Causal mechanisms in the clinical course and treatment of back pain

In recent years, there has been increasing interest in studying causal mechanisms in the development and treatment of back pain. The aim of this article is to provide an overview of our current understanding of causal mechanisms in the field. In the first section, we introduce key concepts and terminology. In the second section, we provide a brief synopsis of systematic reviews of mechanism studies relevant to the clinical course and treatment of back pain. In the third section, we reflect on the findings of our review to explain how understanding causal mechanisms can inform clinical practice and the implementation of best practice. In the final sections, we introduce contemporary methodological advances, highlight the key assumptions of these methods, and discuss future directions to advance the quality of mechanism-related studies in the back pain field

Hepatic Endothelial CCL25 Mediates the Recruitment of CCR9+ Gut-homing Lymphocytes to the Liver in Primary Sclerosing Cholangitis

Primary sclerosing cholangitis (PSC), a chronic inflammatory liver disease characterized by progressive bile duct destruction, develops as an extra-intestinal complication of inflammatory bowel disease (IBD) (Chapman, R.W. 1991. Gut. 32:1433–1435). However, the liver and bowel inflammation are rarely concomitant, and PSC can develop in patients whose colons have been removed previously. We hypothesized that PSC is mediated by long-lived memory T cells originally activated in the gut, but able to mediate extra-intestinal inflammation in the absence of active IBD (Grant, A.J., P.F. Lalor, M. Salmi, S. Jalkanen, and D.H. Adams. 2002. Lancet. 359:150–157). In support of this, we show that liver-infiltrating lymphocytes in PSC include mucosal T cells recruited to the liver by aberrant expression of the gut-specific chemokine CCL25 that activates α4β7 binding to mucosal addressin cell adhesion molecule 1 on the hepatic endothelium. This is the first demonstration in humans that T cells activated in the gut can be recruited to an extra-intestinal site of disease and provides a paradigm to explain the pathogenesis of extra-intestinal complications of IBD

Cosmological solutions from fake N=2 EYM supergravity

We characterise the (fake) supersymmetric solutions of Wick-rotated N=2 d=4 gauged supergravity coupled to non-Abelian vector multiplets. In the time-like case we obtain generalisations of Kastor & Traschen's cosmological black holes: they have a specific time-dependence and the base-space must be 3-dimensional hyperCR/Gauduchon-Tod space. In the null-case, we find that the metric has a holonomy contained in Sim(2), give a general characterisation of the solutions, and give some examples. Finally, we point out that in some cases the solutions we found are non-BPS solutions to N=2 d=4 supergravity coupled to vector multiplets.Comment: 30 pages. Comments and references added, typos correcte

Optimizing automated characterization of liver fibrosis histological images by investigating color spaces at different resolutions

Texture analysis (TA) of histological images has recently received attention as an automated method of characterizing liver fibrosis. The colored staining methods used to identify different tissue components reveal various patterns that contribute in different ways to the digital texture of the image. A histological digital image can be represented with various color spaces. The approximation processes of pixel values that are carried out while converting between different color spaces can affect image texture and subsequently could influence the performance of TA. Conventional TA is carried out on grey scale images, which are a luminance approximation to the original RGB (Red, Green, and Blue) space. Currently, grey scale is considered sufficient for characterization of fibrosis but this may not be the case for sophisticated assessment of fibrosis or when resolution conditions vary. This paper investigates the accuracy of TA results on three color spaces, conventional grey scale, RGB, and Hue-Saturation-Intensity (HSI), at different resolutions. The results demonstrate that RGB is the most accurate in texture classification of liver images, producing better results, most notably at low resolution. Furthermore, the green channel, which is dominated by collagen fiber deposition, appears to provide most of the features for characterizing fibrosis images. The HSI space demonstrated a high percentage error for the majority of texture methods at all resolutions, suggesting that this space is insufficient for fibrosis characterization. The grey scale space produced good results at high resolution; however, errors increased as resolution decreased

Development of Clinical Criteria for Functional Assessment to Predict Primary Nonfunction of High-Risk Livers Using Normothermic Machine Perfusion

