The occurrence of intra-operative hypotension varies between hospitals: observational analysis of more than 147,000 anaesthesia.

BACKGROUND: Hypotension, a common intra-operative incident, bears an important potential for morbidity. It is most often manageable and sometimes preventable, which renders its study important. Therefore, we aimed at examining hospital variations in the occurrence of intra-operative hypotension and its predictors. As secondary endpoints, we determined to what extent hypotension relates to the risk of post-operative incidents and death. METHODS: We used the Anaesthesia Databank Switzerland, built on routinely and prospectively collected data on all anaesthesias in 21 hospitals. The three outcomes were assessed using multi-level logistic regression models. RESULTS: Among 147,573 anaesthesias, hypotension ranged from 0.6% to 5.2% in participating hospitals, and from 0.3% up to 12% in different surgical specialties. Most (73.4%) were minor single events. Age, ASA status, combined general and regional anaesthesia techniques, duration of surgery and hospitalization were significantly associated with hypotension. Although significantly associated, the emergency status of the surgery had a weaker effect. Hospitals' odds ratios for hypotension varied between 0.12 and 2.50 (P < or = 0.001), even after adjusting for patient and anaesthesia factors, and for type of surgery. At least one post-operative incident occurred in 9.7% of the procedures, including 0.03% deaths. Intra-operative hypotension was associated with a higher risk of post-operative incidents and death. CONCLUSION: Wide variations remain in the occurrence of hypotension among hospitals after adjustment for risk factors. Although differential reporting from hospitals may exist, variations in anaesthesia techniques and blood pressure maintenance may also have contributed. Intra-operative hypotension is associated with morbidities and sometimes death, and constant vigilance must thus be advocated.

Hypertension and intra-operative incidents: a multicentre study of 125,000 surgical procedures in Swiss hospitals.

It is debated whether chronic hypertension increases the risk of cardiovascular incidents during anaesthesia. We studied all elective surgical operations performed in adults under general or regional anaesthesia between 2000 and 2004, in 24 hospitals collecting computerised clinical data on all anaesthetics since 1996. The focus was on cardiovascular incidents, though other anaesthesia-related incidents were also evaluated. Among 124,939 interventions, 27,881 (22%) were performed in hypertensive patients. At least one cardiovascular incident occurred in 7549 interventions (6% (95% CI 5.9-6.2%)). The average adjusted odds ratio of cardiovascular risk for chronic hypertension was 1.38 (95% CI 1.27-1.49). However, across hospitals, adjusted odd ratios varied from 0.41 up to 2.25. Hypertension did not increase the risk of other incidents. Hypertensive patients are still at risk of intra-operative cardiovascular incidents, while risk heterogeneity across hospitals, despite taking account of casemix and hospital characteristics, suggests variations in anaesthetic practices.

Monoclonal antibody against carcinoembryonic antigen (CEA) identifies two new forms of crossreacting antigens of molecular weight 90,000 and 160,000 in normal granulocytes.

