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Is the formation of venture capital (VC) markets a national phenomenon? Against the common view that VC emerged in the US in the post-WWII period and later (yet independently) in Europe, we argue that the uneven relation between US and UK VC markets was crucial for British VC formation since the 1980s. Based on an empirical analysis of secondary literature and financial data, the article demonstrates that this relation is better understood through the lens of international financial subordination and identifies three types of dependencies to qualify this relation: the dependencies of UK VC on US start-up investments, US growth capital, and US exit deals. This type of financial subordination is specific to ‘alternative finance’, because highly profitable VC exits kick-started a flywheel effect in UK VC in the 2000s, and the subsequent expansion of British VC went hand in hand with a concentration of capital because UK VC followed a ‘winners-take-all’ logic that is characteristic of alt-finance in general. This suggests, counterintuitively, that after UK VC formed, the US economy benefitted more in financial, economic, and technological terms from the growing British VC market than its UK counterpart mainly because most large exit deals took place in the US.

Epigenetic changes are widely considered to play an important role in aging, but experimental evidence to support this hypothesis has been scarce. We have used array-based analysis to determine genome-scale DNA methylation patterns from human skin samples and to investigate the effects of aging, chronic sun exposure, and tissue variation. Our results reveal a high degree of tissue specificity in the methylation patterns and also showed very little interindividual variation within tissues. Data stratification by age revealed that DNA from older individuals was characterized by a specific hypermethylation pattern affecting less than 1% of the markers analyzed. Interestingly, stratification by sun exposure produced a fundamentally different pattern with a significant trend towards hypomethylation. Our results thus identify defined age-related DNA methylation changes and suggest that these alterations might contribute to the phenotypic changes associated with skin aging.

Background A recent study found serum neurofilament light chain (NfL) levels to be strongly associated with poor neurological outcome in patients after cardiac arrest. Our aim was to confirm these findings in an independent validation study and to investigate whether NfL improves the prognostic value of two cardiac arrest-specific risk scores. Methods This prospective, single-center study included 164 consecutive adult after out-of-hospital cardiac arrest (OHCA) patients upon intensive care unit admission. We calculated two clinical risk scores (OHCA, CAHP) and measured NfL on admission within the first 24 h using the single molecule array NF-light ® assay. The primary endpoint was neurological outcome at hospital discharge assessed with the cerebral performance category (CPC) score. Results Poor neurological outcome (CPC > 3) was found in 60% (98/164) of patients, with 55% (91/164) dying within 30 days of hospitalization. Compared to patients with favorable outcome, NfL was 14-times higher in patients with poor neurological outcome (685 ± 1787 vs. 49 ± 111 pg/mL), with an adjusted odds ratio of 3.4 (95% CI 2.1 to 5.6, p  < 0.001) and an area under the curve (AUC) of 0.82. Adding NfL to the clinical risk scores significantly improved discrimination of both the OHCA score (from AUC 0.82 to 0.89, p  < 0.001) and CAHP score (from AUC 0.89 to 0.92, p  < 0.05). Adding NfL to both scores also resulted in significant improvement in reclassification statistics with a Net Reclassification Index (NRI) of 0.58 ( p  < 0.001) for OHCA and 0.83 ( p  < 0.001) for CAHP. Conclusions Admission NfL was a strong outcome predictor and significantly improved two clinical risk scores regarding prognostication of neurological outcome in patients after cardiac arrest. When confirmed in future outcome studies, admission NfL should be considered as a standard laboratory measures in the evaluation of OHCA patients.

Neurofilament light chain is part of the neuroaxonal cytoskeleton and upon disease-related neuroaxonal damage, it is released to the extracellular space and, based on modern highly sensitive assays, can also be detected in the peripheral blood. Thus, neurofilament light chain in the blood is an emerging marker of neurological disease, including age-related conditions, such as neurodegenerative but also neurovascular diseases. Recently, blood neurofilament light chain has been shown to serve as a potentially interesting marker of disease burden and prognostication also in cerebral small-vessel disease, a condition that is highly prevalent in elderly subjects. Small-vessel disease is a progressive condition, often related to common vascular risk factors such as arterial hypertension and is an important cause of stroke, vascular cognitive impairment, and dementia. As an age-dependent condition, small-vessel disease may occur concomitantly with neurodegenerative diseases, with both conditions having a potential impact on clinical status or cognitive performance. The aim of the present article is to give an overview on the current knowledge on neurofilament light chain as a disease or progression marker in small-vessel disease.

