Amsterdam and William III: the role of influence, interest and patronage on policy-making in the Dutch Republic, 1672-1684

The general theme of the thesis is the relationship between Amsterdam and the restored stadholder, William III, from 1672 to 1684. Within this survey, several subsidiary themes analyse the interests of the decision-makers during a period of war and uneasy peace, and the compromises the principals made to prevent a return to the crisis politics of 1650 and 1672. After three years of the restored stadholdership the relationship tended to the confrontational, but the study shows that effective lines of communication enabled Amsterdam and the stadholder to survive their differences over the peace negotiations in 1677-78, the struggle for alliances, 1679-1681, and the crises over military expenditure, 1682-1684, and eventually to co-operate in the invasion of England in 1688. The two major subsidiary themes are firstly, the regency of Amsterdam, in particular the burgomasters, their backgrounds, interests and ideologies, and secondly, the principal advisers and officials in the service of the stadholder and the States. These two groups were not mutually exclusive and the study also shows how the Amsterdam regents in the 1680s were able to operate as a more coherent group than those in office in the 1670s. The first of these groups is examined within a discussion of the role of party, factional and individual interest in the last quarter of the seventeenth century, which further develops recent theories of party and faction. Analysis of the second centres around the changes in the administration of the Dutch Republic and the emergence of a new kind of raadpensionaris, working both with and for the provincial states and the stadholder. Both are further contextualised by analysis of the political, economic, religious and social changes which had taken place during the "Golden Age" and the first stadholderless period of the mid-seventeenth century, and the changing relations with France and England

Identification of the initial molecular changes in response to circulating angiogenic cells-mediated therapy in critical limb ischemia

BackgroundCritical limb ischemia (CLI) constitutes the most aggressive form of peripheral arterial occlusive disease, characterized by the blockade of arteries supplying blood to the lower extremities, significantly diminishing oxygen and nutrient supply. CLI patients usually undergo amputation of fingers, feet, or extremities, with a high risk of mortality due to associated comorbidities.Circulating angiogenic cells (CACs), also known as early endothelial progenitor cells, constitute promising candidates for cell therapy in CLI due to their assigned vascular regenerative properties. Preclinical and clinical assays with CACs have shown promising results. A better understanding of how these cells participate in vascular regeneration would significantly help to potentiate their role in revascularization.Herein, we analyzed the initial molecular mechanisms triggered by human CACs after being administered to a murine model of CLI, in order to understand how these cells promote angiogenesis within the ischemic tissues.MethodsBalb-c nude mice (n:24) were distributed in four different groups: healthy controls (C, n:4), shams (SH, n:4), and ischemic mice (after femoral ligation) that received either 50 mu l physiological serum (SC, n:8) or 5x10(5) human CACs (SE, n:8). Ischemic mice were sacrificed on days 2 and 4 (n:4/group/day), and immunohistochemistry assays and qPCR amplification of Alu-human-specific sequences were carried out for cell detection and vascular density measurements. Additionally, a label-free MS-based quantitative approach was performed to identify protein changes related.ResultsAdministration of CACs induced in the ischemic tissues an increase in the number of blood vessels as well as the diameter size compared to ischemic, non-treated mice, although the number of CACs decreased within time. The initial protein changes taking place in response to ischemia and more importantly, right after administration of CACs to CLI mice, are shown.ConclusionsOur results indicate that CACs migrate to the injured area; moreover, they trigger protein changes correlated with cell migration, cell death, angiogenesis, and arteriogenesis in the host. These changes indicate that CACs promote from the beginning an increase in the number of vessels as well as the development of an appropriate vascular network.Institute of Health Carlos III, ISCIII; Junta de Andaluci

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) family

The ADAMTS (A Disintegrin and Metalloproteinase with Thrombospondin motifs) enzymes are secreted, multi-domain matrix-associated zinc metalloendopeptidases that have diverse roles in tissue morphogenesis and patho-physiological remodeling, in inflammation and in vascular biology. The human family includes 19 members that can be sub-grouped on the basis of their known substrates, namely the aggrecanases or proteoglycanases (ADAMTS1, 4, 5, 8, 9, 15 and 20), the procollagen N-propeptidases (ADAMTS2, 3 and 14), the cartilage oligomeric matrix protein-cleaving enzymes (ADAMTS7 and 12), the von-Willebrand Factor proteinase (ADAMTS13) and a group of orphan enzymes (ADAMTS6, 10, 16, 17, 18 and 19). Control of the structure and function of the extracellular matrix (ECM) is a central theme of the biology of the ADAMTS, as exemplified by the actions of the procollagen-N-propeptidases in collagen fibril assembly and of the aggrecanases in the cleavage or modification of ECM proteoglycans. Defects in certain family members give rise to inherited genetic disorders, while the aberrant expression or function of others is associated with arthritis, cancer and cardiovascular disease. In particular, ADAMTS4 and 5 have emerged as therapeutic targets in arthritis. Multiple ADAMTSs from different sub-groupings exert either positive or negative effects on tumorigenesis and metastasis, with both metalloproteinase-dependent and -independent actions known to occur. The basic ADAMTS structure comprises a metalloproteinase catalytic domain and a carboxy-terminal ancillary domain, the latter determining substrate specificity and the localization of the protease and its interaction partners; ancillary domains probably also have independent biological functions. Focusing primarily on the aggrecanases and proteoglycanases, this review provides a perspective on the evolution of the ADAMTS family, their links with developmental and disease mechanisms, and key questions for the future

