Parallel linear equation solvers for finite element computations

The overall objective of this research is to develop efficient methods for the solution of linear and nonlinear systems of equations on parallel and supercomputers, and to apply these methods to the solution of problems in structural analysis. Attention has been given so far only to linear equations. The methods considered for the solution of the stiffness equation Kx=f have been Choleski factorization and the conjugate gradient iteration with SSOR and Incomplete Choleski preconditioning. More detail on these methods will be given on subsequent slides. These methods have been used to solve for the static displacements for the mast and panel focus problems in conjunction with the CSM testbed system based on NICE/SPAR

Non-universal Voronoi cell shapes in amorphous ellipsoid packings

In particulate systems with short-range interactions, such as granular matter or simple fluids, local structure plays a pivotal role in determining the macroscopic physical properties. Here, we analyse local structure metrics derived from the Voronoi diagram of configurations of oblate ellipsoids, for various aspect ratios $\alpha$ and global volume fractions $\phi_g$. We focus on jammed static configurations of frictional ellipsoids, obtained by tomographic imaging and by discrete element method simulations. In particular, we consider the local packing fraction $\phi_l$, defined as the particle's volume divided by its Voronoi cell volume. We find that the probability $P(\phi_l)$ for a Voronoi cell to have a given local packing fraction shows the same scaling behaviour as function of $\phi_g$ as observed for random sphere packs. Surprisingly, this scaling behaviour is further found to be independent of the particle aspect ratio. By contrast, the typical Voronoi cell shape, quantified by the Minkowski tensor anisotropy index $\beta=\beta_0^{2,0}$, points towards a significant difference between random packings of spheres and those of oblate ellipsoids. While the average cell shape $\beta$ of all cells with a given value of $\phi_l$ is very similar in dense and loose jammed sphere packings, the structure of dense and loose ellipsoid packings differs substantially such that this does not hold true. This non-universality has implications for our understanding of jamming of aspherical particles.Comment: 6 pages, 5 figure

Somatostatin-expressing parafacial neurons are CO2/H+ sensitive and regulate baseline breathing.

Glutamatergic neurons in the retrotrapezoid nucleus (RTN) function as respiratory chemoreceptors by regulating breathing in response to tissue CO2/H+. The RTN and greater parafacial region may also function as a chemosensing network composed of CO2/H+-sensitive excitatory and inhibitory synaptic interactions. In the context of disease, we showed that loss of inhibitory neural activity in a mouse model of Dravet syndrome disinhibited RTN chemoreceptors and destabilized breathing (Kuo et al., 2019). Despite this, contributions of parafacial inhibitory neurons to control of breathing are unknown, and synaptic properties of RTN neurons have not been characterized. Here, we show the parafacial region contains a limited diversity of inhibitory neurons including somatostatin (Sst)-, parvalbumin (Pvalb)-, and cholecystokinin (Cck)-expressing neurons. Of these, Sst-expressing interneurons appear uniquely inhibited by CO2/H+. We also show RTN chemoreceptors receive inhibitory input that is withdrawn in a CO2/H+-dependent manner, and chemogenetic suppression of Sst+ parafacial neurons, but not Pvalb+ or Cck+ neurons, increases baseline breathing. These results suggest Sst-expressing parafacial neurons contribute to RTN chemoreception and respiratory activity