The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different types of cells by either direct contact or by autocrine and paracrine signalling. Diabetic skin is characterized by itching, numbness, ulcers, eczema, and other pathophysiological changes. These pathogenic phenotypes have been associated with the effects of the reactive glucose metabolite methylglyoxal (MGO) on dermal cells. In this study, dermal fibroblasts were isolated from diabetic and non-diabetic human donors. Cultured dermal fibroblasts from diabetic donors exhibited reduced insulin-induced glucose uptake and reduced expression of the insulin receptor. This diabetic phenotype persists under cell culture conditions. Secretion of IL-6 was increased in fibroblasts from diabetic donors. Increased secretion of IL-6 and MIF was also observed upon the treatment of dermal fibroblasts with MGO, suggesting that MGO is sufficient for triggering these immunomodulatory responses. Remarkably, MIF treatment resulted in decreased activity of MGO-detoxifying glyoxalase-1. Given that reduced glyoxalase activity results in increased MGO levels, these findings suggested a positive-feedback loop for MGO generation, in which MIF, evoked by MGO, in turn blocks MGO-degrading glyoxalase activity. Finally, secretion of procollagen Type I C-Peptide (PICP), a marker of collagen production, was reduced in fibroblast from diabetic donors. Remarkably, treatment of fibroblasts with either MGO or MIF was sufficient for inducing reduced PICP levels. The observations of this study unravel a signalling network in human dermal fibroblasts with the metabolite MGO being sufficient for inflammation and delayed wound healing, hallmarks of T2D.

Purpose - The purpose of this paper is to address the implementation of proactive interorganizational sustainable supply chain strategies by empirically exploring the relationship between key (inter-)organizational resources of the initiating company and the establishment of widely accepted voluntary sustainability initiatives.Design methodology approach - The study is built on comparative case studies as well as literature on institutional entrepreneurship and the resource-based view.Findings - The authors identify capabilities that enable the creation and establishment of company-driven voluntary sustainability initiatives - namely external stakeholder integration, cross-functional integration, the management of loosely coupled business units, supply chain implementation, process improvement and cultural framing.Originality value - With this study, the authors introduce institutional entrepreneurship theory to supply chain management literature and show that institutional entrepreneurship theory may contribute to the question of how organizations implement their interorganizational sustainable supply chain strategies. Specifically, the study derives propositions for key resources enabling the establishment of voluntary sustainability initiatives widely accepted by participants as well as initiative-external stakeholders.

Introduction The clinical picture of hypothyroidism, including neurological symptoms, can be multiform, which may delay or hamper the correct diagnosis. Case presentation We present an uncommon clinical presentation of a 38-year-old Caucasian man with mild facial palsy on the left side, uvular deviation to the left with preserved gag reflex, tongue deviation to the left, lingual dysarthria, and xerosis by severe hypothyroidism. Blood tests on admission showed elevated serum creatinine of 151 μmol/L (glomerular filtration rate 47 ml/min/1.7 CKD-EPI [Chronic Kidney Disease Epidemiology Collaboration equation]), increased creatinine phosphokinase activity (1243 U/L), markedly elevated thyroid-stimulating hormone (292.2 mIU/L), low free thyroxine level (1.1 pmol/L), and free triiodothyronine level below the limit of detection (< 0.4 pmol/L). Results of brain magnetic resonance imaging and renal ultrasound were unremarkable. Lumbar puncture revealed a normal cell count in cerebrospinal fluid, with an increased protein level of 758 mg/L and a cerebrospinal fluid/serum albumin ratio of 10.5 × 10 − 3 /L (reference range < 6.7). Further diagnostic workup did not reveal any inflammatory or infectious systemic pathologies as an underlying cause. The patient’s neurological symptoms, as well as laboratory findings including renal function, creatinine phosphokinase, and initially altered blood lipid levels, normalized with levothyroxine substitution. Conclusions Multiple cranial neuropathy is an uncommon clinical finding in hypothyroidism, which is an important differential diagnosis in the workup of new neurological deficits.

