Less Invasive Phenotype Found in Isocitrate Dehydrogenase-mutated Glioblastomas than in Isocitrate Dehydrogenase Wild-Type Glioblastomas: A Diffusion-Tensor Imaging Study

PURPOSE: To explore the diffusion-tensor (DT) imaging-defined invasive phenotypes of both isocitrate dehydrogenase (IDH-1)-mutated and IDH-1 wild-type glioblastomas. MATERIALS AND METHODS: Seventy patients with glioblastoma were prospectively recruited and imaged preoperatively. All patients provided signed consent, and the local research ethics committee approved the study. Patients underwent surgical resection, and tumor samples underwent immunohistochemistry for IDH-1 R132H mutations. DT imaging data were coregistered to the anatomic magnetic resonance study and reconstructed to provide the anisotropic and isotropic components of the DT. The invasive phenotype was determined by using previously published criteria and correlated with IDH-1 mutation status by using the Freeman-Halton extension of the Fisher exact probability test. RESULTS: Nine patients had an IDH-1 mutation and 61 had IDH-1 wild type. All of the patients with IDH-1 mutation had a minimally invasive DT imaging phenotype. Among the IDH-1 wild-type tumors, 42 of 61 (69%) were diffusively invasive glioblastomas, 14 of 61 (23%) were locally invasive, and five of 61 (8%) were minimally invasive (P < .001). CONCLUSION: IDH-mutated glioblastomas have a less invasive phenotype compared with IDH wild type. This finding may have implications for individualizing the extent of surgical resection and radiation therapy volumes.NIHR Clinician Scientist Fellowship (NIHR/CS/009/011); Chang Gung Medical Foundation; Chang Gung Memorial Hospital; Commonwealth Scholarship Commission; Cambridge Commonwealth Overseas Trust; NIHR Cambridge Biomedical Research Centr

Use of whole-genome sequencing to identify clusters of Shigella flexneri associated with sexual transmission in men who have sex with men in England: a validation study using linked behavioural data

Since the 1970s, shigellosis has been reported as a sexually transmissible infection, and in recent years, genomic data have revealed the breadth of Shigella spp. transmission among global networks of men who have sex with men (MSM). In 2015, Public Health England (PHE) introduced routine whole-genome sequencing (WGS) of Shigella spp. to identify transmission clusters. However, limited behavioural information for the cases hampers interpretation. We investigated whether WGS can distinguish between clusters representing sexual transmission in MSM and clusters representing community (non-sexual) transmission to inform infection control. WGS data for Shigella flexneri from August 2015 to July 2017 were aggregated into single linkage clusters based on SNP typing using a range of SNP distances (the standard for Shigella surveillance at PHE is 10 SNPs). Clusters were classified as 'adult male', 'household', 'travel-associated' or 'community' using routine demographic data submitted alongside laboratory cultures. From August 2015 to March 2017, PHE contacted those with shigellosis as part of routine public-health follow-up and collected exposure data on a structured questionnaire, which for the first time included questions about sexual identity and behaviour. The questionnaire data were used to determine whether clusters classified as 'adult male' represented likely sexual transmission between men, thereby validating the use of the SNP clustering tool for informing appropriate public-health responses. Overall, 1006 S. flexneri cases were reported, of which 563 clustered with at least one other case (10-SNP threshold). Linked questionnaire data were available for 106 clustered cases, of which 84.0 % belonged to an 'adult male' cluster. At the 10-SNP threshold, 95.1 % [95 % confidence interval (CI) 88.0-98.1%] of MSM belonged to an 'adult male' cluster, while 73.2 % (95 % CI 49.1-87.5%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. At the 25-SNP threshold, all MSM (95 % CI 96.0-100%) belonged to an 'adult male' cluster and 77.8 % (95 % CI 59.2-89.4%) of non-MSM belonged to a 'community' or 'travel-associated' cluster. Within one phylogenetic clade of S. flexneri, 9 clusters were identified (7 'adult male'; 2 'community') using a 10-SNP threshold, while a single 'adult male' cluster was identified using a 25-SNP threshold. Genotypic markers of azithromycin resistance were detected in 84.5 % (294/348) of 'adult male' cases and 20.9 % (9/43) of cases in other clusters (10-SNP threshold), the latter of which contained gay-identifying men who reported recent same-sex sexual contact. Our study suggests that SNP clustering can be used to identify Shigella clusters representing likely sexual transmission in MSM to inform infection control. Defining clusters requires a flexible approach in terms of genetic relatedness to ensure a clear understanding of underlying transmission networks

Rural to Urban Migration and Changes in Cardiovascular risk Factors in Tanzania: A Prospective Cohort Study.

