Predicting lung cancer recurrence from circulating tumour DNA. Commentary on 'Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution'

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Controls on the formation of lunar multiring basins

Multiring basins dominate the crustal structure, tectonics, and stratigraphy of the Moon. Understanding how these basins form is crucial for understanding the evolution of ancient planetary crusts. To understand how preimpact thermal structure and crustal thickness affect the formation of multiring basins, we simulate the formation of lunar basins and their rings under a range of target and impactor conditions. We find that ring locations, spacing, and offsets are sensitive to lunar thermal gradient (strength of the lithosphere), temperature of the deep lunar mantle (strength of the asthenosphere), and preimpact crustal thickness. We also explore the effect of impactor size on the formation of basin rings and reproduce the observed transition from peak‐ring basins to multiring basins and reproduced many observed aspects of ring spacing and location. Our results are in broad agreement with the ring tectonic theory for the formation of basin rings and also suggest that ring tectonic theory applies to the rim scarp of smaller peak‐ring basins

Structural characterization and physical properties of P2O5-CaO-Na2O-TiO2 glasses by Fourier transform infrared, Raman and solid-state magic angle spinning nuclear magnetic resonance spectroscopies.

Phosphate-based glasses have been investigated for tissue engineering applications. This study details the properties and structural characterization of titanium ultra-phosphate glasses in the 55(P(2)O(5))-30(CaO)-(25-x)(Na(2)O)-x(TiO(2)) (0≤x≤5) system, which have been prepared via melt-quenching techniques. Structural characterization was achieved by a combination of X-ray diffraction (XRD), and solid-state nuclear magnetic resonance, Raman and Fourier transform infrared spectroscopies. Physical properties were also investigated using density, degradation and ion release studies; additionally, differential thermal analysis was used for thermal analysis of these glasses. The results show that with the addition of TiO(2) the density and glass transition temperature increased whereas the degradation and ion release properties are decreased. From XRD data, TiP(2)O(7) and CaP(2)O(6) were detected in 3 and 5 mol.% TiO(2)-containing glasses. Magic angle spinning nuclear magnetic resonance results confirmed that as TiO(2) is incorporated into the glass; the amount of Q(3) increases as the amount of Q(2) consequently decreases, indicating increasing polymerization of the phosphate network. Spectroscopy results also showed that the local structure of glasses changes with increasing TiO(2) content. As TiO(2) is incorporated into the glass, the phosphate connectivity increases, indicating that the addition of TiO(2) content correlates unequivocally with an increase in glass stability

SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome

OBJECTIVE: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor-1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene. METHODS: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. RESULTS: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN. CONCLUSIONS: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies

The 1958–2009 Greenland ice sheet surface melt and the mid-tropospheric atmospheric circulation

peer reviewedaudience: researcherIn order to assess the impact of the mid-tropospheric circulation over the Greenland ice sheet (GrIS) on surface melt, as simulated by the regional climate model MAR, an automatic Circulation type classification (CTC) based on 500 hPa geopotential height from reanalyses is developed. General circulation correlates significantly with the surface melt anomalies for the summers in the period 1958–2009. The record surface melt events observed during the summers of 2007–2009 are linked to the exceptional persistence of atmospheric circulations favouring warm air advection. The CTC emphasizes that summer 500 hPa circulation patterns have changed since the beginning of the 2000s; this process is partly responsible for the recent warming observed over the GrIS

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine

A mathematical model for breath gas analysis of volatile organic compounds with special emphasis on acetone

