The 1452 or 1453 A.D. Kuwae Eruption Signal Derived from Multiple Ice Core Records: Greatest Volcanic Sulfate Event of the Past 700 Years

We combined 33 ice core records, 13 from the Northern Hemisphere and 20 from the Southern Hemisphere, to determine the timing and magnitude of the great Kuwae eruption in the mid-15th century. We extracted volcanic deposition signals by applying a high-pass loess filter to the time series and examining peaks that exceed twice the 31 year running median absolute deviation. By accounting for the dating uncertainties associated with each record, these ice core records together reveal a large volcanogenic acid deposition event during 1453 - 1457 A. D. The results suggest only one major stratospheric injection from the Kuwae eruption and confirm previous findings that the Kuwae eruption took place in late 1452 or early 1453, which may serve as a reference to evaluate and improve the dating of ice core records. The average total sulfate deposition from the Kuwae eruption was 93 kg SO4/km(2) in Antarctica and 25 kg SO4/km(2) in Greenland. The deposition in Greenland was probably underestimated since it was the average value of only two northern Greenland sites with very low accumulation rates. After taking the spatial variation into consideration, the average Kuwae deposition in Greenland was estimated to be 45 kg SO4/km(2). By applying the same technique to the other major eruptions of the past 700 years our result suggests that the Kuwae eruption was the largest stratospheric sulfate event of that period, probably surpassing the total sulfate deposition of the Tambora eruption of 1815, which produced 59 kg SO4/km(2) in Antarctica and 50 kg SO4/km(2) in Greenland.

Ultra-early intravenous stroke thrombolysis: do all patients benefit similarly?

BACKGROUND AND PURPOSE We previously reported increased benefit and reduced mortality after ultra-early stroke thrombolysis in a single center. We now explored in a large multicenter cohort whether extra benefit of treatment within 90 minutes from symptom onset is uniform across predefined stroke severity subgroups, as compared with later thrombolysis. METHODS Prospectively collected data of consecutive ischemic stroke patients who received i.v. thrombolysis in 10 European stroke centers were merged. Logistic regression tested association between treatment delays, as well as excellent 3-month outcome (modified Rankin scale, 0-1), and mortality. The association was tested separately in tertiles of baseline National Institutes of Health Stroke Scale. RESULTS In the whole cohort (n=6856), shorter onset-to-treatment time as a continuous variable was significantly associated with excellent outcome (P<0.001). Every fifth patient had onset-to-treatment time≤90 minutes, and these patients had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, onset-to-treatment time≤90 minutes was associated with excellent outcome in patients with National Institutes of Health Stroke Scale 7 to 12 (odds ratio, 1.37; 95% confidence interval, 1.11-1.70; P=0.004), but not in patients with baseline National Institutes of Health Stroke Scale>12 (odds ratio, 1.00; 95% confidence interval, 0.76-1.32; P=0.99) and baseline National Institutes of Health Stroke Scale 0 to 6 (odds ratio, 1.04; 95% confidence interval, 0.78-1.39; P=0.80). In the latter, however, an independent association (odds ratio, 1.51; 95% confidence interval, 1.14-2.01; P<0.01) was found when considering modified Rankin scale 0 as outcome (to overcome the possible ceiling effect from spontaneous better prognosis of patients with mild symptoms). Ultra-early treatment was not associated with mortality. CONCLUSIONS I.v. thrombolysis within 90 minutes is, compared with later thrombolysis, strongly and independently associated with excellent outcome in patients with moderate and mild stroke severity.

Relationship between onset-to-door time and door-to-thrombolysis time: a pooled analysis of 10 dedicated stroke centers

BACKGROUND AND PURPOSE Inverse relationship between onset-to-door time (ODT) and door-to-needle time (DNT) in stroke thrombolysis was reported from various registries. We analyzed this relationship and other determinants of DNT in dedicated stroke centers. METHODS Prospectively collected data of consecutive ischemic stroke patients from 10 centers who received IV thrombolysis within 4.5 hours from symptom onset were merged (n=7106). DNT was analyzed as a function of demographic and prehospital variables using regression analyses, and change over time was considered. RESULTS In 6348 eligible patients with known treatment delays, median DNT was 42 minutes and kept decreasing steeply every year (P<0.001). Median DNT of 55 minutes was observed in patients with ODT ≤30 minutes, whereas it declined for patients presenting within the last 30 minutes of the 3-hour time window (median, 33 minutes) and of the 4.5-hour time window (20 minutes). For ODT within the first 30 minutes of the extended time window (181-210 minutes), DNT increased to 42 minutes. DNT was stable for ODT for 30 to 150 minutes (40-45 minutes). We found a weak inverse overall correlation between ODT and DNT (R(2)=-0.12; P<0.001), but it was strong in patients treated between 3 and 4.5 hours (R(2)=-0.75; P<0.001). ODT was independently inversely associated with DNT (P<0.001) in regression analysis. Octogenarians and women tended to have longer DNT. CONCLUSIONS DNT was decreasing steeply over the last years in dedicated stroke centers; however, significant oscillations of in-hospital treatment delays occurred at both ends of the time window. This suggests that further improvements can be achieved, particularly in the elderly.

Safety of thrombolysis in stroke mimics: results from a multicenter cohort study

BACKGROUND AND PURPOSE Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.

IV thrombolysis and renal function

OBJECTIVE To investigate the association of renal impairment on functional outcome and complications in stroke patients treated with IV thrombolysis (IVT). METHODS In this observational study, we compared the estimated glomerular filtration rate (GFR) with poor 3-month outcome (modified Rankin Scale scores 3-6), death, and symptomatic intracranial hemorrhage (sICH) based on the criteria of the European Cooperative Acute Stroke Study II trial. Unadjusted and adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Patients without IVT treatment served as a comparison group. RESULTS Among 4,780 IVT-treated patients, 1,217 (25.5%) had a low GFR (<60 mL/min/1.73 m(2)). A GFR decrease by 10 mL/min/1.73 m(2) increased the risk of poor outcome (OR [95% CI]): (ORunadjusted 1.20 [1.17-1.24]; ORadjusted 1.05 [1.01-1.09]), death (ORunadjusted 1.33 [1.28-1.38]; ORadjusted 1.18 [1.11-1.249]), and sICH (ORunadjusted 1.15 [1.01-1.22]; ORadjusted 1.11 [1.04-1.20]). Low GFR was independently associated with poor 3-month outcome (ORadjusted 1.32 [1.10-1.58]), death (ORadjusted 1.73 [1.39-2.14]), and sICH (ORadjusted 1.64 [1.21-2.23]) compared with normal GFR (60-120 mL/min/1.73 m(2)). Low GFR (ORadjusted 1.64 [1.21-2.23]) and stroke severity (ORadjusted 1.05 [1.03-1.07]) independently determined sICH. Compared with patients who did not receive IVT, treatment with IVT in patients with low GFR was associated with poor outcome (ORadjusted 1.79 [1.41-2.25]), and with favorable outcome in those with normal GFR (ORadjusted 0.77 [0.63-0.94]). CONCLUSION Renal function significantly modified outcome and complication rates in IVT-treated stroke patients. Lower GFR might be a better risk indicator for sICH than age. A decrease of GFR by 10 mL/min/1.73 m(2) seems to have a similar impact on the risk of death or sICH as a 1-point-higher NIH Stroke Scale score measuring stroke severity.

The Good Society. A Comparative Study of Denmark and Switzerland

Denmark and Switzerland are small and successful countries with exceptionally content populations. However, they have very different political institutions and economic models. They have followed the general tendency in the West toward economic convergence, but both countries have managed to stay on top. They both have a strong liberal tradition, but otherwise their economic strategies are a welfare state model for Denmark and a safe haven model for Switzerland. The Danish welfare state is tax-based, while the expenditures for social welfare are insurance-based in Switzerland. The political institutions are a multiparty unicameral system in Denmark, and a permanent coalition system with many referenda and strong local government in Switzerland. Both approaches have managed to ensure smoothly working political power-sharing and economic systems that allocate resources in a fairly efficient way. To date, they have also managed to adapt the economies to changes in the external environment with a combination of stability and flexibility.