High levels of rural to urban migration are a feature of most African countries. Our aim was to investigate changes, and their determinants, in cardiovascular risk factors on rural to urban migration in Tanzania. Men and women (15 to 59 years) intending to migrate from Morogoro rural region to Dar es Salaam for at least 6 months were identified. Measurements were made at least one week but no more than one month prior to migration, and 1 to 3 monthly after migration. Outcome measures included body mass index, blood pressure, fasting lipids, and self reported physical activity and diet. One hundred and three men, 106 women, mean age 29 years, were recruited and 132 (63.2%) followed to 12 months. All the figures presented here refer to the difference between baseline and 12 months in these 132 individuals. Vigorous physical activity declined (79.4% to 26.5% in men, 37.8% to 15.6% in women, p < 0.001), and weight increased (2.30 kg men, 2.35 kg women, p < 0.001). Intake of red meat increased, but so did the intake of fresh fruit and vegetables. HDL cholesterol increased in men and women (0.24, 0.25 mmoll-1 respectively, p < 0.001); and in men, not women, total cholesterol increased (0.42 mmoll-1, p = 0.01), and triglycerides fell (0.31 mmoll-1, p = 0.034). Blood pressure appeared to fall in both men and women. For example, in men systolic blood pressure fell by 5.4 mmHg, p = 0.007, and in women by 8.6 mmHg, p = 0.001. The lower level of physical activity and increasing weight will increase the risk of diabetes and cardiovascular disease. However, changes in diet were mixed, and may have contributed to mixed changes in lipid profiles and a lack of rise in blood pressure. A better understanding of the changes occurring on rural to urban migration is needed to guide preventive measures

The influence of perfusion solution on renal graft viability assessment

BACKGROUND: Kidneys from donors after cardiac or circulatory death are exposed to extended periods of both warm ischemia and intra-arterial cooling before organ recovery. Marshall’s hypertonic citrate (HOC) and Bretschneider’s histidine-tryptophan-ketoglutarate (HTK) preservation solutions are cheap, low viscosity preservation solutions used clinically for organ flushing. The aim of the present study was to evaluate the effects of these two solutions both on parameters used in clinical practice to assess organ viability prior to transplantation and histological evidence of ischemic injury after reperfusion. METHODS: Rodent kidneys were exposed to post-mortem warm ischemia, extended intra-arterial cooling (IAC) (up to 2 h) with preservation solution and reperfusion with either Krebs-Hensleit or whole blood in a transplant model. Control kidneys were either reperfused directly after retrieval or stored in 0.9% saline. Biochemical, immunological and histological parameters were assessed using glutathione-S-transferase (GST) enzymatic assays, polymerase chain reaction and mitochondrial electron microscopy respectively. Vascular function was assessed by supplementing the Krebs-Hensleit perfusion solution with phenylephrine to stimulate smooth muscle contraction followed by acetylcholine to trigger endothelial dependent relaxation. RESULTS: When compared with kidneys reperfused directly post mortem, 2 h of IAC significantly reduced smooth muscle contractile function, endothelial function and upregulated vascular cellular adhesion molecule type 1 (VCAM-1) independent of the preservation solution. However, GST release, vascular resistance, weight gain and histological mitochondrial injury were dependent on the preservation solution used. CONCLUSIONS: We conclude that initial machine perfusion viability tests, including ischemic vascular resistance and GST, are dependent on the perfusion solution used during in situ cooling. HTK-perfused kidneys will be heavier, have higher GST readings and yet reduced mitochondrial ischemic injury when compared with HOC-perfused kidneys. Clinicians should be aware of this when deciding which kidneys to transplant or discard

Paleolimnological Assessment of Six Lakes on the Kissimmee Chain, with Implications for Restoration of the Kissimmee-Okeechobee-Everglades system, Florida, USA