Recommended standardized procedures for determining exhaled lower respiratory nitric oxide and nasal nitric oxide have been developed by task forces of the European Respiratory Society and the American Thoracic Society. These recommendations have paved the way for the measurement of nitric oxide to become a diagnostic tool for specific clinical applications. It would be desirable to develop similar guidelines for the sampling of other trace gases in exhaled breath, especially volatile organic compounds (VOCs) which reflect ongoing metabolism. The concentrations of water-soluble, blood-borne substances in exhaled breath are influenced by: (i) breathing patterns affecting gas exchange in the conducting airways; (ii) the concentrations in the tracheo-bronchial lining fluid; (iii) the alveolar and systemic concentrations of the compound. The classical Farhi equation takes only the alveolar concentrations into account. Real-time measurements of acetone in end-tidal breath under an ergometer challenge show characteristics which cannot be explained within the Farhi setting. Here we develop a compartment model that reliably captures these profiles and is capable of relating breath to the systemic concentrations of acetone. By comparison with experimental data it is inferred that the major part of variability in breath acetone concentrations (e.g., in response to moderate exercise or altered breathing patterns) can be attributed to airway gas exchange, with minimal changes of the underlying blood and tissue concentrations. Moreover, it is deduced that measured end-tidal breath concentrations of acetone determined during resting conditions and free breathing will be rather poor indicators for endogenous levels. Particularly, the current formulation includes the classical Farhi and the Scheid series inhomogeneity model as special limiting cases.Comment: 38 page

Genetic and clinical characteristics of NEFL-related Charcot-Marie-Tooth disease

OBJECTIVES: To analyse and describe the clinical and genetic spectrum of Charcot-Marie-Tooth disease (CMT) caused by mutations in the neurofilament light polypeptide gene (NEFL). METHODS: Combined analysis of newly identified patients with NEFL-related CMT and all previously reported cases from the literature. RESULTS: Five new unrelated patients with CMT carrying the NEFL mutations P8R and N98S and the novel variant L311P were identified. Combined data from these cases and 62 kindreds from the literature revealed four common mutations (P8R, P22S, N98S and E396K) and three mutational hotspots accounting for 37 (55%) and 50 (75%) kindreds, respectively. Eight patients had de novo mutations. Loss of large-myelinated fibres was a uniform feature in a total of 21 sural nerve biopsies and 'onion bulb' formations and/or thin myelin sheaths were observed in 14 (67%) of them. The neurophysiological phenotype was broad but most patients with E90K and N98S had upper limb motor conduction velocities <38 m/s. Age of onset was ≤3 years in 25 cases. Pyramidal tract signs were described in 13 patients and 7 patients were initially diagnosed with or tested for inherited ataxia. Patients with E90K and N98S frequently presented before age 3 years and developed hearing loss or other neurological features including ataxia and/or cerebellar atrophy on brain MRI. CONCLUSIONS: NEFL-related CMT is clinically and genetically heterogeneous. Based on this study, however, we propose mutational hotspots and relevant clinical-genetic associations that may be helpful in the evaluation of NEFL sequence variants and the differential diagnosis with other forms of CMT

Effect of changes over time in the performance of a customized SAPS-II model on the quality of care assessment

Purpose: The aim of our study was to explore, using an innovative method, the effect of temporal changes in the mortality prediction performance of an existing model on the quality of care assessment. The prognostic model (rSAPS-II) was a recalibrated Simplified Acute Physiology Score-II model developed for very elderly Intensive Care Unit (ICU) patients. Methods: The study population comprised all 12,143 consecutive patients aged 80 years and older admitted between January 2004 and July 2009 to one of the ICUs of 21 Dutch hospitals. The prospective dataset was split into 30 equally sized consecutive subsets. Per subset, we measured the model's discrimination [area under the curve (AUC)], accuracy (Brier score), and standardized mortality ratio (SMR), both without and after repeated recalibration. All performance measures were considered to be stable if 1 without and after repeated recalibration for the year 2009. Results: For all subsets, the AUCs were stable, but the Brier scores and SMRs were not. The SMR was downtrending, achieving levels significantly below 1. Repeated recalibration rendered it stable again. The proportions of hospitals with SMR>1 and SMR <1 changed from 15 versus 85% to 35 versus 65%. Conclusions: Variability over time may markedly vary among different performance measures, and infrequent model recalibration can result in improper assessment of the quality of care in many hospitals. We stress the importance of the timely recalibration and repeated validation of prognostic models over tim