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The use of genetic and genomic technology to infer ancestry is commonplace in a variety of contexts, particularly in biomedical research and for direct-to-consumer genetic testing. In 2013 and 2015, two roundtables engaged a diverse group of stakeholders toward the development of guidelines for inferring genetic ancestry in academia and industry. This report shares the stakeholder groups’ work and provides an analysis of, commentary on, and views from the groundbreaking and sustained dialogue. We describe the engagement processes and the stakeholder groups’ resulting statements and proposed guidelines. The guidelines focus on five key areas: application of genetic ancestry inference, assumptions and confidence/laboratory and statistical methods, terminology and population identifiers, impact on individuals and groups, and communication or translation of genetic ancestry inferences. We delineate the terms and limitations of the guidelines and discuss their critical role in advancing the development and implementation of best practices for inferring genetic ancestry and reporting the results. These efforts should inform both governmental regulation and self-regulation.

COVID-19 has highly variable clinical courses. The search for prognostic host factors for COVID-19 outcome is a priority. We performed logistic regression for ICU admission against a polygenic score (PGS) for Cystatin C (CyC) production in patients with COVID-19. We analyzed the predictive value of longitudinal plasma CyC levels in an independent cohort of patients hospitalized with COVID-19. In four cohorts spanning European and African ancestry populations, we identified a significant association between CyC-production PGS and odds of critical illness (n cases=2,319), with the strongest association captured in the UKB cohort (OR 2.13, 95% CI 1.58-2.87, p=7.12e-7). Plasma proteomics from an independent cohort of hospitalized COVID-19 patients ( n cases = 131) demonstrated that CyC production was associated with COVID-specific mortality (p=0.0007). Our findings suggest that CyC may be useful for stratification of patients and it has functional role in the host response to COVID-19.

OBJECTIVE: Deep sequencing offers unparalleled access to rare variants in human populations. Understanding their role in disease is a priority, yet prohibitive sequencing costs mean that many cohorts lack the sample size to discover these effects on their own. Meta-analysis of individual variant scores allows the combination of rare variants across cohorts and study of their aggregated effect at the gene level, boosting discovery power. However, the methods involved have largely not been field-tested. In this study, we aim to perform the first meta-analysis of gene-based rare variant aggregation optimal tests, applied to the human cardiometabolic proteome. METHODS: Here, we carry out this analysis across MANOLIS, Pomak and ORCADES, three isolated European cohorts with whole-genome sequencing (total N=4,422). We examine the genetic architecture of 250 proteomic traits of cardiometabolic relevance. We use a containerised pipeline to harmonise variant lists across cohorts and define four sets of qualifying variants. For every gene, we interrogate protein-damaging variants, exonic variants, exonic and regulatory variants, and regulatory only variants, using the CADD and Eigen scores to weigh variants according to their predicted functional consequence. We perform single-cohort rare variant analysis and meta-analyse variant scores using the SMMAT package. RESULTS: We describe 5 rare variant pQTLs (RV-pQTL) which pass our stringent significance threshold (7.45×10-11) and quality control procedure. These were split between four cis signals for MARCO, TEK, MMP2 and MPO, and one trans association for GDF2 in the SERPINA11 gene. We show that the cis-MPO association, which was not detectable using the single-point data alone, is driven by 5 missense and frameshift variants. These include rs140636390 and rs119468010, which are specific to MANOLIS and ORCADES, respectively. We show how this kind of signal could improve the predictive accuracy of genetic factors in common complex disease such as stroke and cardiovascular disease. CONCLUSIONS: Our proof-of-concept study demonstrates the power of gene-based meta-analyses for discovering disease-relevant associations complementing common-variant signals by incorporating population-specific rare variation.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types., Graphical abstract, D’Antonio et al. characterize associations between GWAS signals for COVID-19 disease and eQTLs in 69 human tissues to identify causal variants and their underlying molecular mechanisms. They show that diverse symptoms and disease severity of COVID-19 are associated with variants affecting gene expression in a wide variety of tissues.

