Carotid Sources of Stroke.

The ancient Greeks used the term karotides for the great arteries in the neck, compression of which could plunge the victim into karoun: deep sleep or stupor. The artery name aside, studies of the patterns of brain infarction and their clinical severity have been an unbroken chain of growing sophistication in the past 150 years. Two main patterns emerged: perfusion failure with high-convexity infarction from hemodynamically important ipsilateral carotid stenosis or embolism from nonstenosing carotid plaque.

Liquid compound refractive X-ray lens.

We introduce the concept of a liquid compound refractive X-ray zoom lens. The lens is generated by pumping a suitable liquid lens material like water, alcohol or heated lithium through a line of nozzles each forming a jet with the cross section of lens elements. The system is housed, so there is a liquid-circulation. This lens can be used in white beam at high brilliance synchrotron sources, as radiation damages are cured by the continuous reformation of the lens. The focal length can be varied by closing nozzles, thus reducing the number of lens elements in the beam.

Design of defect-chemical properties and device performance in memristive systems.

Future development of the modern nanoelectronics and its flagships internet of things, artificial intelligence, and neuromorphic computing is largely associated with memristive elements, offering a spectrum of inevitable functionalities, atomic level scalability, and low-power operation. However, their development is limited by significant variability and still phenomenologically orientated materials' design strategy. Here, we highlight the vital importance of materials' purity, demonstrating that even parts-per-million foreign elements substantially change performance. Appropriate choice of chemistry and amount of doping element selectively enhances the desired functionality. Dopant/impurity-dependent structure and charge/potential distribution in the space-charge layers and cell capacitance determine the device kinetics and functions. The relation between chemical composition/purity and switching/neuromorphic performance is experimentally evidenced, providing directions for a rational design of future memristive devices.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

The original article was published on February 15, 2020 and corrected on March 26, 2020. The revised version of the article amends the table and figure, while leaving the text largely unchanged. The changes appear in the revised online PDF copy of this article.

Long-term follow-up of 22 psoriatic patients treated with ixekizumab after failure of secukinumab.

Switching of biologic agents in treatment of plaque psoriasis is a common strategy. Only a few studies are available on switching between IL17A-blockers. In a retrospective study, we identified 22 psoriasis patients who, after failing secukinumab as a first IL17A-blocker received ixekizumab with an observation period of at least 24 weeks. At last observation 10/22 patients had a good response (PASI75 or PASI<3) using ixekizumab therapy. None of five patients with primary non-response to secukinumab reached a good, durable response to ixekizumab. In conclusion, ixekizumab appears to be a therapeutic option as a second IL17A-blocker in psoriasis patients who did not show a primary non-response to secukinumab.

Super-Resolution Scanning Transmission X-Ray Imaging Using Single Biconcave Parabolic Refractive Lens Array.

A new super resolution imaging technique which potentially enables sub-µm spatial resolution, using a detector of pixels much larger than the spatial resolution, is proposed. The method utilizes sample scanning through a large number of identical X-ray microprobes periodically spaced (the period corresponds to a multiple of the pixel size), which reduces drastically the scanning time. The information about the sample illuminated by the microprobes is stored by large detector pixels. Using these data and sample position information, a super-resolution image reconstruction is performed. With a one-dimensional (1D) high aspect ratio nickel single lens array designed for theoretically expected sub-µm microprobes at 17 keV and fabricated by deep X-ray lithography and electroforming technique, 2 µm X-ray microprobes with a period of 10 µm were achieved. We performed a first experiment at KARA synchrotron facility, and it was demonstrated that the smallest structure of a test pattern with a size of 1.5 µm could be easily resolved by using images generated from a detector having a pixel size of 10.4 µm. This new approach has a great potential for providing a new microscopic imaging modality with a large field of view and short scan time.

X-ray zoom lens allows for energy scans in X-ray microscopy.

We introduce a new design and development of a compound refractive X-ray zoom lens for energy scans in X-ray microscopy. Energy scans are, in principle, equivalent to radial scans in the reciprocal space for X-ray diffraction. Thanks to the absence of sample or detector motions, energy scans are better suited for microscopy, which requires high stability. In addition, close to the absorption edge of an element, energy scans can yield chemical information when coupled with resonant effects in full field diffraction X-ray microscopy (FFDXM) or X-ray absorption near edge structure (XANES) microscopy. Here, we demonstrate the concept by using a customized compound refractive X-ray zoom lens for 11 keV near the Ge Kα-edge. The working distance and magnification were kept constant during the energy scans by adapting the lens composition on switchable zoom lens fingers. This alleviates the need to reposition the lens while changing the energy and makes quantitative analysis more convenient for FFDXM. The fabricated zoom lens was characterized and proven suitable for the proposed measurement.

