Effect of Inhaled Xenon on Cerebral White Matter Damage in Comatose Survivors of Out-of-Hospital Cardiac Arrest: A Randomized Clinical Trial

IMPORTANCE: Evidence from preclinical models indicates that xenon gas can prevent the development of cerebral damage after acute global hypoxic-ischemic brain injury but, thus far, these putative neuroprotective properties have not been reported in human studies. OBJECTIVE: To determine the effect of inhaled xenon on ischemic white matter damage assessed with magnetic resonance imaging (MRI). DESIGN, SETTING, AND PARTICIPANTS: A randomized single-blind phase 2 clinical drug trial conducted between August 2009 and March 2015 at 2 multipurpose intensive care units in Finland. One hundred ten comatose patients (aged 24-76 years) who had experienced out-of-hospital cardiac arrest were randomized. INTERVENTIONS: Patients were randomly assigned to receive either inhaled xenon combined with hypothermia (33°C) for 24 hours (n = 55 in the xenon group) or hypothermia treatment alone (n = 55 in the control group). MAIN OUTCOMES AND MEASURES: The primary end point was cerebral white matter damage as evaluated by fractional anisotropy from diffusion tensor MRI scheduled to be performed between 36 and 52 hours after cardiac arrest. Secondary end points included neurological outcome assessed using the modified Rankin Scale (score 0 [no symptoms] through 6 [death]) and mortality at 6 months. RESULTS: Among the 110 randomized patients (mean age, 61.5 years; 80 men [72.7%]), all completed the study. There were MRI data from 97 patients (88.2%) a median of 53 hours (interquartile range [IQR], 47-64 hours) after cardiac arrest. The mean global fractional anisotropy values were 0.433 (SD, 0.028) in the xenon group and 0.419 (SD, 0.033) in the control group. The age-, sex-, and site-adjusted mean global fractional anisotropy value was 3.8% higher (95% CI, 1.1%-6.4%) in the xenon group (adjusted mean difference, 0.016 [95% CI, 0.005-0.027], P = .006). At 6 months, 75 patients (68.2%) were alive. Secondary end points at 6 months did not reveal statistically significant differences between the groups. In ordinal analysis of the modified Rankin Scale, the median (IQR) value was 1 (1-6) in the xenon group and 1 (0-6) in the control group (median difference, 0 [95% CI, 0-0]; P = .68). The 6-month mortality rate was 27.3% (15/55) in the xenon group and 34.5% (19/55) in the control group (adjusted hazard ratio, 0.49 [95% CI, 0.23-1.01]; P = .053). CONCLUSIONS AND RELEVANCE: Among comatose survivors of out-of-hospital cardiac arrest, inhaled xenon combined with hypothermia compared with hypothermia alone resulted in less white matter damage as measured by fractional anisotropy of diffusion tensor MRI. However, there was no statistically significant difference in neurological outcomes or mortality at 6 months. These preliminary findings require further evaluation in an adequately powered clinical trial designed to assess clinical outcomes associated with inhaled xenon among survivors of out-of-hospital cardiac arrest. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00879892

Localized induction equation and pseudospherical surfaces

We describe a close connection between the localized induction equation hierarchy of integrable evolution equations on space curves, and surfaces of constant negative Gauss curvature.Comment: 21 pages, AMSTeX file. To appear in Journal of Physics A: Mathematical and Genera

Restrictive fluid management versus usual care in acute kidney injury (REVERSE-AKI) : a pilot randomized controlled feasibility trial

Purpose We compared a restrictive fluid management strategy to usual care among critically ill patients with acute kidney injury (AKI) who had received initial fluid resuscitation. Methods This multicenter feasibility trial randomized 100 AKI patients 1:1 in seven ICUs in Europe and Australia. Restrictive fluid management included targeting negative or neutral daily fluid balance by minimizing fluid input and/or enhancing urine output with diuretics administered at the discretion of the clinician. Fluid boluses were administered as clinically indicated. The primary endpoint was cumulative fluid balance 72 h from randomization. Results Mean (SD) cumulative fluid balance at 72 h from randomization was - 1080 mL (2003 mL) in the restrictive fluid management arm and 61 mL (3131 mL) in the usual care arm, mean difference (95% CI) - 1148 mL (- 2200 to - 96) mL, P = 0.033. Median [IQR] duration of AKI was 2 [1-3] and 3 [2-7] days, respectively (median difference - 1.0 [- 3.0 to 0.0], P = 0.071). Altogether, 6 out of 46 (13%) patients in the restrictive fluid management arm and 15 out of 50 (30%) in the usual care arm received renal replacement therapy (RR 0.42; 95% CI 0.16-0.91), P = 0.043. Cumulative fluid balance at 24 h and 7 days was lower in the restrictive fluid management arm. The dose of diuretics was not different between the groups. Adverse events occurred more frequently in the usual care arm. Conclusions In critically ill patients with AKI, a restrictive fluid management regimen resulted in lower cumulative fluid balance and less adverse events compared to usual care. Larger trials of this intervention are justified.Peer reviewe

