Can a novel web-based computer test predict poor simulated driving performance? A pilot study with healthy and cognitive-impaired participants

BACKGROUND Driving a car is a complex instrumental activity of daily living and driving performance is very sensitive to cognitive impairment. The assessment of driving-relevant cognition in older drivers is challenging and requires reliable and valid tests with good sensitivity and specificity to predict safe driving. Driving simulators can be used to test fitness to drive. Several studies have found strong correlation between driving simulator performance and on-the-road driving. However, access to driving simulators is restricted to specialists and simulators are too expensive, large, and complex to allow easy access to older drivers or physicians advising them. An easily accessible, Web-based, cognitive screening test could offer a solution to this problem. The World Wide Web allows easy dissemination of the test software and implementation of the scoring algorithm on a central server, allowing generation of a dynamically growing database with normative values and ensures that all users have access to the same up-to-date normative values. OBJECTIVE In this pilot study, we present the novel Web-based Bern Cognitive Screening Test (wBCST) and investigate whether it can predict poor simulated driving performance in healthy and cognitive-impaired participants. METHODS The wBCST performance and simulated driving performance have been analyzed in 26 healthy younger and 44 healthy older participants as well as in 10 older participants with cognitive impairment. Correlations between the two tests were calculated. Also, simulated driving performance was used to group the participants into good performers (n=70) and poor performers (n=10). A receiver-operating characteristic analysis was calculated to determine sensitivity and specificity of the wBCST in predicting simulated driving performance. RESULTS The mean wBCST score of the participants with poor simulated driving performance was reduced by 52%, compared to participants with good simulated driving performance (P<.001). The area under the receiver-operating characteristic curve was 0.80 with a 95% confidence interval 0.68-0.92. CONCLUSIONS When selecting a 75% test score as the cutoff, the novel test has 83% sensitivity, 70% specificity, and 81% efficiency, which are good values for a screening test. Overall, in this pilot study, the novel Web-based computer test appears to be a promising tool for supporting clinicians in fitness-to-drive assessments of older drivers. The Web-based distribution and scoring on a central computer will facilitate further evaluation of the novel test setup. We expect that in the near future, Web-based computer tests will become a valid and reliable tool for clinicians, for example, when assessing fitness to drive in older drivers.

Bias associated with detrital zircon geochronology and thermochronometry

Detrital studies that utilize zircon U–Pb geochronology and fission-track (FT) thermochronometry are subject to a range of potential sources of bias that should be properly evaluated and minimized. Some of them are common to any single-grain mineral analysis (e.g., variable bedrock mineral fertility, hydraulic sorting during transport, selective grain loss during sample processing), whereas others are intrinsic to zircon, and are related to radiation damage and age discordance. In this article, we quantify the impact of intrinsic bias on detrital studies thanks to the analysis of modern detritus shed from the European Alps, and illustrate the general implications on geological interpretations. We show that detrital zircon U–Pb age distributions based on statistically robust datasets are highly reproducible and representative of the parent bedrock ages in the catchment. Arbitrary or selective removal of discordant grain ages can be minimized by using the Kolmogorov–Smirnov test to identify an appropriate cutoff level. Loss of metamict (α-damaged) zircon has a minor impact on data representativeness, and is mainly controlled by regional metamorphism rather than by mechanical abrasion during river transport. Zircon FT grain-age distributions were found to have poor reproducibility, although age spectra are consistent with bedrock data. However, unlike the U–Pb datasets, U-rich zircon grains (> 1000 ppm) are systematically missed, and undatable grains may exceed 50%. We identify two major sources of distribution bias specific to zircon FT datasets: (i) sediment sources dominated by U-rich zircon grains are markedly underrepresented in the detrital record, because such grains often have uncountable high densities of fission tracks (“U concentration bias”); (ii) sediment sources that shed zircon grains with high levels of α-damage are underrepresented, because these grains are lost during chemical etching for FT revelation (“etching bias”). In the case of multimethod dating on the same grains (e.g., FT and U–Pb double dating), bias affecting detrital zircon FT dating propagates to the entire dataset. These effects may not impact on exhumation-rate studies that utilize the youngest grain ages (i.e., lag-time approach). However, they represent a limiting factor for conventional provenance studies, and generally preclude application of zircon FT dating to sediment budget calculations.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

Predictive value of cerebrospinal fluid (CSF) lactate level versus CSF/blood glucose ratio for the diagnosis of bacterial meningitis following neurosurgery.

