Optimization of a customized simultaneous algebraic reconstruction technique algorithm for phase-contrast breast computed tomography.

Objective.To introduce the optimization of a customized GPU-based simultaneous algebraic reconstruction technique (cSART) in the field of phase-contrast breast computed tomography (bCT). The presented algorithm features a 3D bilateral regularization filter that can be tuned to yield optimal performance for clinical image visualization and tissues segmentation.Approach.Acquisitions of a dedicated test object and a breast specimen were performed at Elettra, the Italian synchrotron radiation (SR) facility (Trieste, Italy) using a large area CdTe single-photon counting detector. Tomographic images were obtained at 5 mGy of mean glandular dose, with a 32 keV monochromatic x-ray beam in the free-space propagation mode. Three independent algorithms parameters were optimized by using contrast-to-noise ratio (CNR), spatial resolution, and noise texture metrics. The results obtained with the cSART algorithm were compared with conventional SART and filtered back projection (FBP) reconstructions. Image segmentation was performed both with gray scale-based and supervised machine-learning approaches.Main results.Compared to conventional FBP reconstructions, results indicate that the proposed algorithm can yield images with a higher CNR (by 35% or more), retaining a high spatial resolution while preserving their textural properties. Alternatively, at the cost of an increased image 'patchiness', the cSART can be tuned to achieve a high-quality tissue segmentation, suggesting the possibility of performing an accurate glandularity estimation potentially of use in the realization of realistic 3D breast models starting from low radiation dose images.Significance.The study indicates that dedicated iterative reconstruction techniques could provide significant advantages in phase-contrast bCT imaging. The proposed algorithm offers great flexibility in terms of image reconstruction optimization, either toward diagnostic evaluation or image segmentation.

Expansion of immature, nucleated red blood cells by transient low-dose methotrexate immune tolerance induction in mice.

Biological treatments such as enzyme-replacement therapies (ERT) can generate anti-drug antibodies (ADA), which may reduce drug efficacy and impact patient safety and consequently led to research to mitigate ADA responses. Transient low-dose methotrexate (TLD-MTX) as a prophylactic ITI regimen, when administered concurrently with ERT, induces long-lived reduction of ADA to recombinant human alglucosidase alfa (rhGAA) in mice. In current clinical practice, a prophylactic ITI protocol that includes TLD-MTX, rituximab and intravenous immunoglobulin (optional), successfully induced lasting control of ADA to rhGAA in high-risk, cross-reactive immunological material (CRIM)-negative infantile-onset Pompe disease (IOPD) patients. More recently, evaluation of TLD-MTX demonstrated benefit in CRIM-positive IOPD patients. To more clearly understand the mechanism for the effectiveness of TLD-MTX, non-targeted transcriptional and proteomic screens were conducted and revealed up-regulation of erythropoiesis signatures. Confirmatory studies showed transiently larger spleens by weight, increased spleen cellularity and that following an initial reduction of mature red blood cells (RBCs) in the bone marrow and blood, a significant expansion of Ter-119+ CD71+ immature RBCs was observed in spleen and blood of mice. Histology sections revealed increased nucleated cells, including hematopoietic precursors, in the splenic red pulp of these mice. This study demonstrated that TLD-MTX induced a transient reduction of mature RBCs in the blood and immature RBCs in the bone marrow followed by significant enrichment of immature, nucleated RBCs in the spleen and blood during the time of immune tolerance induction, which suggested modulation of erythropoiesis may be associated with the induction of immune tolerance to rhGAA.

Residentes de familia en estado de alarma / General practitioners residents at emergency state

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Diagnóstico del delirium en pediatría: una tarea ardua pero imprescindible / The diagnosis of delirium in pediatric intensive care: A burdensome yet essential task

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Evaluation of the intra- and inter-method agreement of brain MRI segmentation software packages: A comparison between SPM12 and FreeSurfer v6.0.

