Global Effects of Focal Brain Tumors on Functional Complexity and Network Robustness: A Prospective Cohort Study.

BACKGROUND: Neurosurgical management of brain tumors has entered a paradigm of supramarginal resections that demands thorough understanding of peritumoral functional effects. Historically, the effects of tumors have been believed to be local, and long-range effects have not been considered. OBJECTIVE: To test the hypothesis that tumors affect the brain globally, producing long-range gradients in cortical function. METHODS: Resting-state functional magnetic resonance imaging (fMRI) data were acquired from 11 participants with glioblastoma and split into discovery and validation datasets in a single-center prospective cohort study. Fractal complexity was computed with a wavelet-based estimator of the Hurst exponent. Distance-related effects of the tumors were tested with a tumor mask-dilation technique and parcellation of the underlying Hurst maps. RESULTS: Fractal complexity demonstrates a penumbra of suppression in the peritumoral region. At a global level, as distance from the tumor increases, this initial suppression is balanced by a subsequent overactivity before finally normalizing. These effects were best fit by a quadratic model and were consistent across different network construction pipelines. The Hurst exponent was correlated with graph theory measures of centrality including network robustness, but graph theory measures did not demonstrate distance-dependent effects. CONCLUSION: This work provides evidence supporting the theory that focal brain tumors produce long-range gradients in function. Consequently, the effects of focal lesions need to be interpreted in terms of the global changes on functional complexity and network architecture rather than purely in terms of functional localization. Determining whether peritumoral changes represent potential plasticity may facilitate extended resection of tumors without functional cost.MGH is funded by the Wellcome Trust Neuroscience in Psychiatry Network with additional support from the National Institute for Health Research Cambridge Biomedical Research Centre. The imaging studies were funded by an NIHR Clinician Scientist Fellowship for SJP (NIHR/CS/009/011)

Three Cases of Canine Dermatomyositis-Like Disease

Background: Dermatomyositis is an idiopathic, inflammatory/immunemediated disease of the skin, muscles and bloodvessels of hereditary nature and unclear pathogenesis. This familial disease has been described in certain breeds, especially collies and Shetland sheep dogs and is of rare occurrence in mongrel dogs. To describe and discuss three clinical cases of dermatomyositis-like disease and provide a brief review of the literature.Cases: Three young mongrel dogs are included in this report. Case 1: Mandarino, a 4-year-old mongrel dog, having a history of skin lesions for at least a year. Showed an underweight patient, skin ulcers, crusts, alopecia, peri-ocular scarring causing severe lagophthalmia and a corneal ulcer. Muscle atrophy was most notable in the head and legs; the dog haddifficulty and pain walking. Treatment was initialised with cephalexin 30 mg/kg BID, pentoxifylline 25 mg/kg BID, and prednisone 2.2 mg/kg SID. The patient was presented after two weeks for follow up; the anaemia and skin condition had improved, the weight had increased by 2 kg, dysphagia and locomotor abnormalities were not present. Case 2: Milagros,a mongrel female dog approximately two years of age, rescued from a shelter. Physical examination showed facial alopecia, erythema and scarring of the periocular skin, crusting and scaling in alopecic areas, pinnae tip necrosis and crusting, ear alopecia, tail tip necrosis and crusting. Also present were distal limb alopecia, crusting and ulcers in areas of trauma in the hock and carpal surfaces; some nails presented onychorhexis and onychoschizia. The patient has been treated for12 months with a good clinical outcome, with pentoxifylline, azathioprine 2.2 mg/kg EOD alternating with prednisone 1 mg/kg EOD. Case 3: Chuchito, an 11-month-old male mongrel rescued dog had been previously hospitalised due to his skin condition. Physical examination showed depigmented and alopecic areas in the nasal planum, perioral and periocular areas, and inflammation of the palpebral tissues. Necrosis of the distal pinnae, alopecia and scales were evident, along with sloughing of scales and ulcers. Skin lesions were also present in the distal limbs, and alopecia, erythema and some crusting and scales in the carpal, tarsal and digital areas. Onychodystrophy was present in several digits. This study describes the physical examination and the clinical pathological findings, including skin scrapings, fungal cultures, and skin biopsies, in three dogs with dermatomyositis-like disease, as well as the clinical outcomes after slightly different treatment protocols were used. The biopsy results of two dogs showed ischaemic dermatopathy.Discussion: The most common initial signs of the disease are erythema, desquamation and alopecia in the facial area, ears, distal limbs and pinnae in young puppies aged between two and six months of age, followed by pigmentary changes. Muscular lesions are uncommon; when present, they represent the most severe form of this disease. Dysphagia is a common sign and mega-oesophagus may be present. Patients with muscular disease can manifest difficulty walking, with a stiff high gait. The immune mediated pathogenesis of dermatomyositis can relate to triggering factors in some dogs, such as drugs, infections, paraneoplasms, or toxins. Other potential inducing stressors include oestrus, whelping and excessive solar exposure. Dermatomyositis-like or familiar dermatomyositis is diagnosed using clinical findings, histopathologyof skin and muscle, and muscle physiology studies. Electromyography, breed predisposition and genetic background can be helpful in some cases. The clinical findings and response to the treatment of all three cases were compatible with dermatomyositis-like disease in mongrel dogs.Keywords: dermatomyositis, dermatopathy, vascular disease, inflammatory myopathies, mongrel dog

