RISK OF SHUNT-DEPENDENT HYDROCEPHALUS AFTER OCCLUSION OF RUPTURED INTRACRANIAL ANEURYSMS BY SURGICAL CLIPPING OR ENDOVASCULAR COILING: A SINGLE-INSTITUTION SERIES AND META-ANALYSIS

OBJECTIVE: To compare the risk of shunt-dependent hydrocephalus after treatment of ruptured intracranial aneurysms by clipping versus coiling. METHODS: We analyzed 596 patients prospectively added to our database from July of 1999 to November of 2005 concerning the risk of shunt dependency after clipping versus coiling. Factors analyzed included age; sex; Hunt and Hess grade; Fisher grade; acute hydrocephalus; intraventricular hemorrhage; angiographic vasospasm; and number, size, and location of aneurysms. In addition, a meta-analysis of available data from the literature was performed identifying four studies with quantitative data on the frequency of clip, coil, and shunt dependency. RESULTS: The institutional series revealed Hunt and Hess grade, Fisher grade, acute hydrocephalus, intraventricular hemorrhage, and angiographic vasospasm as significant (P < 0.05) risk factors for shunt dependency after a univariate analysis. In a multivariate logistic regression analysis, we isolated intraventricular hemorrhage, acute hydrocephalus, and angiographic vasospasm as independent, significant risk factors for shunt dependency. The meta-analysis, including the current data, revealed a significantly higher risk for shunt dependency after coiling than after clipping (P = 0.01). CONCLUSION: Clipping of a ruptured aneurysm may be associated with a lower risk for developing shunt dependency, possibly by clot removal. This might influence long-term outcome and surgical decision making.

Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects

Alkylamides (alkamides) from Echinacea modulate tumor necrosis factor alpha mRNA expression in human monocytes/macrophages via the cannabinoid type 2 (CB2) receptor (Gertsch, J., Schoop, R., Kuenzle, U., and Suter, A. (2004) FEBS Lett. 577, 563-569). Here we show that the alkylamides dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (A1) and dodeca-2E,4E-dienoic acid isobutylamide (A2) bind to the CB2 receptor more strongly than the endogenous cannabinoids. The Ki values of A1 and A2 (CB2 approximately 60 nM; CB1 >1500 nM) were determined by displacement of the synthetic high affinity cannabinoid ligand [3H]CP-55,940. Molecular modeling suggests that alkylamides bind in the solvent-accessible cavity in CB2, directed by H-bonding and pi-pi interactions. In a screen with 49 other pharmacologically relevant receptors, it could be shown that A1 and A2 specifically bind to CB2 and CB1. A1 and A2 elevated total intracellular Ca2+ in CB2-positive but not in CB2-negative promyelocytic HL60 cells, an effect that was inhibited by the CB2 antagonist SR144528. At 50 nM, A1, A2, and the endogenous cannabinoid anandamide (CB2 Ki >200 nM) up-regulated constitutive interleukin (IL)-6 expression in human whole blood in a seemingly CB2-dependent manner. A1, A2, anandamide, the CB2 antagonist SR144528 (Ki <10 nM), and also the non-CB2-binding alkylamide undeca-2E-ene,8,10-diynoic acid isobutylamide all significantly inhibited lipopolysaccharide-induced tumor necrosis factor alpha, IL-1beta, and IL-12p70 expression (5-500 nM) in a CB2-independent manner. Alkylamides and anandamide also showed weak differential effects on anti-CD3-versus anti-CD28-stimulated cytokine expression in human whole blood. Overall, alkylamides, anandamide, and SR144528 potently inhibited lipopolysaccharide-induced inflammation in human whole blood and exerted modulatory effects on cytokine expression, but these effects are not exclusively related to CB2 binding.

Multiparameter flow cytometry characterization of MHC class I negative mouse bone marrow cells

