Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Detection of Cross-Correlation between Gravitational Lensing and γ Rays.

In recent years, many γ-ray sources have been identified, yet the unresolved component hosts valuable information on the faintest emission. In order to extract it, a cross-correlation with gravitational tracers of matter in the Universe has been shown to be a promising tool. We report here the first identification of a cross-correlation signal between γ rays and the distribution of mass in the Universe probed by weak gravitational lensing. We use data from the Dark Energy Survey Y1 weak lensing data and the Fermi Large Area Telescope 9-yr γ-ray data, obtaining a signal-to-noise ratio of 5.3. The signal is mostly localized at small angular scales and high γ-ray energies, with a hint of correlation at extended separation. Blazar emission is likely the origin of the small-scale effect. We investigate implications of the large-scale component in terms of astrophysical sources and particle dark matter emission.

Cosmological Constraints from Multiple Probes in the Dark Energy Survey.

The combination of multiple observational probes has long been advocated as a powerful technique to constrain cosmological parameters, in particular dark energy. The Dark Energy Survey has measured 207 spectroscopically confirmed type Ia supernova light curves, the baryon acoustic oscillation feature, weak gravitational lensing, and galaxy clustering. Here we present combined results from these probes, deriving constraints on the equation of state, w, of dark energy and its energy density in the Universe. Independently of other experiments, such as those that measure the cosmic microwave background, the probes from this single photometric survey rule out a Universe with no dark energy, finding w=-0.80_{-0.11}^{+0.09}. The geometry is shown to be consistent with a spatially flat Universe, and we obtain a constraint on the baryon density of Ω_{b}=0.069_{-0.012}^{+0.009} that is independent of early Universe measurements. These results demonstrate the potential power of large multiprobe photometric surveys and pave the way for order of magnitude advances in our constraints on properties of dark energy and cosmology over the next decade.

Traditional plant functional groups explain variation in economic but not size-related traits across the tundra biome.

AIM: Plant functional groups are widely used in community ecology and earth system modelling to describe trait variation within and across plant communities. However, this approach rests on the assumption that functional groups explain a large proportion of trait variation among species. We test whether four commonly used plant functional groups represent variation in six ecologically important plant traits. LOCATION: Tundra biome. TIME PERIOD: Data collected between 1964 and 2016. MAJOR TAXA STUDIED: 295 tundra vascular plant species. METHODS: We compiled a database of six plant traits (plant height, leaf area, specific leaf area, leaf dry matter content, leaf nitrogen, seed mass) for tundra species. We examined the variation in species-level trait expression explained by four traditional functional groups (evergreen shrubs, deciduous shrubs, graminoids, forbs), and whether variation explained was dependent upon the traits included in analysis. We further compared the explanatory power and species composition of functional groups to alternative classifications generated using post hoc clustering of species-level traits. RESULTS: Traditional functional groups explained significant differences in trait expression, particularly amongst traits associated with resource economics, which were consistent across sites and at the biome scale. However, functional groups explained 19% of overall trait variation and poorly represented differences in traits associated with plant size. Post hoc classification of species did not correspond well with traditional functional groups, and explained twice as much variation in species-level trait expression. MAIN CONCLUSIONS: Traditional functional groups only coarsely represent variation in well-measured traits within tundra plant communities, and better explain resource economic traits than size-related traits. We recommend caution when using functional group approaches to predict tundra vegetation change, or ecosystem functions relating to plant size, such as albedo or carbon storage. We argue that alternative classifications or direct use of specific plant traits could provide new insights for ecological prediction and modelling.

CCL23: a new CC chemokine involved in human brain damage.