PURPOSE: The lack of inter-method agreement can produce inconsistent results in neuroimaging studies. We evaluated the intra-method repeatability and the inter-method reproducibility of two widely-used automatic segmentation methods for brain MRI: the FreeSurfer (FS) and the Statistical Parametric Mapping (SPM) software packages. METHODS: We segmented the gray matter (GM), the white matter (WM) and subcortical structures in test-retest MRI data of healthy volunteers from Kirby-21 and OASIS datasets. We used Pearson's correlation (r), Bland-Altman plot and Dice index to study intra-method repeatability and inter-method reproducibility. In order to test whether different processing methods affect the results of a neuroimaging-based group study, we carried out a statistical comparison between male and female volume measures. RESULTS: A high correlation was found between test-retest volume measures for both SPM (r in the 0.98-0.99 range) and FS (r in the 0.95-0.99 range). A non-null bias between test-retest FS volumes was detected for GM and WM in the OASIS dataset. The inter-method reproducibility analysis measured volume correlation values in the 0.72-0.98 range and the overlap between the segmented structures assessed by the Dice index was in the 0.76-0.83 range. SPM systematically provided significantly greater GM volumes and lower WM and subcortical volumes with respect to FS. In the male vs. female brain volume comparisons, inconsistencies arose for the OASIS dataset, where the gender-related differences appear subtler with respect to the Kirby dataset. CONCLUSIONS: The inter-method reproducibility should be evaluated before interpreting the results of neuroimaging studies.

New TRAP1 and Hsp90 chaperone inhibitors with cationic components: Preliminary studies on mitochondrial targeting.

TRAP1 (Hsp75) is the mitochondrial paralog of the Hsp90 molecular chaperone family. Due to structural similarity among Hsp90 chaperones, a potential strategy to induce apoptosis through mitochondrial TRAP1 ATPase inhibition has been envisaged and a series of compounds has been developed by binding the simple pharmacophoric core of known Hsp90 inhibitors with various appendages bearing a permanent cationic head, or a basic group highly ionizable at physiologic pH. Cationic appendages were selected as vehicles to deliver drugs to mitochondria. Indeed, masses of new derivatives were evidenced to accumulate in the mitochondrial fraction from colon carcinoma cells and a compound in the series, with a guanidine appendage, demonstrated good activity in inhibiting recombinant TRAP1 ATPase and cell growth and in inducing apoptotic cell death in colon carcinoma cells.

Alpha galactosidase A activity in Parkinson's disease.

Glucocerebrosidase (GCase, deficient in Gaucher disease) enzymatic activity measured in dried blood spots of Parkinson's Disease (PD) cases is within healthy range but reduced compared to controls. It is not known whether activities of additional lysosomal enzymes are reduced in dried blood spots in PD. To test whether reduction in lysosomal enzymatic activity in PD is specific to GCase, we measured GCase, acid sphingomyelinase (deficient in Niemann-Pick disease types A and B), alpha galactosidase A (deficient in Fabry), acid alpha-glucosidase (deficient in Pompe) and galactosylceramidase (deficient in Krabbe) enzymatic activities in dried blood spots of PD patients (n = 648) and controls (n = 317) recruited from Columbia University. Full sequencing of glucocerebrosidase (GBA) and the LRRK2 G2019S mutation was performed. Enzymatic activities were compared between PD cases and controls using t-test and regression models adjusted for age, gender, and GBA and LRRK2 G2019S mutation status. Alpha galactosidase A activity was lower in PD cases compared to controls both when only non-carriers were included (excluding all GBA and LRRK2 G2019S carriers and PD cases with age-at-onset below 40) [2.85 µmol/l/h versus 3.12 µmol/l/h, p = 0.018; after controlling for batch effect, p = 0.006 (468 PD cases and 296 controls)], and when including the entire cohort (2.89 µmol/l/h versus 3.10 µmol/l/h, p = 0.040; after controlling for batch effect, p = 0.011). Because the alpha galactosidase A gene is X-linked, we stratified the analyses by sex. Among women who were non-carriers of GBA and LRRK2 G2019S mutations (PD, n = 155; control, n = 194), alpha galactosidase A activity was lower in PD compared to controls (2.77 µmol/l/h versus 3.10 µmol/l/h, p = 0.044; after controlling for a batch effect, p = 0.001). The enzymatic activity of acid sphingomyelinase, acid alpha-glucosidase and galactosylceramidase was not significantly different between PD and controls. In non-carriers, most lysosomal enzyme activities were correlated, with the strongest association in GCase, acid alpha-glucosidase, and alpha galactosidase A (Pearson correlation coefficient between 0.382 and 0.532). In a regression model with all five enzymes among non-carriers (adjusted for sex and age), higher alpha galactosidase A activity was associated with lower odds of PD status (OR = 0.54; 95% CI:0.31-0.95; p = 0.032). When LRRK2 G2019S PD carriers (n = 37) were compared to non-carriers with PD, carriers had higher GCase, acid sphingomyelinase and alpha galactosidase A activity. We conclude that alpha galactosidase A may have a potential independent role in PD, in addition to GCase.