BACKGROUND: MHC-I down-regulation was described in foetal liver progenitors, and two different subsets of adult bone marrow derived stem cells. These cells, namely, MHC-I-/Thy1+ bone marrow derived liver stem cells (BMDLSC) and the multipotent adult progenitors (MAPC) differentiated into functioning hepatocytes. The aim of this paper was to characterize the MHC-I negative bone marrow compartment as it pertains to BMDLSC and MAPC. MATERIAL/METHODS: We performed multiparameter flow-cytometry analyses of the MHC-I negative compartment using hematopoietic (CD45, Ter119), and stem cell markers (Thy1.2, c-Kit, IL-3R, CD34) in adult mice. RESULTS: When analysing CD45 and Ter119 expression, the MHC-I negative bone marrow compartment divides into four sub-populations: 1. CD45-/Ter119+: 86.0+/-4.4%; 2. CD45+/Ter119+: 0.2+/-0.1%; 3. CD45+/Ter119-: 11.6+/-3.0%; 4. CD45-/Ter119-: 2.0+/-2.1%. Stem cells markers were only expressed on MHC-I negative/ CD45+/Ter119- cells. In vivo, MAPC (Ter119-/CD45- cells) are composed of MHC-I negative (24%) and MHC-I positive cells and do not express any of the stem cell markers tested. CONCLUSIONS: In conclusion, mouse BMDLSC and MAPC are two distinct stem cell populations. Down-regulation of MHC-I was the only common characteristic found between BMDLSC and MAPC suggesting that selection of MHC-I negative cells might represent an efficient strategy to enrich for bone marrow stem cells with liver developmental potential.

miR-15a and miR-16 are implicated in cell cycle regulation in a Rb-dependent manner and are frequently deleted or down-regulated in non-small cell lung cancer

MicroRNAs (miRNA) are negative regulators of gene expression at the posttranscriptional level, which are involved in tumorigenesis. Two miRNAs, miR-15a and miR-16, which are located at chromosome 13q14, have been implicated in cell cycle control and apoptosis, but little information is available about their role in solid tumors. To address this question, we established a protocol to quantify miRNAs from laser capture microdissected tissues. Here, we show that miR-15a/miR-16 are frequently deleted or down-regulated in squamous cell carcinomas and adenocarcinomas of the lung. In these tumors, expression of miR-15a/miR-16 inversely correlates with the expression of cyclin D1. In non-small cell lung cancer (NSCLC) cell lines, cyclins D1, D2, and E1 are directly regulated by physiologic concentrations of miR-15a/miR-16. Consistent with these results, overexpression of these miRNAs induces cell cycle arrest in G(1)-G(0). Interestingly, H2009 cells lacking Rb are resistant to miR-15a/miR-16-induced cell cycle arrest, whereas reintroduction of functional Rb resensitizes these cells to miRNA activity. In contrast, down-regulation of Rb in A549 cells by RNA interference confers resistance to these miRNAs. Thus, cell cycle arrest induced by these miRNAs depends on the expression of Rb, confirming that G(1) cyclins are major targets of miR-15a/miR-16 in NSCLC. Our results indicate that miR-15a/miR-16 are implicated in cell cycle control and likely contribute to the tumorigenesis of NSCLC.

Support for the predictions of the pollinator-mediated stabilizing selection hypothesis

Aims Floral traits are frequency used in traditional plant systematics because Of their assumed constancy. One potential reason for the apparent constancy of flower size is that effective pollen transfer between flowers depends oil the accuracy of the physical fit between the flower and pollinator. Therefore, dowels are likely to he under stronger stabilizing selection for uniform size than vegetative plant parts. Moreover, as predicted by the pollinator-mediated stabilizing selection (PMSS) hypothesis, all accurate fit between flowers and their pollinators is likely to he more important for specialized pollination systems as found in many species with bilaterally symmetric (zygomorphic) flowers than for species, with radially symmetric (actinomorphic) flowers. Methods In a comparative study of 15 zygomorphic and 13 actinomorphic species ill Switzerland, we tested whether variation in flower size, among and within individuals, is smaller than variation ill leaf size and whether variation in flower size is smaller ill zygomorphic compared to actinomorphic species. Important findings Indeed, variation ill leaf length was significantly larger than variation in flower length and width. Within-individual variation ill flower and leaf sizes did not differ significantly between zygomorphic and actinomorphic species. In line with the predictions of the PMSS, among-individual variation ill flower length and flower width was significantly smaller for zygomorphic species than for actinomorphic species, while the two groups did not differ in leaf length variation. This suggests that plants with zygomorphic flowers have undergone stronger selection for uniform flowers than plants with actinomorphic flowers. This supports that the uniformity of flowers compared to vegetative structures within species, as already observed in traditional plant systematics, is, at least in part, a consequence of the requirement for effective pollination.