BACKGROUND: CCL23 role in the inflammatory response after acute brain injuries remains elusive. Here, we evaluated whether CCL23 blood levels associate with acquired cerebral lesions and determined CCL23 predictive capacity for assessing stroke prognosis. We used preclinical models to study the CCL23 homologous chemokines in rodents, CCL9 and CCL6. METHODS: Baseline CCL23 blood levels were determined on 245 individuals, including ischaemic strokes (IS), stroke mimics and controls. Temporal profile of circulating CCL23 was explored from baseline to 24 h in 20 of the IS. In an independent cohort of 120 IS with a 3-month follow-up, CCL23 blood levels were included in logistic regression models to predict IS outcome. CCL9/CCL6 cerebral expression was evaluated in rodent models of brain damage. Both chemokines were also profiled in circulation and histologically located on brain following ischaemia. RESULTS: Baseline CCL23 blood levels did not discriminate IS, but permitted an accurate discrimination of patients presenting acute brain lesions (P = 0.003). IS exhibited a continuous increase from baseline to 24 h in circulating CCL23 (P < 0.001). Baseline CCL23 blood levels resulted an independent predictor of IS outcome at hospital discharge (ORadj : 19.702 [1.815-213.918], P = 0.014) and mortality after 3 months (ORadj : 21.47 [3.434-134.221], P = 0.001). In preclinics, expression of rodent chemokines in neurons following cerebral lesions was elevated. CCL9 circulating levels decreased early after ischaemia (P < 0.001), whereas CCL6 did not alter within the first 24 h after ischaemia. CONCLUSIONS: Although preclinical models do not seem suitable to characterize CCL23, it might be a novel promising biomarker for the early diagnosis of cerebral lesions and might facilitate the prediction of stroke patient outcome.

Association of the missense variant p.Arg203Trp in PACS1 as a cause of intellectual disability and seizures.

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.

Practical considerations in the clinical application of whole-exome sequencing.

Despite the exciting advent of whole-exome sequencing (WES) in medical genetics practices, the optimal interpretation of results requires further actions such as reconsidering clinical information and obtaining further laboratory testing. There are no published data to guide clinicians in this process. In a retrospective study on 93 patients who underwent clinical WES, we set out to assess and resolve these practical challenges. With the laboratories reporting a molecular diagnostic rate of 25.8%, the medical geneticists and the laboratories were 90% concordant in their interpretation of the WES results. Divergence occurred when the medical geneticist reconsidered clinical information and/or additional information regarding pathogenicity of a variant. Variants of uncertain significance were reported in 86% of patients, with 53.7% needing follow-up, such as additional laboratory tests and genotyping of family members. By layering clinical data (e.g. mode of inheritance and phenotypic fit) on to the laboratory results, we developed clinical categories for the WES results. These categories of definite diagnosis (14/93), likely diagnosis (8/93), possible diagnosis (13/93) and no diagnosis (58/93) could be used to convey results to patients uniformly. Our framework for a clinically informed interpretation of the results enhances the utility of WES within medical genetics practices.

Wide-Field Lensing Mass Maps from Dark Energy Survey Science Verification Data.

We present a mass map reconstructed from weak gravitational lensing shear measurements over 139 deg2 from the Dark Energy Survey science verification data. The mass map probes both luminous and dark matter, thus providing a tool for studying cosmology. We find good agreement between the mass map and the distribution of massive galaxy clusters identified using a red-sequence cluster finder. Potential candidates for superclusters and voids are identified using these maps. We measure the cross-correlation between the mass map and a magnitude-limited foreground galaxy sample and find a detection at the 6.8σ level with 20 arc min smoothing. These measurements are consistent with simulated galaxy catalogs based on N-body simulations from a cold dark matter model with a cosmological constant. This suggests low systematics uncertainties in the map. We summarize our key findings in this Letter; the detailed methodology and tests for systematics are presented in a companion paper.

Social cognitive training in adolescents with chromosome 22q11.2 deletion syndrome: feasibility and preliminary effects of the intervention.

