Interindividual differences in posterior fossa morphometry affect cerebellar tDCS-induced electric field strength

Objective Clinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed to examine associations between cerebellar tDCS-induced electric field strength, morphometric posterior fossa parameters, and skin-cerebellum distance. As a secondary objective, field characteristics were compared between cephalic and extracephalic electrode configurations. Methods Electric field simulations of midline cerebellar tDCS (7 × 5 cm electrodes, current intensities of 2 mA) were performed on MRI-based head models from 37 healthy adults using buccinator, frontopolar, and lower neck reference electrodes. Average field strengths were determined in eight regions of interest (ROIs) covering the anterior and posterior vermis and cerebellar hemispheres. Besides skin-cerebellum distance, various angles were measured between posterior fossa structures. Multivariable linear regression models were used to identify predictors of field strength in different ROIs. Results Skin-cerebellum distance and “pons angle” were independently associated with field strength in the anterior and posterior vermis. “Cerebellar angle” and skin-cerebellum distance affected field strength in anterior and posterior regions of the right cerebellar hemisphere. Field strengths in all examined cerebellar areas were highest in the frontopolar and lowest in the lower neck montage, while the opposite was found for field focality. The lower neck montage induced considerably less spreading toward anterior cerebellar regions compared with the buccinator and frontopolar montages, which resulted in a more evenly distributed field within the cerebellum. Conclusion In addition to skin-cerebellum distance, interindividual differences in posterior fossa morphometry, specifically pons and cerebellar angle, explain part of the variability in cerebellar tDCS-induced electric field strength. Furthermore, when targeting the midline cerebellum with tDCS, an extracephalic reference electrode is associated with lower field strengths and higher field focality than cephalic montages. Significance This study identifies two novel subject-specific anatomical factors that partly determine cerebellar tDCS-induced electric field strength and reveals differences in field characteristics between electrode montages

Enabling a More Externally Focused and Operational PLA – 2020 PLA Conference Papers

Although the People’s Liberation Army is not yet a global expeditionary force on par with the US military, the former has nevertheless significantly expanded its ability to operate abroad. Through enhanced technological capabilities, robust relationships with foreign militaries, increased access to overseas military bases and dual-use facilities, and the implementation of major structural reforms, the People’s Liberation Army has built a more integrated joint force capable of conducting a wider and more complex array of missions. This volume advances the understanding of the People’s Liberation Army’s capability to conduct overseas missions by examining China’s military relations with Europe, Africa, and Latin America; the country’s military activities in the Indian Ocean, polar regions, and Pacific Island countries; and the emerging roles of the People’s Liberation Army Rocket Force and the Joint Logistic Support Force. This volume finds the People’s Liberation Army is engaged in a wide range of activities throughout the world, including port calls, joint exercises, seminars, and personnel exchanges. China sells weapons to some parts of the world and seeks to acquire military and dual-use technology from others. In addition, the People’s Liberation Army seeks to increase its capability to operate in parts of the world, such as the Indian Ocean, Pacific Island countries, and polar regions, where the organization has only had a minimal presence in the past.https://press.armywarcollege.edu/monographs/1947/thumbnail.jp

“Excellence R Us”: university research and the fetishisation of excellence

The rhetoric of “excellence” is pervasive across the academy. It is used to refer to research outputs as well as researchers, theory and education, individuals and organisations, from art history to zoology. But does “excellence” actually mean anything? Does this pervasive narrative of “excellence” do any good? Drawing on a range of sources we interrogate “excellence” as a concept and find that it has no intrinsic meaning in academia. Rather it functions as a linguistic interchange mechanism. To investigate whether this linguistic function is useful we examine how the rhetoric of excellence combines with narratives of scarcity and competition to show that the hypercompetition that arises from the performance of “excellence” is completely at odds with the qualities of good research. We trace the roots of issues in reproducibility, fraud, and homophily to this rhetoric. But we also show that this rhetoric is an internal, and not primarily an external, imposition. We conclude by proposing an alternative rhetoric based on soundness and capacity-building. In the final analysis, it turns out that that “excellence” is not excellent. Used in its current unqualified form it is a pernicious and dangerous rhetoric that undermines the very foundations of good research and scholarship

