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In-situ single particle analysis of ice particle residuals (IPR) and out-of-cloud aerosol particles was conducted by means of laser ablation mass spectrometry during the intensive INUIT-JFJ/CLACE campaign at the high alpine research station Jungfraujoch (3580 m a.s.l.) in January/February 2013. During the four week campaign more than 70000 out-of-cloud aerosol particles and 595 IPR were analyzed covering a particle size diameter range from 100 nm to 3 μm. The IPR were sampled during 273 hours while the station was covered by mixed-phase clouds at ambient temperatures between -27 °C and -6 °C. The identification of particle types is based on laboratory studies of different types of biological, mineral and anthropogenic aerosol particles. As outcome instrument specific marker peaks for the different investigated particle types were obtained and applied to the field data. The results show that the sampled IPR contain a larger relative amount of natural, primary aerosol, like soil dust (13 %) and minerals (11 %), in comparison to out-of-cloud aerosol particles (2 % and <1 %, respectively). Additionally, anthropogenic aerosol particles, like particles from industrial emissions and lead-containing particles, were found to be more abundant in the IPR than in the out-of-cloud aerosol. The out of-cloud aerosol contained a large fraction of aged particles (30 %, including organic material and secondary inorganics), whereas this particle type was much less abundant (3 %) in the IPR. In a selected subset of the data where a direct comparison between out-of-cloud aerosol particles and IPR in air masses with similar origin was possible, a pronounced enhancement of biological particles was found in the IPR.
Charts are used to measure relative success for a large variety of cultural items. Traditional music charts have been shown to follow self-organizing principles with regard to the distribution of item lifetimes, the on-chart residence times. Here we examine if this observation holds also for (a) music streaming charts (b) book best-seller lists and (c) for social network activity charts, such as Twitter hashtags and the number of comments Reddit postings receive. We find that charts based on the active production of items, like commenting, are more likely to be influenced by external factors, in particular by the 24 h day–night cycle. External factors are less important for consumption-based charts (sales, downloads), which can be explained by a generic theory of decision-making. In this view, humans aim to optimize the information content of the internal representation of the outside world, which is logarithmically compressed. Further support for information maximization is argued to arise from the comparison of hourly, daily and weekly charts, which allow to gauge the importance of decision times with respect to the chart compilation period.
This paper presents results from the "INUIT-JFJ/CLACE 2013" field campaign at the high alpine research station Jungfraujoch in January/February 2013. The chemical composition of ice particle residuals (IPR) in a size diameter range of 200–900 nm was measured in orographic, convective and non-convective clouds with a single particle mass spectrometer (ALABAMA) under ambient conditions characterized by temperatures between −28 and −4 °C and wind speed from 0.1 to 21 km h−1. Additionally, background aerosol particles in cloud free air were investigated. The IPR were sampled from mixed-phase clouds with two inlets which selectively extract small ice crystals in-cloud, namely the Counterflow Virtual Impactor (Ice-CVI) and the Ice Selective Inlet (ISI). The IPR as well as the aerosol particles were classified into seven different particle types: (1) black carbon, (2) organic carbon, (3) black carbon internally mixed with organic carbon, (4) minerals, (5) one particle group (termed "BioMinSal") that may contain biological particles, minerals, or salts, (6) industrial metals, and (7) lead containing particles. For any sampled particle population it was determined by means of single particle mass spectrometer how many of the analyzed particles belonged to each of these categories. Accordingly, between 20 and 30% of the IPR and roughly 42% of the background particles contained organic carbon. The measured fractions of minerals in the IPR composition varied from 6 to 33%, while the values for the "BioMinSal" group were between 15 and 29%. Four percent to 31% of the IPR contained organic carbon mixed with black carbon. Both inlets delivered similar results of the chemical composition and of the particle size distribution, although lead was found only in the IPR sampled by the Ice-CVI. The results show that the ice particle residual composition varies substantially between different cloud events, which indicates the influence of different meteorological conditions, such as origin of the air masses, temperature and wind speed.