The value of cerebrospinal fluid (CSF) lactate level and CSF/blood glucose ratio for the identification of bacterial meningitis following neurosurgery was assessed in a retrospective study. During a 3-year period, 73 patients fulfilled the inclusion criteria and could be grouped by preset criteria in one of three categories: proven bacterial meningitis (n = 12), presumed bacterial meningitis (n = 14), and nonbacterial meningeal syndrome (n = 47). Of 73 patients analyzed, 45% were treated with antibiotics and 33% with steroids at the time of first lumbar puncture. CSF lactate values (cutoff, 4 mmol/L), in comparison with CSF/blood glucose ratios (cutoff, 0.4), were associated with higher sensitivity (0.88 vs. 0.77), specificity (0.98 vs. 0.87), and positive (0.96 vs. 0.77) and negative (0.94 vs. 0.87) predictive values. In conclusion, determination of the CSF lactate value is a quick, sensitive, and specific test to identify patients with bacterial meningitis after neurosurgery.

Regorafenib as second-line therapy for intermediate or advanced hepatocellular carcinoma: Multicentre, open-label, phase II safety study

PURPOSE: We assessed the safety of the multikinase inhibitor regorafenib in patients with hepatocellular carcinoma (HCC) that had progressed following first-line sorafenib. PATIENTS AND METHODS: Thirty-six patients with Barcelona Clinic Liver Cancer stage B or C HCC and preserved to mildly impaired liver function (Child-Pugh class A) received regorafenib 160 mg once daily in cycles of 3 weeks on/1 week off treatment until disease progression, unacceptable toxicity, death or patient/physician decision to discontinue. The primary end-point was safety; secondary end-points included efficacy (including time to progression and overall survival). RESULTS: The median treatment duration was 19.5 weeks (range 2-103). At data cutoff, three patients remained on treatment. Reasons for discontinuation were adverse events (n=20), disease progression (n=10), consent withdrawal (n=2) and death (n=1). Seventeen patients required dose reductions (mostly for adverse events [n=15]); 35 patients had treatment interruption (mostly for adverse events [n=32] or patient error [n=11]). The most frequent treatment-related adverse events were hand-foot skin reaction (any grade n=19; grade ≥3 n=5), diarrhoea (n=19; n=2), fatigue (n=19; n=6), hypothyroidism (n=15; n=0), anorexia (n=13; n=0), hypertension (n=13; n=1), nausea (n=12; n=0) and voice changes (n=10; n=0). Disease control was achieved in 26 patients (partial response n=1; stable disease n=25). Median time to progression was 4.3 months. Median overall survival was 13.8 months. CONCLUSION: Regorafenib had acceptable tolerability and evidence of antitumour activity in patients with intermediate or advanced HCC that progressed following first-line sorafenib.

Search for Extra Dimensions in diphoton events using proton-proton collisions recorded at sqrts=7 TeV with the ATLAS detector at the LHC

The large difference between the Planck scale and the electroweak scale, known as the hierarchy problem, is addressed in certain models through the postulate of extra spatial dimensions. A search for evidence of extra spatial dimensions in the diphoton channel has been performed using the full set of proton-proton collisions at root s = 7 TeV recorded in 2011 with the ATLAS detector at the CERN Large Hadron Collider. This dataset corresponds to an integrated luminosity of 4.9 fb(-1). The diphoton invariant mass spectrum is observed to be in good agreement with the Standard Model expectation. In the context of the model proposed by Arkani-Hamed, Dimopoulos and Dvali, 95% confidence level lower limits of between 2.52 and 3.92 TeV are set on the ultraviolet cutoff scale MS depending on the number of extra dimensions and the theoretical formalism used. In the context of the Randall-Sundrum model, a lower limit of 2.06 (1.00) TeV at 95% confidence level is set on the mass of the lightest graviton for couplings of k/(M) over bar (Pl) = 0.1(0.01). Combining with the ATLAS dilepton searches based on the 2011 data, the 95% confidence level lower limit on the Randall-Sundrum graviton mass is further tightened to 2.23 (1.03) TeV for k/(M) over bar (Pl) = 0.1(0.01).

