insulin administration errors, can lead to complications and death in the pediatric inpatient setting. Despite a lecture-format curriculum on diabetes management at our children’s hospital, resident diabetes-related errors persisted. We hypothesized that a multifaceted, learner-centered diabetes curriculum would help reduce pathway errors. RESEARCH DESIGN AND METHODS: The 8-week curricular intervention consisted of 1) an online tutorial addressing residents’ baseline diabetes management knowledge, 2) an interactive diabetes pathway discussion, 3) a learner-initiated diabetes question and answer session, and 4) a case presentation featuring embedded pathway errors for residents to recognize, resolve, and prevent. Errors in the 9 months before the intervention, as identified through an incident reporting system, were compared with those in the 10 months afterward, with errors classified as relating to insulin, communication, intravenous fluids, nutrition, and discharge delay. RESULTS: Before the curricular intervention, resident errors occurred in 28 patients (19.4% of 144 diabetes admissions) over 9 months. After the intervention, resident errors occurred in 11 patients (6.6% of 166 diabetes admissions) over 10 months, representing a statistically significant (P = 0.0007) decrease in patients with errors from before intervention to after intervention. Throughout the study, the errors were distributed into the categories as follows: insulin, 43.8%; communication, 39.6%; intravenous fluids, 14.6%; nutrition, 0%; and discharge delay, 2.1%. CONCLUSIONS: An interactive learner-centered diabetes curriculum for pediatric residents can be effective in reducing inpatient diabetes errors in a tertiary children’s hospital. This educational model promoting proactive learning has implications for decreasing errors across other medical disciplines