BACKGROUND: Children with chromosome 22q11.2 deletion syndrome (22q11DS) often have deficits in social cognition and social skills that contribute to poor adaptive functioning. These deficits may be of relevance to the later occurrence of serious psychiatric illnesses such as schizophrenia. Yet, there are no evidence-based interventions to improve social cognitive functioning in children with 22q11DS. METHODS: Using a customised social cognitive curriculum, we conducted a pilot small-group-based social cognitive training (SCT) programme in 13 adolescents with 22q11DS, relative to a control group of nine age- and gender-matched adolescents with 22q11DS. RESULTS: We found the SCT programme to be feasible, with high rates of compliance and satisfaction on the part of the participants and their families. Our preliminary analyses indicated that the intervention group showed significant improvements in an overall social cognitive composite index. CONCLUSIONS: SCT in a small-group format for adolescents with 22q11DS is feasible and results in gains in social cognition. A larger randomised controlled trial would permit assessment of efficacy of this promising novel intervention.

Are hospitalizations for rotavirus gastroenteritis associated with meteorologic factors?

Local climatic factors might explain seasonal patterns of rotavirus infections, but few models have been proposed to determine the effects of weather conditions on rotavirus activity. Here, we study the association of meteorologic factors with rotavirus activity, as determined by the number of children hospitalized for rotavirus gastroenteritis on the Mediterranean island of Mallorca (Spain). We conducted a retrospective review of the medical records of children aged 0-5 years admitted for rotavirus gastroenteritis between January 2000 and December 2010. The number of rotavirus hospitalizations was correlated to temperature, humidity, rainfall, atmospheric pressure, water vapor pressure, wind speed, and solar radiation using regression and time-series techniques. A total of 311 patients were hospitalized for rotavirus gastroenteritis in the 11-year study period, with a seasonal pattern from December to June, and a peak incidence in February. After multiple regressions, weekly rotavirus activity could be explained in 82 % of cases (p < 0.001) with a one-week lag meteorologic model. Rotavirus activity was negatively associated to temperature and positively associated to atmospheric pressure, solar radiation, and wind speed. Temperature and solar radiation were the factors that contributed most to the model, with a peak rotavirus activity at 9 °C and 800 10KJ/m(2), respectively. In conclusion, hospitalization for rotavirus was strongly associated with mean temperature, but an association of rotavirus activity with solar radiation, atmospheric pressure, and wind speed was also demonstrated. This model predicted more than 80 % of rotavirus hospitalizations.

Decreased levels of angiogenic growth factors in intracranial atherosclerotic disease despite severity-related increase in endothelial progenitor cell counts.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is an important cause of ischemic stroke (IS) and endothelial dysfunction plays a critical role in its onset and progression. Endothelial progenitor cells (EPCs) and endothelial production of angiogenic growth factors (AGFs) may play an essential role in this process. This study investigated the association of EPCs and AGFs with ICAD severity. METHODS: A total of 42 patients who had experienced a transient ischemic attack (TIA) or IS attributable to symptomatic ICAD were included. Clinical and neurosonological evaluations were conducted between 2.4 and 8.7 years after the initial cerebrovascular event. Severe ICAD was defined as the presence of at least 1 severe intracranial stenosis, and extensive ICAD as 3 or more intracranial stenoses. Blood samples were obtained to determine EPC levels using flow cytometry (CD34+KDR+ cells), and the plasma levels of several growth factors were assessed with a protein array (Searchlight(®)). Twenty-two individuals without cerebrovascular disease and with normal ultrasonographic examination were also included. RESULTS: No difference in the count of circulating EPCs was found between patients and controls, and a moderate increase in the number of EPCs/ml was noted in patients with extensive ICAD (p = 0.05). Patients presented decreased levels of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF-BB) compared with controls (p = 0.002, p = 0.079 and p = 0.061, respectively). Higher levels of FGF, VEGF and PDGF-BB were found in patients with severe ICAD (p = 0.007, p = 0.07 and p = 0.07, respectively), but there was no correlation between any AGFs and EPCs. CONCLUSIONS: Symptomatic ICAD patients have decreased levels of AGFs with no correlation to the number of circulating EPCs, while patients with severe ICAD have higher levels of EPCs, FGF, VEGF and PDGF-BBs. This suggests that reduced EPC and proangiogenic factor production capacity is implicated in ICAD pathogenesis, while the more severe forms of chronic brain hypoperfusion in ICAD patients might stimulate EPC mobilization and AGF production.