Two new forms of non-specific crossreacting antigens (NCAs) were identified in the Nonidet P40 (NP-40) extracts of normal granulocytes by precipitation with the monoclonal antibody (MAb) 192 directed against carcinoembryonic antigen (CEA) and already known to crossreact with the perchloric acid soluble NCA-55. The NP-40 soluble NCAs recognized by MAb 192 have apparent mol. wts of 90,000 and 160,000 in sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Both NCAs appear to consist of a single monomeric polypeptide chain, since they have the same electrophoretic mobility in SDS-PAGE under reduced and non-reduced conditions. When granulocytes were extracted with perchloric acid instead of NP-40, only the 55,000 mol. wt antigen, corresponding to the previously described NCA-55, was precipitated by MAb 192. Furthermore, it was shown that NCA-55 is not a degradation product of NCA-90 or NCA-160 due to the perchloric acid treatment because exposure to perchloric acid of NCA preparations purified from NP-40 extracts did not change their apparent mol. wts in SDS-PAGE. It was also shown that NCA-160 is not a granulocytic form of CEA because it was not precipitated by the MAb 35 reacting exclusively with CEA. Immunocytochemical studies of granulocytes and macrophages showed that MAb 192 stained both types of cells whereas MAb 47 stained only the granulocytes and MAb 35 none of these cells. In granulocytes both MAbs reacted with antigens associated with granules and also present at the periphery of the nucleus as well as in the Golgi apparatus. The NCA-90 identified by MAb 192 was found by sequential immunodepletion to be antigenically distinct from the NCA-95 precipitated by MAb 47. The epitope recognized by MAb 192 on CEA and NCA molecules appears to be on the peptidic moiety because the antigens deglycosylated by the enzyme Endo F were still precipitated by this MAb. Taken together, the results indicate that MAb 192 identifies two novel forms of NCA (NCA-90 and NCA-160) in NP-40 extracts of granulocytes, which are distinct from CEA and the previously described NCA-55 and NCA-95 identified by MAbs 192 and 47, respectively, in perchloric acid extracts of granulocytes.

Contribution pollinique à l'étude du pléistocène de la région lémanique (Suisse) : paléoenvironnement des derniers 800'000 ans