Whitmore TJ, Riedinger-Whitmore MA, Reed ZE, Curtis JH, Yang H, Evans DE, Cropper NR, Alvarado KS, Lauterman FM, Scott A, Leonard CR, Franklin DL. 2020. Paleolimnological assessment of six lakes on the Kissimmee Chain, with implications for restoration of the Kissimmee–Okeechobee–Everglades system, Florida, USA. Lake Reserv Manage. 36:218–242. The Kissimmee Basin in south central Florida contains a large, freshwater network that includes the Kissimmee River and nearly 2 dozen lakes that are headwaters of the Florida Everglades. Management of these lakes is an important part of Everglades restoration. We report a paleolimnological investigation of 6 lakes in the Upper Kissimmee Basin. Engineering activities connected the lakes and permanently altered hydrology in the 19th and 20th centuries. The lakes were naturally meso-eutrophic, but changes in lake levels and nutrient loading contributed to different degrees of eutrophication. Cyanobacteria were present historically at low levels in Lakes East Tohopekaliga, Cypress, and Tohopekaliga, but increased during the 20th century. Lake Jackson lacked cyanobacteria until recently, but Lakes Kissimmee and Marian have had high levels of cyanobacteria since predisturbance times. Profound changes in the lakes occurred after engineering activities eliminated natural large fluctuations in water levels that periodically dried large portions of the basins. Salt-tolerant biological indicators previously alternated with freshwater organisms. Large water-level fluctuations moderated aquatic-plant standing crops and reduced organic matter accumulation. Lakes Kissimmee and Marian showed greatest evidence of former associated wetlands, but lacked large variations in water levels. We recommend disconnecting these lakes from each other and from the Kissimmee River to reestablish large, natural fluctuations in water levels that were part of healthy ecosystem function. Former wetlands should be restored to slow the downstream cascade of nutrients to Lake Okeechobee and the Everglades. This study demonstrates that paleolimnology is useful for assessing hydrological changes that potentially affect lake restoration efforts

Clinical and Imaging Characteristics of Arteriopathy Subtypes in Children with Arterial Ischemic Stroke: Results of the VIPS Study.

Background and purposeChildhood arteriopathies are rare but heterogenous, and difficult to diagnose and classify, especially by nonexperts. We quantified clinical and imaging characteristics associated with childhood arteriopathy subtypes to facilitate their diagnosis and classification in research and clinical settings.Materials and methodsThe Vascular Effects of Infection in Pediatric Stroke (VIPS) study prospectively enrolled 355 children with arterial ischemic stroke (2010-2014). A central team of experts reviewed all data to diagnose childhood arteriopathy and classify subtypes, including arterial dissection and focal cerebral arteriopathy-inflammatory type, which includes transient cerebral arteriopathy, Moyamoya disease, and diffuse/multifocal vasculitis. Only children whose stroke etiology could be conclusively diagnosed were included in these analyses. We constructed logistic regression models to identify characteristics associated with each arteriopathy subtype.ResultsAmong 127 children with definite arteriopathy, the arteriopathy subtype could not be classified in 18 (14%). Moyamoya disease (n = 34) occurred mostly in children younger than 8 years of age; focal cerebral arteriopathy-inflammatory type (n = 25), in children 8-15 years of age; and dissection (n = 26), at all ages. Vertigo at stroke presentation was common in dissection. Dissection affected the cervical arteries, while Moyamoya disease involved the supraclinoid internal carotid arteries. A banded appearance of the M1 segment of the middle cerebral artery was pathognomonic of focal cerebral arteriopathy-inflammatory type but was present in &lt;25% of patients with focal cerebral arteriopathy-inflammatory type; a small lenticulostriate distribution infarct was a more common predictor of focal cerebral arteriopathy-inflammatory type, present in 76%. It remained difficult to distinguish focal cerebral arteriopathy-inflammatory type from intracranial dissection of the anterior circulation. We observed only secondary forms of diffuse/multifocal vasculitis, mostly due to meningitis.ConclusionsChildhood arteriopathy subtypes have some typical features that aid diagnosis. Better imaging methods, including vessel wall imaging, are needed for improved classification of focal cerebral arteriopathy of childhood

Multiparametric MR Imaging of Diffusion and Perfusion in Contrast-enhancing and Nonenhancing Components in Patients with Glioblastoma

Purpose To determine whether regions of low apparent diffusion coefficient (ADC) with high relative cerebral blood volume (rCBV) represented elevated choline (Cho)-to-N-acetylaspartate (NAA) ratio (hereafter, Cho/NAA ratio) and whether their volumes correlated with progression-free survival (PFS) and overall survival (OS) in patients with glioblastoma (GBM). Materials and Methods This retrospective analysis was approved by the local research ethics committee. Volumetric analysis of imaging data from 43 patients with histologically confirmed GBM was performed. Patients underwent preoperative 3-T magnetic resonance imaging with conventional, diffusion-weighted, perfusion-weighted, and spectroscopic sequences. Patients underwent subsequent surgery with adjuvant chemotherapy and radiation therapy. Overlapping low-ADC and high-rCBV regions of interest (ROIs) (hereafter, ADC-rCBV ROIs) were generated in contrast-enhancing and nonenhancing regions. Cho/NAA ratio in ADC-rCBV ROIs was compared with that in control regions by using analysis of variance. All resulting ROI volumes were correlated with patient survival by using multivariate Cox regression. Results ADC-rCBV ROIs within contrast-enhancing and nonenhancing regions showed elevated Cho/NAA ratios, which were significantly higher than those in other abnormal tumor regions (P < .001 and P = .008 for contrast-enhancing and nonenhancing regions, respectively) and in normal-appearing white matter (P < .001 for both contrast-enhancing and nonenhancing regions). After Cox regression analysis controlling for age, tumor size, resection extent, O-6-methylguanine-DNA methyltransferase-methylation, and isocitrate dehydrogenase mutation status, the proportional volume of ADC-rCBV ROIs in nonenhancing regions significantly contributed to multivariate models of OS (hazard ratio, 1.132; P = .026) and PFS (hazard ratio, 1.454; P = .017). Conclusion Volumetric analysis of ADC-rCBV ROIs in nonenhancing regions of GBM can be used to identify patients with poor survival trends after accounting for known confounders of GBM patient outcome.Supported by a Clinician Scientist Award from the National Institute for Health Research (NIHR/CS/009/011) and by the NIHR Cambridge Biomedical Research Center and Commonwealth Scholarship Commission