Scores to identify patients at high risk of progression of coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), may become instrumental for clinical decision-making and patient management. We used patient data from the multicentre Lean European Open Survey on SARS-CoV-2-Infected Patients (LEOSS) and applied variable selection to develop a simplified scoring system to identify patients at increased risk of critical illness or death. A total of 1946 patients who tested positive for SARS-CoV-2 were included in the initial analysis and assigned to derivation and validation cohorts (n = 1297 and n = 649, respectively). Stability selection from over 100 baseline predictors for the combined endpoint of progression to the critical phase or COVID-19-related death enabled the development of a simplified score consisting of five predictors: C-reactive protein (CRP), age, clinical disease phase (uncomplicated vs. complicated), serum urea, and D-dimer (abbreviated as CAPS-D score). This score yielded an area under the curve (AUC) of 0.81 (95% confidence interval [CI]: 0.77–0.85) in the validation cohort for predicting the combined endpoint within 7 days of diagnosis and 0.81 (95% CI: 0.77–0.85) during full follow-up. We used an additional prospective cohort of 682 patients, diagnosed largely after the “first wave” of the pandemic to validate the predictive accuracy of the score and observed similar results (AUC for the event within 7 days: 0.83 [95% CI: 0.78–0.87]; for full follow-up: 0.82 [95% CI: 0.78–0.86]). An easily applicable score to calculate the risk of COVID-19 progression to critical illness or death was thus established and validated.
In this study we show how size-resolved measurements of aerosol particles and cloud condensation nuclei (CCN) can be used to characterize the supersaturation of water vapor in a cloud. The method was developed and applied for the investigation of a cloud event during the ACRIDICON-Zugspitze campaign (17 September to 4 October 2012) at the high-alpine research station Schneefernerhaus (German Alps, 2650 m a.s.l.). Number size distributions of total and interstitial aerosol particles were measured with a scanning mobility particle sizer (SMPS), and size-resolved CCN efficiency spectra were recorded with a CCN counter system operated at different supersaturation levels.
During the evolution of a cloud, aerosol particles are exposed to different supersaturation levels. We outline and compare different estimates for the lower and upper bounds (Slow, Shigh) and the average value (Savg) of peak supersaturation encountered by the particles in the cloud. For the investigated cloud event, we derived Slow ≈ 0.19–0.25%, Shigh ≈ 0.90–1.64% and Savg ≈ 0.38–0.84%. Estimates of Slow, Shigh and Savg based on aerosol size distribution data require specific knowledge or assumptions of aerosol hygroscopicity, which are not required for the derivation of Slow and Savg from the size-resolved CCN efficiency spectra.
In this study we show how size-resolved measurements of aerosol particles and cloud condensation nuclei (CCN) can be used to characterize the supersaturation of water vapor in a cloud. The method was developed and applied during the ACRIDICON-Zugspitze campaign (17 September to 4 October 2012) at the high-Alpine research station Schneefernerhaus (German Alps, 2650 m a.s.l.). Number size distributions of total and interstitial aerosol particles were measured with a scanning mobility particle sizer (SMPS), and size-resolved CCN efficiency spectra were recorded with a CCN counter system operated at different supersaturation levels.
During the evolution of a cloud, aerosol particles are exposed to different supersaturation levels. We outline and compare different estimates for the lower and upper bounds (Slow, Shigh) and the average value (Savg) of peak supersaturation encountered by the particles in the cloud. A major advantage of the derivation of Slow and Savg from size-resolved CCN efficiency spectra is that it does not require the specific knowledge or assumptions about aerosol hygroscopicity that are needed to derive estimates of Slow, Shigh, and Savg from aerosol size distribution data. For the investigated cloud event, we derived Slow ≈ 0.07–0.25%, Shigh ≈ 0.86–1.31% and Savg ≈ 0.42–0.68%.
The three-dimensional quantification of small scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe and TACTS/ESMVal aircraft campaigns. The focus of this work is on the so-called dynamics mode data characterized by a medium spectral and a very high spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3 and CFC-12) and their spatial resolution are discussed. During ESSenCe, high resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in-situ data indicate a good agreement between the data sets. During TACTS/ESMVal a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere has been performed. This filament could be reconstructed with an unprecedented spatial resolution of better than 500 m vertically and 20 km × 20 km horizontally.