Abstact : Pollinic contribution to a Pleistocene study of the Lake Geneva region (Switzerland) Palaeoenvironment of the last 800,000 years. Although the "Plateau Romand" (tableland of French-speaking Switzerland) has been marked by the repetitive action of different Quaternary glacial thrusts, numerous preserved outcrops here and there, thanks to favourable topographical conditions, provide sufficient pollinic content to reconstitute the significant botanical fluctuations and allow bio- and chrono-stratigraphical correlations with the long European sequences. The present study examines around ten Pleistocene deposits rich in pollens, whose presumed ages cover a range of 800,000 years. - The Early and Early-Middle Pleistocene are examined at Ecoteaux (VD), undeniably the oldest site in this study. The "Lower Formation of Ecoteaux", whose low pollinic content reveals an environment of the cold desert type, shows an inverse palaeomagnetic remanence. An age earlier than 780,000 years BP (Matuyama period or earlier) is proposed. The "Upper Formation of Ecoteaux" contains over eight major fluctuations in the vegetal covering, of which at least four temporal phases and one climatic optimum. The presence of botanical genera, relics of the Tertiary in particular Pterocarya and Carya, associated with the vegetal dynamic made up of short oscillations, contrives to link this formation to the Cromerian Complex. The thermomeres recorded could correspond to one or several interglacial periods from Middle Pleistocene. Possible correlations with marine isotopic stages 15, 17 and 19 are discussed. - The Middle and Late Pleistocene is approached through the sediments of Onnens (VD), Creux d'Enfer (FR), Port-Valais (VS), La Dénériaz (VD) and Cortaillod (NE). Each site provides a temperate interglacial flora, whose pollinic content is evaluated according to the different conceivable bio-stratigraphic correlations. - Finally the Würm is studied thanks to the outcrop of Marly (FR), together with the excavations at Villars-sous-Yens (VD), Versoix (GE) and Ollon (VD). Together, these observations tend to show that the west of the Swiss Plateau is a zone of transition between the meridian vegetation of the lower Rhone valley and that of beyond the Jura. At the outlet of the Rhone glacier, and on the borders of the prealpine and Jurassian glaciers, the region is situated at the crossroads of post-glacial botanical migrations, between the major axis of the Rhone valley and the Eastern refuge zones; this situation confers particular importance on it. Although believed to be deeply scraped by ice, one notices today that the "Plateau Romand" harbours overtwenty interglacial and interstadial sites. The abrasive action of the Rhone glacier has thus been more modest than previously estimated. The effective extension of glacial tongues, together with atmospheric circulation, are doubtless varying from one interglacial to another. Finally, the speeds of glacial movements, and the unbelievable vegetal vitality, are important parameters, capable of leading to deposits, very early enriched in pollens. RÉSUMÉS : Contribution pollinique à l'étude du Pléistocène de la région lémanique (Suisse) - Paléoenvironnement des derniers 800'000 ans Bien que le Plateau romand soit marqué par l'action répétitive des différentes poussées glaciaires quaternaires, de nombreux affleurements préservés ça et là, à la faveur de conditions topographiques favorables, livrent un contenu pollinique suffisant pour reconstituer des fluctuations botaniques significatives et autoriser des corrélations bioet chronostratigraphiques avec les longues séquences européennes. Le présent travail étudie une dizaine de dépôts pléistocènes riches en pollens, dont les âges présumés balaient un éventail de plus de 800'000 ans. - Le Pléistocène Ancien et Moyen inférieur, sont examinés à Ecoteaux (VD); indéniablement le site le plus ancien de cette étude. La "Formation inférieure d'Ecoteaux", dont le maigre contenu pollinique traduit un environnement de type désertique froid, présente une rémanence magnétique inverse. Un âge antérieur à 780'000 ans BP (période de Matuyama ou antérieure) est proposé. La "Formation supérieure d'Ecoteaux" comprend plus de huit fluctuations majeures du couvert végétal, parmi lesquelles on compte au moins quatre épisodes tempérés et un optimum climatique. La présence de genres botaniques reliques du Tertiaire, en particulier Pterocarya et Carya, associée à la dynamique végétale faite de courtes oscillations, concourent à lier cette formation au Complexe Cromérien. Les thermomères enregistrées pourraient correspondre à un- ou plusieurs interglaciaires du Pléistocène moyen. Les corrélations possibles avec les stades isotopiques marins, MIS 15, 17 et 19 sont discutées. - Le Pléistocène Moyen et Récent est abordé à travers les sédiments d'Onnens (VD), du Creux d'Enfer (FR), de Port-Valais (VS), de La Dénériaz (VD) et de Cortaillod (NE). Chaque site livre une flore tempérée interglaciaire, dont le contenu pollinique est évalué en fonction des différentes corrélations bio-stratigraphiques envisageables. - Enfin le Würm est étudié grâce à l'affleurement de Marly (FR), accompagné des forages de Villars-sous-Yens (VD), Versoix (GE) et Ollon (VD). L'ensemble de ces observations tend à montrer que l'ouest du Plateau suisse est une zone charnière entre la végétation méridionale de la basse vallée du Rhône et celle d'au-delà du Jura. Au débouché du glacier du Rhône et aux confins des glaciers préalpins et jurassiens, cette région est située au carrefour des migrations botaniques post-glaciaires, entre l'axe majeur de la vallée du Rhône et les zones refuges de l'Est. Cette situation lui confère une importance toute particulière. Alors qu'on pensait le Plateau romand profondément raboté par les glaces, on constate aujourd'hui qu'il recèle plus d'une vingtaine de sites interglaciaires et interstadiaires. L'action abrasive du glacier rhodanien a donc été plus modeste qu'envisagée jusqu'ici. L'extension effective des langues glaciaires, tout comme la circulation atmosphérique, diffèrent sans doute d'un interglaciaire à l'autre. Enfin la vitesse des mouvements glaciaires et l'incroyable vitalité végétale sont des paramètres importants, susceptibles d'avoir entraîné des dépôts, très précocement enrichis en pollens.