A novel clinical scoring system for outcome prediction in dogs with acute kidney injury managed by hemodialysis.

BACKGROUND No reliable tool to predict outcome of acute kidney injury (AKI) exists. HYPOTHESIS A statistically derived scoring system can accurately predict outcome in dogs with AKI managed with hemodialysis. ANIMALS One hundred and eighty-two client-owned dogs with AKI. METHODS Logistic regression analyses were performed initially on clinical variables available on the 1st day of hospitalization for relevance to outcome. Variables with P< or = .1 were considered for further analyses. Continuous variables outside the reference range were divided into quartiles to yield quartile-specific odds ratios (ORs) for survival. Models were developed by incorporating weighting factors assigned to each quartile based on the OR, using either the integer value of the OR (Model A) or the exact OR (Models B or C, when the etiology was known). A predictive score for each model was calculated for each dog by summing all weighting factors. In Model D, actual values for continuous variables were used in a logistic regression model. Receiver-operating curve analyses were performed to assess sensitivities, specificities, and optimal cutoff points for all models. RESULTS Higher scores were associated with decreased probability of survival (P < .001). Models A, B, C, and D correctly classified outcomes in 81, 83, 87, and 76% of cases, respectively, and optimal sensitivities/specificities were 77/85, 81/85, 83/90 and 92/61%, respectively. CONCLUSIONS AND CLINICAL RELEVANCE The models allowed outcome prediction that corresponded with actual outcome in our cohort. However, each model should be validated further in independent cohorts. The models may also be useful to assess AKI severity.

Relationship of individual scapular anatomy and degenerative rotator cuff tears.

BACKGROUND The etiology of rotator cuff disease is age related, as documented by prevalence data. Despite conflicting results, growing evidence suggests that distinct scapular morphologies may accelerate the underlying degenerative process. The purpose of the present study was to evaluate the predictive power of 5 commonly used radiologic parameters of scapular morphology to discriminate between patients with intact rotator cuff tendons and those with torn rotator cuff tendons. METHODS A pre hoc power analysis was performed to determine the sample size. Two independent readers measured the acromion index, lateral acromion angle, and critical shoulder angle on standardized anteroposterior radiographs. In addition, the acromial morphology according to Bigliani and the acromial slope were determined on true outlet views. Measurements were performed in 51 consecutive patients with documented degenerative rotator cuff tears and in an age- and sex-matched control group of 51 patients with intact rotator cuff tendons. Receiver operating characteristic analyses were performed to determine cutoff values and to assess the sensitivity and specificity of each parameter. RESULTS Patients with degenerative rotator cuff tears demonstrated significantly higher acromion indices, smaller lateral acromion angles, and larger critical shoulder angles than patients with intact rotator cuffs. However, no difference was found between the acromial morphology according to Bigliani and the acromial slope. With an area under the receiver operating characteristic curve of 0.855 and an odds ratio of 10.8, the critical shoulder angle represented the strongest predictor for the presence of a rotator cuff tear. CONCLUSION The acromion index, lateral acromion angle, and critical shoulder angle accurately predict the presence of degenerative rotator cuff tears.