Divergent selection and phenotypic plasticity during incipient speciation in Lake Victoria cichlid fish

Divergent selection acting on several different traits that cause multidimensional shifts are supposed to promote speciation, but the outcome of this process is highly dependent on the balance between the strength of selection vs. gene flow. Here, we studied a pair of sister species of Lake Victoria cichlids at a location where they hybridize and tested the hypothesis that divergent selection acting on several traits can maintain phenotypic differentiation despite gene flow. To explore the possible role of selection we tested for correlations between phenotypes and environment and compared phenotypic divergence (P-ST) with that based on neutral markers (F-ST). We found indications for disruptive selection acting on male breeding colour and divergent selection acting on several morphological traits. By performing common garden experiments we also separated the environmental and heritable components of divergence and found evidence for phenotypic plasticity in some morphological traits contributing to species differences.

Clinical and molecular features of methicillin-resistant, coagulase-negative staphylococci of pets and horses

OBJECTIVES To determine the antibiotic resistance and fingerprint profiles of methicillin-resistant coagulase-negative staphylococci (MRCoNS) from animal infections among different practices and examine the history of antibiotic treatment. METHODS Isolates were identified by mass spectrometry and tested for antimicrobial resistance by broth dilution, microarrays and sequence analysis of the topoisomerases. Diversity was assessed by PFGE, icaA PCR and staphylococcal cassette chromosome mec (SCCmec), arginine catabolic mobile element (ACME) and multilocus sequence typing. Clinical records were examined retrospectively. RESULTS MRCoNS were identified as Staphylococcus epidermidis (n=20), Staphylococcus haemolyticus (n=17), Staphylococcus hominis (n=3), Staphylococcus capitis (n=1), Staphylococcus cohnii (n=1) and Staphylococcus warneri (n=1). PFGE identified one clonal lineage in S. hominis isolates and several in S. haemolyticus and S. epidermidis. Fourteen sequence types were identified in S. epidermidis, with sequence type 2 (ST2) and ST5 being predominant. Ten isolates contained SCCmec IV, seven contained SCCmec V and the others were non-typeable. ACMEs were detected in 11 S. epidermidis isolates. One S. hominis and 10 S. epidermidis isolates were icaA positive. In addition to mecA-mediated β-lactam resistance, the most frequent resistance was to gentamicin/kanamycin [aac(6')-Ie-aph(2')-Ia, aph(3')-III] (n=34), macrolides/lincosamides [erm(C), erm(A), msr, lnu(A)] (n=31), tetracycline [tet(K)] (n=22), streptomycin [str, ant(6)-Ia] (n=20), trimethoprim [dfr(A), dfr(G)] (n=17), sulfamethoxazole (n = 34) and fluoroquinolones [amino acid substitutions in GyrA and GrlA] (n=30). Clinical data suggest selection through multiple antibiotic courses and emphasize the importance of accurate diagnosis and antibiograms. CONCLUSIONS MRCoNS from animal infection sites are genetically heterogeneous multidrug-resistant strains that represent a new challenge in the prevention and therapy of infections in veterinary clinics.

Extended-spectrum cephalosporin-resistant Gram-negative organisms in livestock: an emerging problem for human health?

Escherichia coli, Salmonella spp. and Acinetobacter spp. are important human pathogens. Serious infections due to these organisms are usually treated with extended-spectrum cephalosporins (ESCs). However, in the past two decades we have faced a rapid increasing of infections and colonization caused by ESC-resistant (ESC-R) isolates due to production of extended-spectrum-β-lactamases (ESBLs), plasmid-mediated AmpCs (pAmpCs) and/or carbapenemase enzymes. This situation limits drastically our therapeutic armamentarium and puts under peril the human health. Animals are considered as potential reservoirs of multidrug-resistant (MDR) Gram-negative organisms. The massive and indiscriminate use of antibiotics in veterinary medicine has contributed to the selection of ESC-R E. coli, ESC-R Salmonella spp. and, to less extent, MDR Acinetobacter spp. among animals, food, and environment. This complex scenario is responsible for the expansion of these MDR organisms which may have life-threatening clinical significance. Nowadays, the prevalence of food-producing animals carrying ESC-R E. coli and ESC-R Salmonella (especially those producing CTX-M-type ESBLs and the CMY-2 pAmpC) has reached worryingly high values. More recently, the appearance of carbapenem-resistant isolates (i.e., VIM-1-producing Enterobacteriaceae and NDM-1 or OXA-23-producing Acinetobacter spp.) in livestock has even drawn greater concerns. In this review, we describe the aspects related to the spread of the above MDR organisms among pigs, cattle, and poultry, focusing on epidemiology, molecular mechanisms of resistance, impact of antibiotic use, and strategies to contain the overall problem. The link and the impact of ESC-R organisms of livestock origin for the human scenario are also discussed.

