Morally injurious symptomatology: a qualitative examination of the NVVRS

As with all psychological constructs in their infancy, it is important to operationalize a definition as part of the construct validation process. As a phenomenon that continues to gain recognition amongst the psychological community, Moral Injury (MI) is no different. Although Litz et al. (2009) introduced and defined MI as the psychological, biological, spiritual, behavioral, and social impact of perpetrating, failing to prevent, or bearing witness to acts that transgress deeply held more beliefs and expectations, Drescher et al. (2011) found that a similar working definition was inadequate and lacked clarity according to trauma experts\u27 opinion. The following exploratory, qualitative study attempts to validate and enhance the current definitional understanding of MI by identifying associated thematic signs and symptoms as reported by 100 randomly selected veterans from the Combat Subsample of the National Vietnam Veterans Readjustment Study (NVVRS). Major themes generated by blind coders were compared with thematic signs and symptoms of MI as developed by Drescher et al. (2011). Although MI was not identified as a theme by coders, signs and symptoms of MI were identified throughout the data

Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival

1. Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design. 2. We evaluated two-dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angle SD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (midpoint: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance). 3. In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleye Sander vitreus, common carp Cyprinus carpio and channel catfish Ictalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted. 4. By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids

Evaluation of acoustic telemetry grids for determining aquatic animal movement and survival

1. Acoustic telemetry studies have frequently prioritized linear configurations of hydrophone receivers, such as perpendicular from shorelines or across rivers, to detect the presence of tagged aquatic animals. This approach introduces unknown bias when receivers are stationed for convenience at geographic bottlenecks (e.g. at the mouth of an embayment or between islands) as opposed to deployments following a statistical sampling design. 2. We evaluated two-dimensional acoustic receiver arrays (grids: receivers spread uniformly across space) as an alternative approach to provide estimates of survival, movement and habitat use. Performance of variably spaced receiver grids (5–25 km spacing) was evaluated by simulating (1) animal tracks as correlated random walks (speed: 0.1–0.9 m/s; turning angle SD: 5–30°); (2) variable tag transmission intervals along each track (nominal delay: 15–300 s); and (3) probability of detection of each transmission based on logistic detection range curves (midpoint: 200–1,500 m). From simulations, we quantified (i) time between successive detections on any receiver (detection time), (ii) time between successive detections on different receivers (transit time), and (iii) distance between successive detections on different receivers (transit distance). 3. In the most restrictive detection range scenario (200 m), the 95th percentile of transit time was 3.2 days at 5 km, 5.7 days at 7 km and 15.2 days at 25 km grid spacing; for the 1,500 m detection range scenario, it was 0.1 days at 5 km, 0.5 days at 7 km and 10.8 days at 25 km. These values represented upper bounds on the expected maximum time that an animal could go undetected. Comparison of the simulations with pilot studies on three fishes (walleye Sander vitreus, common carp Cyprinus carpio and channel catfish Ictalurus punctatus) from two independent large lake ecosystems (lakes Erie and Winnipeg) revealed shorter detection and transit times than what simulations predicted. 4. By spreading effort uniformly across space, grids can improve understanding of fish migration over the commonly employed receiver line approach, but at increased time cost for maintaining grids

Prevalence and architecture of de novo mutations in developmental disorders.

The genomes of individuals with severe, undiagnosed developmental disorders are enriched in damaging de novo mutations (DNMs) in developmentally important genes. Here we have sequenced the exomes of 4,293 families containing individuals with developmental disorders, and meta-analysed these data with data from another 3,287 individuals with similar disorders. We show that the most important factors influencing the diagnostic yield of DNMs are the sex of the affected individual, the relatedness of their parents, whether close relatives are affected and the parental ages. We identified 94 genes enriched in damaging DNMs, including 14 that previously lacked compelling evidence of involvement in developmental disorders. We have also characterized the phenotypic diversity among these disorders. We estimate that 42% of our cohort carry pathogenic DNMs in coding sequences; approximately half of these DNMs disrupt gene function and the remainder result in altered protein function. We estimate that developmental disorders caused by DNMs have an average prevalence of 1 in 213 to 1 in 448 births, depending on parental age. Given current global demographics, this equates to almost 400,000 children born per year

Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data.

Trio-based whole-exome sequence (WES) data have established confident genetic diagnoses in ∼40% of previously undiagnosed individuals recruited to the Deciphering Developmental Disorders (DDD) study. Here we aim to use the breadth of phenotypic information recorded in DDD to augment diagnosis and disease variant discovery in probands. Median Euclidean distances (mEuD) were employed as a simple measure of similarity of quantitative phenotypic data within sets of ≥10 individuals with plausibly causative de novo mutations (DNM) in 28 different developmental disorder genes. 13/28 (46.4%) showed significant similarity for growth or developmental milestone metrics, 10/28 (35.7%) showed similarity in HPO term usage, and 12/28 (43%) showed no phenotypic similarity. Pairwise comparisons of individuals with high-impact inherited variants to the 32 individuals with causative DNM in ANKRD11 using only growth z-scores highlighted 5 likely causative inherited variants and two unrecognized DNM resulting in an 18% diagnostic uplift for this gene. Using an independent approach, naive Bayes classification of growth and developmental data produced reasonably discriminative models for the 24 DNM genes with sufficiently complete data. An unsupervised naive Bayes classification of 6,993 probands with WES data and sufficient phenotypic information defined 23 in silico syndromes (ISSs) and was used to test a "phenotype first" approach to the discovery of causative genotypes using WES variants strictly filtered on allele frequency, mutation consequence, and evidence of constraint in humans. This highlighted heterozygous de novo nonsynonymous variants in SPTBN2 as causative in three DDD probands

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

The contribution of X-linked coding variation to severe developmental disorders

Abstract: Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders

Large-scale discovery of novel genetic causes of developmental disorders

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders1, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach2 to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing3,4,5,6,7,8,9,10,11 and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders