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The paper examines the current hard-bordered concept of the state and its inability to address the needs of non-national identities. The rise of European micro-nationalism in the latter half of the Twentieth Century led many to question the future of the Westphalian state. This paper examines this claim from the perspective of non-national identities and concludes that the essential elements of the model remained intact. In particular the territorial basis of the dominant governance model and the requirement of hard-borders remains the norm. For this reason, non-territorial identities were largely unsuccessful in their demands for constitutional recognition. The needs of such identities demand that such a shift take place, particularly if the spectre of exclusive territorial nationalism is to be exorcised. Yet the difficulties experienced by the few examples that exist in Europe emphasise the fundamental shift in approach that such a move towards soft-borders entails. [ABSTRACT FROM AUTHOR]

Malignant hyperthermia (MH) is a condition that manifests in susceptible individuals only on exposure to certain anaesthetic agents. Although genetically heterogeneous, mutations in the RYR1 gene (19q13.1) are associated with the majority of reported MH cases. Guidelines for the genetic diagnosis for MH susceptibility have recently been introduced by the European MH Group (EMHG). These are designed to supplement the muscle biopsy testing procedure, the in vitro contracture test (IVCT), which has been the only means of patient screening for the last 30 years and which remains the method for definitive diagnosis in suspected probands. Discordance observed in some families between IVCT phenotype and susceptibility locus genotype could limit the confidence in genetic diagnosis. We have therefore assessed the prevalence of 15 RYR1 mutations currently used in the genetic diagnosis of MH in a sample of over 500 unrelated European MH susceptible individuals and have recorded the frequency of RYR1 genotype/IVCT phenotype discordance. RYR1 mutations were detected in up to ∼30% of families investigated. Phenotype/genotype discordance in a single individual was observed in 10 out of 196 mutation-positive families. In five families a mutation-positive/IVCT-negative individual was observed, and in the other five families a mutation-negative/IVCT-positive individual was observed. These data represent the most comprehensive assessment of RYR1 mutation prevalence and genotype/phenotype correlation analysis and highlight the possible limitations of MH screening methods. The implications for genetic diagnosis are discussed. [ABSTRACT FROM AUTHOR]

Purpose To compare 5-year survival of lung transplant (LTx) recipients in donation after circulatory death (DCD) versus donation after brain-death (DBD) donors. Methods We examined the ISHLT Thoracic Transplant Registry data for LTx patients transplanted between 2003 and 06/2017 at 23 centers in North America, Europe and Australia participating in the DCD Registry. Distribution of continuous variables was summarized as median and interquartile (IQR) values. Mann-Whitney test was used to compare distribution of continuous variables and chi-square or Fisher's exact test for categorical variables. Kaplan-Meier survival rates after LTx during 2003-06/2016 were compared between DCD-III [Maastricht category III withdrawal of life sustaining therapy (WLST)] only and DBD using the log-rank test. Risk factors for 5-year mortality were investigated using Cox multivariate proportional-hazards model. Results The study cohort included 11,516 lung transplants, of which 1,090 (9.5%) were DCD transplants. DCD-III category comprised 94.1% of the DCD cohort. Among the participating centers, the proportion of DCD-LTx increased from 0.6% in 2003 to 15.2% in 2017. DCD donor management included extubation in 91%, intravenous heparin in 51% and pre-transplant normothermic ex-situ pulmonary allograft perfusion in 15%. Median time interval from WLST to cardiac arrest was 15 min [IQR: 11-22 min] and to cold flush 32 min [IQR: 26-41 min]. Compared to DBD, donor age was higher (47 [IQR: 34-55] vs 40 [IQR: 24-52] years), bilateral LTx was performed more often (88.3% vs 76.6%), more recipients had COPD/emphysema as transplant indication, and recipient hospital stay was longer (25 [IQR: 17-39] versus 18 [IQR: 12-29] days) in DCD-III (all p<0.0001). Five-year survival rates were comparable (63% vs 61%; p=NS). In multivariable analysis, recipient and donor ages, diagnosis, transplant type (single vs double LTx) and transplant era (2003-2009 vs 2010-6/2016) were independently associated with survival (all p<0.001); but donor type (DCD-III versus DBD) was not (HR 1.03 [0.90-1.18]; p=0.63). Conclusion This ISHLT DCD Registry report with 5-year follow-up demonstrated similar excellent long-term survival in DCD-III and DBD lung donor recipients in 23 experienced centers. These data support measures to implement and increase DCD LTx more widely. [ABSTRACT FROM AUTHOR]

It is 30 yr since the British Journal of Anaesthesia published the first consensus protocol for the laboratory diagnosis of malignant hyperthermia susceptibility from the European Malignant Hyperthermia Group. This has subsequently been used in more than 10 000 individuals worldwide to inform use of anaesthetic drugs in these patients with increased risk of developing malignant hyperthermia during general anaesthesia, representing an early and successful example of stratified medicine. In 2001, our group also published a guideline for the use of DNA-based screening of malignant hyperthermia susceptibility. We now present an updated and complete guideline for the diagnostic pathway for patients potentially at increased risk of developing malignant hyperthermia. We introduce the new guideline with a narrative commentary that describes its development, the changes to previously published protocols and guidelines, and new sections, including recommendations for patient referral criteria and clinical interpretation of laboratory findings., (© The Author 2015. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Serum- and glucocorticoid-inducible kinase 1 (SGK1) has a central role in epithelial sodium channel (ENaC)-dependent Na(+) transport in the distal nephron. We hypothesized that SGK1 gene variants may contribute to the effect of dietary salt intake on blood pressure (BP) in humans with hypertension, and consequentially influence renin-angiotensin-aldosterone (RAA) system activity. Our study population included 421 hypertensive Caucasian participants of the HyperPath group who had completed a dietary salt protocol with measurement of BP and RAA system activity. Three SGK1 tagging single nucleotide polymorphisms (SNPs) from the HapMap CEU population captured the genetic variation in the SGK1 region. Assuming an additive genetic model, two SNPs (rs2758151 and rs9402571) were associated with BP and plasma renin activity (PRA) effects of dietary salt intake. Major alleles were associated with higher systolic BP on high salt and decreased PRA on low salt. In contrast, low salt neutralized genotype differences. Similar, non-significant trends were observed in a normotensive population (N=152). Genotype was also associated with two salt-sensitive subtypes of hypertension. SGK1 genetic variants are associated with salt sensitivity of BP and PRA in human hypertension. Genotype status at these SGK1 variants may identify individuals prone to salt-sensitive hypertension.

Introduction: Endoscopic lung volume reduction has been developed as a therapeutic option for advanced emphysema. Six-month results following treatment with endoscopic thermal vapor ablation (InterVapor; Uptake Medical, Tustin, CA) were described previously, and here we report observations from the 12-month assessment., Methods: Two multicenter, international, single-arm trials of InterVapor (unilateral upper lobe treatment) in patients with upper lobe predominant emphysema were conducted., Inclusion Criteria: forced expiratory volume in 1 second (FEV(1)) 15%-45% predicted, residual volume > 150%, total lung capacity > 100%, 6-minute walk distance (6MWD) > 140 m, and diffusing capacity for carbon monoxide > 20% predicted. Efficacy endpoints: spirometry, body plethysmography, lung volumes by high-resolution computed tomography, St George's Respiratory Questionnaire, modified Medical Research Council dyspnea scale, and 6MWD. All adverse events were collected and independently adjudicated., Results: Forty four patients were treated at a mean (standard deviation) age of 63 (5.6) years, FEV(1) 0.86 mL (0.25 mL) (n = 22 men and 22 women). Mean (standard deviation) changes from baseline at 12 months were: FEV(1) 86.2 mL (173.8 mL), St George's Respiratory Questionnaire -11.0 (14.0) units, treated lobar volume from high-resolution computed tomography -751.8 mL (653.9 mL), residual volume -302.8 mL (775.6 mL), 6MWD 18.5 m (63.7 m), and modified Medical Research Council dyspnea scale score -0.83 (0.97) (P < 0.05 for all except 6MWD). Improvements were numerically larger at 6 versus 12 months. GOLD stage III and IV patients had similar outcomes at 6 months; however, improvements relative to baseline were numerically higher in GOLD stage IV patients. Larger improvements were observed in patients with higher heterogeneity. In total, 39 serious adverse events were reported in 23 patients with 10 events in 8 patients between 6 and 12 months., Conclusion: Unilateral lobar InterVapor treatment of heterogeneous emphysema improved lung function and health outcomes 1 year following treatment. The magnitude of improvement was larger at 6 months compared to 12 months. Improvements relative to baseline continue to be exhibited at 12 months despite the expected disease related decline over time.

Malignant hyperthermia (MH) is an autosomal dominant disorder which is potentially lethal in susceptible individuals on exposure to commonly used inhalational anaesthetics and depolarising muscle relaxants. Crises reflect the consequences of disturbed skeletal muscle calcium homeostasis. Susceptibility was first localised to chromosome 19q13.1 and the skeletal muscle ryanodine receptor, RYR1 (the calcium release channel of the sarcoplasmic reticulum). Defects in this gene have been identified which cosegregate with the MHS phenotype and evidence as to their potential causal roles has accumulated. MH has, however, been shown to be genetically heterogeneous, additional loci on chromosomes 3q, 17q and 7q being proposed. Pedigrees remain in Europe where linkage status is still unclear. In a collaborative search of the human genome conducted with three pedigrees whose disease status was classified according to the European IVCT protocol we have evidence to suggest that at least two further loci exist for MH susceptibility. One of these locates to chromosome 1q, the site of a candidate gene, CACNL1A3, encoding the alpha-subunit of the dihydropyridine receptor. The second region resides on chromosome 5p to where no known candidate has been mapped to date. The third family exhibited inconclusive results which suggests the existence of at least one other locus. This study adds to the evidence for considerable genetic heterogeneity in MH and will provide a route to further our understanding of the molecular pathology of the condition.