Frederiksenia canicola gen. nov., sp. nov. isolated from dogs and human dog-bite wounds.

Polyphasic analysis was done on 24 strains of Bisgaard taxon 16 from five European countries and mainly isolated from dogs and human dog-bite wounds. The isolates represented a phenotypically and genetically homogenous group within the family Pasteurellaceae. Their phenotypic profile was similar to members of the genus Pasteurella. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry clearly identified taxon 16 and separated it from all other genera of Pasteurellaceae showing a characteristic peak combination. Taxon 16 can be further separated and identified by a RecN protein signature sequence detectable by a specific PCR. In all phylogenetic analyses based on 16S rRNA, rpoB, infB and recN genes, taxon 16 formed a monophyletic branch with intraspecies sequence similarity of at least 99.1, 90.8, 96.8 and 97.2 %, respectively. Taxon 16 showed closest genetic relationship with Bibersteinia trehalosi as to the 16S rRNA gene (95.9 %), the rpoB (89.8 %) and the recN (74.4 %), and with Actinobacillus lignieresii for infB (84.9 %). Predicted genome similarity values based on the recN gene sequences between taxon 16 isolates and the type strains of known genera of Pasteurellaceae were below the genus level. Major whole cell fatty acids for the strain HPA 21(T) are C14:0, C16:0, C18:0 and C16:1 ω7c/C15:0 iso 2OH. Major respiratory quinones are menaquinone-8, ubiquinone-8 and demethylmenaquinone-8. We propose to classify these organisms as a novel genus and species within the family of Pasteurellaceae named Frederiksenia canicola gen. nov., sp. nov. The type strain is HPA 21(T) (= CCUG 62410(T) = DSM 25797(T)).

Transcatheter aortic valve implantation in failed bioprosthetic surgical valves.

IMPORTANCE Owing to a considerable shift toward bioprosthesis implantation rather than mechanical valves, it is expected that patients will increasingly present with degenerated bioprostheses in the next few years. Transcatheter aortic valve-in-valve implantation is a less invasive approach for patients with structural valve deterioration; however, a comprehensive evaluation of survival after the procedure has not yet been performed. OBJECTIVE To determine the survival of patients after transcatheter valve-in-valve implantation inside failed surgical bioprosthetic valves. DESIGN, SETTING, AND PARTICIPANTS Correlates for survival were evaluated using a multinational valve-in-valve registry that included 459 patients with degenerated bioprosthetic valves undergoing valve-in-valve implantation between 2007 and May 2013 in 55 centers (mean age, 77.6 [SD, 9.8] years; 56% men; median Society of Thoracic Surgeons mortality prediction score, 9.8% [interquartile range, 7.7%-16%]). Surgical valves were classified as small (≤21 mm; 29.7%), intermediate (>21 and <25 mm; 39.3%), and large (≥25 mm; 31%). Implanted devices included both balloon- and self-expandable valves. MAIN OUTCOMES AND MEASURES Survival, stroke, and New York Heart Association functional class. RESULTS Modes of bioprosthesis failure were stenosis (n = 181 [39.4%]), regurgitation (n = 139 [30.3%]), and combined (n = 139 [30.3%]). The stenosis group had a higher percentage of small valves (37% vs 20.9% and 26.6% in the regurgitation and combined groups, respectively; P = .005). Within 1 month following valve-in-valve implantation, 35 (7.6%) patients died, 8 (1.7%) had major stroke, and 313 (92.6%) of surviving patients had good functional status (New York Heart Association class I/II). The overall 1-year Kaplan-Meier survival rate was 83.2% (95% CI, 80.8%-84.7%; 62 death events; 228 survivors). Patients in the stenosis group had worse 1-year survival (76.6%; 95% CI, 68.9%-83.1%; 34 deaths; 86 survivors) in comparison with the regurgitation group (91.2%; 95% CI, 85.7%-96.7%; 10 deaths; 76 survivors) and the combined group (83.9%; 95% CI, 76.8%-91%; 18 deaths; 66 survivors) (P = .01). Similarly, patients with small valves had worse 1-year survival (74.8% [95% CI, 66.2%-83.4%]; 27 deaths; 57 survivors) vs with intermediate-sized valves (81.8%; 95% CI, 75.3%-88.3%; 26 deaths; 92 survivors) and with large valves (93.3%; 95% CI, 85.7%-96.7%; 7 deaths; 73 survivors) (P = .001). Factors associated with mortality within 1 year included having small surgical bioprosthesis (≤21 mm; hazard ratio, 2.04; 95% CI, 1.14-3.67; P = .02) and baseline stenosis (vs regurgitation; hazard ratio, 3.07; 95% CI, 1.33-7.08; P = .008). CONCLUSIONS AND RELEVANCE In this registry of patients who underwent transcatheter valve-in-valve implantation for degenerated bioprosthetic aortic valves, overall 1-year survival was 83.2%. Survival was lower among patients with small bioprostheses and those with predominant surgical valve stenosis.

