Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study.

BACKGROUND Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING European Commission and the Wellcome Trust.

Randomized Trial to Evaluate Tandosporine in Geographic Atrophy Secondary to Age-Related Macular Degeneration: the GATE Study.

PURPOSE To determine the safety and efficacy of AL-8309B (tandospirone) in the management of patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) and obtain standardized data on GA lesion growth progression. DESIGN Prospective, controlled, double-masked, randomized, multicenter phase 3 clinical trial. METHODS Setting: 48 clinical sites. PATIENTS Patients with GA associated with AMD were enrolled. All patients were followed for a minimum of 30 months, and up to 36 months. Intervention Procedures: Patients were randomized (1:1:1) to receive AL-8309B ophthalmic solution 1.0%, 1.75%, or vehicle, administered as a twice-daily topical ocular drop. MAIN OUTCOME MEASURES The primary efficacy endpoint was mean annualized lesion enlargement from baseline as assessed with fundus autofluorescence (FAF) imaging. RESULTS A total of 768 eyes of 768 patients were enrolled and treated with AL-8309B 1.0% (N=250), AL-8309B 1.75% (N=258), or vehicle (N= 260). An increase in mean lesion size was observed in both the AL-8309B and vehicle treatment groups, and growth rates were similar in all treatment groups. Annualized lesion growth rates were 1.73, 1.76 and 1.71 mm(2) for AL-8309B 1.0%, AL-8309B 1.75%, and vehicle, respectively. CONCLUSIONS AL-8309B 1.0% and 1.75% did not affect lesion growth in eyes with GA secondary to AMD. There were no clinically relevant safety issues identified for AL-8309B. The large natural history dataset from this study is a valuable repository for future comparisons.

Neurogenic thoracic outlet syndrome due to subclavius posticus muscle with dynamic brachial plexus compression: a case report.

BACKGROUND Neurogenic thoracic outlet syndrome is an underestimated cause of brachial weakness and pain. The subclavius posticus muscle (SPM) is an aberrant muscle originating from the medial aspect of the first rib reaching to superior border of the scapula, which may cause, depending on its activation, dynamic compression of the brachial plexus. CASE PRESENTATION In the present study, we report about a 32-year-old male caucasian patient with weakness in radial deviation of his left hand. An isolated macrodactyly of his left middle finger had been operated twice. Electroneurography showed a carpal-tunnel-syndrome (CTS) on the left side. MRI of the brachial plexus revealed an additional muscle in the costoclavicular space, identified as SPM. To our knowledge, this is the second case report of a neurogenic thoracic outlet syndrome due to SPM, and the first case described with isolated macrodactyly and CTS in the same patient. CONCLUSION If complaints about hand weakness are only reported in cases of distinct hand positions, a dynamic compression of the brachial plexus by SPM may be the cause. A neurogenic thoracic outlet syndrome may facilitate the development of CTS.

The impacts of volcanic aerosol on stratospheric ozone and the Northern Hemisphere polar vortex: separating radiative-dynamical changes from direct effects due to enhanced aerosol heterogeneous chemistry

After major volcanic eruptions the enhanced aerosol causes ozone changes due to greater heterogeneous chemistry on the particle surfaces (HET-AER) and from dynamical effects related to the radiative heating of the lower stratosphere (RAD-DYN). We carry out a series of experiments with an atmosphere–ocean–chemistry–climate model to assess how these two processes change stratospheric ozone and Northern Hemispheric (NH) polar vortex dynamics. Ensemble simulations are performed under present day and preindustrial conditions, and with aerosol forcings representative of different eruption strength, to investigate changes in the response behaviour. We show that the halogen component of the HET-AER effect dominates under present-day conditions with a global reduction of ozone (−21 DU for the strongest eruption) particularly at high latitudes, whereas the HET-AER effect increases stratospheric ozone due to N2O5 hydrolysis in a preindustrial atmosphere (maximum anomalies +4 DU). The halogen-induced ozone changes in the present-day atmosphere offset part of the strengthening of the NH polar vortex during mid-winter (reduction of up to −16 m s-1 in January) and slightly amplify the dynamical changes in the polar stratosphere in late winter (+11 m s-1 in March). The RAD-DYN mechanism leads to positive column ozone anomalies which are reduced in a present-day atmosphere by amplified polar ozone depletion (maximum anomalies +12 and +18 DU for present day and preindustrial, respectively). For preindustrial conditions, the ozone response is consequently dominated by RAD-DYN processes, while under present-day conditions, HET-AER effects dominate. The dynamical response of the stratosphere is dominated by the RAD-DYN mechanism showing an intensification of the NH polar vortex in winter (up to +10 m s-1 in January). Ozone changes due to the RAD-DYN mechanism slightly reduce the response of the polar vortex after the eruption under present-day conditions.

Earth system commitments due to delayed mitigation

As long as global CO₂ emissions continue to increase annually, long-term committed Earth system changes grow much faster than current observations. A novel metric linking this future growth to policy decisions today is the mitigation delay sensitivity (MDS), but MDS estimates for Earth system variables other than peak temperature (ΔT max) are missing. Using an Earth System Model of Intermediate Complexity, we show that the current emission increase rate causes a ΔT max increase roughly 3–7.5 times as fast as observed warming, and a millenial steric sea level rise (SSLR) 7–25 times as fast as observed SSLR, depending on the achievable rate of emission reductions after the peak of emissions. These ranges are only slightly affected by the uncertainty range in equilibrium climate sensitivity, which is included in the above values. The extent of ocean acidification at the end of the century is also strongly dependent on the starting time and rate of emission reductions. The preservable surface ocean area with sufficient aragonite supersaturation for coral reef growth is diminished globally at an MDS of roughly 25%–80% per decade. A near-complete loss of this area becomes unavoidable if mitigation is delayed for a few years to decades. Also with respect to aragonite, 12%–18% of the Southern Ocean surface become undersaturated per decade, if emission reductions are delayed beyond 2015–2040. We conclude that the consequences of delaying global emission reductions are much better captured if the MDS of relevant Earth system variables is communicated in addition to current trends and total projected future changes.

Intensification of tropical Pacific biological productivity due to volcanic eruptions

Major volcanic eruptions generate widespread ocean cooling, which reduces upper ocean stratification. This effect has the potential to increase nutrient delivery into the euphotic zone and boost biological productivity. Using externally forced last millennium simulations of three climate/Earth System models (Model for Interdisciplinary Research On Climate (MIROC), Community Earth System Model (CESM), and LOch-Vecode-Ecbilt-CLio-agIsm Model (LOVECLIM)), we test the hypothesis that large volcanic eruptions intensify nutrient-driven export production. It is found that strong volcanic radiative forcing enhances the likelihood of eastern Pacific El Niño-like warming in CESM and LOVECLIM. This leads to an initial reduction of nutrients and export production in the eastern equatorial Pacific. However, this initial response reverses after about 3 years in association with La Niña cooling. The resulting delayed enhancement of biological production resembles the multiyear response in MIROC. The model simulations show that volcanic impacts on tropical Pacific dynamics and biogeochemistry persist for several years, thus providing a new source for potential multiyear ecosystem predictability.

Findings in uteri and ovaries from Eringer cows, slaughtered due to fertility problems

Eringer cows are often slaughtered due to fertility problems which result from inflammatory and degenerative changes of the uterus or hormonal imbalances. Twenty-one genital tracts from Eringer cows suffering from fertility problems were collected in the abattoir. The purpose of the study was the macroscopic evaluation of the ovaries and the uterus followed by a histological and microbiological analysis of the uterus. Data from inseminations and calvings were provided by the Eringer breeding association and through the internet portal www.agate.ch. Median age of the cows was 6.9 years, number of calves per cow was 2.5 and median period between last calving and slaughter was 1.5 years. In 13 from 21 of the urogenital tracts examined, macroscopic abnormalities of the ovaries and/or histologic or microbiologic findings in the uterus could explain fertility-associated slaughter.

False normal Lung Clearance Index in infants with cystic fibrosis due to software algorithms.

BACKGROUND Lung clearance index (LCI), a marker of ventilation inhomogeneity, is elevated early in children with cystic fibrosis (CF). However, in infants with CF, LCI values are found to be normal, although structural lung abnormalities are often detectable. We hypothesized that this discrepancy is due to inadequate algorithms of the available software package. AIM Our aim was to challenge the validity of these software algorithms. METHODS We compared multiple breath washout (MBW) results of current software algorithms (automatic modus) to refined algorithms (manual modus) in 17 asymptomatic infants with CF, and 24 matched healthy term-born infants. The main difference between these two analysis methods lies in the calculation of the molar mass differences that the system uses to define the completion of the measurement. RESULTS In infants with CF the refined manual modus revealed clearly elevated LCI above 9 in 8 out of 35 measurements (23%), all showing LCI values below 8.3 using the automatic modus (paired t-test comparing the means, P < 0.001). Healthy infants showed normal LCI values using both analysis methods (n = 47, paired t-test, P = 0.79). The most relevant reason for false normal LCI values in infants with CF using the automatic modus was the incorrect recognition of the end-of-test too early during the washout. CONCLUSION We recommend the use of the manual modus for the analysis of MBW outcomes in infants in order to obtain more accurate results. This will allow appropriate use of infant lung function results for clinical and scientific purposes.

