Annotated computed tomography coronary angiogram images and associated data of normal and diseased arteries.

Computed Tomography Coronary Angiography (CTCA) is a non-invasive method to evaluate coronary artery anatomy and disease. CTCA is ideal for geometry reconstruction to create virtual models of coronary arteries. To our knowledge there is no public dataset that includes centrelines and segmentation of the full coronary tree. We provide anonymized CTCA images, voxel-wise annotations and associated data in the form of centrelines, calcification scores and meshes of the coronary lumen in 20 normal and 20 diseased cases. Images were obtained along with patient information with informed, written consent as part of the Coronary Atlas. Cases were classified as normal (zero calcium score with no signs of stenosis) or diseased (confirmed coronary artery disease). Manual voxel-wise segmentations by three experts were combined using majority voting to generate the final annotations. Provided data can be used for a variety of research purposes, such as 3D printing patient-specific models, development and validation of segmentation algorithms, education and training of medical personnel and in-silico analyses such as testing of medical devices.

Snow on Arctic Sea Ice in a Warming Climate as Simulated in CESM.

Earth system models are valuable tools for understanding how the Arctic snow-ice system and the feedbacks therein may respond to a warming climate. In this analysis, we investigate snow on Arctic sea ice to better understand how snow conditions may change under different forcing scenarios. First, we use in situ, airborne, and satellite observations to assess the realism of the Community Earth System Model (CESM) in simulating snow on Arctic sea ice. CESM versions one and two are evaluated, with V1 being the Large Ensemble experiment (CESM1-LE) and V2 being configured with low- and high-top atmospheric components. The assessment shows CESM2 underestimates snow depth and produces overly uniform snow distributions, whereas CESM1-LE produces a highly variable, excessively-thick snow cover. Observations indicate that snow in CESM2 accumulates too slowly in autumn, too quickly in winter-spring, and melts too soon and rapidly in late spring. The 1950-2050 trends in annual mean snow depths are markedly smaller in CESM2 (-0.8 cm decade-1) than in CESM1-LE (-3.6 cm decade-1) due to CESM2 having less snow overall. A perennial, thick sea-ice cover, cool summers, and excessive summer snowfall facilitate a thicker, longer-lasting snow cover in CESM1-LE. Under the SSP5-8.5 forcing scenario, CESM2 shows that, compared to present-day, snow on Arctic sea ice will: (1) undergo enhanced, earlier spring melt, (2) accumulate less in summer-autumn, (3) sublimate more, and (4) facilitate marginally more snow-ice formation. CESM2 also reveals that summers with snow-free ice can occur ∼30-60 years before an ice-free central Arctic, which may promote faster sea-ice melt.

The role of cyclone activity in snow accumulation on Arctic sea ice.

Identifying the mechanisms controlling the timing and magnitude of snow accumulation on sea ice is crucial for understanding snow's net effect on the surface energy budget and sea-ice mass balance. Here, we analyze the role of cyclone activity on the seasonal buildup of snow on Arctic sea ice using model, satellite, and in situ data over 1979-2016. On average, 44% of the variability in monthly snow accumulation was controlled by cyclone snowfall and 29% by sea-ice freeze-up. However, there were strong spatio-temporal differences. Cyclone snowfall comprised ~50% of total snowfall in the Pacific compared to 83% in the Atlantic. While cyclones are stronger in the Atlantic, Pacific snow accumulation is more sensitive to cyclone strength. These findings highlight the heterogeneity in atmosphere-snow-ice interactions across the Arctic, and emphasize the need to scrutinize mechanisms governing cyclone activity to better understand their effects on the Arctic snow-ice system with anthropogenic warming.

Consistency of fish-shoal social network structure under laboratory conditions.

We investigated the consistency of association network structure for groups of sticklebacks Gasterosteus aculeatus. Each group was observed twice and we varied the duration between observations and the size of the experimental arena that they were observed in. At the dyad level, we found positive correlations between dyad interaction frequencies across observations. At the group level we found variation in four network metrics between observations, but only in treatments where the duration between observations was short. Specifically, fish formed more and smaller groups in the second observation in this treatment. Fish were also organized into more subunits in the larger arenas. Finally, we saw positive correlations between some group network metrics across observations suggesting relative consistency at the group level. There are several processes that might drive these interaction patterns. Our findings have implications for experimental design and the comparison and integration of findings of experiments from different studies carried out under different conditions.