Genomic signatures of relaxed disruptive selection associated with speciation reversal in whitefish

Background: Speciation reversal: the erosion of species differentiation via an increase in introgressive hybridization due to the weakening of previously divergent selection regimes, is thought to be an important, yet poorly understood, driver of biodiversity loss. Our study system, the Alpine whitefish (Coregonus spp.) species complex is a classic example of a recent postglacial adaptive radiation: forming an array of endemic lake flocks, with the independent origination of similar ecotypes among flocks. However, many of the lakes of the Alpine radiation have been seriously impacted by anthropogenic nutrient enrichment, resulting in a collapse in neutral genetic and phenotypic differentiation within the most polluted lakes. Here we investigate the effects of eutrophication on the selective forces that have shaped this radiation, using population genomics. We studied eight sympatric species assemblages belonging to five independent parallel adaptive radiations, and one species pair in secondary contact. We used AFLP markers, and applied FST outlier (BAYESCAN, DFDIST) and logistic regression analyses (MATSAM), to identify candidate regions for disruptive selection in the genome and their associations with adaptive traits within each lake flock. The number of outlier and adaptive trait associated loci identified per lake were then regressed against two variables (historical phosphorus concentration and contemporary oxygen concentration) representing the strength of eutrophication. Results: Whilst we identify disruptive selection candidate regions in all lake flocks, we find similar trends, across analysis methods, towards fewer disruptive selection candidate regions and fewer adaptive trait/candidate loci associations in the more polluted lakes. Conclusions: Weakened disruptive selection and a concomitant breakdown in reproductive isolating mechanisms in more polluted lakes has lead to increased gene flow between coexisting Alpine whitefish species. We hypothesize that the resulting higher rates of interspecific recombination reduce either the number or extent of genomic islands of divergence surrounding loci evolving under disruptive natural selection. This produces the negative trend seen in the number of selection candidate loci recovered during genome scans of whitefish species flocks, with increasing levels of anthropogenic eutrophication: as the likelihood decreases that AFLP restriction sites will fall within regions of heightened genomic divergence and therefore be classified as FST outlier loci. This study explores for the first time the potential effects of human-mediated relaxation of disruptive selection on heterogeneous genomic divergence between coexisting species.

Holocene flood frequency across the Central Alps – solar forcing and evidence for variations in North Atlantic atmospheric circulation

The frequency of large-scale heavy precipitation events in the European Alps is expected to undergo substantial changes with current climate change. Hence, knowledge about the past natural variability of floods caused by heavy precipitation constitutes important input for climate projections. We present a comprehensive Holocene (10,000 years) reconstruction of the flood frequency in the Central European Alps combining 15 lacustrine sediment records. These records provide an extensive catalog of flood deposits, which were generated by flood-induced underflows delivering terrestrial material to the lake floors. The multi-archive approach allows suppressing local weather patterns, such as thunderstorms, from the obtained climate signal. We reconstructed mainly late spring to fall events since ice cover and precipitation in form of snow in winter at high-altitude study sites do inhibit the generation of flood layers. We found that flood frequency was higher during cool periods, coinciding with lows in solar activity. In addition, flood occurrence shows periodicities that are also observed in reconstructions of solar activity from C-14 and Be-10 records (2500-3000, 900-1200, as well as of about 710, 500, 350, 208 (Suess cycle), 150, 104 and 87 (Gleissberg cycle) years). As atmospheric mechanism, we propose an expansion/shrinking of the Hadley cell with increasing/decreasing air temperature, causing dry/wet conditions in Central Europe during phases of high/low solar activity. Furthermore, differences between the flood patterns from the Northern Alps and the Southern Alps indicate changes in North Atlantic circulation. Enhanced flood occurrence in the South compared to the North suggests a pronounced southward position of the Westerlies and/or blocking over the northern North Atlantic, hence resembling a negative NAO state (most distinct from 4.2 to 2.4 kyr BP and during the Little Ice Age). South-Alpine flood activity therefore provides a qualitative record of variations in a paleo-NAO pattern during the Holocene. Additionally, increased South Alpine flood activity contrasts to low precipitation in tropical Central America (Cariaco Basin) on the Holocene and centennial time scale. This observation is consistent with a Holocene southward migration of the Atlantic circulation system, and hence of the ITCZ, driven by decreasing summer insolation in the Northern hemisphere, as well as with shorter-term fluctuations probably driven by solar activity. (C) 2013 Elsevier Ltd. All rights reserved.