Transplant patients are at risk for hemodynamic injury and glomerular diseases such as focal segmental glomerulosclerosis (FSGS) and thrombotic microangiopathy (TMA). Calcineurin inhibitors (CNI) can cause various patterns of acute kidney injury (AKI) in transplant patients and their effects must be differentiated from kidney injury due to other agents. Transplant populations are also at risk for atypical infections and malignancies. These conditions and the agents that are used to treat them can then induce their own set of glomerular diseases. We report a patient with hepatitis C who had received an orthotopic liver transplant and then developed recurrent hepatocellular carcinoma, which was treated with the oral tyrosine kinase inhibitor (TKI) sorafenib. In a manner temporally related to the initiation of the TKI, progressive AKI and high-grade rising proteinuria were noted. A biopsy disclosed FSGS and concomitant TMA. Despite the discontinuation of the TKI and high-dose steroid treatment, the patient developed end-stage renal disease and was initiated on hemodialysis. After determining the TKI as the probable culprit, as opposed to CNIs, the patient successfully received a living related renal transplant. CNIs are used to maintain renal and hepatic allografts without the development of hematuria, significant proteinuria, or significant impairment of renal function. It is noted that the pathologic phenotype observed in this case is only the second reported case of concomitant TMA and FSGS in a sorafenib-treated patient.

Pseudohyponatremia represents an artifactual reduction of blood (serum or plasma) sodium concentration measured with indirect ion selective electrode (ISE) methods. One mechanism of such artifacts is usually due to an abnormal increase in lipids or protein, the nonaqueous components of blood, that result in errors due to water displacement artifacts.1, 2 Other mechanisms that cause pseudohyponatremia may be associated with monoclonal proteins when a sample’s hyperviscosity causes aspiration errors.3 In classic hyperlipidemia (hypertriglyceridemia)-induced hyponatremia, several equations have been published to correct errors in serum potassium, chloride, and sodium measurements. One such equation is as follows: Corrected Na+ = Measured Na+ + [{[0.21 × triglycerides (g/l)] − 0.6} × (Na+/100)].4 Using this equation, the estimated decrease of plasma sodium concentration could be as low as 3.9 mmol/l in a sample with triglyceride concentration of 1500 mg/dl (15 g/l) and sodium concentration of 130 mmol/l. We report a case of a 41-year-old man who developed pseudohyponatremia due to hypercholesterolemia with concomitant hypertriglyceridemia and hyperglycemia. The hyponatremia was not fully accounted for by the true dilutional hyponatremia due to hyperglycemia,5 and examination of the sample revealed that hypercholesterolemia is the culprit for the pseudohyponatremia. Institutional review was not required for this study because this case study does not provide patient identification and the blood samples used in the study were obtained for patient care, not for research purposes.

As health policy-makers around the world seek to make progress towards universal health coverage they must navigate between two important ethical imperatives: to set national spending priorities fairly and efficiently; and to safeguard the right to health. These imperatives can conflict, leading some to conclude that rights-based approaches present a disruptive influence on health policy, hindering states’ efforts to set priorities fairly and efficiently. Here, we challenge this perception. We argue first that these points of tension stem largely from inadequate interpretations of the aims of priority setting as well as the right to health. We then discuss various ways in which the right to health complements traditional concerns of priority setting and vice versa. Finally, we set out a three-step process by which policy-makers may navigate the ethical and legal considerations at play.

In ISO New England and PJM it was assumed that sponsors of new capacity projects would offer them into the newly established forward centralized capacity markets at prices based on their levelized net cost of new entry, or “Net CONE.” But the FCCMs have not operated in the way their proponents had expected. To clear up the CONEfusion, FCCM designs should be reconsidered to adapt them to the changing circumstances and to be grounded in realistic expectations of market conduct.

The main purpose of this study is to investigate the role of footfall surface compliance on the physical parameters affecting barefoot racewalkers and runners. These parameters are identified using a new inverted pendulum body model with a forward moving foot pivot. Model correlations of footfall loads measured for four compliant surface mats showed leg-foot compression stiffness for both gaits were in the range of 10.8-12.9 kN/m, with the initial stiffness spikes in the range of 6.5-52 kN/m. The average leg damping factor was about 0.6% for racewalkers and 6% for runners. For both gaits there was negative leg damping just prior to foot lift-off. Compared to the peak reactions for the rigid surface, a mat of intermediate compliance (1020 kN/m) was effective in reducing the runners' peak reaction spikes by as much as 17%.