Blocking extracellular activation of myostatin as a strategy for treating muscle wasting.

Many growth factors are intimately bound to the extracellular matrix, with regulated processing and release leading to cellular stimulation. Myostatin and GDF11 are closely related members of the TGFß family whose activation requires two proteolytic cleavages to release the growth factor from the prodomain. Specific modulation of myostatin and GDF11 activity by targeting growth factor-receptor interactions has traditionally been challenging. Here we demonstrate that a novel strategy for blocking myostatin and GDF11, inhibition of growth factor release, specifically and potently inhibits signaling both in vitro and in vivo. We developed human monoclonal antibodies that selectively bind the myostatin and GDF11 precursor forms, including a subset that inhibit myostatin proteolytic activation and prevent muscle atrophy in vivo. The most potent myostatin activation-blocking antibodies promoted robust muscle growth and resulted in significant gains in muscle performance in healthy mice. Altogether, we show that blocking the extracellular activation of growth factors is a potent method for preventing signaling, serving as proof of concept for a novel therapeutic strategy that can be applied to other members of the TGFß family of growth factors.

Cohesion, order and information flow in the collective motion of mixed-species shoals.

Despite the frequency with which mixed-species groups are observed in nature, studies of collective behaviour typically focus on single-species groups. Here, we quantify and compare the patterns of interactions between three fish species, threespine sticklebacks (Gasterosteus aculeatus), ninespine sticklebacks (Pungitius pungitius) and roach (Rutilus rutilus) in both single- and mixed-species shoals in the laboratory. Pilot data confirmed that the three species form both single- and mixed-species shoals in the wild. In our laboratory study, we found that single-species groups were more polarized than mixed-species groups, while single-species groups of threespine sticklebacks and roach were more cohesive than mixed shoals of these species. Furthermore, while there was no difference between the inter-individual distances between threespine and ninespine sticklebacks within mixed-species groups, there was some evidence of segregation by species in mixed groups of threespine sticklebacks and roach. There were differences between treatments in mean pairwise transfer entropy, and in particular we identify species-differences in information use within the mixed-species groups, and, similarly, differences in responses to conspecifics and heterospecifics in mixed-species groups. We speculate that differences in the patterns of interactions between species in mixed-species groups may determine patterns of fission and fusion in such groups.

Characterizing selection in black-throated blue warblers using a sexual network approach.

Our understanding of trait evolution is built upon studies that examine the correlation between traits and fitness, most of which implicitly assume all individuals experience similar selective environments. However, accounting for differences in selective pressures, such as variation in the social environment, can advance our understanding of how selection shapes individual traits and subsequent fitness. In this study, we test whether variation in the social environment affects selection on individual phenotype. We apply a new sexual network framework to quantify each male's social environment as the mean body size of his primary competitors. We test for direct and social selection on male body size using a 10-year data set on black-throated blue warblers (Setophaga caerulescens), a territorial species for which body size is hypothesized to mediate competition for mates. We found that direct selection on body size was weak and nonsignificant, as was social selection via the body size of the males' competitors. Analysing both types of selection simultaneously allows us to firmly reject a role for body size in competitive interactions between males and subsequent male fitness in this population. We evaluate the application of the sexual network approach to empirical data and suggest that other phenotypic traits such as song characteristics and plumage may be more relevant than body size for male-male competition in this small passerine bird.

Effect of yeast supplementation on performance, rumination time, and rumen pH of dairy cows in commercial farm environments.

The aims of the present study were to evaluate the effects of live yeast supplementation (Vistacell MUCL 39855, AB Vista, Marlborough, UK) on performance, rumination time, and rumen pH on dairy cows in commercial farm environments. Three trials were carried out, the trials lasted 12 (trial 1), 15 (trial 2), and 19 wk (trial 3). In each trial, 14 multiparous Holstein dairy cows were allocated to 2 groups that received (trial 1) a standard diet plus yeast, (trial 2) an acidogenic diet plus yeast, and (trial 3) grazing pasture plus yeast. Milk production, milk chemical characteristics, body weight and body condition score, rumination time, and rumen pH were monitored for each group throughout the 3 trials. No statistically significant differences were observed in any of the 3 trials for any of the recorded variables. In contrast, an effect of time (period or days in milk) on rumen pH was observed in all 3 of the trials, as time spent under the acidotic thresholds increased across the experimental periods; however the differences were not associated with live yeast supplementation. No effect of live yeast supplementation was observed in any of the 3 trials reported. Further research should include studies on animals at different stages of lactation (with emphasis on transition period and early lactation), consuming more challenging diets (higher level of inclusion of concentrates or starch), or under different environments such as grazing of succulent forages. Such studies might be required to elucidate any possible effect of live yeast supplementation of dairy cows when the rumen environment is under challenge.