Ten simple rules for aspiring graduate students.

Several supervillains have higher degrees—why don’t you? There can be a variety of reasons for wanting to go to grad school and for applying to a particular school and program. But often, one can only tell apart good and bad reasons from hindsight. Failing at something is perhaps the best way to know what can go wrong and what advice would have been useful when considering graduate school applications.We should know: one of us started graduate school 4 separate times, and another learned what a PhD was only after having started one; lost 2 supervisors before even starting to write her thesis, and yet another accepted a PhD offer from the lab where she was working, without considering any alternatives; finally, one of us had applied to graduate schools for 5 years (with 19 rejections) before finally landing a PhD offer from their dream school. We hope that our hard-earned lessons will help you to avoid some of the pitfalls that we ourselves fell prey to. In this article, we address how to choose a graduate program, how to apply strategically, and some of the key challenges that may arise along the way toward graduate school. Conveniently, our advice can be summarized as 10 simple rules . . . so here they are.The authors acknowledge the support of the Gates Cambridge Trust [AIL], Cancer Research UK [RRG], Alzheimer’s Society [CCN], Merck [CCN], and the Isaac Newton Trust [EG]

Anomalous Hall conductivity control in Mn3_3NiN antiperovskite by epitaxial strain along the kagome plane

Antiferromagnetic manganese-based nitride antiperovskites, such as Mn$_3$NiN, hold a triangular frustrated magnetic ordering over their kagome lattice formed by the Mn atoms along the (111)-plane. As such, frustration imposes a non-trivial interplay between the symmetric and asymmetric magnetic interactions, which can only reach equilibrium in a noncollinear magnetic configuration. Consequently, the associated electronic interactions and their possible tuning by external constraints, such as applied epitaxial strain, play a crucial role in defining the microscopic and macroscopic properties of such topological condensed matter systems. Thus, in the present work, we explored and explained the effect of the epitaxial strain imposed within the (111)-plane, in which the magnetic and crystallographic symmetry operations are kept fixed, and only the magnitude of the ionic and electronic interactions are tuned. We found a linear shifting in the energy of the band structure and a linear increase/decrease of the available states near the Fermi level with the applied strain. Concretely, the compression strain reduces the Mn-Mn distances in the (111) kagome plane but linearly increases the separation between the stacked kagome lattices and the available states near the Fermi level. Despite the linear controlling of the available states across the Fermi energy, the anomalous Hall conductivity shows a non-linear behavior where the $\sigma_{111}$ conductivity nearly vanishes for tensile strain. On the other hand, $\sigma_{111}$ fetches a maximum increase of 26\% about the unstrained structure for a compression value close to $-$1.5\%.This behavior found an explanation in the non-divergent Berry curvature within the kagome plane, which is increased for constraining but significantly reduced for expansion strain values..

Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas.

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers and large-scale connectivity networks. By applying independent component analysis to lesion data from 242 adult patients with high- and low-grade glioma, we identified three lesion covariance networks, which reflect clusters of frequent glioma localization. Replicability of the lesion covariance networks was assessed in an independent sample of 168 glioma patients. We related the lesion covariance networks to important clinical variables, including tumour grade and patient survival, as well as genomic information such as molecular genetic subtype and bulk transcriptomic profiles. Finally, we systematically cross-correlated the lesion covariance networks with structural and functional connectivity networks derived from neuroimaging data of over 4000 healthy UK BioBank participants to uncover intrinsic brain networks that may that underlie tumour development. The three lesion covariance networks overlapped with the anterior, posterior and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal and temporal cortices. These locations were independently replicated. The first lesion covariance network, which overlapped with the anterior horn, was associated with low-grade, isocitrate dehydrogenase -mutated/1p19q-codeleted tumours, as well as a neural transcriptomic signature and improved overall survival. Each lesion covariance network significantly coincided with multiple structural and functional connectivity networks, with the first bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each lesion covariance network. In conclusion, we demonstrated replicable patterns of glioma localization with clinical relevance and spatial correspondence with large-scale functional and structural connectivity networks. These results are consistent with prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Our findings describe how the locations of gliomas relate to their proposed subventricular origins, suggesting a model wherein periventricular brain connectivity guides tumour development