A stratigraphic framework for abrupt climatic changes during the Last Glacial period based on three synchronized Greenland ice-core records: refining and extending the INTIMATE event stratigraphy

Due to their outstanding resolution and well-constrained chronologies, Greenland ice-core records provide a master record of past climatic changes throughout the Last Interglacial–Glacial cycle in the North Atlantic region. As part of the INTIMATE (INTegration of Ice-core, MArine and TErrestrial records) project, protocols have been proposed to ensure consistent and robust correlation between different records of past climate. A key element of these protocols has been the formal definition and ordinal numbering of the sequence of Greenland Stadials (GS) and Greenland Interstadials (GI) within the most recent glacial period. The GS and GI periods are the Greenland expressions of the characteristic Dansgaard–Oeschger events that represent cold and warm phases of the North Atlantic region, respectively. We present here a more detailed and extended GS/GI template for the whole of the Last Glacial period. It is based on a synchronization of the NGRIP, GRIP, and GISP2 ice-core records that allows the parallel analysis of all three records on a common time scale. The boundaries of the GS and GI periods are defined based on a combination of stable-oxygen isotope ratios of the ice (δ18O, reflecting mainly local temperature) and calcium ion concentrations (reflecting mainly atmospheric dust loading) measured in the ice. The data not only resolve the well-known sequence of Dansgaard–Oeschger events that were first defined and numbered in the ice-core records more than two decades ago, but also better resolve a number of short-lived climatic oscillations, some defined here for the first time. Using this revised scheme, we propose a consistent approach for discriminating and naming all the significant abrupt climatic events of the Last Glacial period that are represented in the Greenland ice records. The final product constitutes an extended and better resolved Greenland stratotype sequence, against which other proxy records can be compared and correlated. It also provides a more secure basis for investigating the dynamics and fundamental causes of these climatic perturbations.

Comparison of a Novel Biodegradable Polymer Sirolimus-Eluting Stent With a Durable Polymer Everolimus-Eluting Stent: Results of the Randomized BIOFLOW-II Trial.