Pharmacogenetics of efficiency and tolerance of the peroral antidiabetic drug metformin

Elektroniskā versija nesatur pielikumusMetformīns ir pirmās izvēles medikaments jaundiagnosticētu 2.tipa cukura diabēta (T2DM) pacientu ārstēšanā. Mēs identificējām asociāciju starp metformīna blakusparādībām un 2 ģenētiskiem variantiem (rs628031 and rs36056065) Organisko Katjonu transportierī 1 (OCT1/SLC22A1). Polimorfismiem rs3119309, rs2481030 un rs7757336, lokalizētiem Organisko Katjonu transportieru 2 un 3 (OCT2/SLC22A2 un OCT3/SLC22A3) starpgēnu reģionā, tika noteikta būtiska asociācija ar metformīna īstermiņa terapijas efektivitāti. Divi no šiem variantiem tika analizēti replikācijas pētījumā ar 126 T2DM pacientiem no Slovākijas un farmakokinētikas pētījumā ar 15 veseliem brīvprātīgajiem. Visbeidzot, 33 ģenētiskas variācijas tika izpētītas ATM, STK11 un T2DM kandidātgēnos, bet tikai dažas no tām bija nomināli asociētas ar metformīna īstermiņa terapijas efektivitāti. Atslēgas vārdi: OCTs, metformīns, farmakoģenētika, blakusparādības, efektivitāte.Metformin is the first-line medication used in treatment of newly-diagnosticed Type 2 diabetes mellitus (T2DM). We show an association between metformin side-effects and two genetic variants (rs628031 and rs36056065) in Organic Cation Transporter 1 (OCT1/SLC22A1). Polymorphisms rs3119309, rs2481030 un rs7757336 in intergenic region between Organic Cation Transporter 2 and 3 (OCT2/SLC22A2 and OCT3/ SLC22A3) were found to be associated with short-term efficiency of metformin therapy. Two of these variants were analysed in replication study in 126 T2DM patients from Slovakia and in pharmacokinetic study with 15 healthy participants. At last, 33 genetic variants in ATM, STK11 and list of T2DM susceptibility genes were investigated, but only few showed a nominal association with short-term efficiency of metformin monotherapy. Keywords: OCTs, metformin, pharmacogenetics, side-effects, efficiency

Constructing global firms? National, transnational and neocolonial effects in international management consultancies

Drawing on an empirical study of four major international management consultancies, this article examines managerial efforts to construct ‘global’ organizations. We show how these efforts are undermined by inter-office conflicts over the staffing of client projects. We argue that such constraints cannot be adequately understood as an outcome of inappropriate organizational structures and incentives since this explanation ignores the important role of institutional contexts. In this vein, we outline and develop four different institutionalist lenses and apply them to the empirical findings. In so doing, we reveal the need to adopt a multi-dimensional institutionalist approach to the study of ‘global’ firms, one that can account for not only national effects but also transnational and neocolonial influences on these organizations

Mutations in Rb1 pathway-related genes are associated with poor prognosis in Anaplastic Astrocytomas

Anaplastic astrocytoma (AA, WHO grade III) is, second to Glioblastoma, the most common and most malignant type of adult CNS tumour. Since survival for patients with AA varies markedly and there are no known useful prognostic or therapy response indicators, the primary purpose of this study was to examine whether knowledge of the known genetic abnormalities found in AA had any clinical value. The survival data on 37 carefully sampled AA was correlated with the results of a detailed analysis of the status of nine genes known to be involved in the development of astrocytic tumours. These included three genes coding for proteins in the p53 pathway (TP53, p14ARF and MDM2), four in the Rb1 pathway (CDKN2A, CDKN2B, RB1 and CDK4) and PTEN and EGFR. We found that loss of both wild-type copies of any of the three tumour suppressor genes CDKN2A, CDKN2B and RB1 or gene amplification of CDK4, disrupting the Rb1 pathway, were associated with shorter survival (P=0.009). This association was consistent in multivariate analysis, including adjustment for age (P=0.013). The findings suggest that analysis of the genes coding for Rb1 pathway components provides additional prognostic information in AA patients receiving conventional therapy

Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas

Medulloblastoma is the most common malignant brain tumor in childhood. Molecular studies from several groups around the world demonstrated that medulloblastoma is not one disease but comprises a collection of distinct molecular subgroups. However, all these studies reported on different numbers of subgroups. The current consensus is that there are only four core subgroups, which should be termed WNT, SHH, Group 3 and Group 4. Based on this, we performed a meta-analysis of all molecular and clinical data of 550 medulloblastomas brought together from seven independent studies. All cases were analyzed by gene expression profiling and for most cases SNP or array-CGH data were available. Data are presented for all medulloblastomas together and for each subgroup separately. For validation purposes, we compared the results of this meta-analysis with another large medulloblastoma cohort (n = 402) for which subgroup information was obtained by immunohistochemistry. Results from both cohorts are highly similar and show how distinct the molecular subtypes are with respect to their transcriptome, DNA copy-number aberrations, demographics, and survival. Results from these analyses will form the basis for prospective multi-center studies and will have an impact on how the different subgroups of medulloblastoma will be treated in the future

Dysphagia in Intensive Care Evaluation (DICE): An International Cross-Sectional Survey.

Dysphagia occurs commonly in the intensive care unit (ICU). Despite the clinical relevance, there is little worldwide research on prevention, assessment, evaluation, and/or treatment of dysphagia for ICU patients. We aimed to gain insight into this international knowledge gap. We conducted a multi-center, international online cross-sectional survey of adult ICUs. Local survey distribution champions were recruited through professional and personal networks. The survey was administered from November 2017 to June 2019 with three emails and a final telephone reminder. Responses were received from 746 ICUs (26 countries). In patients intubated > 48 h, 17% expected a > 50% chance that dysphagia would develop. This proportion increased to 43% in patients intubated > 7 days, and to 52% in tracheotomized patients. Speech-language pathologist (SLP) consultation was available in 66% of ICUs, only 4% reported a dedicated SLP. Although 66% considered a routine post-extubation dysphagia protocol important, most (67%) did not have a protocol. Few ICUs routinely assessed for dysphagia after 48 h of intubation (30%) or tracheostomy (41%). A large proportion (46%) used water swallow screening tests to determine aspiration, few (8%) used instrumental assessments (i.e., flexible endoscopic evaluation of swallowing). Swallowing exercises were used for dysphagia management by 30% of ICUs. There seems to be limited awareness among ICU practitioners that patients are at risk of dysphagia, particularly as ventilation persists, protocols, routine assessment, and instrumental assessments are generally not used. We recommend the development of a research agenda to increase the quality of evidence and ameliorate the implementation of evidence-based dysphagia protocols by dedicated SLPs

Identification of a novel proinsulin-associated SNP and demonstration that proinsulin is unlikely to be a causal factor in subclinical vascular remodelling using Mendelian randomisation

Background and aims Increased proinsulin relative to insulin levels have been associated with subclinical atherosclerosis (measured by carotid intima-media thickness (cIMT)) and are predictive of future cardiovascular disease (CVD), independently of established risk factors. The mechanisms linking proinsulin to atherosclerosis and CVD are unclear. A genome-wide meta-analysis has identified nine loci associated with circulating proinsulin levels. Using proinsulin-associated SNPs, we set out to use a Mendelian randomisation approach to test the hypothesis that proinsulin plays a causal role in subclinical vascular remodelling. Methods We studied the high CVD-risk IMPROVE cohort (n = 3345), which has detailed biochemical phenotyping and repeated, state-of-the-art, high-resolution carotid ultrasound examinations. Genotyping was performed using Illumina Cardio-Metabo and Immuno arrays, which include reported proinsulin-associated loci. Participants with type 2 diabetes (n = 904) were omitted from the analysis. Linear regression was used to identify proinsulin-associated genetic variants. Results We identified a proinsulin locus on chromosome 15 (rs8029765) and replicated it in data from 20,003 additional individuals. An 11-SNP score, including the previously identified and the chromosome 15 proinsulin-associated loci, was significantly and negatively associated with baseline IMTmean and IMTmax (the primary cIMT phenotypes) but not with progression measures. However, MR-Eggers refuted any significant effect of the proinsulin-associated 11-SNP score, and a non-pleiotropic SNP score of three variants (including rs8029765) demonstrated no effect on baseline or progression cIMT measures. Conclusions We identified a novel proinsulin-associated locus and demonstrated that whilst proinsulin levels are associated with cIMT measures, proinsulin per se is unlikely to have a causative effect on cIMT