The three-dimensional quantification of small-scale processes in the upper troposphere and lower stratosphere is one of the challenges of current atmospheric research and requires the development of new measurement strategies. This work presents the first results from the newly developed Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) obtained during the ESSenCe (ESa Sounder Campaign) and TACTS/ESMVal (TACTS: Transport and composition in the upper troposphere/lowermost stratosphere, ESMVal: Earth System Model Validation) aircraft campaigns. The focus of this work is on the so-called dynamics-mode data characterized by a medium-spectral and a very-high-spatial resolution. The retrieval strategy for the derivation of two- and three-dimensional constituent fields in the upper troposphere and lower stratosphere is presented. Uncertainties of the main retrieval targets (temperature, O3, HNO3, and CFC-12) and their spatial resolution are discussed. During ESSenCe, high-resolution two-dimensional cross-sections have been obtained. Comparisons to collocated remote-sensing and in situ data indicate a good agreement between the data sets. During TACTS/ESMVal, a tomographic flight pattern to sense an intrusion of stratospheric air deep into the troposphere was performed. It was possible to reconstruct this filament at an unprecedented spatial resolution of better than 500 m vertically and 20 × 20 km horizontally.
We investigate what statistical properties drive risk-taking in a large set of observational panel data on online poker games (n=4,450,585). Each observation refers to a choice between a safe 'insurance' option and a binary lottery of winning or losing the game. Our setting offers a real-world choice situation with substantial incentives where probability distributions are simple, transparent, and known to the individuals. We find that individuals reveal a strong and robust preference for skewness. The effect of skewness is most pronounced among experienced and losing players but remains highly significant for winning players, in contrast to the variance effect.
Investigation of the sympathetic regulation in delayed onset muscle soreness: results of an RCT
(2021)
Sports-related pain and injury is directly linked to tissue inflammation, thus involving the autonomic nervous system (ANS). In the present experimental study, we disable the sympathetic part of the ANS by applying a stellate ganglion block (SGB) in an experimental model of delayed onset muscle soreness (DOMS) of the biceps muscle. We included 45 healthy participants (female 11, male 34, age 24.16 ± 6.67 years [range 18–53], BMI 23.22 ± 2.09 kg/m2) who were equally randomized to receive either (i) an SGB prior to exercise-induced DOMS (preventive), (ii) sham intervention in addition to DOMS (control/sham), or (iii) SGB after the induction of DOMS (rehabilitative). The aim of the study was to determine whether and to what extent sympathetically maintained pain (SMP) is involved in DOMS processing. Focusing on the muscular area with the greatest eccentric load (biceps distal fifth), a significant time × group interaction on the pressure pain threshold was observed between preventive SGB and sham (p = 0.034). There was a significant effect on pain at motion (p = 0.048), with post hoc statistical difference at 48 h (preventive SGB Δ1.09 ± 0.82 cm VAS vs. sham Δ2.05 ± 1.51 cm VAS; p = 0.04). DOMS mediated an increase in venous cfDNA -as a potential molecular/inflammatory marker of DOMS- within the first 24 h after eccentric exercise (time effect p = 0.018), with a peak at 20 and 60 min. After 60 min, cfDNA levels were significantly decreased comparing preventive SGB to sham (unpaired t-test p = 0.008). At both times, 20 and 60 min, cfDNA significantly correlated with observed changes in PPT. The 20-min increase was more sensitive, as it tended toward significance at 48 h (r = 0.44; p = 0.1) and predicted the early decrease of PPT following preventive stellate blocks at 24 h (r = 0.53; p = 0.04). Our study reveals the broad impact of the ANS on DOMS and exercise-induced pain. For the first time, we have obtained insights into the sympathetic regulation of pain and inflammation following exercise overload. As this study is of a translational pilot character, further research is encouraged to confirm and specify our observations.
As part of the CLACE-6 campaign we performed size-resolved CCN measurements for a~supersaturation range of S = 0.079 % to 0.66% at the high-alpine research station Jungfraujoch, Switzerland, in March~2007. The derived effective hygroscopicity parameter κ describing the influence of particle composition on CCN activity was on average 0.23–0.30 for Aitken (50–100 nm) and 0.32–0.43 for accumulation mode particles (100–200 nm). The campaign average value of κ = 0.3 is similar to the average value of κ for other continental locations. When air masses came from southeasterly directions crossing the Po Valley in Italy, particles were much more hygroscopic (κ ≈ 0.42) due to large sulfate mass fractions. The κ values obtained at S = 0.079 % exhibited a good negative correlation with the organic mass fractions derived from PM1 aerosol mass spectrometer (AMS) measurements. Applying a simple mixing rule the organic and inorganic mass fractions observed by the AMS could be used to reproduce the temporal fluctuations of the hygroscopicity of accumulation mode particles quite well.
We show how during a cloud event the aerosol particles were activated as cloud droplets and then removed from the air by precipitation leaving behind only a small amount of accumulation mode particles consisting mainly of weakly CCN-active particles, most likely externally mixed unprocessed soot particles.
