Motion-corrected multiparametric renal arterial spin labelling at 3T: Reproducibility and effect of vasodilator challenge

Objectives We investigated the feasibility and reproducibility of free-breathing motion-corrected multiple inversion time (multi-TI) pulsed renal arterial spin labelling (PASL), with general kinetic model parametric mapping, to simultaneously quantify renal perfusion (RBF), bolus arrival time (BAT) and tissue T1. Methods In a study approved by the Health Research Authority, 12 healthy volunteers (mean age, 27.6 ± 18.5 years; 5 male) gave informed consent for renal imaging at 3 T using multi-TI ASL and conventional single-TI ASL. Glyceryl trinitrate (GTN) was used as a vasodilator challenge in six subjects. Flow-sensitive alternating inversion recovery (FAIR) preparation was used with background suppression and 3D-GRASE (gradient and spin echo) read-out, and images were motion-corrected. Parametric maps of RBF, BAT and T1 were derived for both kidneys. Agreement was assessed using Pearson correlation and Bland-Altman plots. Results Inter-study correlation of whole-kidney RBF was good for both single-TI (r2 = 0.90), and multi-TI ASL (r2 = 0.92). Single-TI ASL gave a higher estimate of whole-kidney RBF compared to multi-TI ASL (mean bias, 29.3 ml/min/100 g; p <0.001). Using multi-TI ASL, the median T1 of renal cortex was shorter than that of medulla (799.6 ms vs 807.1 ms, p = 0.01), and mean whole-kidney BAT was 269.7 ± 56.5 ms. GTN had an effect on systolic blood pressure (p < 0.05) but the change in RBF was not significant. Conclusions Free-breathing multi-TI renal ASL is feasible and reproducible at 3 T, providing simultaneous measurement of renal perfusion, haemodynamic parameters and tissue characteristics at baseline and during pharmacological challenge

Randomly hyperbranched polymers

We describe a model for the structures of randomly hyperbranched polymers in solution, and find a logarithmic growth of radius with polymer mass. We include segmental overcrowding, which puts an upper limit on the density. The model is tested against simulations, against data on amylopectin, a major component of starch, on glycogen, and on polyglycerols. For samples of synthetic polyglycerol and glycogen, our model holds well for all the available data. The model reveals higher-level scaling structure in glycogen, related to the beta particles seen in electron microscopy

Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis

BACKGROUND: In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. RESULTS: Gene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses. CONCLUSIONS: This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work

Iron Age and Anglo-Saxon genomes from East England reveal British migration history

British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain

Public Reasoning and Health-Care Priority Setting: The Case of NICE

Health systems that aim to secure universal patient access through a scheme of prepayments—whether through taxes, social insurance, or a combination of the two—need to make decisions on the scope of coverage that they guarantee: such tasks often falling to a priority-setting agency. This article analyzes the decision-making processes at one such agency in particular—the UK’s National Institute for Health and Care Excellence (NICE)—and appraises their ethical justifiability. In particular, we consider the extent to which NICE’s model can be justified on the basis of Rawls’s conception of “reasonableness.” This test shares certain features with the well-known Accountability for Reasonableness (AfR) model but also offers an alternative to it, being concerned with how far the values used by priority-setting agencies such as NICE meet substantive conditions of reasonableness irrespective of their procedural virtues. We find that while there are areas in which NICE’s processes may be improved, NICE’s overall approach to evaluating health technologies and setting priorities for health-care coverage is a reasonable one, making it an exemplar for other health-care systems facing similar coverage dilemmas. In so doing we offer both a framework for analysing the ethical justifiability of NICE’s processes and one that might be used to evaluate others

An additional k-means clustering step improves the biological features of WGCNA gene co-expression networks

Background: Weighted Gene Co-expression Network Analysis (WGCNA) is a widely used R software package for the generation of gene co-expression networks (GCN). WGCNA generates both a GCN and a derived partitioning of clusters of genes (modules). We propose k-means clustering as an additional processing step to conventional WGCNA, which we have implemented in the R package km2gcn (k-means to gene co-expression network, https://github.com/juanbot/km2gcn). Results: We assessed our method on networks created from UKBEC data (10 different human brain tissues), on networks created from GTEx data (42 human tissues, including 13 brain tissues), and on simulated networks derived from GTEx data. We observed substantially improved module properties, including: (1) few or zero misplaced genes; (2) increased counts of replicable clusters in alternate tissues (x3.1 on average); (3) improved enrichment of Gene Ontology terms (seen in 48/52 GCNs) (4) improved cell type enrichment signals (seen in 21/23 brain GCNs); and (5) more accurate partitions in simulated data according to a range of similarity indices. Conclusions: The results obtained from our investigations indicate that our k-means method, applied as an adjunct to standard WGCNA, results in better network partitions. These improved partitions enable more fruitful downstream analyses, as gene modules are more biologically meaningful

Hanging-related injury in Pietermaritzburg, South Africa

Background. Hanging is a common form of self-harm, and emergency care physicians will not infrequently be called upon to manage a survivor.Despite the relative frequency of the injury, there is a paucity of literature on the topic and the spectrum and incidence of associated injuries are poorly described.Objectives. To review experience with management of victims of hanging at a major trauma centre in South Africa.Methods. All patients treated by the Pietermaritzburg Metropolitan Trauma Service following a hanging incident between December 2012 and December 2018 were identified from the Hybrid Electronic Medical Registry. Basic demographics were recorded, and the management and outcome of each patient were noted.Results. During the 6-year period under review, a total of 154 patients were seen following a hanging incident. The mean age was 29.4 years. There were 24 females (15.6%) and 130 males (84.4%). The vast majority (n=150; 97.5%) had attempted suicide, and only 4 hangings (2.5%) were accidental. A total of 92 patients (60.9%) had consumed alcohol prior to the incident. There were 23 patients with a Glasgow Coma Score (GCS) &lt;9 (severe traumatic brain injury (TBI)), 14 with a GCS of 9 - 12 (moderate TBI) and 117 with a GCS &gt;12 (mild TBI). A total of 7 patients (4.5%) required intensive care unit admission, and 25 (16.2%) required intubation. The following extracranial injuries were documented on computed tomography scans: hyoid bone fractures (n=2), cervical spine fracture (n=10), mandible fracture (n=4) and oesophageal injury (n=1). Intracranial pathology was evident on 27.0% of scans, with the most common finding being global cerebral ischaemia. The mortality rate was 2.5% (4/154).Conclusions. Hanging is a common mechanism of self-harm. It is associated with significant injuries and mortality. The acute management of hanging should focus on airway protection followed by detailed imaging of the head and neck. Further work must attempt to include mortuary data on hanging.