Increased use of high-risk allografts is critical to meet the demand for liver transplantation. We aimed to identify criteria predicting viability of organs, currently declined for clinical transplantation, using functional assessment during normothermic machine perfusion (NMP). Twelve discarded human livers were subjected to NMP following static cold storage. Livers were perfused with a packed red cell-based fluid at 37°C for 6 hours. Multilevel statistical models for repeated measures were employed to investigate the trend of perfusate blood gas profiles and vascular flow characteristics over time and the effect of lactate-clearing (LC) and non-lactate-clearing (non-LC) ability of the livers. The relationship of lactate clearance capability with bile production and histological and molecular findings were also examined. After 2 hours of perfusion, median lactate concentrations were 3.0 and 14.6 mmol/L in the LC and non-LC groups, respectively. LC livers produced more bile and maintained a stable perfusate pH and vascular flow &gt;150 and 500 mL/minute through the hepatic artery and portal vein, respectively. Histology revealed discrepancies between subjectively discarded livers compared with objective findings. There were minimal morphological changes in the LC group, whereas non-LC livers often showed hepatocellular injury and reduced glycogen deposition. Adenosine triphosphate levels in the LC group increased compared with the non-LC livers. We propose composite viability criteria consisting of lactate clearance, pH maintenance, bile production, vascular flow patterns, and liver macroscopic appearance. These have been tested successfully in clinical transplantation. In conclusion, NMP allows an objective assessment of liver function that may reduce the risk and permit use of currently unused high-risk livers.</p

Close binary stars in the solar-age Galactic open cluster M67

We present multi-colour time-series CCD photometry of the solar-age galactic open cluster M67 (NGC 2682). About 3600 frames spread over 28 nights were obtained with the 1.5 m Russian-Turkish and 1.2 m Mercator telescopes. High-precision observations of the close binary stars AH Cnc, EV Cnc, ES Cnc, the $\delta$ Scuti type systems EX Cnc and EW Cnc, and some long-period variables belonging to M67 are presented. Three full multi-colour light curves of the overcontact binary AH Cnc were obtained during three observing seasons. Likewise we gathered three light curves of EV Cnc, an EB-type binary, and two light curves of ES Cnc, a blue straggler binary. Parts of the light change of long-term variables S1024, S1040, S1045, S1063, S1242, and S1264 are obtained. Period variation analysis of AH Cnc, EV Cnc, and ES Cnc were done using all times of mid-eclipse available in the literature and those obtained in this study. In addition, we analyzed multi-colour light curves of the close binaries and also determined new frequencies for the $\delta$ Scuti systems. The physical parameters of the close binary stars were determined with simultaneous solutions of multi-colour light and radial velocity curves. Finally we determined the distance of M67 as 857(33) pc via binary star parameters, which is consistent with an independent method from earlier studies.Comment: 12 pages, 9 Figures, 13 Table

Hazardous explosive eruptions of a recharging multi-cyclic island arc caldera

Caldera-forming eruptions of silicic volcanic systems are among the most devastating events on Earth. By contrast, post-collapse volcanic activity initiating new caldera cycles is generally considered less hazardous. Formed after Santorini’s latest caldera-forming eruption of ~1600 bce, the Kameni Volcano in the southern Aegean Sea enables the eruptive evolution of a recharging multi-cyclic caldera to be reconstructed. Santorini’s eruptive record has been documented by onshore products and historical descriptions of mainly effusive eruptions dating back to 197 bce. Here we combine high-resolution seismic reflection data with cored lithologies from International Ocean Discovery Program Expedition 398 at four sites to determine the submarine architecture and volcanic history of intra-caldera deposits from Kameni. Our shore-crossing analysis reveals the deposits of a submarine explosive eruption that produced up to 3.1 km3 of pumice and ash, which we relate to a historical eruption in 726 ce. The estimated volcanic explosivity index of magnitude 5 exceeds previously considered worst-case eruptive scenarios for Santorini. Our finding that the Santorini caldera is capable of producing large explosive eruptions at an early stage in the caldera cycle implies an elevated hazard potential for the eastern Mediterranean region, and potentially for other recharging silicic calderas

Origin of high Mg and SO 4 fluids in sediments of the Terceira Rift, Azores – indications for caminite dissolution in a waning hydrothermal system