Immediate versus deferred chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder (EORTC 30994): an intergroup, open-label, randomised phase 3 trial

BACKGROUND Patients with muscle-invasive urothelial carcinoma of the bladder have poor survival after cystectomy. The EORTC 30994 trial aimed to compare immediate versus deferred cisplatin-based combination chemotherapy after radical cystectomy in patients with pT3-pT4 or N+ M0 urothelial carcinoma of the bladder. METHODS This intergroup, open-label, randomised, phase 3 trial recruited patients from hospitals across Europe and Canada. Eligible patients had histologically proven urothelial carcinoma of the bladder, pT3-pT4 disease or node positive (pN1-3) M0 disease after radical cystectomy and bilateral lymphadenectomy, with no evidence of any microscopic residual disease. Within 90 days of cystectomy, patients were centrally randomly assigned (1:1) by minimisation to either immediate adjuvant chemotherapy (four cycles of gemcitabine plus cisplatin, high-dose methotrexate, vinblastine, doxorubicin, and cisplatin [high-dose MVAC], or MVAC) or six cycles of deferred chemotherapy at relapse, with stratification for institution, pT category, and lymph node status according to the number of nodes dissected. Neither patients nor investigators were masked. Overall survival was the primary endpoint; all analyses were by intention to treat. The trial was closed after recruitment of 284 of the planned 660 patients. This trial is registered with ClinicalTrials.gov, number NCT00028756. FINDINGS From April 29, 2002, to Aug 14, 2008, 284 patients were randomly assigned (141 to immediate treatment and 143 to deferred treatment), and followed up until the data cutoff of Aug 21, 2013. After a median follow-up of 7·0 years (IQR 5·2-8·7), 66 (47%) of 141 patients in the immediate treatment group had died compared with 82 (57%) of 143 in the deferred treatment group. No significant improvement in overall survival was noted with immediate treatment when compared with deferred treatment (adjusted HR 0·78, 95% CI 0·56-1·08; p=0·13). Immediate treatment significantly prolonged progression-free survival compared with deferred treatment (HR 0·54, 95% CI 0·4-0·73, p<0·0001), with 5-year progression-free survival of 47·6% (95% CI 38·8-55·9) in the immediate treatment group and 31·8% (24·2-39·6) in the deferred treatment group. Grade 3-4 myelosuppression was reported in 33 (26%) of 128 patients who received treatment in the immediate chemotherapy group versus 24 (35%) of 68 patients who received treatment in the deferred chemotherapy group, neutropenia occurred in 49 (38%) versus 36 (53%) patients, respectively, and thrombocytopenia in 36 (28%) versus 26 (38%). Two patients died due to toxicity, one in each group. INTERPRETATION Our data did not show a significant improvement in overall survival with immediate versus deferred chemotherapy after radical cystectomy and bilateral lymphadenectomy for patients with muscle-invasive urothelial carcinoma. However, the trial is limited in power, and it is possible that some subgroups of patients might still benefit from immediate chemotherapy. An updated individual patient data meta-analysis and biomarker research are needed to further elucidate the potential for survival benefit in subgroups of patients. FUNDING Lilly, Canadian Cancer Society Research.

Velocity of early BCR-ABL transcript elimination as an optimized predictor of outcome in chronic myeloid leukemia (CML) patients in chronic phase on treatment with imatinib

UNLABELLED Early assessment of response at 3 months of tyrosine kinase inhibitor treatment has become an important tool to predict favorable outcome. We sought to investigate the impact of relative changes of BCR-ABL transcript levels within the initial 3 months of therapy. In order to achieve accurate data for high BCR-ABL levels at diagnosis, beta glucuronidase (GUS) was used as a reference gene. Within the German CML-Study IV, samples of 408 imatinib-treated patients were available in a single laboratory for both times, diagnosis and 3 months on treatment. In total, 301 of these were treatment-naïve at sample collection. RESULTS (i) with regard to absolute transcript levels at diagnosis, no predictive cutoff could be identified; (ii) at 3 months, an individual reduction of BCR-ABL transcripts to the 0.35-fold of baseline level (0.46-log reduction, that is, roughly half-log) separated best (high risk: 16% of patients, 5-year overall survival (OS) 83% vs 98%, hazard ratio (HR) 6.3, P=0.001); (iii) at 3 months, a 6% BCR-ABL(IS) cutoff derived from BCR-ABL/GUS yielded a good and sensitive discrimination (high risk: 22% of patients, 5-year OS 85% vs 98%, HR 6.1, P=0.002). Patients at risk of disease progression can be identified precisely by the lack of a half-log reduction of BCR-ABL transcripts at 3 months.