Transcriptome sequencing of the choroid plexus in schizophrenia.

The choroid plexus (CP) has a key role in maintaining brain homeostasis by producing cerebrospinal fluid (CSF), by mediating transport of nutrients and removing metabolic products from the central nervous system and by responding to peripheral inflammatory signals. Although abnormal markers of immune response and inflammation are apparent in individuals with schizophrenia, the CP of these individuals has not been characterized. We therefore sequenced mRNA from the CP from two independent collections of individuals with schizophrenia and unaffected controls. Genes related to immune function and inflammation were upregulated in both collections. In addition, a co-expression module related to immune/inflammation response that was generated by combining mRNA-Seq data from both collections was significantly associated with disease status. The immune/inflammation-related co-expression module was positively correlated with levels of C-reactive protein (CRP), cortisol and several immune modulator proteins in the serum of the same individuals and was also positively correlated with CRP, cortisol and pro-inflammatory cytokines in the frontal cortex of the same individuals. In addition, we found a substantial number of nodes (genes) that were common to our schizophrenia-associated immune/inflammation module from the pooled data and a module we generated from lippopolysaccharides-treated mouse model data. These results suggest that the CP of individuals with schizophrenia are responding to signals from the periphery by upregulating immune/inflammation-related genes to protect the brain and maintain the homeostasis but nevertheless fails to completely prevent immune/inflammation related changes in the brain.

Differential activation of immune/inflammatory response-related co-expression modules in the hippocampus across the major psychiatric disorders.

The Stanley Neuropathology Consortium Integrative Database (SNCID, http://sncid.stanleyresearch.org) is a data-mining tool that includes 379 neuropathology data sets from hippocampus, as well as RNA-Seq data measured in 15 well-matched cases in each of four groups: schizophrenia, bipolar disorder (BPD), major depression (MD) and unaffected controls. We analyzed the neuropathology data from the hippocampus to identify those abnormalities that are shared between psychiatric disorders and those that are specific to each disorder. Of the 379 data sets, 20 of them showed a significant abnormality in at least one disorder as compared with unaffected controls. GABAergic markers and synaptic proteins were mainly abnormal in schizophrenia and the two mood disorders, respectively. Two immune/inflammation-related co-expression modules built from RNA-seq data from both schizophrenia and controls combined were associated with disease status, as well as negatively correlated with the GABAergic markers. The correlation between immune-related modules and schizophrenia was replicated using microarray data from an independent tissue collection. Immune/inflammation-related co-expression modules were also built from RNA-seq data from BPD cases or from MD cases but were not preserved when using data from control cases. Moreover, there was no overlap in the genes that comprise the immune/inflammation response-related modules across the different disorders. Thus, there appears to be differential activation of the immune/inflammatory response, as determined by co-expression of genes, which is associated with the major psychiatric disorders and which is also associated with the abnormal neuropathology in the disorders.

The utility of a 'non-significant' coronary angiogram.

BACKGROUND: Coronary angiography is the gold standard for assessing coronary artery disease (CAD). In many patients with chest pain, no or mild CAD (< 50% stenosis) is found. It is uncertain whether this 'non-significant' result influences management and outcomes. We reviewed characteristics and outcomes in a contemporary cohort of chest pain referrals who had mild or absent CAD on coronary angiography. METHOD: All patients undergoing coronary angiography at Auckland City Hospital during July 2010-October 2011 were reviewed (n = 2983). Of these, 12.3% (n = 366) underwent coronary angiography for evaluation of chest pain and were found to have absent or mild CAD. These patients were followed up for 2.3 ± 0.6 years. RESULTS: Mean age was 60.0 ± 12.3 years, 56.1% were female. The ECG was abnormal in 55.0% of patients. Stress testing for inducible ischaemia was undertaken in 40.7% of patients and was abnormal in 57.7%. Following angiography, 43.2% had no changes to cardiac medications. Additional drug therapy (aspirin, statin, beta-blockers, ACE-inhibitor) was commenced in around 14.2-22.1% of cases. These drugs were discontinued in 4.1-8.2% of patients. Rates of major adverse cardiovascular events and readmissions with chest pain were 0.3% (1) and 1.9% (7) respectively at 30 days, and 1.9% (7) and 6.0% (22) at 1 year. CONCLUSION: Although even non-obstructive atheroma may justify medical therapy to limit disease progression, our findings may suggest that in these cases, invasive coronary angiography, may not lead to the patient/physician reassurance justified by historical data.