A systematic review of patient and health system characteristics associated with late referral in chronic kidney disease

<p>Abstract</p> <p>Background</p> <p>To identify patient and health system characteristics associated with late referral of patients with chronic kidney disease to nephrologists.</p> <p>Methods</p> <p>MEDLINE, CENTRAL, and CINAHL were searched using the appropriate MESH terms in March 2007. Two reviewers individually and in duplicate reviewed the abstracts of 256 articles and selected 18 observational studies for inclusion. The reasons for late referral were categorized into patient or health system characteristics. Data extraction and content appraisal were done using a prespecified protocol.</p> <p>Results</p> <p>Older age, the existence of multiple comorbidities, race other than Caucasian, lack of insurance, lower socioeconomic status and educational levels were patient characteristics associated with late referral of patients with chronic kidney disease. Lack of referring physician knowledge about the appropriate timing of referral, absence of communication between referring physicians and nephrologists, and dialysis care delivered at tertiary medical centers were health system characteristics associated with late referral of patients with chronic kidney disease. Most studies identified multiple factors associated with late referral, although the relative importance and the combined effect of these factors were not systematically evaluated.</p> <p>Conclusion</p> <p>A combination of patient and health system characteristics is associated with late referral of patients with chronic kidney disease. Overall, being older, belonging to a minority group, being less educated, being uninsured, suffering from multiple comorbidities, and the lack of communication between primary care physicians and nephrologists contribute to late referral of patients with chronic kidney disease. Both primary care physicians and nephrologists need to engage in multisectoral collaborative efforts that ensure patient education and enhance physician awareness to improve the care of patients with chronic kidney disease.</p

Impaired respiratory burst contributes to infections in PKCδ-deficient patients

Patients with autosomal recessive protein kinase C δ (PKCδ) deficiency suffer from childhood-onset autoimmunity, including systemic lupus erythematosus. They also suffer from recurrent infections that overlap with those seen in patients with chronic granulomatous disease (CGD), a disease caused by defects of the phagocyte NADPH oxidase and a lack of reactive oxygen species (ROS) production. We studied an international cohort of 17 PKCδ-deficient patients and found that their EBV-B cells and monocyte-derived phagocytes produced only small amounts of ROS and did not phosphorylate p40phox normally after PMA or opsonized Staphylococcus aureus stimulation. Moreover, the patients' circulating phagocytes displayed abnormally low levels of ROS production and markedly reduced neutrophil extracellular trap formation, altogether suggesting a role for PKCδ in activation of the NADPH oxidase complex. Our findings thus show that patients with PKCδ deficiency have impaired NADPH oxidase activity in various myeloid subsets, which may contribute to their CGD-like infectious phenotype

Managing patients with ICD shocks and programming tachycardia therapies during acute heart failure syndromes

We review the pharmacologic, interventional and device programming treatment options for patients with implantable cardioverter-defibrillators who present with acute heart failure and implantable cardioverter-defibrillator shocks

Should the Arteriovenous Fistula Be Created before Starting Dialysis?: A Decision Analytic Approach

Background: An arteriovenous fistula (AVF) is considered the vascular access of choice, but uncertainty exists about the\ud optimal time for its creation in pre-dialysis patients. The aim of this study was to determine the optimal vascular access\ud referral strategy for stage 4 (glomerular filtration rate ,30 ml/min/1.73 m2) chronic kidney disease patients using a decision\ud analytic framework.\ud Methods: A Markov model was created to compare two strategies: refer all stage 4 chronic kidney disease patients for an\ud AVF versus wait until the patient starts dialysis. Data from published observational studies were used to estimate the\ud probabilities used in the model. A Markov cohort analysis was used to determine the optimal strategy with life expectancy\ud and quality adjusted life expectancy as the outcomes. Sensitivity analyses, including a probabilistic sensitivity analysis, were\ud performed using Monte Carlo simulation.\ud Results: The wait strategy results in a higher life expectancy (66.6 versus 65.9 months) and quality adjusted life expectancy\ud (38.9 versus 38.5 quality adjusted life months) than immediate AVF creation. It was robust across all the parameters except\ud at higher rates of progression and lower rates of ischemic steal syndrome.\ud Conclusions: Early creation of an AVF, as recommended by most guidelines, may not be the preferred strategy in all predialysis\ud patients. Further research on cost implications and patient preferences for treatment options needs to be done\ud before recommending early AVF creation