Anthropometric profiles of elite athletes

Quantifying body composition is central to monitoring performance and training in athletes, however limited sport-specific anthropometric reference data, assessed and reported in a standardised manner, is available. This study provides anthropometric profiles in elite male athletes from different sports. Elite male athletes (n = 73) from National squads of boxing (n = 10), cricket (n = 21), swimming (n = 23), hockey (n = 10) and eventing (n = 9) were assessed for body mass, height, eight skinfolds (triceps, subscapular, biceps, iliac crest, supraspinal, abdominal, thigh and medial calf), body circumferences (arm, waist, hip, thigh and calf) and muscle circumferences (arm, thigh, calf) using ISAK standardised guidelines. For all athletes, large variability exists for measures of skinfold thickness at each skinfold site. Swimming (64.6 ± 16.1 mm) and boxing (63.5 ± 16.1 mm) were similar for the sum of eight skinfolds (Σ8SKF) but swimming had lower Σ8SKF compared to cricket (86.1 ± 21.3 mm; p = .011) and eventing (89.9 ± 30.7 mm; p = .028). Hockey (81.9 ± 26.3 mm) and eventing had the most varied Σ8SKF. Thigh body (p=.006) and muscle circumferences (p = .005) were significantly reduced in boxing compared to hockey. No differences were seen between sports for arm (p = .346; ES = .06) and calf (p = .382; ES = .06) muscle circumferences. The anthropometric profiles for elite athletes from various sports during pre-season training will be a useful resource for sports professionals when monitoring and interpreting body composition data. Large variation exists in anthropometric profiles between the different athletes and different sports, highlighting the necessity to have sport-specific normative ranges available to allow optimal monitoring of individual athletes particularly varying across sports as well as age, training status and position

Antitumour activity of neratinib in patients with HER2-mutant advanced biliary tract cancers

Antitumour activity; Neratinib; Biliary tract cancersActividad antitumoral; Neratinib; Cánceres de vías biliaresActivitat antitumoral; Neratinib; Càncers de vies biliarsHER2 mutations are infrequent genomic events in biliary tract cancers (BTCs). Neratinib, an irreversible, pan-HER, oral tyrosine kinase inhibitor, interferes with constitutive receptor kinase activation and has activity in HER2-mutant tumours. SUMMIT is an open-label, single-arm, multi-cohort, phase 2, ‘basket’ trial of neratinib in patients with solid tumours harbouring oncogenic HER2 somatic mutations (ClinicalTrials.gov: NCT01953926). The primary objective of the BTC cohort, which is now complete, is first objective response rate (ORR) to neratinib 240 mg orally daily. Secondary objectives include confirmed ORR, clinical benefit rate, progression-free survival, duration of response, overall survival, safety and tolerability. Genomic analyses were exploratory. Among 25 treatment-refractory patients (11 cholangiocarcinoma, 10 gallbladder, 4 ampullary cancers), the ORR is 16% (95% CI 4.5–36.1%). The most common HER2 mutations are S310F (n = 11; 48%) and V777L (n = 4; 17%). Outcomes appear worse for ampullary tumours or those with co-occurring oncogenic TP53 and CDKN2A alterations. Loss of amplified HER2 S310F and acquisition of multiple previously undetected oncogenic co-mutations are identified at progression in one responder. Diarrhoea is the most common adverse event, with any-grade diarrhoea in 14 patients (56%). Although neratinib demonstrates antitumour activity in patients with refractory BTC harbouring HER2 mutations, the primary endpoint was not met and combinations may be explored.The SUMMIT trial was sponsored/funded by Puma Biotechnology, Inc. Investigators from MSKCC who participated in the trial were also supported in part by a Cancer Center Support Grant (P30 CA008748) and Cycle for Survival. Puma Biotechnology, Inc was involved in the following: study design; data collection, analysis and interpretation of the data; writing of the report; the decision to submit the article for publication. The authors would like to thank all patients and their families for participating in the SUMMIT trial. The authors acknowledge David Hyman (Memorial Sloan Kettering), Richard Bryce (Puma Biotechnology), and Alshad Lalani (Puma Biotechnology) for their important contributions to the original SUMMIT study design, oversight, and interpretation, and Feng Xu (Puma Biotechnology) and Jane Liang (Puma Biotechnology) for statistical and programming support. The authors also thank Lee Miller and Deirdre Carman (Miller Medical Communications Ltd) for medical writing/editing assistance, which was funded by Puma Biotechnology, Inc

Characterisation of the Cullin-3 mutation that causes a severe form of familial hypertension and hyperkalaemia