NO-dependent CaMKII activation during -adrenergic stimulation of cardiac muscle

AIMS:During β-adrenergic receptor (β-AR) stimulation, phosphorylation of cardiomyocyte ryanodine receptors by protein kinases may contribute to an increased diastolic Ca(2+) spark frequency. Regardless of prompt activation of protein kinase A during β-AR stimulation, this appears to rely more on activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), by a not yet identified signalling pathway. The goal of the present study was to identify and characterize the mechanisms which lead to CaMKII activation and elevated Ca(2+) spark frequencies during β-AR stimulation in single cardiomyocytes in diastolic conditions. METHODS AND RESULTS:Confocal imaging revealed that β-AR stimulation increases endogenous NO production in cardiomyocytes, resulting in NO-dependent activation of CaMKII and a subsequent increase in diastolic Ca(2+) spark frequency. These changes of spark frequency could be mimicked by exposure to the NO donor GSNO and were sensitive to the CaMKII inhibitors KN-93 and AIP. In vitro, CaMKII became nitrosated and its activity remained increased independent of Ca(2+) in the presence of GSNO, as assessed with biochemical assays. CONCLUSIONS:β-AR stimulation of cardiomyocytes may activate CaMKII by a novel direct pathway involving NO, without requiring Ca(2+) transients. This crosstalk between two established signalling pathways may contribute to arrhythmogenic diastolic Ca(2+) release and Ca(2+) waves during adrenergic stress, particularly in combination with cardiac diseases. In addition, NO-dependent activation of CaMKII is likely to have repercussions in many cellular signalling systems and cell types.

"Eventless" InsP 3 -dependent SR-Ca 2+ Release Affecting Atrial Ca 2+ Sparks

Augmented inositol 1,4,5-trisphosphate receptor (InsP3R) function has been linked to a variety of cardiac pathologies, including cardiac arrhythmia. The contribution of inositol 1,4,5-trisphosphate-induced Ca2+ release (IP3ICR) in excitation-contraction coupling (ECC) under physiological conditions, as well as under cellular remodelling, remains controversial. Here we test the hypothesis that local IP3ICR directly affects ryanodine receptor (RyR) function and subsequent Ca2+-induced Ca2+ release in atrial myocytes. IP3ICR was evoked by UV-flash photolysis of caged InsP3 under whole-cell configuration of the voltage-clamp technique in atrial myocytes isolated from C57/BL6 mice. Photolytic release of InsP3 was accompanied by a significant increase in the Ca2+ release event frequency (4.14±0.72 vs. 6.20±0.76 events (100 μm)−1 s−1). These individual photolytically triggered Ca2+ release events were identified as Ca2+ sparks, which originated from RyR openings. This was verified by Ca2+ spark analysis and pharmacological separation between RyR and InsP3R-dependent sarcoplasmic reticulum (SR)-Ca2+ release (2-aminoethoxydiphenyl borate, xestospongin C, tetracaine). Significant SR-Ca2+ flux but eventless SR-Ca2+ release through InsP3R were characterized using SR-Ca2+ leak/SR-Ca2+ load measurements. These results strongly support the idea that IP3ICR can effectively modulate RyR openings and Ca2+ spark probability. We conclude that eventless and highly efficient InsP3-dependent SR-Ca2+ flux is the main mechanism of functional cross-talk between InsP3Rs and RyRs, which may be an important factor in the modulation of ECC sensitivity.

Peer victimisation and depressive symptoms: can specific coping strategies buffer the negative impact of cybervictimisation?

This longitudinal study investigated whether cybervictimisation is an additional risk factor for depressive symptoms over and beyond traditional victimisation in adolescents. Furthermore, it explored whether certain coping strategies moderate the impact of cybervictimisation on depressive symptoms. A total of 765 Swiss seventh graders (mean age at time-point 1 (t1) = 13.18 years) reported on the frequency of traditional and cybervictimisation, and of depressive symptoms twice in six months. At time-point 2 (t2) students also completed a questionnaire on coping strategies in response to a hypothetical cyberbullying scenario. Analyses showed that both traditional and cybervictimisation were associated with higher levels of depressive symptoms. Cybervictimisation also predicted increases in depressive symptoms over time. Regarding coping strategies, it was found that helpless reactions were positively associated with depressive symptoms. Moreover, support seeking from peers and family showed a significant buffering effect: cybervictims who recommended seeking close support showed lower levels of depressive symptoms at t2. In contrast, cybervictims recommending assertive coping strategies showed higher levels of depressive symptoms at t2.