Optimizing illumination for full field imaging at high brilliance hard X-ray synchrotron sources.

A new technique is presented to overcome beam size limitation in full field imaging at high brilliance synchrotron sources using specially designed refractive X-ray optics. These optics defocus the incoming beam in vertical direction and reshape the intensity distribution from a Gaussian to a more desirable top-hat-shaped profile at the same time. With these optics X-ray full-field imaging of extended objects becomes possible without having to stack several scans or applying a cone beam geometry in order to image the entire specimen. For in situ experiments in general and for diffraction limited sources in particular this gain in field of view and the optimization of the intensity distribution is going to be very beneficial.

Early endothelial progenitor cells and vascular stiffness in psoriasis and psoriatic arthritis.

BACKGROUND: Both psoriasis (Ps) and psoriasis arthritis (PsA) have been associated with increased cardiovascular risk. Also, both are characterized by increased neovascularization. Endothelial progenitor cells (EPCs) have been implicated in promoting vascular repair in ischemic diseases. The aim of the study was to correlate the EPC system with CV risk factors and with parameters of vascular stiffness in Ps and PsA. METHODS: Twenty-six healthy subjects, 30 patients with Ps, and 31 patients PsA were included in the study. eEPC regeneration was evaluated by a colony-forming assay, circulating eEPCs were measured by cytometric analysis. For vascular analysis, all subjects underwent quantification of pulse wave velocity (PWV) and augmentation index (AIX). RESULTS: Patients were categorized upon the duration of disease, severity of skin involvement (PASI-Ps), individual pain as reflected by the VAS (PsA), CRP values, and history of treatment with one or more biologicals. Regarding the eEPC system, no significant differences were observed between the respective categories. Correlation analyses between parameters of vascular stiffness (PWV and AIX) and patterns of colony formation/circulating eEPCs did not show any correlation at all. CONCLUSION: Parameters of vascular stiffness are not significantly deteriorated in Ps/PsA. Thus, pulse wave analysis may not be suitable for CVR assessment in certain autoimmune-mediated diseases. Regenerative activity of the eEPC system/circulating eEPC numbers are not altered in Ps/PsA. One may conclude that malfunctions of the eEPC are not substantially involved in perpetuating the micro-/macrovascular alterations in Ps/PsA.

Heart Failure Severity and Quality of Warfarin Anticoagulation Control (From the WARCEF Trial).

Previous studies in patients with atrial fibrillation showed that a history of heart failure (HF) could negatively impact anticoagulation quality, as measured by the average time in therapeutic range (TTR). Whether additional markers of HF severity are associated with TTR has not been investigated thoroughly. We aimed to examine the potential role of HF severity in the quality of warfarin control in patients with HF with reduced ejection fraction. Data from the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction Trial were used to investigate the association between TTR and HF severity. Multivariable logistic regression models were used to examine the association of markers of HF severity, including New York Heart Association (NYHA) class, Minnesota Living with HF (MLWHF) score, and frequency of HF hospitalization, with TTR ≥70% (high TTR). We included 1,067 participants (high TTR, N = 413; low TTR, N = 654) in the analysis. In unadjusted analysis, patients with a high TTR were older and less likely to have had strokes or receive other antiplatelet agents. Those patients also had lower NYHA class, better MLWHF scores, greater 6-minute walk distance, and lower frequency of HF hospitalizations. Multivariable analysis showed that NYHA class III and/or IV (Odds ratio [OR] 0.68 [95% confidence intervals [CIs] 0.49 to 0.94]), each 10-point increase in MLWHF score (i.e., worse health-related quality of life) (OR 0.92 [0.86 to 0.99]), and higher number of HF hospitalization per year (OR0.45 [0.30 to 0.67]) were associated with decreased likelihood of having high TTR. In HF patients with systolic dysfunction, NYHA class III and/or IV, poor health-related quality of life, and a higher rate of HF hospitalization were independently associated with suboptimal quality of warfarin anticoagulation control. These results affirm the need to assess the new approaches, such as direct oral anticoagulants, to prevent thromboembolism in this patient population.

Microbiome-driven allergic lung inflammation is ameliorated by short-chain fatty acids.

The mammalian gastrointestinal tract harbors a microbial community with metabolic activity critical for host health, including metabolites that can modulate effector functions of immune cells. Mice treated with vancomycin have an altered microbiome and metabolite profile, exhibit exacerbated T helper type 2 cell (Th2) responses, and are more susceptible to allergic lung inflammation. Here we show that dietary supplementation with short-chain fatty acids (SCFAs) ameliorates this enhanced asthma susceptibility by modulating the activity of T cells and dendritic cells (DCs). Dysbiotic mice treated with SCFAs have fewer interleukin-4 (IL4)-producing CD4+ T cells and decreased levels of circulating immunoglobulin E (IgE). In addition, DCs exposed to SCFAs activate T cells less robustly, are less motile in response to CCL19 in vitro, and exhibit a dampened ability to transport inhaled allergens to lung draining nodes. Our data thus demonstrate that gut dysbiosis can exacerbate allergic lung inflammation through both T cell- and DC-dependent mechanisms that are inhibited by SCFAs.