Nonreciprocal reconfigurable microwave optomechanical circuit.

Nonreciprocal microwave devices are ubiquitous in radar and radio communication and indispensable in the readout chains of superconducting quantum circuits. Since they commonly rely on ferrite materials requiring large magnetic fields that make them bulky and lossy, there has been significant interest in magnetic-field-free on-chip alternatives, such as those recently implemented using the Josephson nonlinearity. Here, we realize reconfigurable nonreciprocal transmission between two microwave modes using purely optomechanical interactions in a superconducting electromechanical circuit. The scheme relies on the interference in two mechanical modes that mediate coupling between the microwave cavities and requires no magnetic field. We analyse the isolation, transmission and the noise properties of this nonreciprocal circuit. Finally, we show how quantum-limited circulators can be realized with the same principle. All-optomechanically mediated nonreciprocity demonstrated here can also be extended to directional amplifiers, and it forms the basis towards realizing topological states of light and sound.Nonreciprocal optical devices traditionally rely on magnetic fields and magnetic-free approaches are rather recent. Here, Bernier et al. propose and demonstrate a purely optomechanical circulator with reconfigurable transmission without the need for direct coupling between input and output modes.This work was supported by the SNF, the NCCR Quantum Science and Technology (QSIT), and the EU Horizon 2020 research and innovation programme under grant agreement No. 732894 (FET Proactive HOT). DM acknowledges support by the UK Engineering and Physical Sciences Research Council (EPSRC) under Grant No. EP/M506485/1. T.J.K. acknowledges financial support from an ERC AdG (QuREM). A.N. holds a University Research Fellowship from the Royal Society and acknowledges support from the Winton Programme for the Physics of Sustainability. A.K. holds INSPIRE scholarship from the Department of Science and Technology, India. All samples were fabricated in the Center of MicroNanoTechnology (CMi) at EPFL

Trail laying during tandem-running recruitment in the ant Temnothorax albipennis

Tandem running is a recruitment strategy whereby one ant leads a single naïve nest mate to a resource. While tandem running progresses towards the goal, the leader ant and the follower ant maintain contact mainly by tactile signals. In this paper, we investigated whether they also deposit chemical signals on the ground during tandem running. We filmed tandem-running ants and analysed the position of the gasters of leaders and followers. Our results show that leader ants are more likely to press their gasters down to the substrate compared to follower ants, single ants and transporter ants. Forward tandem-run leaders (those moving towards a new nest site) performed such trail-marking procedures three times more often than reverse tandem leaders (those moving towards an old nest site). That leader ants marked the trails more often during forward tandem runs may suggest that it is more important to maintain the bond with the follower ant on forward tandem runs than on reverse tandem runs. Marked trails on the ground may serve as a safety line that improves both the efficiency of tandem runs and their completion rates. © 2014 Springer-Verlag Berlin Heidelberg

Rabies screen reveals GPe control of cocaine-triggered plasticity.

Identification of neural circuit changes that contribute to behavioural plasticity has routinely been conducted on candidate circuits that were preselected on the basis of previous results. Here we present an unbiased method for identifying experience-triggered circuit-level changes in neuronal ensembles in mice. Using rabies virus monosynaptic tracing, we mapped cocaine-induced global changes in inputs onto neurons in the ventral tegmental area. Cocaine increased rabies-labelled inputs from the globus pallidus externus (GPe), a basal ganglia nucleus not previously known to participate in behavioural plasticity triggered by drugs of abuse. We demonstrated that cocaine increased GPe neuron activity, which accounted for the increase in GPe labelling. Inhibition of GPe activity revealed that it contributes to two forms of cocaine-triggered behavioural plasticity, at least in part by disinhibiting dopamine neurons in the ventral tegmental area. These results suggest that rabies-based unbiased screening of changes in input populations can identify previously unappreciated circuit elements that critically support behavioural adaptations