During the campaign we had the opportunity to directly compare two DMT CCN counters for a certain time. The total CCN concentration (NCCN,tot) obtained by the two instruments at equal supersaturations agreed well for both possible operating modes: detecting NCCN,tot directly by sampling the polydisperse aerosol with the CCNC, or indirectly by combining size-resolved measurements of the activated fraction with parallel measurements of the particle size distribution (e.g., by SMPS). However, some supersaturation setpoints differed between the two CCNCs by as much as 20% after applying the instrument calibrations, which resulted in differences of the corresponding NCCN,tot of up to 50%. This emphasizes that it is extremely important to carefully calibrate the supersaturation of the instrument, especially at low S.
Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy.
Methods: The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables.
Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6 (14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm.
Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influence of various surface modifications on the ice nucleating ability of Arizona Test Dust (ATD) particles in the immersion freezing mode. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤T≤−28 °C. The pure ATD particles nucleated ice over a broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T>−35 °C) and a slight increase in the second branch (T≤−35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. The strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor and the resulting significant reductions in IN potential are of importance for atmospheric ice cloud formation. Our findings suggest that the IN concentration can decrease by up to one order of magnitude for the conditions investigated.
In the present work, three different techniques are used to separate ice-nucleating particles (INP) and ice particle residuals (IPR) from non-ice-active particles: the Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI), which sample ice particles from mixed phase clouds and allow for the analysis of the residuals, as well as the combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Virtual Impactor (IN-PCVI), which provides ice-activating conditions to aerosol particles and extracts the activated ones for analysis. The collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine their size, chemical composition and mixing state. Samples were taken during January/February 2013 at the High Alpine Research Station Jungfraujoch. All INP/IPR-separating techniques had considerable abundances (median 20–70%) of contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH + IN-PCVI: steel particles). Also, potential measurement artifacts (soluble material) occurred (median abundance < 20%). After removal of the contamination particles, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Minor types include soot and Pb-bearing particles. Sea-salt and sulfates were identified by all three methods as INP/IPR. Lead was identified in less than 10% of the INP/IPR. It was mainly present as an internal mixture with other particle types, but also external lead-rich particles were found. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also sampled many submicron particles. Probably owing to the different meteorological conditions, the INP/IPR composition was highly variable on a sample to sample basis. Thus, some part of the discrepancies between the different techniques may result from the (unavoidable) non-parallel sampling. The observed differences of the particles group abundances as well as the mixing state of INP/IPR point to the need of further studies to better understand the influence of the separating techniques on the INP/IPR chemical composition.
During January/February 2013, at the High Alpine Research Station Jungfraujoch a measurement campaign was carried out, which was centered on atmospheric ice-nucleating particles (INP) and ice particle residuals (IPR). Three different techniques for separation of INP and IPR from the non-ice-active particles are compared. The Ice Selective Inlet (ISI) and the Ice Counterflow Virtual Impactor (Ice-CVI) sample ice particles from mixed phase clouds and allow for the analysis of the residuals. The combination of the Fast Ice Nucleus Chamber (FINCH) and the Ice Nuclei Pumped Counterflow Virtual Impactor (IN-PCVI) provides ice-activating conditions to aerosol particles and extracts the activated INP for analysis.Collected particles were analyzed by scanning electron microscopy and energy-dispersive X-ray microanalysis to determine size, chemical composition and mixing state. All INP/IPR-separating techniques had considerable abundances (median 20 – 70 %) of instrumental contamination artifacts (ISI: Si-O spheres, probably calibration aerosol; Ice-CVI: Al-O particles; FINCH+IN-PCVI: steel particles). Also, potential sampling artifacts (e.g., pure soluble material) occurred with a median abundance of < 20 %. While these could be explained as IPR by ice break-up, for INP their IN-ability pathway is less clear. After removal of the contamination artifacts, silicates and Ca-rich particles, carbonaceous material and metal oxides were the major INP/IPR particle types separated by all three techniques. Soot was a minor contributor. Lead was detected in less than 10 % of the particles, of which the majority were internal mixtures with other particle types. Sea-salt and sulfates were identified by all three methods as INP/IPR. Most samples showed a maximum of the INP/IPR size distribution at 400 nm geometric diameter. In a few cases, a second super-micron maximum was identified. Soot/carbonaceous material and metal oxides were present mainly in the submicron range. ISI and FINCH yielded silicates and Ca-rich particles mainly with diameters above 1 μm, while the Ice-CVI also separated many submicron IPR. As strictly parallel sampling could not be performed, a part of the discrepancies between the different techniques may result from variations in meteorological conditions and subsequent INP/IPR composition. The observed differences in the particle group abundances as well as in the mixing state of INP/IPR express the need for further studies to better understand the influence of the separating techniques on the INP/IPR chemical
composition.