BACKGROUND Biodegradable polymers for release of antiproliferative drugs from drug-eluting stents aim to improve vascular healing. We assessed noninferiority of a novel ultrathin strut drug-eluting stent releasing sirolimus from a biodegradable polymer (Orsiro, O-SES) compared with the durable polymer Xience Prime everolimus-eluting stent (X-EES) in terms of the primary end point in-stent late lumen loss at 9 months. METHODS AND RESULTS A total of 452 patients were randomly assigned 2:1 to treatment with O-SES (298 patients, 332 lesions) or X-EES (154 patients, 173 lesions) in a multicenter, noninferiority trial. The primary end point was in-stent late loss at 9 months. O-SES was noninferior to X-EES for the primary end point (0.10±0.32 versus 0.11±0.29 mm; difference=0.00063 mm; 95% confidence interval, -0.06 to 0.07; Pnoninferiority<0.0001). Clinical outcome showed similar rates of target-lesion failure at 1 year (O-SES 6.5% versus X-EES 8.0%; hazard ratio=0.82; 95% confidence interval, 0.40-1.68; log-rank test: P=0.58) without cases of stent thrombosis. A subgroup of patients (n=55) underwent serial optical coherence tomography at 9 months, which demonstrated similar neointimal thickness among lesions allocated to O-SES and X-EES (0.10±0.04 mm versus 0.11±0.04 mm; -0.01 [-0.04, -0.01]; P=0.37). Another subgroup of patients (n=56) underwent serial intravascular ultrasound at baseline and 9 months indicating a potential difference in neointimal area at follow-up (O-SES, 0.16±0.33 mm(2) versus X-EES, 0.43±0.56 mm(2); P=0.04). CONCLUSIONS Compared with durable polymer X-EES, novel biodegradable polymer-based O-SES was found noninferior for the primary end point in-stent late lumen loss at 9 months. Clinical event rates were comparable without cases of stent thrombosis throughout 1 year of follow-up. CLINICAL TRIAL REGISTRATION URL http://www.clinicaltrials.gov. Unique identifier: NCT01356888.

Complete rupture of the popliteal artery complicating high tibial osteotomy.

We present two cases of high tibial osteotomies performed at our institution. Both cases were complicated with the immediate postoperative occurrence of an ischaemic syndrome of the lower leg. Urgent diagnostics revealed a complete rupture of the popliteal artery that required re-operation and a vascular repair. Although neurovascular complications during high tibial osteotomies are rare the awareness of this potentially catastrophic complication should be present when performing this common procedure. All precautions to minimize the harm to the neurovascular bundle should be put into practice. A summary of the surgical precautions is presented and discussed in this paper.

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65,046 European population controls (5/393 cases versus 32/65,046 controls; Fisher's exact test P = 2.83 × 10(-6), odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10(-4)). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE.

Recovery of large carnivores in Europe's modern human-dominated landscapes.

The conservation of large carnivores is a formidable challenge for biodiversity conservation. Using a data set on the past and current status of brown bears (Ursus arctos), Eurasian lynx (Lynx lynx), gray wolves (Canis lupus), and wolverines (Gulo gulo) in European countries, we show that roughly one-third of mainland Europe hosts at least one large carnivore species, with stable or increasing abundance in most cases in 21st-century records. The reasons for this overall conservation success include protective legislation, supportive public opinion, and a variety of practices making coexistence between large carnivores and people possible. The European situation reveals that large carnivores and people can share the same landscape.

Persistence of endocrine disruption in zebrafish (Danio rerio) after discontinued exposure to the androgen 17β-trenbolone.

The aim of the present study was to investigate the effects of the androgenic endocrine disruptor 17β-trenbolone on the sexual development of zebrafish (Danio rerio) with special emphasis on the question of whether adverse outcomes of developmental exposure are reversible or persistent. An exposure scenario including a recovery phase was chosen to assess the potential reversibility of androgenic effects. Zebrafish were exposed to environmentally relevant concentrations of 17β-trenbolone (1 ng/L-30 ng/L) from fertilization until completion of gonad sexual differentiation (60 d posthatch). Thereafter, exposure was either followed by 40 d of recovery in clean water or continued until 100 d posthatch, the age when zebrafish start being able to reproduce. Fish exposed for 100 d to 10 ng/L or 30 ng/L 17β-trenbolone were masculinized at different biological effect levels, as evidenced from a concentration-dependent shift of the sex ratio toward males as well as a significantly increased maturity of testes. Gonad morphological masculinization occurred in parallel with decreased vitellogenin concentrations in both sexes. Changes of brain aromatase (cyp19b) mRNA expression showed no consistent trend with respect to either exposure duration or concentration. Gonad morphological masculinization as well as the decrease of vitellogenin persisted after depuration over 40 d in clean water. This lack of recovery suggests that androgenic effects on sexual development of zebrafish are irreversible.