The FReedom from Ischemic Events-New Dimensions for Survival (FRIENDS) registry: design of a prospective cohort study of patients with advanced peripheral artery disease.

BACKGROUND Advanced lower extremity peripheral artery disease (PAD), whether presenting as acute limb ischemia (ALI) or chronic critical limb ischemia (CLI), is associated with high rates of cardiovascular ischemic events, amputation, and death. Past research has focused on strategies of revascularization, but few data are available that prospectively evaluate the impact of key process of care factors (spanning pre-admission, acute hospitalization, and post-discharge) that might contribute to improving short and long-term health outcomes. METHODS/DESIGN The FRIENDS registry is designed to prospectively evaluate a range of patient and health system care delivery factors that might serve as future targets for efforts to improve limb and systemic outcomes for patients with ALI or CLI. This hypothesis-driven registry was designed to evaluate the contributions of: (i) pre-hospital limb ischemia symptom duration, (ii) use of leg revascularization strategies, and (iii) use of risk-reduction pharmacotherapies, as pre-specified factors that may affect amputation-free survival. Sequential patients would be included at an index "vascular specialist-defined" ALI or CLI episode, and patients excluded only for non-vascular etiologies of limb threat. Data including baseline demographics, functional status, co-morbidities, pre-hospital time segments, and use of medical therapies; hospital-based use of revascularization strategies, time segments, and pharmacotherapies; and rates of systemic ischemic events (e.g., myocardial infarction, stroke, hospitalization, and death) and limb ischemic events (e.g., hospitalization for revascularization or amputation) will be recorded during a minimum of one year follow-up. DISCUSSION The FRIENDS registry is designed to evaluate the potential impact of key factors that may contribute to adverse outcomes for patients with ALI or CLI. Definition of new "health system-based" therapeutic targets could then become the focus of future interventional clinical trials for individuals with advanced PAD.

Theoretical framework for the assessment of vulnerability to natural hazards and climate change [in Europe]

Reducing risk that emerges from hazards of natural origin and societal vulnerability is a key challenge for the development of more resilient communities and the overall goal of sustainable development. The following chapter outlines a framework for multidimensional, holistic vulnerability assessment that is understood as part of risk evaluation and risk management in the context of Disaster Risk Management (DRM) and Climate Change Adaptation (CCA). As a heuristic, the framework is a thinking tool to guide systematic assessments of vulnerability and to provide a basis for comparative indicators and criteria development to assess key factors and various dimensions of vulnerability, particularly in regions in Europe, however, it can also be applied in other world regions. The framework has been developed within the context of the research project MOVE (Methods for the Improvement of Vulnerability Assessment in Europe; ) sponsored by the European Commission within the framework of the FP 7 program.

Bacteriological diagnosis and molecular strain typing of Mycobacterium bovis and Mycobacterium caprae

The primary isolation of a Mycobacterium sp. of the Mycobacterium tuberculosis complex from an infected animal provides a definitive diagnosis of tuberculosis. However, as Mycobacterium bovis and Mycobacterium caprae are difficult to isolate, particularly for animals in the early stages of disease, success is dependent on the optimal performance of all aspects of the bacteriological process, from the initial choice of tissue samples at post-mortem examination or clinical samples, to the type of media and conditions used to cultivate the microorganism. Each step has its own performance characteristics, which can contribute to sensitivity and specificity of the procedure, and may need to be optimized in order to achieve the gold standard diagnosis. Having isolated the slow-growing mycobacteria, species identification and fine resolution strain typing are keys to understanding the epidemiology of the disease and to devise strategies to limit transmission of infection. New technologies have emerged that can now even discriminate different isolates from the same animal. In this review we highlight the key factors that contribute to the accuracy of bacteriological diagnosis of M. bovis and M. caprae, and describe the development of advanced genotyping techniques that are increasingly used in diagnostic laboratories for the purpose of supporting detailed epidemiological investigations.

The impact of prolonged lower limb ischemia on amputation, mortality, and functional status: the FRIENDS registry.