A Prospective Study of the Association of Metacognitive Beliefs and Processes with Persistent Emotional Distress After Diagnosis of Cancer

Two hundred and six patients, diagnosed with primary breast or prostate cancer completed self-report questionnaires on two occasions: before treatment (T1) and 12 months later (T2). The questionnaires included: the Hospital Anxiety and Depression Scale; Impact of Events Scale; the Metacognitions Questionnaire-30 (MCQ-30) and the Illness Perceptions Questionnaire-revised. A series of regression analyses indicated that metacognitive beliefs at T1 predicted between 14 and 19 % of the variance in symptoms of anxiety, depression and trauma at T2 after controlling for age and gender. For all three outcomes, the MCQ-30 subscale ‘negative beliefs about worry’ made the largest individual contribution with ‘cognitive confidence’ also contributing in each case. For anxiety, a third metacognitive variable, ‘positive beliefs about worry’ also predicted variance in T2 symptoms. In addition, hierarchical analyses indicated that metacognitive beliefs explained a small but significant amount of variance in T2 anxiety (2 %) and T2 depression (4 %) over and above that explained by demographic variables, T1 symptoms and T1 illness perceptions. The findings suggest that modifying metacognitive beliefs and processes has the potential to alleviate distress associated with cancer

Empowerment or Engagement? Digital Health Technologies for Mental Healthcare

We argue that while digital health technologies (e.g. artificial intelligence, smartphones, and virtual reality) present significant opportunities for improving the delivery of healthcare, key concepts that are used to evaluate and understand their impact can obscure significant ethical issues related to patient engagement and experience. Specifically, we focus on the concept of empowerment and ask whether it is adequate for addressing some significant ethical concerns that relate to digital health technologies for mental healthcare. We frame these concerns using five key ethical principles for AI ethics (i.e. autonomy, beneficence, non-maleficence, justice, and explicability), which have their roots in the bioethical literature, in order to critically evaluate the role that digital health technologies will have in the future of digital healthcare

A 30-Min Nucleic Acid Amplification Point-of-Care Test for Genital Chlamydia trachomatis Infection in Women: A Prospective, Multi-center Study of Diagnostic Accuracy.

BACKGROUND: Rapid Point-Of-Care Tests for Chlamydia trachomatis (CT) may reduce onward transmission and reproductive sexual health (RSH) sequelae by reducing turnaround times between diagnosis and treatment. The io® single module system (Atlas Genetics Ltd.) runs clinical samples through a nucleic acid amplification test (NAAT)-based CT cartridge, delivering results in 30min. METHODS: Prospective diagnostic accuracy study of the io® CT-assay in four UK Genito-Urinary Medicine (GUM)/RSH clinics on additional-to-routine self-collected vulvovaginal swabs. Samples were tested "fresh" within 10days of collection, or "frozen" at -80°C for later testing. Participant characteristics were collected to assess risk factors associated with CT infection. RESULTS: CT prevalence was 7.2% (51/709) overall. Sensitivity, specificity, positive and negative predictive values of the io® CT assay were, respectively, 96.1% (95% Confidence Interval (CI): 86.5-99.5), 97.7% (95%CI: 96.3-98.7), 76.6% (95%CI: 64.3-86.2) and 99.7% (95%CI: 98.9-100). The only risk factor associated with CT infection was being a sexual contact of an individual with CT. CONCLUSIONS: The io® CT-assay is a 30-min, fully automated, high-performing NAAT currently CE-marked for CT diagnosis in women, making it a highly promising diagnostic to enable specific treatment, initiation of partner notification and appropriately intensive health promotion at the point of care

A Bayesian approach to linking archaeological, paleoenvironmental and documentary datasets relating to the settlement of Iceland (Landnám)