Characterization of microsatellite markers for the Restinga Antwren, Formicivora littoralis (Thamnophilidae), an endangered bird endemic to Brazil.

Molecular markers are important tools in determining parentage, gene flow, and the genetic structure of species. In the case of rare, endemic, and/or threatened species, these markers can be used to understand key ecological questions and support conservation actions. We developed seven microsatellite markers for the only bird endemic to the Restinga ecosystem. Microsatellite loci were isolated from a library that was based on 10 individuals (six males and four females). Primers were tested in 107 individuals of the same population. The number of alleles per locus ranged from 4 to 19, and the observed and expected heterozygosity varied from 0.15 to 0.84 and from 0.60 to 0.89, respectively. We expect that the polymorphic microsatellite loci we describe will be useful for other studies, particularly in the Tropics.

Quantifying BTEX in aqueous solutions with potentially interfering hydrocarbons using a partially selective sensor array.

Partially selective gold nanoparticle sensors have the sensitivity and selectivity to discriminate and quantify benzene, toluene, ethylbenzene, p-xylene and naphthalene (BTEXN) at concentrations relevant to the US Environmental Protection Agency. In this paper we demonstrate that gold nanoparticle chemiresistors can do so in the presence of 16 other hydrocarbons and that they did not reduce the discriminating power of the array. A two-level full factorial designed experiment was performed on unary, binary, ternary, quaternary, quinary combinations of BTEXN analytes with and without the possibly interfering hydrocarbons. The nominal component concentration of the mixtures was 100 µg L(-1), equivalent to approximately 100 parts per billion (ppb). Concentrations predicted with the random forests method had an average root mean square error of 10-20% of the component concentrations. This level of accuracy was achieved regardless of whether or not the 16 possibly interfering hydrocarbons were present. This work shows that the sensitivity and selectivity of gold nanoparticles chemiresistor sensors towards BTEXN analytes are not unduly affected by the other hydrocarbons that are expected to be present at a petroleum remediation site.

Health care delivery for head-and-neck cancer patients in Alberta: a practice guideline.

BACKGROUND: The treatment of head-and-neck cancer is complex and requires the involvement of various health care professionals with a wide range of expertise. We describe the process of developing a practice guideline with recommendations about the organization and delivery of health care services for head-and-neck cancer patients in Alberta. METHODS: Outcomes of interest included composition of the health care team, qualification requirements for team members, cancer centre and team member volumes, infrastructure needs, and wait times. A search for existing practice guidelines and a systematic review of the literature addressing the organization and delivery of health care services for head-and-neck cancer patients were conducted. The search included the Standards and Guidelines Evidence (sage) directory of cancer guidelines and PubMed. RESULTS: One practice guideline was identified for adaptation. Three additional practice guidelines provided supplementary evidence to inform guideline recommendations. Members of the Alberta Provincial Head and Neck Tumour Team (consisting of various health professionals from across the province) provided expert feedback on the adapted recommendations through an online and in-person review process. Selected experts in head-and-neck cancer from outside the province participated in an external online review. SUMMARY: The recommendations outlined in this practice guideline are based on existing guidelines that have been modified to fit the Alberta context. Although specific to Alberta, the recommendations lend credence to similar published guidelines and could be considered for use by groups lacking the resources of appointed guideline panels. The recommendations are meant to be a guide rather than a fixed protocol. The implementation of this practice guideline will depend on many factors, including but not limited to availability of trained personnel, adequate funding of infrastructure, and collaboration with other associations of health care professionals in the province.

Familiarity affects social network structure and discovery of prey patch locations in foraging stickleback shoals.