A bellows, or a closed thin-walled elastic tube with corrugated walls, undergoes longitudinal extension when subjected to internal fluid pressure. Investigated herein is the mechanical behavior of several pressurized bellows in clusters, which are designed to bend and twist as well as to extend and compress longitudinally. Bellows in clusters can be employed as robotic limbs, such as manipulator arms and legs for walking machines. For limb bending, analysis shows that there is an optimal geometry for satellite bellows, or a set of identical bellows clustered longitudinally about a central core. For limb torsion, the bellows are clustered in a cylindrical helix whose angle is chosen to produce the desired load–displacement relationships, for instance the highest rotation for a given torque. For both bending and torsional limbs, experimental results are included that exhibit the predicted mechanical behavior.

The fatigue life of foamed polymers in compression impact was measured using a cam-driven compound pendulum system. Impact-induced fatigue data are presented for two open-celled foamed polymers having different densities, which are often used for shock mitigation. Material measurements at constant incident energy included the static compression modulus and peak dynamic stress, which progressively degraded as the number of impacts approached one million. Other indicators of fatigue life were cell breakdown, in which microscopic edge cracks were observed in both dry and water-saturated test specimens. The dry material had the longer fatigue life. In both cases, cell breakdown occurred after a million or more impacts at peak compressive stresses in the 200–300 kN/m 2 range.

Loosely jointed structures have joint connections that exhibit non-linear lateral force–displacement behavior in bending. Examples include scaffolds, bleachers and other temporary frames. Formulated herein is a lumped parameter, dynamic sway model of a multi-bay, n-story scaffold with bilinear elastic joint connections. Responses are evaluated numerically for an approximate model: a two degree of freedom scaffold in plane sway motion caused by harmonic base excitation. Chaotic, quasi-periodic, and periodic responses are investigated over a practical range of non-dimensional system parameters. The results show that the type of response is especially sensitive to the magnitude of joint damping.

Critical dynamic stresses and segmented fracture lengths are predicted for a tall, initially upright, truncated right circular cone as it rotates about its base point and as the cone tip impacts the ground plane. This cone can represent a tall masonry structure such as a tapered stone tower or a brick chimney which has a foundation failure; or the trunk of a tree which topples in a windstorm. In any case, ground impacts can induce sequential fractures along the cone's length, resulting in multiple in-line cone segments that come to rest on the ground plane. A dynamic analysis for the cone's bending moment and stress distributions during impact is used to predict the primary fracture points for the broken segment lengths. The dynamic bending stresses controlled the failures since they were found to be about two orders of magnitude higher than the longitudinal stresses caused by the self-weight and the centrifugal acceleration of a rotating cone. In a case study, this dynamic analysis is shown to correlate well with observed fracture patterns of fallen segments for a dead tree toppled by wind. An unexpected secondary fracture point observed in this case study is also explained using the dynamic theory.

As a lightning channel on its way to ground meets a standing masonry or rock structure, radiant energy from the channel can induce a thermal shock of sufficient intensity to cause the structure to fracture and collapse. Mathematical models for two such structural failure mechanisms are proposed: one describing violent surface separations or spalling, and the other characterizing internal cracking from sudden increased pore pressure in the solid. Experimental data and case studies are used to complement these theories of lightning-induced failure.