Retrocrural space involvement on computed tomography as a predictor of mortality and disease severity in acute pancreatitis

BACKGROUND Because computed tomography (CT) has advantages for visualizing the manifestation of necrosis and local complications, a series of scoring systems based on CT manifestations have been developed for assessing the clinical outcomes of acute pancreatitis (AP), including the CT severity index (CTSI), modified CTSI, etc. Despite the internationally accepted CTSI having been successfully used to predict the overall mortality and disease severity of AP, recent literature has revealed the limitations of the CTSI. Using the Delphi method, we establish a new scoring system based on retrocrural space involvement (RCSI), and compared its effectiveness at evaluating the mortality and severity of AP with that of the CTSI. METHODS We reviewed CT images of 257 patients with AP taken within 3-5 days of admission in 2012. The RCSI scoring system, which includes assessment of infectious conditions involving the retrocrural space and the adjacent pleural cavity, was established using the Delphi method. Two radiologists independently assessed the RCSI and CTSI scores. The predictive points of the RCSI and CTSI scoring systems in evaluating the mortality and severity of AP were estimated using receiver operating characteristic (ROC) curves. PRINCIPAL FINDINGS The RCSI score can accurately predict the mortality and disease severity. The area under the ROC curve for the RCSI versus CTSI score was 0.962±0.011 versus 0.900±0.021 for predicting the mortality, and 0.888±0.025 versus 0.904±0.020 for predicting the severity of AP. Applying ROC analysis to our data showed that a RCSI score of 4 was the best cutoff value, above which mortality could be identified. CONCLUSION The Delphi method was innovatively adopted to establish a scoring system to predict the clinical outcome of AP. The RCSI scoring system can predict the mortality of AP better than the CTSI system, and the severity of AP equally as well.

Tumor budding in colorectal cancer revisited: results of a multicenter interobserver study.

Tumor budding in colorectal cancer (CRC) is recognized as a valuable prognostic factor but its translation into daily histopathology practice has been delayed by lack of agreement on the optimal method of assessment. Within the context of the Swiss Association of Gastrointestinal Pathology (SAGIP), we performed a multicenter interobserver study on tumor budding, comparing hematoxylin and eosin (H&E) with pan-cytokeratin staining using a 10 high power field (10HPF) and hotspot (1HPF) method. Two serial sections of 50 TNM stage II-IV surgically treated CRC were stained for H&E and pan-cytokeratin. Tumor buds were scored by independent observers at six participating centers in Switzerland and Austria using the 10HPF and 1HPF method on a digital pathology platform. Pearson correlation (r) and intra-class correlation coefficients (ICC) comparing scores between centers were calculated. Three to four times more tumor buds were detected in pan-cytokeratin compared to H&E slides. Correlation coefficients for tumor budding counts between centers ranged from r = 0.46 to r = 0.91 for H&E and from r = 0.73 to r = 0.95 for pan-cytokeratin slides. Interobserver agreement across all centers was excellent for pan-cytokeratin [10HPF: ICC = 0.83 and 1HPF: ICC = 0.8]. In contrast, assessment of tumor budding on H&E slides reached only moderate agreement [10HPF: ICC = 0.58 and 1HPF: ICC = 0.49]. Based on previous literature and our findings, we recommend (1) pan-cytokeratin staining whenever possible, (2) 10HPF method for resection specimens, and (3) 1HPF method for limited material (preoperative biopsy or pT1). Since tumor budding counts can be used to determine probabilities of relevant outcomes and as such more optimally complement clinical decision making, we advocate the avoidance of cutoff scores.