Brain natriuretic peptide is associated with worsening and mortality in acute stroke patients but adds no prognostic value to clinical predictors of outcome.

BACKGROUND: At the present time, the determination of the outcome of stroke patients is based on the analysis of clinical and neuroimaging data. The use of prognostic blood biomarkers could aid in decision-making processes, e.g. admitting patients to specialized stroke units. Although the prognostic role of natriuretic peptides has been studied in heart failure and coronary diseases, the value of brain natriuretic peptide (BNP) is less known within the field of strokes. OBJECTIVE: We aimed to study the relationship between plasma levels of BNP and acute neurological worsening or mortality after stroke in a large cohort of patients (investigating both ischemic and hemorrhagic disease). METHODS: Consecutive stroke patients (ischemic and hemorrhagic) admitted to the Stroke Unit of our University Hospital within 24 h of the onset of symptoms were included. Stroke severity was assessed according to the National Institutes of Health Stroke Scale (NIHSS) at admission and at discharge. Neurological worsening was defined as an increase of 4 or more points in the NIHSS score or death during the patient's stay at the Stroke Unit. Blood samples were drawn upon admission to measure plasma levels of BNP (Biosite Inc., San Diego, Calif., USA). Statistical analysis was performed using SPSS 15.0 and R software. RESULTS: Altogether, 896 patients were included in the study. BNP plasma levels were higher among patients who deteriorated the most over time (n = 112; 90.5 vs. 61.2 ng/l; p = 0.006) or died (n = 83; 118.2 vs. 60.9 ng/l; p < 0.001). Multivariate logistic regression analysis indicated that plasma BNP level was an independent predictor of neurological worsening [BNP >56.7 ng/l; odds ratio (OR) = 1.64; p = 0.04] and death after stroke (BNP >65.3 ng/l; OR = 1.97; p = 0.034). Adding BNP level to other well-known clinical predictors of bad outcome did not significantly increase the predictive value. CONCLUSIONS: Plasma levels of BNP measured during the acute phase of stroke are associated both with early neurological worsening and mortality. However, this biological information does not supply prognostic information which would add to clinical variables, which limits its use as a biomarker. Further investigation and systematic reviews are needed to clarify the role of natriuretic peptides in stroke outcome.

The gender gap in stroke: a meta-analysis.

UNLABELLED: Several studies have indicated that gender differences might exist in stroke. OBJECTIVES AND METHODS: Our goal was to perform a comprehensive meta-analysis in order to evaluate and quantify stroke gender disparities through a systematic search of relevant articles published up to October 2009 and addressing gender related differences in ischemic stroke risk factors, stroke subtype and severity, diagnostic tests, and acute phase and secondary prevention treatments. RESULTS: Forty-five articles were included in the analysis, representing a total of 673,935 patients. Women were globally older than men (+5.2 years) and suffered more hypertension (P = 0.017) and atrial fibrillation (P < 0.001), although they were less likely to drink alcohol (P < 0.001), smoke cigarettes (P < 0.001), present hyperlipidemia (P = 0.033) or diabetes (P = 0.003) than men. Baseline stroke severity was not different between genders. Women suffered more cardioembolic strokes, while men had more atherothrombotic strokes. Moreover, women were less likely to receive stroke-related treatments, such as antiplatelets (P < 0.001), statins (P < 0.001), and tPA (P < 0.001) than men. Although meta-regression did not identify age or stroke etiology as sources of heterogeneity, caution should be taken as that analysis was possible only for gender differences in secondary prevention with antiplatelets because of limited data for other end points. CONCLUSIONS: Gender differences have been identified on the risk factors profile and diagnostic and therapeutic management of patients with ischemic stroke. Active measures should thus be taken to avoid bias in clinical practice.