Hypothermia does not influence liver damage and function in a porcine polytrauma model.

BACKGROUND: Previous studies revealed evidence that induced hypothermia attenuates ischemic organ injuries after severe trauma. In the present study, the effect of hypothermia on liver damage was investigated in a porcine long term model of multi-system injury, consisting of blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shockMETHODS: In 30 pigs, a standardized polytrauma including blunt chest trauma, penetrating abdominal trauma, musculoskeletal injury, and hemorrhagic shock of 45% of total blood volume was induced. Following trauma, hypothermia of 33∘C was induced for 12 h and intensive care treatment was evaluated for 48 h. As outcome parameters, we assessed liver function and serum transaminase levels as well as a histopathological analysis of tissue samples. A further 10 animals served as controls. RESULTS: Serum transaminase levels were increased at the end of the observation period following hypothermia without reaching statistical significance compared to normothermic groups. Liver function was preserved (p⩽ 0.05) after the rewarming period in hypothermic animals but showed no difference at the end of the observation period. In H&E staining, cell death was slightly increased hypothermic animals and caspase-3 staining displayed tendency towards more apoptosis in hypothermic group as well. CONCLUSIONS: Induction of hypothermia could not significantly improve hepatic damage during the first 48 h following major trauma. Further studies focusing on multi-organ failure including a longer observation period are required to illuminate the impact of hypothermia on hepatic function in multiple trauma patients.

DeltaMS: a tool to track isotopologues in GC- and LC-MS data.

INTRODUCTION: Stable isotopic labeling experiments are powerful tools to study metabolic pathways, to follow tracers and fluxes in biotic and abiotic transformations and to elucidate molecules involved in metal complexing. OBJECTIVE: To introduce a software tool for the identification of isotopologues from mass spectrometry data. METHODS: DeltaMS relies on XCMS peak detection and X13CMS isotopologue grouping and then analyses data for specific isotope ratios and the relative error of these ratios. It provides pipelines for recognition of isotope patterns in three experiment types commonly used in isotopic labeling studies: (1) search for isotope signatures with a specific mass shift and intensity ratio in one sample set, (2) analyze two sample sets for a specific mass shift and, optionally, the isotope ratio, whereby one sample set is isotope-labeled, and one is not, (3) analyze isotope-guided perturbation experiments with a setup described in X13CMS. RESULTS: To illustrate the versatility of DeltaMS, we analyze data sets from case-studies that commonly pose challenges in evaluation of natural isotopes or isotopic signatures in labeling experiment. In these examples, the untargeted detection of sulfur, bromine and artificial metal isotopic patterns is enabled by the automated search for specific isotopes or isotope signatures. CONCLUSION: DeltaMS provides a platform for the identification of (pre-defined) isotopologues in MS data from single samples or comparative metabolomics data sets.

Miniaturized compound refractive X-ray zoom lens.

We introduce the concept of a miniaturized compound refractive X-ray zoom lens consisting of SU-8 lenses fabricated by deep X-ray lithography. The focal length can be varied by changing the number of lens elements placed in the beam. We use suitable actuators to move single lens elements reversibly out of the beam. The X-ray zoom lens can accept different X-ray energies while keeping a fixed working distance, or vary the focal distance for a fixed energy. The latter is useful in tuning the magnification factor in full field microscopy.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs.

OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Aspirin Does Not Increase Heart Failure Events in Heart Failure Patients: From the WARCEF Trial.

OBJECTIVES: The aim of this study was to determine whether aspirin increases heart failure (HF) hospitalization or death in patients with HF with reduced ejection fraction receiving an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). BACKGROUND: Because of its cyclooxygenase inhibiting properties, aspirin has been postulated to increase HF events in patients treated with ACE inhibitors or ARBs. However, no large randomized trial has addressed the clinical relevance of this issue. METHODS: We compared aspirin and warfarin for HF events (hospitalization, death, or both) in the 2,305 patients enrolled in the WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) trial (98.6% on ACE inhibitor or ARB treatment), using conventional Cox models for time to first event (489 events). In addition, to examine multiple HF hospitalizations, we used 2 extended Cox models, a conditional model and a total time marginal model, in time to recurrent event analyses (1,078 events). RESULTS: After adjustment for baseline covariates, aspirin- and warfarin-treated patients did not differ in time to first HF event (adjusted hazard ratio: 0.87; 95% confidence interval: 0.72 to 1.04; p = 0.117) or first hospitalization alone (adjusted hazard ratio: 0.88; 95% confidence interval: 0.73 to 1.06; p = 0.168). The extended Cox models also found no significant differences in all HF events or in HF hospitalizations alone after adjustment for covariates. CONCLUSIONS: Among patients with HF with reduced ejection fraction in the WARCEF trial, there was no significant difference in risk of HF events between the aspirin and warfarin-treated patients. (Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction trial [WARCEF]; NCT00041938).