YesIcelandic settlement (Landnám) period farmsteads offer opportunities to explore the nature and timing of anthropogenic activities and environmental impacts of the first Holocene farming communities. We employ Bayesian statistical modelling of archaeological, paleoenvironmental and documentary datasets to present a framework for improving chronological robustness of archaeological events. Specifically, we discuss events relevant to the farm Hrísbrú, an initial and complex settlement site in southwest Iceland. We demonstrate that tephra layers are key in constraining reliable chronologies, especially when combined with related datasets and treated in a Bayesian framework. The work presented here confirms earlier interpretations of the chronology of the site while providing increased confidence in the robustness of the chronology. Most importantly, integrated modelling of AMS radiocarbon dates on Hordeum vulgare grains, palynological data, documented evidence from textual records and typologically diagnostic artefacts yield increased dating reliability. The analysis has also shown that AMS radiocarbon dates on bone collagen need further scrutiny. Specifically for the Hrísbrú farm, first anthropogenic footprint palynomorph taxa are estimated to around AD 830–881 (at 95.4% confidence level), most likely before the tephra fall out of AD 877 ± 1 (the Landnám tephra layer), demonstrating the use of arable fields before the first known structures were built at Hrísbrú (AD 874–951) and prior to the conventionally accepted date of the settlement of Iceland. Finally, we highlight the importance of considering multidisciplinary factors for other archaeological and paleoecological studies of early farming communities of previously uninhabited island areas

Spatially-resolved optical and structural properties of semi-polar [Formula: see text] Al x Ga1-x N with x up to 0.56

Pushing the emission wavelength of efficient ultraviolet (UV) emitters further into the deep-UV requires material with high crystal quality, while also reducing the detrimental effects of built-in electric fields. Crack-free semi-polar [Formula: see text] Al x Ga1-x N epilayers with AlN contents up to x = 0.56 and high crystal quality were achieved using an overgrowth method employing GaN microrods on m-sapphire. Two dominant emission peaks were identified using cathodoluminescence hyperspectral imaging. The longer wavelength peak originates near and around chevron-shaped features, whose density is greatly increased for higher contents. The emission from the majority of the surface is dominated by the shorter wavelength peak, influenced by the presence of basal-plane stacking faults (BSFs). Due to the overgrowth technique BSFs are bunched up in parallel stripes where the lower wavelength peak is broadened and hence appears slightly redshifted compared with the higher quality regions in-between. Additionally, the density of threading dislocations in these region is one order of magnitude lower compared with areas affected by BSFs as ascertained by electron channelling contrast imaging. Overall, the luminescence properties of semi-polar AlGaN epilayers are strongly influenced by the overgrowth method, which shows that reducing the density of extended defects improves the optical performance of high AlN content AlGaN structures

The resilience of postglacial hunter-gatherers to abrupt climate change

Understanding the resilience of early societies to climate change is an essential part of exploring the environmental sensitivity of human populations. There is significant interest in the role of abrupt climate events as a driver of early Holocene human activity, but there are very few well-dated records directly compared with local climate archives. Here, we present evidence from the internationally important Mesolithic site of Star Carr showing occupation during the early Holocene, which is directly compared with a high-resolution palaeoclimate record from neighbouring lake beds. We show that-once established-there was intensive human activity at the site for several hundred years when the community was subject to multiple, severe, abrupt climate events that impacted air temperatures, the landscape and the ecosystem of the region. However, these results show that occupation and activity at the site persisted regardless of the environmental stresses experienced by this society. The Star Carr population displayed a high level of resilience to climate change, suggesting that postglacial populations were not necessarily held hostage to the flickering switch of climate change. Instead, we show that local, intrinsic changes in the wetland environment were more significant in determining human activity than the large-scale abrupt early Holocene climate events

The cost-effectiveness of screening for ovarian cancer: results from the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS)

Background: To assess the within trial cost-effectiveness of an NHS ovarian cancer screening (OCS) programme using data from UKCTOCS and extrapolate results based on average life expectancy. Methods: Within trial economic evaluation of no screening (C) versus either (1) an annual OCS programme using transvaginal ultrasound (USS) or (2) an annual ovarian cancer multimodal screening programme with serum CA125 interpreted using a risk algorithm (ROCA) and transvaginal ultrasound as a second line test (MMS), plus comparison of lifetime extrapolation of the no screening arm and the MMS programme using both a predictive and a Markov model. Results: Using a CA125-ROCA cost of £20, the within trial results show USS to be strictly dominated by MMS, with the MMS versus C comparison returning an Incremental Cost-Effectiveness ratio (ICER) of £91,452 per life year gained (LYG). If the CA125-ROCA unit cost is reduced to £15 the ICER becomes £77,818 per LYG. Predictive extrapolation over the expected lifetime of the UKCTOCS women returns an ICER of £30,033 per LYG, while Markov modelling produces an ICER of £46,922 per QALY. Conclusions: Analysis suggests that, after accounting for the lead-time required to establish full mortality benefits, a national OCS programme based on the MMS strategy quickly approaches the current NICE thresholds for cost-effectiveness when extrapolated out to lifetime as compared to the within trial ICER estimates. Whether MMS could be recommended on economic grounds would depend on the confirmation and size of the mortality benefit at the end of an ongoing follow-up of the UKCTOCS cohort