Tall cell papillary thyroid carcinoma: new diagnostic criteria and mutations in BRAF and TERT

The tall cell (TC) variant of papillary thyroid carcinoma (PTC) has an unfavorable prognosis. The diagnostic criteria remain inconsistent, and the role of a minor TC component is unclear. Molecular diagnostic markers are not available; however, there are two potential candidates: BRAF V600E and telomerase reverse transcriptase (TERT) promoter mutations. Using a novel approach, we enriched a collective with PTCs that harbored an adverse outcome, which overcame the limited statistical power of most studies. This enabled us to review 125 PTC patients, 57 of which had an adverse outcome. The proportion of TCs that constituted a poor prognosis was assessed. All of the tumors underwent sequencing for TERT promoter and BRAF V600E mutational status and were stained with an antibody to detect the BRAF V600E mutation. A 10% cutoff for TCs was significantly associated with advanced tumor stage and lymph node metastasis. Multivariate analysis showed that TCs above 10% were the only significant factor for overall, tumor-specific, and relapse-free survival. Seven percent of the cases had a TERT promoter mutation, whereas 61% demonstrated a BRAF mutation. The presence of TC was significantly associated with TERT promoter and BRAF mutations. TERT predicted highly significant tumor relapse (P<0.001). PTCs comprised of at least 10% TCs are associated with an adverse clinical outcome and should be reported accordingly. BRAF did not influence patient outcome. Nevertheless, a positive status should encourage the search for TCs. TERT promoter mutations are a strong predictor of tumor relapse, but their role as a surrogate marker for TCs is limited.

Quantification of Mitral Regurgitation with Multiple Jets: In Vitro Comparison of Two-dimensional PISA techniques

Purpose: Traditionally, the proximal isovelocity surface area (PISA) is based on the assumption of a single hemisphere (hemispheric PISA), but this technique has not been validated for the quantification of mitral regurgitation (MR) with multiple jets. Methods: The left heart simulator was actuated by a pulsatile pump at various stroke amplitudes. The regurgitant volume (Rvol) passing through the mitral valve phantoms with single and double regurgitant orifices of varying size and interspace was quantified by a flowmeter as reference technique. Color Doppler 3-D full-volumes were obtained, and Rvol were derived from 2-D PISA surfaces on the basis of hemispheric and hemicylindric assumption with one base (partial hemicylindric PISA) or 2 bases (total hemicylindric PISA). Results: 72 regurgitant volumes (Rvol range: 8 to 76 ml/beat) were obtained. Hemispheric PISA Rvol correlated well with reference Rvol by one orifice (R²=0.97; bias -2.7±3.2ml), but less by ≥ one orifice (R²=0.89). When a fusion of two PISAs occured, addition of two hemispheric PISA overestimated Rvol (bias 9.1±12.2ml, fig.1), and single hemispheric PISA underestimated Rvol (bias -12.4±4.9ml). If an integrated approach was used (hemispheric in single orifice, total hemicylindric in two non-fused PISAs and partial hemicylindric in two fused PISAs), the correlation was R²=0.95, bias -1.6±5.6ml (fig.2). In the ROC analysis, the cutoff to detect ≥ moderate-to-severe Rvol (≥45ml) was 42ml (AUC 0.99, sens. 100%, spec. 93%). Conclusions: In MR with two regurgitant jets, the 2-D hemicylindric assumption of the PISA offers a better quantification of Rvol than the hemispheric assumption. Quantification of MR using 2-D PISA requires an integrated approach that considers number of regurgitant orifices and fusion of the PISAs.

Toxicity of eosinophil MBP is repressed by intracellular crystallization and promoted by extracellular aggregation.

Eosinophils are white blood cells that function in innate immunity and participate in the pathogenesis of various inflammatory and neoplastic disorders. Their secretory granules contain four cytotoxic proteins, including the eosinophil major basic protein (MBP-1). How MBP-1 toxicity is controlled within the eosinophil itself and activated upon extracellular release is unknown. Here we show how intragranular MBP-1 nanocrystals restrain toxicity, enabling its safe storage, and characterize them with an X-ray-free electron laser. Following eosinophil activation, MBP-1 toxicity is triggered by granule acidification, followed by extracellular aggregation, which mediates the damage to pathogens and host cells. Larger non-toxic amyloid plaques are also present in tissues of eosinophilic patients in a feedback mechanism that likely limits tissue damage under pathological conditions of MBP-1 oversecretion. Our results suggest that MBP-1 aggregation is important for innate immunity and immunopathology mediated by eosinophils and clarify how its polymorphic self-association pathways regulate toxicity intra- and extracellularly.