BOLD Coupling between Lesioned and Healthy Brain Is Associated with Glioma Patients’ Recovery

Predicting functional outcomes after surgery and early adjuvant treatment is difficult due to the complex, extended, interlocking brain networks that underpin cognition. The aim of this study was to test glioma functional interactions with the rest of the brain, thereby identifying the risk factors of cognitive recovery or deterioration. Seventeen patients with diffuse non-enhancing glioma (aged 22–56 years) were longitudinally MRI scanned and cognitively assessed before and after surgery and during a 12-month recovery period (55 MRI scans in total after exclusions). We initially found, and then replicated in an independent dataset, that the spatial correlation pattern between regional and global BOLD signals (also known as global signal topography) was associated with tumour occurrence. We then estimated the coupling between the BOLD signal from within the tumour and the signal extracted from different brain tissues. We observed that the normative global signal topography is reorganised in glioma patients during the recovery period. Moreover, we found that the BOLD signal within the tumour and lesioned brain was coupled with the global signal and that this coupling was associated with cognitive recovery. Nevertheless, patients did not show any apparent disruption of functional connectivity within canonical functional networks. Understanding how tumour infiltration and coupling are related to patients’ recovery represents a major step forward in prognostic development.Consejeria de Economia, Innovacion, Ciencia y Empleo.Junta de Andalucia CV20-45250; A-TIC-080-UGR18; B-TIC-586-UGR20; P20-0052

Lesion covariance networks reveal proposed origins and pathways of diffuse gliomas.

Diffuse gliomas have been hypothesized to originate from neural stem cells in the subventricular zone and develop along previously healthy brain networks. Here, we evaluated these hypotheses by mapping independent sources of glioma localization and determining their relationships with neurogenic niches, genetic markers and large-scale connectivity networks. By applying independent component analysis to lesion data from 242 adult patients with high- and low-grade glioma, we identified three lesion covariance networks, which reflect clusters of frequent glioma localization. Replicability of the lesion covariance networks was assessed in an independent sample of 168 glioma patients. We related the lesion covariance networks to important clinical variables, including tumour grade and patient survival, as well as genomic information such as molecular genetic subtype and bulk transcriptomic profiles. Finally, we systematically cross-correlated the lesion covariance networks with structural and functional connectivity networks derived from neuroimaging data of over 4000 healthy UK BioBank participants to uncover intrinsic brain networks that may that underlie tumour development. The three lesion covariance networks overlapped with the anterior, posterior and inferior horns of the lateral ventricles respectively, extending into the frontal, parietal and temporal cortices. These locations were independently replicated. The first lesion covariance network, which overlapped with the anterior horn, was associated with low-grade, isocitrate dehydrogenase -mutated/1p19q-codeleted tumours, as well as a neural transcriptomic signature and improved overall survival. Each lesion covariance network significantly coincided with multiple structural and functional connectivity networks, with the first bearing an especially strong relationship with brain connectivity, consistent with its neural transcriptomic profile. Finally, we identified subcortical, periventricular structures with functional connectivity patterns to the cortex that significantly matched each lesion covariance network. In conclusion, we demonstrated replicable patterns of glioma localization with clinical relevance and spatial correspondence with large-scale functional and structural connectivity networks. These results are consistent with prior reports of glioma growth along white matter pathways, as well as evidence for the coordination of glioma stem cell proliferation by neuronal activity. Our findings describe how the locations of gliomas relate to their proposed subventricular origins, suggesting a model wherein periventricular brain connectivity guides tumour development

EuroEco (European Health Economic Trial on Home Monitoring in ICD Patients): a provider perspective in five European countries on costs and net financial impact of follow-up with or without remote monitoring