The degree of population replacement in the British Isles associated with cultural changes has been extensively debated [1–3]. Recent work has demonstrated that comparisons of genetic variation in the British Isles and on the European Continent can illuminate specific demographic processes in the history of the British Isles. For example, Wilson et al. [4] used the similarity of Basque and Celtic Y chromosomes to argue for genetic continuity from the Upper Palaeolithic to the present in the paternal history of these populations (see also [5]). Differences in the Y chromosome composition of these groups also suggested genetic signatures of Norwegian influence in the Orkney Islands north of the Scottish mainland, an important center of Viking activities between 800 and 1300 A.D. [6]. More recently, Weale et al. [7] argued for substantial Anglo-Saxon male migration into central England based on the analysis of eight British sample sets collected on an east-west transect across England and Wales. To provide a more complete assessment of the paternal genetic history of the British Isles, we have compared the Y chromosome composition of multiple geographically distant British sample sets with collections from Norway (two sites), Denmark, and Germany and with collections from central Ireland, representing, respectively, the putative invading and the indigenous populations. By analyzing 1772 Y chromosomes from 25 predominantly small urban locations, we found that different parts of the British Isles have sharply different paternal histories; the degree of population replacement and genetic continuity shows systematic variation across the sampled areas.

We have analyzed the maternally inherited mitochondrial DNA from each of nine geographically separated Jewish groups, eight non-Jewish host populations, and an Israeli Arab/Palestinian population, and we have compared the differences found in Jews and non-Jews with those found using Y-chromosome data that were obtained, in most cases, from the same population samples. The results suggest that most Jewish communities were founded by relatively few women, that the founding process was independent in different geographic areas, and that subsequent genetic input from surrounding populations was limited on the female side. In sharp contrast to this, the paternally inherited Y chromosome shows diversity similar to that of neighboring populations and shows no evidence of founder effects. These sex-specific differences demonstrate an important role for culture in shaping patterns of genetic variation and are likely to have significant epidemiological implications for studies involving these populations. We illustrate this by presenting data from a panel of X-chromosome microsatellites, which indicates that, in the case of the Georgian Jews, the female-specific founder event appears to have resulted in elevated levels of linkage disequilibrium.

A gravity-driven, weak helical spring such as the toy Slinky may be activated to tumble end-over-end. One way to activate this spring motion is to bend the coil assembly in a 180° arc, set each end on a horizontal support surface, and suddenly pull away one end support so that the spring impacts a step below. The nature of subsequent tumbling depends on critical step heights, the lower bounds of which are predicted for 180° and 360° somersaults. Such predictions, presented in terms of non-dimensional system parameters, are based on structural analysis and energy threshholds: an ideal balance of gravity potential energy and elastic spring energy. The predictions are complemented with experimental results, which include the effects of the compliance of the impacted surface and spring payload. Results may be applicable to the future design of unique tumbling spring “wheels” for all-terrain mobile robots.

Measures to limit the market power that can occur during hours of tight supply may be warranted, but designing them requires distinguishing market power from scarcity and other causal factors. The difficulty of making such distinctions, and concerns over the potential negative consequences of market intervention, have led independent system operators and FERC to adopt a cautious approach.

Due to a flawed structure, the market power screens fail to accurately distinguish significant from insignificant conduct and material impacts. The mitigation also has a discriminatory impact on smaller participants who are least likely to attempt to exercise market power.

Dynamics are investigated for a rigid spinner with a hole, concentric with its mass center, into which a pivot is loosely fitted. As the spinner is excited by the motion of the contacting pivot, the spinner may sustain a quasi-steady spin angular velocity θ in the pivot's orbiting plane. This spin motion, defined as parametric spin resonance (PSR), is investigated for the case of prescribed, bi-directional, harmonic pivot motion of frequency ω. The ranges of the system's non-dimensional parameters needed to achieve PSR are determined. Experimental data both explain the spinner's direction of rotation and complement the predicted existence of quasi-steady values of θ. The analysis explains the characteristic motions of such toys as the Hula-Hoop and the Indian Windmill (the Gee-Haw Whimmy Diddle), and in general may explain certain unwanted vibrations in machinery with worn or loosely-fitting bearings.

Experiments were used to identify the II-groups that best scaled the fracture of monolithic plate glass under central impact by a projectile mass. Threshold impact velocities for glass fracture were measured for three groups of geometrically similar, laboratory-scale, rectangular specimens, for two types of edge constraints: (i) all edges clamped, and (ii) short edges clamped and long edges free. Different sets of Π-groups were needed for the two types of edge constraints, if the threshold impact velocities measured for the smallest specimens are to be used to predict those for the larger ones. Furthermore, edge flaws on the specimen face, caused by the diamond cutter used to size the specimens, and the orientation of the cut face to the oncoming projectile, affected the threshold impact velocities significantly. Extensive drop tests showed that, for other parameters remaining constant, the threshold projectile impact velocity is higher for a window glass whose previously cut surface faces toward, rather than away from, the oncoming projectile, regardless of the edge constraints.