BACKGROUND Peripheral artery disease (PAD) is a major cause of cardiovascular ischemic events and amputation. Knowledge gaps exist in defining and measuring key factors that predict these events. The objective of this study was to assess whether duration of limb ischemia would serve as a major predictor of limb and patient survival. METHODS The FReedom from Ischemic Events: New Dimensions for Survival (FRIENDS) registry enrolled consecutive patients with limb-threatening peripheral artery disease at a single tertiary care hospital. Demographic information, key clinical care time segments, functional status and use of revascularization, and pharmacotherapy data were collected at baseline, and vascular ischemic events, cardiovascular mortality, and all-cause mortality were recorded at 30 days and 1 year. RESULTS A total of 200 patients with median (interquartile range) age of 76 years (65-84 years) were enrolled in the registry. Median duration of limb ischemia was 0.75 days for acute limb ischemia (ALI) and 61 days for chronic critical limb ischemia (CLI). Duration of limb ischemia of <12, 12 to 24, and >24 hours in patients with ALI was associated with much higher rates of first amputation (P = .0002) and worse amputation-free survival (P = .037). No such associations were observed in patients with CLI. CONCLUSIONS For individuals with ischemic symptoms <14 days, prolonged limb ischemia is associated with higher 30-day and 1-year amputation, systemic ischemic event rates, and worse amputation-free survival. No such associations are evident for individuals with chronic CLI. These data imply that prompt diagnosis and revascularization might improve outcomes for patients with ALI.

Multidisciplinary consensus on assessment of unruptured intracranial aneurysms: proposal of an international research group.

BACKGROUND AND PURPOSE To address the increasing need to counsel patients about treatment indications for unruptured intracranial aneurysms (UIA), we endeavored to develop a consensus on assessment of UIAs among a group of specialists from diverse fields involved in research and treatment of UIAs. METHODS After composition of the research group, a Delphi consensus was initiated to identify and rate all features, which may be relevant to assess UIAs and their treatment by using ranking scales and analysis of inter-rater agreement (IRA) for each factor. IRA was categorized as very high, high, moderate, or low. RESULTS Ultimately, 39 specialists from 4 specialties agreed (high or very high IRAs) on the following key factors for or against UIA treatment decisions: (1) patient age, life expectancy, and comorbid diseases; (2) previous subarachnoid hemorrhage from a different aneurysm, family history for UIA or subarachnoid hemorrhage, nicotine use; (3) UIA size, location, and lobulation; (4) UIA growth or de novo formation on serial imaging; (5) clinical symptoms (cranial nerve deficit, mass effect, and thromboembolic events from UIAs); and (6) risk factors for UIA treatment (patient age and life expectancy, UIA size, and estimated risk of treatment). However, IRAs for features rated with low relevance were also generally low, which underlined the existing controversy about the natural history of UIAs. CONCLUSIONS Our results highlight that neurovascular specialists currently consider many features as important when evaluating UIAs but also highlight that the appreciation of natural history of UIAs remains uncertain, even within a group of highly informed individuals.

Approaches to Ensure Quality Standards for Standardized/ Simulated Patient Performance in High Stakes Objective Structured Clinical Exams (OSCEs)

Introduction To meet the quality standards for high-stakes OSCEs, it is necessary to ensure high quality standardized performance of the SPs involved.[1] One of the ways this can be assured is through the assessment of the quality of SPs` performance in training and during the assessment. There is some literature concerning validated instruments that have been used to assess SP performance in formative contexts but very little related to high stakes contexts.[2], [3], [4]. Content and structure During this workshop different approaches to quality control for SPs` performance, developed in medicine, pharmacy and nursing OSCEs, will be introduced. Participants will have the opportunity to use these approaches in simulated interactions. Advantages and disadvantages of these approaches will be discussed. Anticipated outcomes By the end of this session, participants will be able to discuss the rationale for quality control of SPs` performance in high stakes OSCEs, outline key factors in creating strategies for quality control, identify various strategies for assuring quality control, and reflect on applications to their own practice. Who should attend The workshop is designed for those interested in quality assurance of SP performance in high stakes OSCEs. Level All levels are welcome. References Adamo G. 2003. Simulated and standardized patients in OSCEs: achievements and challenges:1992-2003. Med Teach. 25(3), 262- 270. Wind LA, Van Dalen J, Muijtjens AM, Rethans JJ. Assessing simulated patients in an educational setting: the MaSP (Maastricht Assessment of Simulated Patients). Med Educ 2004, 38(1):39-44. Bouter S, van Weel-Baumgarten E, Bolhuis S. Construction and validation of the Nijmegen Evaluation of the Simulated Patient (NESP): Assessing Simulated Patients' ability to role-play and provide feedback to students. Acad Med: Journal of the Association of American Medical Colleges 2012. May W, Fisher D, Souder D: Development of an instrument to measure the quality of standardized/simulated patient verbal feedback. Med Educ 2012, 2(1).