VAC14 nucleates a protein complex essential for the acute interconversion of PI3P and PI(3,5)P2 in yeast and mouse

The signalling lipid PI(3,5)P2 is generated on endosomes and regulates retrograde traffic to the trans-Golgi network. Physiological signals regulate rapid, transient changes in PI(3,5)P2 levels. Mutations that lower PI(3,5)P2 cause neurodegeneration in human patients and mice. The function of Vac14 in the regulation of PI(3,5)P2 was uncharacterized previously. Here, we predict that yeast and mammalian Vac14 are composed entirely of HEAT repeats and demonstrate that Vac14 exerts an effect as a scaffold for the PI(3,5)P2 regulatory complex by direct contact with the known regulators of PI(3,5)P2: Fig4, Fab1, Vac7 and Atg18. We also report that the mouse mutant ingls (infantile gliosis) results from a missense mutation in Vac14 that prevents the association of Vac14 with Fab1, generating a partial complex. Analysis of ingls and two additional mutants provides insight into the organization of the PI(3,5)P2 regulatory complex and indicates that Vac14 mediates three distinct mechanisms for the rapid interconversion of PI3P and PI(3,5)P2. Moreover, these studies show that the association of Fab1 with the complex is essential for viability in the mouse

A Large Scale shRNA Barcode Screen Identifies the Circadian Clock Component ARNTL as Putative Regulator of the p53 Tumor Suppressor Pathway

BACKGROUND: The p53 tumor suppressor gene is mutated in about half of human cancers, but the p53 pathway is thought to be functionally inactivated in the vast majority of cancer. Understanding how tumor cells can become insensitive to p53 activation is therefore of major importance. Using an RNAi-based genetic screen, we have identified three novel genes that regulate p53 function. RESULTS: We have screened the NKI shRNA library targeting 8,000 human genes to identify modulators of p53 function. Using the shRNA barcode technique we were able to quickly identify active shRNA vectors from a complex mixture. Validation of the screening results indicates that the shRNA barcode technique can reliable identify active shRNA vectors from a complex pool. Using this approach we have identified three genes, ARNTL, RBCK1 and TNIP1, previously unknown to regulate p53 function. Importantly, ARNTL (BMAL1) is an established component of the circadian regulatory network. The latter finding adds to recent observations that link circadian rhythm to the cell cycle and cancer. We show that cells having suppressed ARNTL are unable to arrest upon p53 activation associated with an inability to activate the p53 target gene p21(CIP1). CONCLUSIONS: We identified three new regulators of the p53 pathway through a functional genetic screen. The identification of the circadian core component ARNTL strengthens the link between circadian rhythm and cancer

RET PLCγ Phosphotyrosine Binding Domain Regulates Ca2+ Signaling and Neocortical Neuronal Migration

The receptor tyrosine kinase RET plays an essential role during embryogenesis in regulating cell proliferation, differentiation, and migration. Upon glial cell line-derived neurotrophic factor (GDNF) stimulation, RET can trigger multiple intracellular signaling pathways that in concert activate various downstream effectors. Here we report that the RET receptor induces calcium (Ca2+) signaling and regulates neocortical neuronal progenitor migration through the Phospholipase-C gamma (PLCγ) binding domain Tyr1015. This signaling cascade releases Ca2+ from the endoplasmic reticulum through the inositol 1,4,5-trisphosphate receptor and stimulates phosphorylation of ERK1/2 and CaMKII. A point mutation at Tyr1015 on RET or small interfering RNA gene silencing of PLCγ block the GDNF-induced signaling cascade. Delivery of the RET mutation to neuronal progenitors in the embryonic ventricular zone using in utero electroporation reveal that Tyr1015 is necessary for GDNF-stimulated migration of neurons to the cortical plate. These findings demonstrate a novel RET mediated signaling pathway that elevates cytosolic Ca2+ and modulates neuronal migration in the developing neocortex through the PLCγ binding domain Tyr1015