Numerous factors affect the fine-scale social structure of animal groups, but it is unclear how important such factors are in determining how individuals encounter resources. Familiarity affects shoal choice and structure in many social fishes. Here, we show that familiarity between shoal members of sticklebacks (Gasterosteus aculeatus) affects both fine-scale social organization and the discovery of resources. Social network analysis revealed that sticklebacks remained closer to familiar than to unfamiliar individuals within the same shoal. Network-based diffusion analysis revealed that there was a strong untransmitted social effect on patch discovery, with individuals tending to discover a task sooner if a familiar individual from their group had previously done so than if an unfamiliar fish had done so. However, in contrast to the effect of familiarity, the frequency with which individuals had previously associated with one another had no effect upon the likelihood of prey patch discovery. This may have been due to the influence of fish on one another's movements; the effect of familiarity on discovery of an empty 'control' patch was as strong as for discovery of an actual prey patch. Our results demonstrate that factors affecting fine-scale social interactions can also influence how individuals encounter and exploit resources.

Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders.

Abnormalities in brain-derived neurotrophic factor (BDNF)/trkB signaling have been implicated in the etiology of schizophrenia and mood disorders. Patients with schizophrenia, bipolar disorder (BPD) and major depression (MDD) have reduced levels of neurotrophins in their brains when compared with normal unaffected individuals; however, only a few brain areas have been examined to date. Owing to the broad range of symptoms manifested in these disorders, we hypothesized that multiple associative areas of the neocortex may be implicated and that the degree of change in BDNF and trkB-TK+ mRNA expression and the cortical region or layers involved may vary according to Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnosis. We compared BDNF and trkB-TK+ mRNA levels across all layers of the prefrontal cortex (dorsolateral prefrontal cortex, DLPFC), orbital frontal cortex (OFC), anterior cingulate cortex (ACC), inferior temporal gyrus (ITG) and superior temporal gyrus (STG) in four groups: schizophrenia, BPD, MDD and unaffected controls (n=60). BDNF mRNA levels were significantly decreased in layers IV and V of DLPFC in schizophrenia patients, in layer VI of ACC in schizophrenia and MDD and in layer VI of ITG in schizophrenia, BPD and MDD. BDNF mRNA levels were also significantly decreased in layer V and/or VI of STG in schizophrenia, BPD and MDD. TrkB-TK+ mRNA levels were only significantly decreased in the cortical layer VI of OFC in BPD. The shared and distinct patterns of neurotrophin transcript reductions, with some specific to each group, may compromise the function and plasticity of distinct cortical areas to various degrees in the different groups and contribute to the range and overlap of symptoms manifested across the diagnoses.

Markers of inflammation and stress distinguish subsets of individuals with schizophrenia and bipolar disorder.

Schizophrenia and bipolar disorder share a number of common features, both symptomatically and biologically. Abnormalities in the neuroimmune and the stress-signaling pathways have been previously identified in brains of individuals with both diseases. However, the possible relationship between abnormalities in stress and neuroimmune signaling within the cortex of people with psychotic illness has not been defined. To test the hypothesis that combined alterations in brain stress responsiveness and neuroimmune/inflammatory status are characteristic of some individuals suffering from major mental illness, we examined gene expression in the Stanley Array Cohort of 35 controls, 35 individuals with schizophrenia and 34 individuals with bipolar disorder. We used levels of 8 inflammatory-related transcripts, of which SERPINA3 was significantly elevated in individuals with schizophrenia (F(2,88)=4.137, P<0.05), and 12 glucocorticoid receptor signaling (stress) pathway transcripts previously examined, to identify two clusters of individuals: a high inflammation/stress group (n=32) and a low (n=68) inflammation/stress group. The high inflammation/stress group has a significantly greater number of individuals with schizophrenia (n=15), and a trend toward having more bipolar disorder individuals (n=11), when compared with controls (n=6). Using these subgroups, we tested which microarray-assessed transcriptional changes may be associated with high inflammatory/stress groups using ingenuity analysis and found that an extended network of gene expression changes involving immune, growth factors, inhibitory signaling and cell death factors also distinguished these groups. Our work demonstrates that some of the heterogeneity in schizophrenia and bipolar disorder may be partially explained by inflammation/stress interactions, and that this biological subtype cuts across Diagnostic and Statistical Manual of Mental Disorders (DSM)-defined categories.

Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia.