Deletion of exon 9 from Cullin‐3 (CUL3, residues 403–459: CUL3Δ403–459) causes pseudohypoaldosteronism type IIE (PHA2E), a severe form of familial hyperkalaemia and hypertension (FHHt). CUL3 binds the RING protein RBX1 and various substrate adaptors to form Cullin‐RING‐ubiquitin‐ligase complexes. Bound to KLHL3, CUL3‐RBX1 ubiquitylates WNK kinases, promoting their ubiquitin‐mediated proteasomal degradation. Since WNK kinases activate Na/Cl co‐transporters to promote salt retention, CUL3 regulates blood pressure. Mutations in both KLHL3 and WNK kinases cause PHA2 by disrupting Cullin‐RING‐ligase formation. We report here that the PHA2E mutant, CUL3Δ403–459, is severely compromised in its ability to ubiquitylate WNKs, possibly due to altered structural flexibility. Instead, CUL3Δ403–459 auto‐ubiquitylates and loses interaction with two important Cullin regulators: the COP9‐signalosome and CAND1. A novel knock‐in mouse model of CUL3WT/Δ403–459 closely recapitulates the human PHA2E phenotype. These mice also show changes in the arterial pulse waveform, suggesting a vascular contribution to their hypertension not reported in previous FHHt models. These findings may explain the severity of the FHHt phenotype caused by CUL3 mutations compared to those reported in KLHL3 or WNK kinases

Angular position of nodes in the superconducting gap of YBCO

The thermal conductivity of a YBCO single crystal has been studied as a function of the relative orientation of the crystal axes and a magnetic field rotating in the Cu-O planes. Measurements were carried out at several temperatures below T_c and at a fixed field of 30 kOe. A four-fold symmetry characteristic of a superconducting gap with nodes at odd multiples of 45 degrees in k-space was resolved. Experiments were performed to exclude a possible macroscopic origin for such a four-fold symmetry such as sample shape or anisotropic pinning. Our results impose an upper limit of 10% on the weight of the s-wave component of the essentially d-wave superconducting order parameter of YBCO.Comment: 10 pages, 4 figure

16S sequencing and functional analysis of the fecal microbiome during treatment of newly diagnosed pediatric inflammatory bowel disease

JJA is funded by a National Institute of Health Research Academic Clinical Fellowship and has received an Action Medical Research training fellowship. TC is funded by a Crohn’s in Childhood research association fellowship. CMC received a PhD studentship from SULSA Spirit industrial studentship. The NGS analysis was made possible by the award of a grant from the Source Bioscience 110th year anniversary promotion to CMC. The Rowett Institute receives funding from the Scottish Government (RESAS).Peer reviewedPublisher PD

An eHealth System Supporting Palliative Care for Patients with Non-Small Cell Lung Cancer: A Randomized Trial

BACKGROUND: In this study, the authors examined the effectiveness of an online support system (Comprehensive Health Enhancement Support System [CHESS]) versus the Internet in relieving physical symptom distress in patients with non-small cell lung cancer (NSCLC). METHODS: In total, 285 informal caregiver-patient dyads were assigned randomly to receive, for up to 25 months, standard care plus training on and access to either use of the Internet and a list of Internet sites about lung cancer (the Internet arm) or CHESS (the CHESS arm). Caregivers agreed to use CHESS or the Internet and to complete bimonthly surveys; for patients, these tasks were optional. The primary endpoint-patient symptom distress-was measured by caregiver reports using a modified Edmonton Symptom Assessment Scale. RESULTS: Caregivers in the CHESS arm consistently reported lower patient physical symptom distress than caregivers in the Internet arm. Significant differences were observed at 4 months (P = .031; Cohen d = .42) and at 6 months (P = .004; d = .61). Similar but marginally significant effects were observed at 2 months (P = .051; d = .39) and at 8 months (P = .061; d = .43). Exploratory analyses indicated that survival curves did not differ significantly between the arms (log-rank P = .172), although a survival difference in an exploratory subgroup analysis suggested an avenue for further study. CONCLUSIONS: The current results indicated that an online support system may reduce patient symptom distress. The effect on survival bears further investigation