The characteristics of antigen-specific IgG in patients with multiple sclerosis and patients with encephalitis have been compared. Both groups of patients showed antigen-specific oligoclonal bands locally synthesised in the CSF. When the affinity distribution of the antigen-specific IgG was measured there was a marked difference between the two groups. Encephalitis patients had high affinity antibody against the causative antigen. This was consistent with the antibody undergoing affinity maturation as a result of the immune system fighting a primary infection. Multiple sclerosis patients lacked high affinity response. This lack of high affinity antibody was also seen in those encephalitis patients when antigens other than the causative antigen were studied.

Pb isotope data for greenstone belt volcanic units, plutons and gneisses of the Archean Craton of Zimbabwe are presented together with SmNd isotopic analyses and model Nd mantle derivation (tDM) ages for selected samples. Pb/Pb whole-rock isochrons yield well-determined dates for the Cardiff Hill rhyolite of the Shamva-Harare greenstone belt (2659−39+38 Ma), the Somabula tonalite (2752−52+50 Ma), the Gwenoro Dam migmatitic gneisses (2705∂3+60 Ma), and for various suites from the Chingezi tonalite (from 2874±32 to 2686−94+88 Ma). Comparison of geochronological results from this study with those of earlier work (mainly RbSr whole-rock dating) shows some significant discordances, and their possible causes are discussed with regard to time-integrated Th/U ratios and the geological settings of the relevant rock units. The Chingezi and Sesombi plutons show good agreement between RbSr and Pb/Pb whole-rock isochron dates and also display a limited range of Th/U ratios, appropriate to a purely igneous differentiation history. Early to mid-Archean gneisses show large ranges of Th/U ratios, probably the results of U disturbances during metamorphism. In these rocks Pb/Pb dates may be older or younger than the corresponding RbSr dates, but tDM model ages generally agree with the older of the isochron results. The behaviour of the RbSr and UPb whole-rock systems during metamorphism may depend critically on the nature of the fluid phase evolved. CO2-rich fluids appear to be implicated in U enrichment of early Archean gneisses at the Shabanie Mine. It is argued that CO2-rich fluids may cause disturbance of the UPb system without resetting the RbSr system, while a H2O-rich fluid phase could have the reverse effect.

Tractor semitrailer accidents are often caused by impact loading to some part of the vehicle and this leads to a loss of steering control and jackknifing. Impact loading may come from contact with another vehicle, or may occur on an isolated tractor semitrailer from maneuvers such as braking with subsequent brake lock-up, from suddenly steering into a turn where the cornering may lead to lateral wheel skidding, or from some combination of these factors. Without regard to the location, magnitude, or cause of impact loading, the accident reconstruction analyses herein rely on a knowledge of the tractor semitrailer's pre- and post-jackknife trajectories leading to a rest state. The tractor semitrailer is modeled as two rigid bodies hinged together and in-plane motion, to which is applied a system energy balance and Gauss's principle of least constraints. Explicit results are derived for the pre- and post-impact vehicle speeds as a function of the system parameters. Results of a case study for a tractor semitrailer initially in straight line motion show the sensitivity of the velocities to a range of trajectory surface-tyre friction conditions. Further, for constant friction conditions, the maximum post-impact linear velocities are from 1–2% less than the velocities just prior to impact; and for impending jackknife, the angular velocities of the tractor are about three times that of the trailer.

peaking 10-20min post-TSST. HC injection resulted in comparable values in CAI patients, while placebo-treated patients showed no cortisol response (all p< .001). On WL1 (encoding pre-stress), healthy controls and patients did not differ in learning or immediate recall. Compared to the other two groups, placebo-treated patients recalled more neutral words in post-stress delayed recall (F(2,40) =3.72, p= .03). Similarly, on WL2 (encoding under stress) placebo-treated CAI patients learned significantly more neutral words (F(2,40) =4.07, p= .03) and tended to recall more negative words (immediate recall: F(2,40) =2.84, p= .07). Findings suggest that increasing cortisol levels, even acutely in the form of HC injection, restored cortisol interference with learning and recall comparable to effects seen in healthy individuals. In contrast, independent of psychological stress, sustained lack of cortisol stress responses counteractednegative effects of cortisol onboth learning and recall.