Whole-genome expression profiling in postmortem brain tissue has recently provided insight into the pathophysiology of schizophrenia. Previous microarray and RNA-Seq studies identified several biological processes including synaptic function, mitochondrial function and immune/inflammation response as altered in the cortex of subjects with schizophrenia. Now using RNA-Seq data from the hippocampus, we have identified 144 differentially expressed genes in schizophrenia cases as compared with unaffected controls. Immune/inflammation response was the main biological process over-represented in these genes. The upregulation of several of these genes, IFITM1, IFITM2, IFITM3, APOL1 (Apolipoprotein L1), ADORA2A (adenosine receptor 2A), IGFBP4 and CD163 were validated in the schizophrenia subjects using data from the SNCID database and with quantitative RT-PCR. We identified a co-expression module associated with schizophrenia that includes the majority of differentially expressed genes related to immune/inflammation response as well as with the density of parvalbumin-containing neurons in the hippocampus. The results indicate that abnormal immune/inflammation response in the hippocampus may underlie the pathophysiology of schizophrenia and may be associated with abnormalities in the parvalbumin-containing neurons that lead to the cognitive deficits of the disease.

Doctors' willingness to give honest answers about end-of-life practices: a cross-sectional study.

OBJECTIVES: We aimed to (1) evaluate the extent to which doctors in New Zealand would be willing to answer honestly questions about their care of patients at the end of their lives and (2) identify the assurances that would encourage this. Results were compared with findings from a previous pilot study from the UK. DESIGN: Survey study involving a mailed questionnaire. SETTING: New Zealand hospital and community-based medical care settings. PARTICIPANTS: The questionnaire was mailed to a random sample of 800 doctors in New Zealand who were vocationally registered with the Medical Council of New Zealand in disciplines involving caring for patients at the end of their lives. PRIMARY AND SECONDARY OUTCOME MEASURES: Willingness to provide honest answers about various aspects of end-of-life care; assurances that might increase willingness to provide honest answers to questions about end-of-life practices. RESULTS: Completed questionnaires were returned by 436 doctors. The majority of respondents (59.9-91.5%) indicated willingness to provide honest answers to such questions. However, more than a third of doctors were unwilling to give honest answers to certain questions regarding euthanasia. These results are comparable with the UK data. Complete anonymity was the assurance most likely to encourage honest answering, with most of the respondents preferring the use of anonymous written replies. Respondents were less reassured by survey endorsements from regulatory bodies. Themes in free comments included the deterrent effect of medicolegal consequences, fear of censure from society, peers and the media and concerns about the motivations and potential uses of such research. CONCLUSIONS: Many New Zealand doctors were willing to give honest answers to questions about end-of-life practices, particularly if anonymity was guaranteed; others, however, expressed doubts or indicated that they would not be willing to provide honest answers to questions of this sort.

Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: a Canadian consensus statement.

Approximately 22,700 Canadian women were expected to be diagnosed with breast cancer in 2012. Despite improvements in screening and adjuvant treatment options, a substantial number of postmenopausal women with hormone receptor positive (hr+) breast cancer will continue to develop metastatic disease during or after adjuvant endocrine therapy. Guidance on the selection of endocrine therapy for patients with hr+ disease that is negative for the human epidermal growth factor receptor 2 (her2-) and that has relapsed or progressed on earlier nonsteroidal aromatase inhibitor (nsai) therapy is of increasing clinical importance. Exemestane, fulvestrant, and tamoxifen are approved therapeutic options in this context. Four phase iii trials involving 2876 patients-efect, sofea, confirm, and bolero-2-have assessed the efficacy of various treatment options in this clinical setting. Data from those trials suggest that standard-dose fulvestrant (250 mg monthly) and exemestane are of comparable efficacy, that doubling the dose of fulvestrant from 250 mg to 500 mg monthly results in a 15% reduction in the risk of progression, and that adding everolimus to exemestane (compared with exemestane alone) results in a 57% reduction in the risk of progression, albeit with increased toxicity. Multiple treatment options are now available to women with hr+ her2- advanced breast cancer recurring or progressing on earlier nsai therapy, although current clinical trial data suggest more robust clinical efficacy with everolimus plus exemestane. Consideration should be given to the patient's age, functional status, and comorbidities during selection of an endocrine therapy, and use of a proactive everolimus safety management strategy is encouraged.