Genetic Variants of Serum Uric Acid and Gout: An Analysis of > 170,000 Individuals

Background/Purpose: Gout is a common and excruciatingly painful inflammatory arthritis caused by hyperuricemia. In addition to various lifestyle risk factors, a substantial genetic predisposition to gout has long been recognized. The Global Urate Genetics Consortium (GUGC) has aimed to comprehensively investigate the genetics of serum uric acid and gout using data from _ 140,000 individuals of European-ancestry, 8,340 individuals of Indian ancestry, 5,820 African-Americans, and 15,286 Japanese. Methods: We performed discovery GWAS meta-analyses of serum urate levels (n_110,347 individuals) followed by replication analyses (n_32,813 different individuals). Our gout analysis involved 3,151 cases and 68,350 controls, including 1,036 incident gout cases that met the American College of Rheumatology Criteria. We also examined the association of gout with fractional excretion of uric acid (n_6,799). A weighted genetic urate score was constructed based on the number of risk alleles across urate-associated loci, and their association with the risk of gout was evaluated. Furthermore, we examined implicated transcript expression in cis (expression quantitative trait loci databases) for potential insights into the gene underlying the association signal. Finally, in order to further identify urate-associated genomic regions, we performed functional network analyses that incorporated prior knowledge on molecular interactions in which the gene products of implicated genes operate. Results: We identified and replicated 28 genome-wide significant loci in association with serum urate (P 5_10_8), including all previously-reported loci as well as 18 novel genetic loci. Unlike the majority of previouslyidentified loci, none of the novel loci appeared to be obvious candidates for urate transport. Rather, they were mapped to genes that encode for purine production, transcription, or growth factors with broad downstream responses. Besides SLC2A9 and ABCG2, no additional regions contained SNPs that differed significantly (P _ 5_10_8) between sexes. Urateincreasing alleles were associated with an increased risk of gout for all loci. The urate genetic risk score (ranging from 10 to 45) was significantly associated with an increased odds of prevalent gout (OR per unit increase, 1.11; 95% CI, 1.09-1.14) and incident gout (OR, 1.10; 95% CI, 1.08-1.13). Associations for many of the loci were of similar magnitude in individuals of non-European ancestry. Detailed characterization of the loci revealed associations with transcript expression and the fractional excretion of urate. Network analyses implicated the inhibins-activins signaling pathways and glucose metabolism in systemic urate control. Conclusion: The novel genetic candidates identified in this urate/gout consortium study, the largest to date, highlight the importance of metabolic control of urate production and urate excretion. The modulation by signaling processes that influence metabolic pathways such as glycolysis and the pentose phosphate pathway appear to be central mechanisms underpinned by the novel GWAS candidates. These findings may have implications for further research into urate-lowering drugs to treat and prevent gout.

A mutation in the gene encoding the vaccinia virus 37,000-M(r) protein confers resistance to an inhibitor of virus envelopment and release.

Plaque formation in vaccinia virus is inhibited by the compound N1-isonicotinoyl-N2-3-methyl-4-chlorobenzoylhydrazine (IMCBH). We have isolated a mutant virus that forms wild-type plaques in the presence of the drug. Comparison of wild-type and mutant virus showed that both viruses produced similar amounts of infectious intracellular naked virus in the presence of the drug. In contrast to the mutant, no extracellular enveloped virus was obtained from IMCBH-treated cells infected with wild-type virus. Marker rescue experiments were used to map the mutation conferring IMCBH resistance to the mutant virus. The map position coincided with that of the gene encoding the viral envelope antigen of M(r) 37,000. Sequence analysis of both wild-type and mutant genes showed a single nucleotide change (G to T) in the mutant gene. In the deduced amino acid sequence, the mutation changes the codon for an acidic Asp residue in the wild-type gene to one for a polar noncharged Tyr residue in the mutant.

Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.

Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.

Subgroup-specific structural variation across 1,000 medulloblastoma genomes.

Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

Building the niche through time: using 13,000 years of data to predict the effects of climate change on three tree species in Europe

Aim Species distribution models (SDMs) based on current species ranges underestimate the potential distribution when projected in time and/or space. A multi-temporal model calibration approach has been suggested as an alternative, and we evaluate this using 13,000 years of data. Location Europe. Methods We used fossil-based records of presence for Picea abies, Abies alba and Fagus sylvatica and six climatic variables for the period 13,000 to 1000yr bp. To measure the contribution of each 1000-year time step to the total niche of each species (the niche measured by pooling all the data), we employed a principal components analysis (PCA) calibrated with data over the entire range of possible climates. Then we projected both the total niche and the partial niches from single time frames into the PCA space, and tested if the partial niches were more similar to the total niche than random. Using an ensemble forecasting approach, we calibrated SDMs for each time frame and for the pooled database. We projected each model to current climate and evaluated the results against current pollen data. We also projected all models into the future. Results Niche similarity between the partial and the total-SDMs was almost always statistically significant and increased through time. SDMs calibrated from single time frames gave different results when projected to current climate, providing evidence of a change in the species realized niches through time. Moreover, they predicted limited climate suitability when compared with the total-SDMs. The same results were obtained when projected to future climates. Main conclusions The realized climatic niche of species differed for current and future climates when SDMs were calibrated considering different past climates. Building the niche as an ensemble through time represents a way forward to a better understanding of a species' range and its ecology in a changing climate.

Seasonality of cardiovascular risk factors: an analysis including over 230 000 participants in 15 countries.

OBJECTIVE: To assess the seasonality of cardiovascular risk factors (CVRF) in a large set of population-based studies. METHODS: Cross-sectional data from 24 population-based studies from 15 countries, with a total sample size of 237 979 subjects. CVRFs included Body Mass Index (BMI) and waist circumference; systolic (SBP) and diastolic (DBP) blood pressure; total, high (HDL) and low (LDL) density lipoprotein cholesterol; triglycerides and glucose levels. Within each study, all data were adjusted for age, gender and current smoking. For blood pressure, lipids and glucose levels, further adjustments on BMI and drug treatment were performed. RESULTS: In the Northern and Southern Hemispheres, CVRFs levels tended to be higher in winter and lower in summer months. These patterns were observed for most studies. In the Northern Hemisphere, the estimated seasonal variations were 0.26 kg/m(2) for BMI, 0.6 cm for waist circumference, 2.9 mm Hg for SBP, 1.4 mm Hg for DBP, 0.02 mmol/L for triglycerides, 0.10 mmol/L for total cholesterol, 0.01 mmol/L for HDL cholesterol, 0.11 mmol/L for LDL cholesterol, and 0.07 mmol/L for glycaemia. Similar results were obtained when the analysis was restricted to studies collecting fasting blood samples. Similar seasonal variations were found for most CVRFs in the Southern Hemisphere, with the exception of waist circumference, HDL, and LDL cholesterol. CONCLUSIONS: CVRFs show a seasonal pattern characterised by higher levels in winter, and lower levels in summer. This pattern could contribute to the seasonality of CV mortality.

The TREAT-NMD DMD Global Database: Analysis of More than 7,000 Duchenne Muscular Dystrophy Mutations.

Analyzing the type and frequency of patient-specific mutations that give rise to Duchenne muscular dystrophy (DMD) is an invaluable tool for diagnostics, basic scientific research, trial planning, and improved clinical care. Locus-specific databases allow for the collection, organization, storage, and analysis of genetic variants of disease. Here, we describe the development and analysis of the TREAT-NMD DMD Global database (http://umd.be/TREAT_DMD/). We analyzed genetic data for 7,149 DMD mutations held within the database. A total of 5,682 large mutations were observed (80% of total mutations), of which 4,894 (86%) were deletions (1 exon or larger) and 784 (14%) were duplications (1 exon or larger). There were 1,445 small mutations (smaller than 1 exon, 20% of all mutations), of which 358 (25%) were small deletions and 132 (9%) small insertions and 199 (14%) affected the splice sites. Point mutations totalled 756 (52% of small mutations) with 726 (50%) nonsense mutations and 30 (2%) missense mutations. Finally, 22 (0.3%) mid-intronic mutations were observed. In addition, mutations were identified within the database that would potentially benefit from novel genetic therapies for DMD including stop codon read-through therapies (10% of total mutations) and exon skipping therapy (80% of deletions and 55% of total mutations).