Hyperketonemia during lipopolysaccharide-induced mastitis affects systemic and local intramammary metabolism in dairy cows

Hyperketonemia interferes with the metabolic regulation in dairy cows. It is assumed that metabolic and endocrine changes during hyperketonemia also affect metabolic adaptations during inflammatory processes. We therefore studied systemic and local intramammary effects of elevated plasma β-hydroxybutyrate (BHBA) before and during the response to an intramammary lipopolysaccharide (LPS) challenge. Thirteen dairy cows received intravenously either a Na-DL-β-OH-butyrate infusion (n = 5) to achieve a constant plasma BHBA concentration (1.7 ± 0.1 mmol/L), with adjustments of the infusion rates made based on immediate measurements of plasma BHBA every 15 min, or an infusion with a 0.9% NaCl solution (control; n = 8) for 56 h. Infusions started at 0900 h on d 1 and continued until 1700 h 2 d later. Two udder quarters were challenged with 200 μg of Escherichia coli LPS and 2 udder quarters were treated with 0.9% saline solution as control quarters at 48 h after the start of infusion. Blood samples were taken at 1 wk and 2h before the start of infusions as reference samples and hourly during the infusion. Mammary gland biopsies were taken 1 wk before, and 48 and 56 h (8h after LPS challenge) after the start of infusions. The mRNA abundance of key factors related to BHBA and fatty acid metabolism, and glucose transporters was determined in mammary tissue biopsies. Blood samples were analyzed for plasma glucose, BHBA, nonesterified fatty acid, urea, insulin, glucagon, and cortisol concentrations. Differences were not different for effects of BHBA infusion on the mRNA abundance of any of the measured target genes in the mammary gland before LPS challenge. Intramammary LPS challenge increased plasma glucose, cortisol, glucagon, and insulin concentrations in both groups but increases in plasma glucose and glucagon concentration were less pronounced in the Na-DL-β-OH-butyrate infusion group than in controls. In response to LPS challenge, plasma BHBA concentration decreased in controls and decreased also slightly in the BHBA-infused animals because the BHBA concentration could not be fully maintained despite a rapid increase in BHBA infusion rate. The change in mRNA abundance of citrate synthase in LPS quarters was significant between the 2 treatment groups. The results indicate that elevated circulating BHBA concentration inhibits gluconeogenesis before and during immune response to LPS challenge, likely because BHBA can replace glucose as an energy source.

Cholesterol metabolism, transport, and hepatic regulation in dairy cows during transition and early lactation

The transition from the nonlactating to the lactating state represents a critical period for dairy cow lipid metabolism because body reserves have to be mobilized to meet the increasing energy requirements for the initiation of milk production. The purpose of this study was to provide a comprehensive overview on cholesterol homeostasis in transition dairy cows by assessing in parallel plasma, milk, and hepatic tissue for key factors of cholesterol metabolism, transport, and regulation. Blood samples and liver biopsies were taken from 50 multiparous Holstein dairy cows in wk 3 antepartum (a.p.), wk 1 postpartum (p.p.), wk 4 p.p., and wk 14 p.p. Milk sampling was performed in wk 1, 4, and 14 p.p. Blood and milk lipid concentrations [triglycerides (TG), cholesterol, and lipoproteins], enzyme activities (phospholipid transfer protein and lecithin:cholesterol acyltransferase) were analyzed using enzymatic assays. Hepatic gene expression patterns of 3-hydroxy-3-methylglutaryl-coenzyme A (HMGC) synthase 1 (HMGCS1) and HMGC reductase (HMGCR), sterol regulatory element-binding factor (SREBF)-1 and -2, microsomal triglyceride transfer protein (MTTP), ATP-binding cassette transporter (ABC) A1 and ABCG1, liver X receptor (LXR) α and peroxisome proliferator activated receptor (PPAR) α and γ were measured using quantitative RT-PCR. Plasma TG, cholesterol, and lipoprotein concentrations decreased from wk 3 a.p. to a minimum in wk 1 p.p., and then gradually increased until wk 14 p.p. Compared with wk 4 p.p., phospholipid transfer protein activity was increased in wk 1 p.p., whereas lecithin:cholesterol acyltransferase activity was lowest at this period. Total cholesterol concentration and mass, and cholesterol concentration in the milk fat fraction decreased from wk 1 p.p. to wk 4 p.p. Both total and milk fat cholesterol concentration were decreased in wk 4 p.p. compared with wk 1 and 14 p.p. The mRNA abundance of genes involved in cholesterol synthesis (SREBF-2, HMGCS1, and HMGCR) markedly increased from wk 3 a.p. to wk 1 p.p., whereas SREBF-1 was downregulated. The expression of ABCA1 increased from wk 3 a.p. to wk 1 p.p., whereas ABCG1 was increased in wk 14 p.p. compared with other time points. In conclusion, hepatic expression of genes involved in the biosynthesis of cholesterol as well as the ABCA1 transporter were upregulated at the onset of lactation, whereas plasma concentrations of total cholesterol, phospholipids, lipoprotein-cholesterol, and TG were at a minimum. Thus, at the gene expression level, the liver seems to react to the increased demand for cholesterol after parturition. Whether the low plasma cholesterol and TG levels are due to impaired hepatic export mechanisms or reflect an enhanced transfer of these compounds into the milk to provide essential nutrients for the newborn remains to be elucidated.