During the measurement campaign FROST 2 (FReezing Of duST 2), the Leipzig Aerosol Cloud Interaction Simulator (LACIS) was used to investigate the influences of various surface modifications on the immersion freezing behavior of Arizona Test Dust (ATD) particles. The dust particles were exposed to sulfuric acid vapor, to water vapor with and without the addition of ammonia gas, and heat using a thermodenuder operating at 250 °C. Size selected, quasi monodisperse particles with a mobility diameter of 300 nm were fed into LACIS and droplets grew on these particles such that each droplet contained a single particle. Temperature dependent frozen fractions of these droplets were determined in a temperature range between −40 °C ≤ T ≤ −28 °C. The pure ATD particles nucleated ice over a~broad temperature range with their freezing behavior being separated into two freezing branches characterized through different slopes in the frozen fraction vs. temperature curves. Coating the ATD particles with sulfuric acid resulted in the particles' IN potential significantly decreasing in the first freezing branch (T > −35 °C) and a slight increase in the second branch (T≤ −35 °C). The addition of water vapor after the sulfuric acid coating caused the disappearance of the first freezing branch and a strong reduction of the IN ability in the second freezing branch. The presence of ammonia gas during water vapor exposure had a negligible effect on the particles' IN ability compared to the effect of water vapor. Heating in the thermodenuder led to a decreased IN ability of the sulfuric acid coated particles for both branches but the additional heat did not or only slightly change the IN ability of the pure ATD and the water vapor exposed sulfuric acid coated particles. In other words, the combination of both sulfuric acid and water vapor being present is a main cause for the ice active surface features of the ATD particles being destroyed. A possible explanation could be the chemical transformation of ice active metal silicates to metal sulfates. From an atmospheric point of view, and here specifically the influences of atmospheric aging on the IN ability of dust particles, the strongly enhanced reaction between sulfuric acid and dust in the presence of water vapor, and the resulting significant reductions in IN potential, are certainly very interesting.
Antibody library technology represents a powerful tool for the discovery and design of antibodies with high affinity and specificity for their targets. To extend the technique to the expression and selection of antibody libraries in an eukaryotic environment, we provide here a proof of concept that retroviruses can be engineered for the display and selection of variable single-chain fragment (scFv) libraries. A retroviral library displaying the repertoire obtained after a single round of selection of a human synthetic scFv phage display library on laminin was generated. For selection, antigen-bound virus was efficiently recovered by an overlay with cells permissive for infection. This approach allowed more than 10(3)-fold enrichment of antigen binders in a single selection cycle. After three selection cycles, several scFvs were recovered showing similar laminin-binding activities but improved expression levels in mammalian cells as compared with a laminin-specific scFv selected by the conventional phage display approach. Thus, translational problems that occur when phage-selected antibodies have to be transferred onto mammalian expression systems to exert their therapeutic potential can be avoided by the use of retroviral display libraries.
Bipolar disorder (BD) is a genetically complex mental illness characterized by severe oscillations of mood and behavior. Genome-wide association studies (GWAS) have identified several risk loci that together account for a small portion of the heritability. To identify additional risk loci, we performed a two-stage meta-analysis of >9 million genetic variants in 9,784 bipolar disorder patients and 30,471 controls, the largest GWAS of BD to date. In this study, to increase power we used ~2,000 lithium-treated cases with a long-term diagnosis of BD from the Consortium on Lithium Genetics, excess controls, and analytic methods optimized for markers on the Xchromosome. In addition to four known loci, results revealed genome-wide significant associations at two novel loci: an intergenic region on 9p21.3 (rs12553324, p = 5.87×10-9; odds ratio = 1.12) and markers within ERBB2 (rs2517959, p = 4.53×10-9; odds ratio = 1.13). No significant X-chromosome associations were detected and X-linked markers explained very little BD heritability. The results add to a growing list of common autosomal variants involved in BD and illustrate the power of comparing well-characterized cases to an excess of controls in GWAS.