Neutrophil extracellular traps promote cancer-associated inflammation and myocardial stress.

Cancer is associated with systemic pathologies that contribute to mortality, such as thrombosis and distant organ failure. The aim of this study was to investigate the potential role of neutrophil extracellular traps (NETs) in myocardial inflammation and tissue damage in treatment-naïve individuals with cancer. Mice with mammary carcinoma (MMTV-PyMT) had increased plasma levels of NETs measured as H3Cit-DNA complexes, paralleled with elevated coagulation, compared to healthy littermates. MMTV-PyMT mice displayed upregulation of pro-inflammatory markers in the heart, myocardial hypertrophy and elevated cardiac disease biomarkers in the blood, but not echocardiographic heart failure. Moreover, increased endothelial proliferation was observed in hearts from tumor-bearing mice. Removal of NETs by DNase I treatment suppressed the myocardial inflammation, expression of cardiac disease biomarkers and endothelial proliferation. Compared to a healthy control group, treatment-naïve cancer patients with different malignant disorders had increased NET formation, which correlated to plasma levels of the inflammatory marker CRP and the cardiac disease biomarkers NT-proBNP and sTNFR1, in agreement with the mouse data. Altogether, our data indicate that NETs contribute to inflammation and myocardial stress during malignancy. These findings suggest NETs as potential therapeutic targets to prevent cardiac inflammation and dysfunction in cancer patients.

A panel of biomarkers including caspase-3 and D-dimer may differentiate acute stroke from stroke-mimicking conditions in the emergency department.

BACKGROUND AND AIMS: At present, a rapid and widely available diagnostic test for stroke remains elusive. The aim of this study was to examine the predictive value of a panel of blood-borne biochemical markers for stroke diagnosis. DESIGN: Consecutive patients with strokes or stroke-mimicking conditions (mimics) were evaluated within 24 h from symptom onset (915 strokes and 90 mimics). Blood samples were analysed by enzyme-linked immunosorbent assay for C-reactive protein, d-dimer, soluble receptor for advanced glycation end products (sRAGE), metalloproteinase 9 (MMP-9), S100B, brain natriuretic peptide, caspase-3, neurotrophin-3, chimerin and secretagogin. RESULTS: The main independent predictors of stroke versus mimics were caspase-3 >1.96 ng mL(-1) [odds ratio (OR) = 3.32; 95% confidence interval (CI) 1.88-5.88, P < 0.0001], d-dimer >0.27 µg mL(-1) (OR = 2.97; 95% CI 1.72-5.16, P = 0.0001), sRAGE >0.91 ng mL(-1) (OR = 2.19; 95% CI 1.26-3.83, P = 0.006), chimerin <1.11 ng mL(-1) (OR = 0.4; 95% CI 0.19-0.81, P = 0.011), secretagogin <0.24 ng mL(-1) (OR = 0.51; 95% CI 0.27-0.97, P = 0.041) and MMP-9 > 199 ng mL(-1) (OR = 1.66; 95% CI 1.01-2.73, P = 0.046). The model's predictive probability of stroke when the six biomarkers are above/below these cut-off levels was 99.01%. The best combination of biomarkers in the model was caspase-3 and d-dimer. Moreover, a model developed for samples obtained within the first 3 h showed high sensitivity (Se) and specificity (Sp) (threshold at 25th percentile: Se 0.87, Sp 0.55; threshold at 75th percentile: Se 0.28, Sp 0.99). CONCLUSIONS: A combination of biomarkers including caspase-3 and d-dimer appears to be the most promising to achieve a rapid biochemical diagnosis of stroke. If replicated, this approach could be used as a tool for urgent referral of stroke patients to hospitals in which acute treatments are available.

Leukoaraiosis is associated with genes regulating blood-brain barrier homeostasis in ischaemic stroke patients.