During R/V Meteor cruise 141/1, pore fluids of near surface sediments were investigated to find indications for hydrothermal activity in the Terceira Rift (TR), a hyper‐slow spreading center in the Central North Atlantic Ocean. To date, submarine hydrothermal fluid venting in the TR has only been reported for the D. João de Castro seamount, which presently seems to be inactive. Pore fluids sampled close to a volcanic cone at 2800 m water depth show an anomalous composition with Mg, SO4, and total alkalinity (TA) concentrations significantly higher than seawater and a nearby reference core. The most straightforward way of interpreting these deviations is the dissolution of the hydrothermally formed mineral caminite (MgSO4 0.25Mg(OH)2 0.2H2O). This interpretation is corroborated by a thorough investigation of fluid isotope systems (δ26Mg, δ30Si, δ34S, δ44/42Ca, and 87Sr/86Sr). Caminite is known from mineral assemblages with anhydrite, and forms in hydrothermal recharge zones only under specific conditions such as high fluid temperatures and in altered oceanic crust, which are conditions generally met at the TR. We hypothesize that caminite was formed during hydrothermal activity and is now dissolving during the waning state of the hydrothermal system, so that caminite mineralization is shifted out of its stability zone. Ongoing fluid circulation through the basement is transporting the geochemical signal via slow advection towards the seafloor

Targeted Gene Panel Sequencing for Early-onset Inflammatory Bowel Disease and Chronic Diarrhea

Background: In contrast to adult-onset inflammatory bowel disease (IBD), where many genetic loci have been shown to be involved in complex disease etiology, early-onset IBD (eoIBD) and associated syndromes can sometimes present as monogenic conditions. As a result, the clinical phenotype and ideal disease management in these patients often differ from those in adult-onset IBD. However, due to high costs and the complexity of data analysis, high-throughput screening for genetic causes has not yet become a standard part of the diagnostic work-up of eoIBD patients. Methods: We selected 28 genes of interest associated with monogenic IBD and performed targeted panel sequencing in 71 patients diagnosed with eoIBD or early-onset chronic diarrhea to detect causative variants. We compared these results to whole-exome sequencing (WES) data available for 25 of these patients. Results: Target coverage was significantly higher in the targeted gene panel approach compared with WES, whereas the cost of the panel was considerably lower (approximately 25% of WES). Disease-causing variants affecting protein function were identified in 5 patients (7%), located in genes of the IL10 signaling pathway (3), WAS (1), and DKC1 (1). The functional effects of 8 candidate variants in 5 additional patients (7%) are under further investigation. WES did not identify additional causative mutations in 25 patients. Conclusions: Targeted gene panel sequencing is a fast and effective screening method for monogenic causes of eoIBD that should be routinely established in national referral centers.info:eu-repo/semantics/publishedVersio

Consensus Recommendations for Histological Criteria of Autoimmune Hepatitis from the International AIH Pathology Group

Background & Aims Diagnostic histological criteria for autoimmune hepatitis (AIH) have not been clearly established. Previously published criteria focused mainly on chronic AIH, in which inflammatory changes mainly occur in portal/periportal regions and may not be applicable to acute presentation of AIH, in which inflammatory changes are typically predominantly lobular in location. International consensus criteria for the diagnosis and assessment of disease severity in both acute and chronic AIH are thus urgently needed. Methods Seventeen expert liver pathologists convened at an international workshop and subsequently used a modified Delphi panel approach to establish consensus criteria for the histopathological diagnosis of AIH. Results The consensus view is that liver biopsy should remain standard for diagnosing AIH. AIH is considered likely, if there is a predominantly portal lymphoplasmacytic hepatitis with more than mild interface activity and/or more than mild lobular hepatitis in the absence of histological features suggestive of another liver disease. AIH is also considered likely if there is predominantly lobular hepatitis with or without centrilobular necroinflammation and at least one of the following features: portal lymphoplasmacytic hepatitis, interface hepatitis or portal-based fibrosis, in the absence of histological features suggestive of another liver disease. Emperipolesis and hepatocellular rosettes are not regarded as being specific for AIH. Conclusions The criteria proposed in this consensus statement provide a uniform approach to the histological diagnosis of AIH, which is relevant for patients with an acute as well as a chronic presentation and to more accurately reflect the current understanding of liver pathology in AIH