New perioperative fluid and pharmacologic management protocol results in reduced blood loss, faster return of bowel function, and overall recovery.

Cystectomy and urinary diversion have high morbidity, and strategies to reduce complications are of utmost importance. Epidural analgesia and optimized fluid management are considered key factors contributing to successful enhanced recovery after surgery. In colorectal surgery, there is strong evidence that an intraoperative fluid management aiming for a postoperative zero fluid balance results in lower morbidity including a faster return of bowel function. Recently, a randomized clinical trial focusing on radical cystectomy demonstrated that a restrictive intraoperative hydration combined with a concomitant administration of norepinephrine reduced intraoperative blood loss, the need for blood transfusion and morbidity. The purpose of this review is to highlight specific anesthesiological aspects which have been shown to improve outcome after RC with urinary diversion.

High-flow venous pouch aneurysm in the rabbit carotid artery: A model for large aneurysms.

BACKGROUND AND PURPOSE Currently one of the most widely used models for the development of endovascular techniques and coiling devices for treatment of aneurysm is the elastase-induced aneurysm model in the rabbit carotid artery. Microsurgical techniques for creating an aneurysm with a venous pouch have also been established, although both techniques usually result in aneurysms less than 1 cm in diameter. We investigated whether an increase in blood flow toward the neck would produce larger aneurysms in a microsurgical venous pouch model. MATERIALS AND METHODS Microsurgical operations were performed on 11 New Zealand white rabbits. Both carotid arteries and the right jugular vein were dissected, and the right carotid artery was temporarily clipped followed by an arteriotomy. The left carotid artery was also clipped proximally, ligated distally, and sutured onto the proximal half of the arteriotomy in the right carotid artery. The venous graft was sutured onto the distal half of the arteriotomy. Digital subtraction angiography was also performed. RESULTS Angiography showed patent anastomosed vessels and aneurysms in the seven surviving rabbits. Mean aneurysm measurements among surviving rabbits with patent vessels were: 13.9 mm length, 9.3 mm width, and neck diameter 4.7 mm. The resulting mean aspect ratio was 3.35 and the mean bottleneck ratio was 3.05. CONCLUSION A large venous graft and increased blood flow toward the base of the aneurysm seem to be key factors in the creation of large venous pouch aneurysms. These large aneurysms allow testing of endovascular devices designed for large and giant aneurysms.

Labour Migration, Trade and Investment: From Fragmentation to Coherence

Trade, investment and migration are strongly intertwined, being three key factors in international production. Yet, law and regulation of the three has remained highly fragmented. Trade is regulated by the WTO on the multilateral level, and through preferential trade agreements on the regional and bilateral levels – it is fragmented and complex in its own right. Investment, on the other hand, is mainly regulated through bilateral investment treaties with no strong links to the regulation of trade or migration. And, finally, migration is regulated by a web of different international, regional and bilateral agreements which focus on a variety of different aspects of migration ranging from humanitarian to economic. The problems of institutional fragmentation in international law are well known. There is no organizational forum for coherent strategy-making on the multilateral level covering all three areas. Normative regulations may thus contradict each other. Trade regulation may bring about liberalization of access for service providers, but eventually faces problems in recruiting the best people from abroad. Investors may withdraw investment without being held liable for disruptions to labour and to the livelihood and infrastructure of towns and communities affected by disinvestment. Finally, migration policies do not seem to have a significant impact as long as trade policies and investment policies are not working in a way that is conducive to reducing migration pressure, as trade and investment are simply more powerful on the regulatory level than migration. This chapter addresses the question as to how fragmentation of the three fields could be reme-died and greater coherence between these three areas of factor allocation in international economic relations and law could be achieved. It shows that migration regulation on the international level is lagging behind that on trade and investment. Stronger coordination and consideration of migration in trade and investment policy, and stronger international cooperation in migration, will provide the foundations for a coherent international architecture in the field.