BACKGROUND: The biologic agents causing leukoaraiosis are unknown. Our aim was to study the genetic basis of leukoaraiosis. METHODS: We analyzed 212 single nucleotide polymorphisms (SNPs) in 142 patients with ischaemic stroke, generating a total of 30,104 genotypes. Seventy-nine subjects (55.6%) presented leukoaraiosis measured by the Fazekas scale and 69 (48.6%) by ARWMC scale. We analyzed the presence of synergic associations between SNPs using the hfcc software. Finally, functional studies were performed in 56 subjects. The Ingenuity Pathways software (ipa) was used to examine the role of the identified genes. RESULTS: Six SNPs were associated with leukoaraiosis using both measuring scales. After logistic regression adjusted for leukoaraiosis risk factors, the rs2252070 of MMP13 (OR = 4.9, 95%CI: 1.34-17.9, P = 0.016), rs662 of PON1 (OR = 0.37, 95%CI: 0.15-0.87, P = 0.024) and rs1800779 of NOS3 (OR = 3.9, 95%CI: 1.38-11.38, P = 0.01) were independently associated with leukoaraiosis under a dominant/recessive model and the rs2290608 of IL5RA (OR = 0.46, 95%CI: 0.25-0.85, P = 0.013) and rs669 of A2M (OR = 2.5, 95%CI: 1.36-4.83, P = 0.004) under an additive model. Computational analysis showed a synergic association of rs10497212-AA of ITGB6 and rs2290608-GG of IL5RA with leukoaraiosis using both scales. (i) ARWMC (P = 1.3 × 10(-4) ) and (ii) Fazekas (P = 4.5 × 10(-5) ). Functional studies showed that the rs669 SNP was associated with plasma levels of A2M (P = 0.012) and A2M levels with leukoaraiosis in Fazekas scale (P = 0.02). ipa analysis revealed that the genes associated with leukoaraiosis were involved in blood-brain barrier (BBB) homeostasis. CONCLUSIONS: Amongst patients with ischaemic stroke, several genes associated with BBB homeostasis could be involved with a higher risk of leukoaraiosis.

Recommendations guide for experimental animal models in stroke research.

INTRODUCTION: The progress of effective therapies for stroke has become a challenging task for both researchers and clinicians. Some pitfalls in clinical trials might have their origins in the pre-clinical experimental ischaemic models for the evaluation of potential neuro-protective agents. METHODS: We aim to standardise the methods for the development of stroke animal models throughout Spain, to produce document with appropriate recommendations and best practice in order to improve experimental methods in the field of stroke research. RESULTS: Members of several experienced stroke research groups prepared a guide with recommendations in the application of focal cerebral ischaemic models. The main features of this guide are based on the selection of the most appropriate animal model, taking in account the objective of the study, the species, strain, age, sex of animals, as well as risk factors. The experimental design must include a sham control group and the sample size calculation. Animal randomisation and blind analysis, masked assessment of outcomes, monitoring of body temperature and cerebral blood flow, and the reporting of reasons for excluding animals from the study, as well as the mortality rate, are other main points to fulfil in the application of stroke models. CONCLUSIONS: Standardised methods are essential to increase the success of the pre-clinical findings in the stroke neuroprotection field to be able to translate to the clinical practice.

Learning curves for endobronchial ultrasound using cusum analysis.

BACKGROUND: The assessment of medical trainees is becoming an increasingly prominent issue, with current methods having varying degrees of inherent subjectivity and bias. Cusum analysis is a technique used in quality control systems, and is starting to be employed in medical training. Endobronchial ultrasound (EBUS) is an established tool in the diagnosis and staging of lung cancer, although its use in the UK is currently restricted. As it becomes more widespread, there will be a need to assess trainees' competence accurately to ensure that those performing EBUS at new centres are appropriately skilled. METHODS: A retrospective review of clinical practice in tertiary referral centres in England, Scotland and Spain was carried out. The study group comprised 500 patients undergoing EBUS for the diagnosis and staging of lung cancer as part of a clinical service. Using cusum analysis, the first 100 cases from each of the five centres are presented. Each centre has one consultant physician as the primary EBUS operator, and all operators began using EBUS at their current centre (ie, no learning from prior experience). The data are presented as learning curves. RESULTS: It is evident that there is a wide range of time over which EBUS-guided transbronchial needle aspiration (TBNA) competence is attained. The pooled sensitivity was 67.4% (individual sensitivities 66.7, 70.7, 61.2, 80.3 and 59.7%). CONCLUSION: Cusum analysis is well suited to the assessment of procedures with a binary outcome, but accurate and appropriate standards of practice must be determined prior to assessment to ensure correct identification of underperformance. This report suggests that the learning curve for EBUS is greater than previously reported using different methods, and that even experienced bronchoscopists vary in their speed of learning.