High-energy x-ray Talbot-Lau radiography of a human knee.

We report on a radiographic measurement of an ex vivo human knee using a grating-based phase-contrast imaging setup and a medical x-ray tube at a tube voltage of 70 kV. The measurement has been carried out using a Talbot-Lau setup that is suitable to achieve a high visibility in the energy regime of medical imaging. In a medical reading by an experienced trauma surgeon signatures of chondrocalcinosis in the medial meniscus have been identified more evidently using the dark-field image in comparison to the conventional attenuation image. The analysis has been carried out at various dose levels down to 0.14 mGy measured as air kerma, which is a dose comparable to clinically used radiographic devices. The diagnosis has been confirmed by a histological analysis of the meniscus tissue. In the introduced high-frequency filtered phase-contrast image the anterior and posterior horn of the medial meniscus and the posterior cruciate ligament have also been visible. Furthermore, atherosclerotic plaque is visible in both imaging modalities, attenuation and dark-field, despite the presence of overlaying bone. This measurement, for the first time, proves the feasibility of Talbot-Lau x-ray imaging at high-energy spectra above 40 kVp and reasonable dose levels with regard to spacious and dense objects.

Protein interaction networks at the host-microbe interface in Diaphorina citri, the insect vector of the citrus greening pathogen.

The Asian citrus psyllid (Diaphorina citri) is the insect vector responsible for the worldwide spread of 'Candidatus Liberibacter asiaticus' (CLas), the bacterial pathogen associated with citrus greening disease. Developmental changes in the insect vector impact pathogen transmission, such that D. citri transmission of CLas is more efficient when bacteria are acquired by nymphs when compared with adults. We hypothesize that expression changes in the D. citri immune system and commensal microbiota occur during development and regulate vector competency. In support of this hypothesis, more proteins, with greater fold changes, were differentially expressed in response to CLas in adults when compared with nymphs, including insect proteins involved in bacterial adhesion and immunity. Compared with nymphs, adult insects had a higher titre of CLas and the bacterial endosymbionts Wolbachia, Profftella and Carsonella. All Wolbachia and Profftella proteins differentially expressed between nymphs and adults are upregulated in adults, while most differentially expressed Carsonella proteins are upregulated in nymphs. Discovery of protein interaction networks has broad applicability to the study of host-microbe relationships. Using protein interaction reporter technology, a D. citri haemocyanin protein highly upregulated in response to CLas was found to physically interact with the CLas coenzyme A (CoA) biosynthesis enzyme phosphopantothenoylcysteine synthetase/decarboxylase. CLas pantothenate kinase, which catalyses the rate-limiting step of CoA biosynthesis, was found to interact with a D. citri myosin protein. Two Carsonella enzymes involved in histidine and tryptophan biosynthesis were found to physically interact with D. citri proteins. These co-evolved protein interaction networks at the host-microbe interface are highly specific targets for controlling the insect vector responsible for the spread of citrus greening.

Disinfection of human musculoskeletal allografts in tissue banking: a systematic review.

Musculoskeletal allografts are typically disinfected using antibiotics, irradiation or chemical methods but protocols vary significantly between tissue banks. It is likely that different disinfection protocols will not have the same level of microorganism kill; they may also have varying effects on the structural integrity of the tissue, which could lead to significant differences in terms of clinical outcome in recipients. Ideally, a disinfection protocol should achieve the greatest bioburden reduction with the lowest possible impact on tissue integrity. A systematic review of three databases found 68 laboratory and clinical studies that analyzed the microbial bioburden or contamination rates of musculoskeletal allografts. The use of peracetic acid-ethanol or ionizing radiation was found to be most effective for disinfection of tissues. The use of irradiation is the most frequently published method for the terminal sterilization of musculoskeletal allografts; it is widely used and its efficacy is well documented in the literature. However, effective disinfection results were still observed using the BioCleanse™ Tissue Sterilization process, pulsatile lavage with antibiotics, ethylene oxide, and chlorhexidine. The variety of effective methods to reduce contamination rate or bioburden, in conjunction with limited high quality evidence provides little support for the recommendation of a single bioburden reduction method.