Paleolimnological evidence for increased landslide activity due to forest clearing and land-use since 3600 cal BP in the western Swiss Alps

Schwarzsee is located in the western Swiss Alps, in a region that has been affected by numerous landslides during the Holocene, as evidenced by geological surveys. Lacustrine sediments were cored to a depth of 13 m. The vegetation history of the lake's catchment was reconstructed and investigated to identify possible impacts on slope stability. The pollen analyses record development of forest cover during the middle and late Holocene, and provide strong evidence for regional anthropogenic influence such as forest clearing and agricultural activity. Vegetation change is characterized by continuous landscape denudation that begins at ca. 4300 cal. yrs BP, with five distinct pulses of increased deforestation, at 3650, 2700, 1500, 900, and 450 cal. yrs BP. Each pulse can be attributed to increased human impact, recorded by the appearance or increase of specific anthropogenic indicator plant taxa. These periods of intensified deforestation also appear to be correlated with increased landslide activity in the lake's catchment and increased turbidite frequency in the sediment record. Therefore, this study gives new evidence for a strong influence of vegetation changes on slope stability during the middle and late Holocene in the western Swiss Alps, and may be used as a case study for anthropogenically induced landslide activity.

Effects of genetic diversity of grass on insect species diversity at higher trophic levels are not due to cascading diversity effects

Genetic diversity in plant populations has been shown to affect the species diversity of insects. In grasses, infection with fungal endophytes can also have strong effects on insects, potentially modifying the effects of plant genetic diversity. We manipulated the genetic diversity and endophyte infection of a grass in a field experiment. We show that diversity of primary parasitoids (3rd trophic level) and, especially, secondary parasitoids (4th trophic level) increases with grass genetic diversity while there was no effect of endophyte infection. The increase in insect diversity appeared to be due to a complementarity effect rather than a sampling effect. The higher parasitoid diversity could not be explained by a cascading diversity effect because herbivore diversity was not affected and the same herbivore species were present in all treatments. The effects on the higher trophic levels must therefore be due to a direct response to plant traits or mediated by effects on traits at intermediate trophic levels.

Plant species decline due to abandonment of meadows cannot easily be reversed by mowing. A case study from the southern Alps

Abstract. We resumed mowing in two plots of ca. 100 m2 in an abandoned meadow dominated by Brachypodium pinnatum on the slope of Monte Generoso (Switzerland). We monitored species composition and hay yield using point quadrats and biomass samples. Species frequencies changed little during 10 yr (1988–1997) while hay yields showed large fluctuations according to mean relative humidity in April-June. We performed a seed-addition experiment to test whether the establishment of meadow species is limited by lack of diaspores or favourable microsites for germination and recruitment from the seed bank. We sowed ca. 12 000 seeds of 12 species originating from a nearby meadow individually in plots of a 4 × 6 unbalanced Latin square with four treatments, burning, mowing, mowing and removal of a layer of decayed organic matter, and a control. We monitored the fate of seedling individuals for 24 months. Seedlings of all species were established and survived for 12 months, 10 species survived during at least 24 months, some reached a reproductive stage. Species responded to different qualities of microsites provided by the different treatments thus required different regeneration niches. Spontaneous long-distance immigration was insignificant. We conclude that the former species composition of abandoned meadows cannot easily be restored by mowing alone because many plant species of meadows do not have persistent seed banks and immigration over distances of more than 25 m and successful establishment is very unlikely.

Indications for treatment in adults with tricuspid valve dysfunction due to a congential cardiac anomaly

The tricuspid valve is frequently affected in adults with congenital heart disease (CHD). Disease of this valve can occur primarily or develop secondary to changes in the right ventricle caused by other defects. Quantitative echocardiographic assessment of tricuspid regurgitation is essential to assess its cause and prognosis. Treatment options vary depending on the underlying defect and right ventricular function. Surgical management of tricuspid valve disease is complex and evolving.