Indicators of anxiety and depression in women with the fragile X premutation: assessment of a clinical sample.

BACKGROUND: Current research suggests that depression and anxiety may be common problems in women with the fragile X (FMR1) premutation. METHODS: To learn more about this in a clinical setting, we asked 33 women with the FMR1 premutation and 20 women without the FMR1 premutation to complete the Brief Carroll Depression Scale (Brief CDS) and the Multidimensional Anxiety Questionnaire (MAQ) and to provide information about mental health medication use. Questionnaire findings were compared between groups and with normative samples. Trinucleotide (CGG) repeat counts were also correlated to checklist findings. RESULTS: Both women with the FMR1 premutation and the comparison group had high current mental health medication use (33% vs. 35%). Approximately 1/3 of the women from both groups had high Brief CDS Total T-scores (33% vs. 30%). More women with the FMR1 premutation had at least one elevated MAQ Total or sub-scale T-score than the comparison group (39% vs. 10%, P = 0.03). Twenty-one per cent of women with the FMR1 premutation had all three of the indicators of distress targeted in this study vs. none of the women in the comparison samples (P < 0.05). There was no statistically significant correlation between CGG repeat size and abnormal checklist findings using the Spearman rank correlation, although a higher percentage of women with >100 CGG repeats (57%) had an elevated Brief CDS Total T-score than women with 100 CGG repeats also had all three indicators of anxiety and depression (P = 0.03). CONCLUSIONS: Women with the FMR1 premutation appear to have a high incidence of depression and increased symptoms of anxiety. Screening tools like the Brief CDS and the MAQ may be useful to identify these women in the clinic setting. Positive identification could lead to increased mental health care and treatment.

PAI-1 4G/5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients.

BACKGROUND: Despite t-PA proven benefits related to vessel reopening, up to 13% of stroke patients suffer reocclusions after t-PA. We aimed to analyze whether a functional polymorphism in a fibrinolysis inhibitor gene [plasminogen activator inhibitor-1 (PAI-1)] might be associated with reocclusion rates after stroke thrombolytic therapy. METHODS: 165 patients with ischemic stroke who received t-PA < 3 h were studied. Reocclusion and recanalization was diagnosed by transcranial Doppler. PAI-1 4G/5G polymorphism determination was performed by sequencing. PAI-1 mRNA was studied by real-time PCR analysis. National institutes of health stroke scale (NIHSS) was serially measured since patients arrival to assess the neurological outcome, and modified ranking scale (mRS) at 3rd month was used to evaluate functional outcome following stroke. RESULTS: PAI-1 4G/4G patients had higher reocclusion rates (4G/4G = 12.5% versus other genotypes = 2.7%, p = 0.025). . In a logistic regression, the 4G/4G genotype was the only factor associated with reocclusion (OR = 15.16 95%, CI = 1.4-163.4, p = 0.025). 4G/4G genotype was also associated with poor functional outcome at 3rd month (4G/4G = 4 versus others genotypes = 3, p = 0.017) and with mRNA levels at 12 h post stroke symptoms onset (4G/4G patients = 2.01% versus other genotypes = 0.68%, p = 0.034). CONCLUSIONS: PAI-1 4G/4G genotype is associated with reocclusion rates and poor functional outcome among stroke patients treated with t-PA.