The dynamic system consists of two uniform, vertical beams, one above the other, with a hinge between them and an achor hinge at the base. For a transverse load suddenly applied anywhere along the upper beam, the critical or peak moment in the lower beam of length l occurs at a distance yc = l/√3 from its base. When this impact load is applied to the lower beam in the neighborhood of the hinge, a primary critical moment always occurs at the impact point; but a secondary critical moment may also occur at a predictable distance yc

The prostate glands of rats, mice, guinea pigs and hamsters were found to be a rich source of enzymes catalyzing the Mn2+-dependent transfer of galactose from UDP-galactose to glycoprotein acceptors such as ovomucoid and ovalbumin. The rat ventral prostate was also very active in promoting transfer of fucose from GDP-fucose to ovomucoid. The prostatic enzymes promoting both galactosyl and fucosyl transfers to glycoproteins were very largely membranebound, and were markedly activated by the non-ionic detergent Triton X-100. Castration of adult male rats resulted in a many-fold and roughly parallel decline in both glycosyltransferase activities over a period of two weeks, which was reversed by subsequent daily treatment with testosterone for 8 days. The very low galactosyltransferase of the ventral prostate of hypophysectomized rats was markedly enhanced by testosterone administration, whereas prolactin alone or in combination with androgen had no significant effect.

UDP-galactose: glycoprotein galactosyltransferase and GDP-focuse: glycoprotein fucosyltransferase activities were found to be exceptionally high in homogenates of rat ventral prostate and certain other male secondary sexual organs. Nearly all of the intracellular forms of these glycosyltransferases in prostate were associated with readily sedimentable membranous structures and were maximally active only in the presence of non-ionic detergents. Rat and human prostatic secretions, and especially human seminal plasma, also are strikingly rich, in comparison with blood serum, in glycoprotein galactosyl-transferases that are present in these fluids in soluble forms that are not activated by detergents. Very little galactosyltransferase is associated with spermatozoa. The properties of prostatic fluid and seminal plasma galactosyl-transferases are very similar to those of the enzyme present in mammary gland and milk, although functional modifier proteins resembling α-lactalbumin appear to be absent from male genital glands and their fluids. The glycoprotein galactosyltransferase and fucosyltransferase activities of rat prostate decline fairly slowly after orchiectomy and are gradually enhanced in castrates by androgen treatment in a manner which suggests that their levels vary coordinately with elaboration of endoplasmic reticulum and Golgi membranes in this tissue. Prolactin does not affect prostatic galactosyltransferase in hypophysectomized animals or its enhancement by androgens.

The key consideration in controlling the dynamic response of an offshore guyed tower subjected to environmental loading is the selection of the stiffness characteristics of the cable mooring array. In the present study, each cable in the array consists of three segments: a leading segment attached to the tower, a short heavy middle segment, and a seabed trailing segment attached at the extremity to an anchor pile. A nonlinear static model is presented in algorithmic form that defines the stiffness characteristics of the cable array. The model involves the inelastic static catenary equations coupled with conditions of geometric compatibility, formulated in terms of seven nondimensional system parameters. The effects of varying each of the system parameters on the stiffness characteristics of example cable arrays are presented and the implications for cable design are discussed.

The problem of designing stiff, lightweight, and least expensive elevated spans to support ground vehicles is investigated. A computer program using the direct search method was developed to calculate optimum geometric configurations of prestressed concrete girders with nonlinear constraint conditions involving stresses and deflections; with specified inputs on loading, unit costs and overall size; and with checks on buckling, shear and ultimate section strength. Parameters allow-for choices between stiff, expensive configurations or flexible, less expensive designs. Several numerical results for simple spans are included.