Aim: Remote follow-up (FU) of implantable cardiac defibrillators (ICDs) allows for fewer in-office visits in combination with earlier detection of relevant findings. Its implementation requires investment and reorganization of care. Providers (physicians or hospitals) are unsure about the financial impact. The primary end-point of this randomized prospective multicentre health economic trial was the total FU-related cost for providers, comparing Home Monitoring facilitated FU (HM ON) to regular in-office FU (HM OFF) during the first 2 years after ICD implantation. Also the net financial impact on providers (taking national reimbursement into account) and costs from a healthcare payer perspective were evaluated. Methods and results: Atotal of 312 patients with VVI-or DDD-ICD implants from 17 centres in six EU countries were randomised to HMON or OFF, of which 303 were eligible for data analysis. For all contacts (in-office, calendar-or alert-triggered web-based review, discussions, calls) time-expenditure was tracked. Country-specific cost parameters were used to convert resource use into monetary values. Remote FU equipment itself was not included in the cost calculations. Given only two patients from Finland (one in each group) a monetary valuation analysis was not performed for Finland. Average age was 62.4 +/- 13.1 years, 81% were male, 39% received a DDD system, and 51% had a prophylactic ICD. Resource use with HM ON was clearly different: less FU visits (3.79 +/- 1.67 vs. 5.53 +/- 2.32; P < 0.001) despite a small increase of unscheduled visits (0.95 +/- 1.50 vs. 0.62 +/- 1.25; P < 0.005), more non-office-based contacts (1.95+3.29 vs. 1.01 +/- 2.64; P < 0.001), more Internet sessions (11.02 +/- 15.28 vs. 0.06 +/- 0.31; P < 0.001) and more in-clinic discussions (1.84 +/- 4.20 vs. 1.28 +/- 2.92; P < 0.03), but with numerically fewer hospitalizations (0.67 +/- 1.18 vs. 0.85 +/- 1.43, P = 0.23) and shorter length-of-stay (6.31 +/- 15.5 vs. 8.26 +/- 18.6; P = 0.27), although not significant. For the whole study population, the total FU cost for providers was not different for HM ON vs. OFF [mean (95% CI): (sic)204 169-238) vs. (sic)213 (182-243); range for difference ((sic)-36 to 54), NS]. From a payer perspective, FU-related costs were similar while the total cost per patient (including other physician visits, examinations, and hospitalizations) was numerically (but not significantly) lower. There was no difference in the net financial impact on providers [profit of (sic)408 (327-489) vs. (sic)400 (345-455); range for difference ((sic)-104 to 88), NS], but there was heterogeneity among countries, with less profit for providers in the absence of specific remote FU reimbursement (Belgium, Spain, and the Netherlands) and maintained or increased profit in cases where such reimbursement exists (Germany and UK). Quality of life (SF-36) was not different. Conclusion: For all the patients as a whole, FU-related costs for providers are not different for remote FU vs. purely in-office FU, despite reorganized care. However, disparity in the impact on provider budget among different countries illustrates the need for proper reimbursement to ensure effective remote FU implementation

End of life care in nursing homes in Spain: exploratory analysis and evidences of validity of a new scale.

This document is the accepted manuscript version of the following article: Maria Remedios Sánchez-GarcÍa, Jose Antonio Gutiérrez-Romero, Manuel Fernández Alcántara, César Hueso-Montoro, Claire Goodman, and Rafael Montoya-Juárez, ‘End of life care in nursing homes in Spain: Exploratory analysis and evidences of validity of a new scale’, Applied Nursing Research, Vol. 37: 6-12, October 2017. Under embargo until 5 July 2018. The final, definite version is available online at DOI: https://doi.org/10.1016/j.apnr.2017.07.001.Quality end-of-life care is a central issue in nursing homes, requiring the assessment of individual and family needs by health professionals. Although previous instruments have been developed, they usually rely on family reports and have been adapted from other clinical contexts (hospital or primary care). It is important to consider how health care professionals working in nursing homes perceive what is necessary to achieve quality end-of-life care. In this study, the objective was to develop an instrument to assess quality of end-of-life care in the context of Spanish care homes. A 24 item scale Nursing Home End of Life Care Scale (NHEOLC) was developed through a systematic evaluation of existing tools combined with an iterative process of consultation with group experts in end of life care in long term care settings. A total of 307 health care professionals agreed to participate in the study and completed the scale. The scale was grouped in six dimensions: physical, psychological aspects and spiritual aspects of care, family care, bereavement, and patient/family preferences management. The results suggest an adequate factorial structure of the scale and good internal consistency for the total score and the subscales. In addition, the results showed significant differences depending on the size of the nursing home, the category of health professionals, and their own perceptions of his work regarding end-of-life care.Peer reviewe