A Nicotiana attenuata cell wall invertase inhibitor (NaCWII) reduces growth and increases secondary metabolite biosynthesis in herbivore-attacked plants

Plant invertases are sucrolytic enzymes that are essential for the regulation of carbohydrate metabolism and source–sink relationships. While their activity has been well documented during abiotic and biotic stresses, the role of proteinaceous invertase inhibitors in regulating these changes is unknown. Here, we identify a putative Nicotiana attenuata cell wall invertase inhibitor (NaCWII) which is strongly up-regulated in a jasmonate (JA)-dependent manner following simulated attack by the specialist herbivore Manduca sexta. To understand the role of NaCWII in planta, we silenced its expression by RNA interference and measured changes in primary and secondary metabolism and plant growth following simulated herbivory. NaCWII-silenced plants displayed a stronger depletion of carbohydrates and a reduced capacity to increase secondary metabolite pools relative to their empty vector control counterparts. This coincided with the attenuation of herbivore-induced CWI inhibition and growth suppression characteristic of wild-type plants. Together our findings suggest that NaCWII may act as a regulatory switch located downstream of JA accumulation which fine-tunes the plant's balance between growth and defense metabolism under herbivore attack. Although carbohydrates are not typically viewed as key factors in plant growth and defense, our study shows that interfering with their catabolism strongly influences plant responses to herbivory.

The unruptured intracranial aneurysm treatment score: a multidisciplinary consensus.

OBJECTIVE We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research. METHODS An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement). RESULTS The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1-4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1-4.4) for panel members and 4.5 (95% CI 4.3-4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1-4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9-4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019-0.033). CONCLUSIONS This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA.

The Honey Bee Pathosphere of Mongolia: European Viruses in Central Asia

Parasites and pathogens are apparent key factors for the detrimental health of managed European honey bee subspecies, Apis mellifera. Apicultural trade is arguably the main factor for the almost global distribution of most honey bee diseases, thereby increasing chances for multiple infestations/infections of regions, apiaries, colonies and even individual bees. This imposes difficulties to evaluate the effects of pathogens in isolation, thereby creating demand to survey remote areas. Here, we conducted the first comprehensive survey for 14 honey bee pathogens in Mongolia (N = 3 regions, N = 9 locations, N = 151 colonies), where honey bee colonies depend on humans to overwinter. In Mongolia, honey bees, Apis spp., are not native and colonies of European A. mellifera subspecies have been introduced ~60 years ago. Despite the high detection power and large sample size across Mongolian regions with beekeeping, the mite Acarapis woodi, the bacteria Melissococcus plutonius and Paenibacillus larvae, the microsporidian Nosema apis, Acute bee paralysis virus, Kashmir bee virus, Israeli acute paralysis virus and Lake Sinai virus strain 2 were not detected, suggesting that they are either very rare or absent. The mite Varroa destructor, Nosema ceranae and four viruses (Sacbrood virus, Black queen cell virus, Deformed wing virus (DWV) and Chronic bee paralysis virus) were found with different prevalence. Despite the positive correlation between the prevalence of V. destructor mites and DWV, some areas had only mites, but not DWV, which is most likely due to the exceptional isolation of apiaries (up to 600 km). Phylogenetic analyses of the detected viruses reveal their clustering and European origin, thereby supporting the role of trade for pathogen spread and the isolation of Mongolia from South-Asian countries. In conclusion, this survey reveals the distinctive honey bee pathosphere of Mongolia, which offers opportunities for exciting future research.

The machinery underlying malaria parasite virulence is conserved between rodent and human malaria parasites

Sequestration of red blood cells infected with the human malaria parasite Plasmodium falciparum in organs such as the brain is considered important for pathogenicity. A similar phenomenon has been observed in mouse models of malaria, using the rodent parasite Plasmodium berghei, but it is unclear whether the P. falciparum proteins known to be involved in this process are conserved in the rodent parasite. Here we identify the P. berghei orthologues of two such key factors of P. falciparum, SBP1 and MAHRP1. Red blood cells infected with P. berghei parasites lacking SBP1 or MAHRP1a fail to bind the endothelial receptor CD36 and show reduced sequestration and virulence in mice. Complementation of the mutant P. berghei parasites with the respective P. falciparum SBP1 and MAHRP1 orthologues restores sequestration and virulence. These findings reveal evolutionary conservation of the machinery underlying sequestration of divergent malaria parasites and support the notion that the P. berghei rodent model is an adequate tool for research on malaria virulence.