Are Greenhouse Gas Signals of Northern Hemisphere winter extra-tropical cyclone activity dependent on the identification and tracking algorithm?

For Northern Hemisphere extra-tropical cyclone activity, the dependency of a potential anthropogenic climate change signal on the identification method applied is analysed. This study investigates the impact of the used algorithm on the changing signal, not the robustness of the climate change signal itself. Using one single transient AOGCM simulation as standard input for eleven state-of-the-art identification methods, the patterns of model simulated present day climatologies are found to be close to those computed from re-analysis, independent of the method applied. Although differences in the total number of cyclones identified exist, the climate change signals (IPCC SRES A1B) in the model run considered are largely similar between methods for all cyclones. Taking into account all tracks, decreasing numbers are found in the Mediterranean, the Arctic in the Barents and Greenland Seas, the mid-latitude Pacific and North America. Changing patterns are even more similar, if only the most severe systems are considered: the methods reveal a coherent statistically significant increase in frequency over the eastern North Atlantic and North Pacific. We found that the differences between the methods considered are largely due to the different role of weaker systems in the specific methods.

Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial

BACKGROUND The addition of bevacizumab to chemotherapy improves progression-free survival in metastatic breast cancer and pathological complete response rates in the neoadjuvant setting. Micrometastases are dependent on angiogenesis, suggesting that patients might benefit from anti-angiogenic strategies in the adjuvant setting. We therefore assessed the addition of bevacizumab to chemotherapy in the adjuvant setting for women with triple-negative breast cancer. METHODS For this open-label, randomised phase 3 trial we recruited patients with centrally confirmed triple-negative operable primary invasive breast cancer from 360 sites in 37 countries. We randomly allocated patients aged 18 years or older (1:1 with block randomisation; stratified by nodal status, chemotherapy [with an anthracycline, taxane, or both], hormone receptor status [negative vs low], and type of surgery) to receive a minimum of four cycles of chemotherapy either alone or with bevacizumab (equivalent of 5 mg/kg every week for 1 year). The primary endpoint was invasive disease-free survival (IDFS). Efficacy analyses were based on the intention-to-treat population, safety analyses were done on all patients who received at least one dose of study drug, and plasma biomarker analyses were done on all treated patients consenting to biomarker analyses and providing a measurable baseline plasma sample. This trial is registered with ClinicalTrials.gov, number NCT00528567. FINDINGS Between Dec 3, 2007, and March 8, 2010, we randomly assigned 1290 patients to receive chemotherapy alone and 1301 to receive bevacizumab plus chemotherapy. Most patients received anthracycline-containing therapy; 1638 (63%) of the 2591 patients had node-negative disease. At the time of analysis of IDFS, median follow-up was 31·5 months (IQR 25·6-36·8) in the chemotherapy-alone group and 32·0 months (27·5-36·9) in the bevacizumab group. At the time of the primary analysis, IDFS events had been reported in 205 patients (16%) in the chemotherapy-alone group and in 188 patients (14%) in the bevacizumab group (hazard ratio [HR] in stratified log-rank analysis 0·87, 95% CI 0·72-1·07; p=0·18). 3-year IDFS was 82·7% (95% CI 80·5-85·0) with chemotherapy alone and 83·7% (81·4-86·0) with bevacizumab and chemotherapy. After 200 deaths, no difference in overall survival was noted between the groups (HR 0·84, 95% CI 0·64-1·12; p=0·23). Exploratory biomarker assessment suggests that patients with high pre-treatment plasma VEGFR-2 might benefit from the addition of bevacizumab (Cox interaction test p=0·029). Use of bevacizumab versus chemotherapy alone was associated with increased incidences of grade 3 or worse hypertension (154 patients [12%] vs eight patients [1%]), severe cardiac events occurring at any point during the 18-month safety reporting period (19 [1%] vs two [<0·5%]), and treatment discontinuation (bevacizumab, chemotherapy, or both; 256 [20%] vs 30 [2%]); we recorded no increase in fatal adverse events with bevacizumab (four [<0·5%] vs three [<0·5%]). INTERPRETATION Bevacizumab cannot be recommended as adjuvant treatment in unselected patients with triple-negative breast cancer. Further follow-up is needed to assess the potential effect of bevacizumab on overall survival.