Background: Stroke often results in physical impairments. Physical activity is crucial for rehabilitation, enhancing mobility, strength, and overall health. This study examines the association between Timed Up-and-Go (TUG) test performance and changes in physical activity to improve lower extremity physical function. Methods: The MOBITEC-Stroke Cohort Study (“Recovery of mobility function and life-space mobility after ischemic stroke”) included patients with a first incidence of stroke. Data assessed 3 and 12 months after stroke were used for analysis. Linear regression model adjusted for age, sex, instrumental activities of daily living, Falls Efficacy Scale-International, modified Ranking Scale, and National Institutes of Health Stroke Scale-score was used to examine the relationship between lower extremity physical function (i.e., TUG) and change in physical activity (i.e., minutes of physical activity measured with a wrist-worn accelerometer over 1 week). Results: Longitudinal data of 49 patients (65% male, mean age 71.2 (SD: 10.4) years) were analyzed. Mean daily physical activity was 291.6 (SD: 96.2) min at 3 months and 298.9 (SD: 94.4) min at 12 months, with a change from 3 to 12 months of 7.3 min (95% CI: −9.4 to 24.0; p = 0.394) post-stroke. We observed significant relationships between the baseline TUG performance and the change in total physical activity over 9 months (p = 0.011) and between the change of TUG performance over time and the change in total physical activity (p = 0.022). Conclusion: Our findings indicate that better initial lower extremity physical function and higher improvements in function over time are associated with a greater increase in physical activity levels after stroke. This suggests that interventions aimed at maintaining and improving lower extremity physical function may positively affect physical activity levels.

Objective To determine the feasibility and safety of image-guided brachytherapy employing a modified open high-field MR system. Methods This is a follow-up study of a development project enabling technologies for interventional use of 1.0T open MRI. Modifications included coils and in-bore visualization, fluoroscopic sequences and user interfaces. We recruited 104 patients with 224 liver malignancies to receive MR-guided brachytherapy. Interventions were performed >20 min after Gd-EOB-DTPA. We recorded interventional parameters including the intervention time (from acquisition of the first scout until the final sequence for brachytherapy treatment planning). Two reviewers assessed MR-fluoroscopic images in comparison to plain CT as used in CT intervention, applying a rating scale of 1–10. Statistical analysis included Friedman and Kendall’s W tests. Results We employed freehand puncture with interactive dynamic imaging for navigation. Technical success rate was 218 complete ablations in 224 tumours (97%). The median intervention time was 61 min. We recorded no adverse events related to the use of MRI. No major complications occurred. The rate of minor complications was 4%. Local control at 3 months was 96%. Superiority of MR-fluoroscopic, Gd-EOB-DTPA-enhanced images over plain CT was highly significant ( P  < 0.001). Conclusion MR-guided brachytherapy employing open high-field MRI is feasible and safe.

ObjectivesSerum neurofilament light chain (NfL) has been proposed as prognostic markers in neurogenerative disease. A cross-sectional study in cerebral small vessel disease (SVD) reported an association with cognition and disability. If NfL is to be used to predict outcome, studies are required to demonstrate baseline NfL predicts future dementia risk. Furthermore, if it is to be used as a surrogate marker in clinical trials, change in NfL over time periods typical of a clinical trial must be linked to clinical progression. In a longitudinal study of patients with lacunar stroke and confluent white matter hyperintensities, we determined whether both baseline, and change, in NfL levels were linked to changes in MRI markers, cognitive decline and dementia risk.MethodsPatients underwent MRI, cognitive testing and blood taking at baseline and annually for 3 years. Clinical and cognitive follow-up continued for 5 years.ResultsNfL data were available for 113 subjects for baseline analysis, and 90 patients for the longitudinal analysis. Baseline NfL predicted cognitive decline (global cognition β=−0.335, SE=0.094, p=0.001) and risk of converting to dementia (HR=1.676 (95% CI 1.183 to 2.373), p=0.004). In contrast to imaging, there was no change in NfL values over the follow-up period.ConclusionsBaseline NfL predicts changes in MRI markers, cognitive decline and dementia rate over a 5 years follow-up period in SVD, suggesting NfL may be a useful prognostic marker. However, change in NfL values was not detected, and therefore NfL may not be a useful surrogate marker in clinical trials in SVD.