Incidence and risk factors of superficial and deep vein thrombosis associated with peripherally inserted central catheters in children.

Essentials Pediatric studies on peripherally inserted central catheter (PICC)-related thrombosis are scarce. This study analyzes incidence and risk factors for PICC-related venous thrombosis in children. PICC-related thrombosis is a common, and nearly always, asymptomatic complication. Echo-guided insertion and a catheter to vein ratio < 0.33 may notably decrease this complication. SUMMARY: Background Upper-extremity venous thrombosis is associated with the use of peripherally inserted central catheters (PICCs). Few pediatric studies have focused on this issue. Objectives To determine the incidence and risk factors for PICC-related superficial vein thrombosis (SVT) and deep vein thrombosis (DVT) in children. Patients/methods An observational follow-up cohort study was conducted at a single hospital between June 2012 and June 2015. All patients receiving a PICC were enrolled and followed up, with weekly Doppler ultrasound examination of the catheterized limb until PICC removal. Patient, procedural and follow-up data were analyzed. Results In the study period, 265 PICCs were inserted (median age of patients 6.5 years, interquartile range [IQR] 2.4-13 years; median weight 20 kg, IQR 11-38 kg; 54% males; 67.9% chronically ill), and patients were followed up for a total of 9743 days. The median indwelling time was 21 days (IQR 12-37 days). During follow-up, 88 (33.2% of insertions) PICC-related thromboses (incidence rate [IR] 9.03 per 1000 catheter-days) were diagnosed, 66 (24.9%) as isolated SVT, seven (2.6%) as isolated DVT, and 15 (5.7%) as SVT with associated DVT (IR 6.78, 0.71 and 1.54 per 1000 catheter-days, respectively). Only 9.9% of patients with SVT and 18.2% of those with DVT were symptomatic. The main risk factors for PICC-related SVT and DVT were a catheter/vein ratio of > 0.33 and thrombosis of the catheterized superficial vein, respectively. Conclusions PICC-related thrombosis is a common and nearly always asymptomatic complication in children, the SVT rate being approximately three times higher than the DVT rate. Optimal vein and catheter selection, yielding the lowest possible catheter/vein ratio, may decrease the rate of PICC-related thrombosis.

Imaging performance of phase-contrast breast computed tomography with synchrotron radiation and a CdTe photon-counting detector.

PURPOSE: Within the SYRMA-CT collaboration based at the ELETTRA synchrotron radiation (SR) facility the authors investigated the imaging performance of the phase-contrast computed tomography (CT) system dedicated to monochromatic in vivo 3D imaging of the female breast, for breast cancer diagnosis. METHODS: Test objects were imaged at 38keV using monochromatic SR and a high-resolution CdTe photon-counting detector. Signal and noise performance were evaluated using modulation transfer function (MTF) and noise power spectrum. The analysis was performed on the images obtained with the application of a phase retrieval algorithm as well as on those obtained without phase retrieval. The contrast to noise ratio (CNR) and the capability of detecting test microcalcification clusters and soft masses were investigated. RESULTS: For a voxel size of (60µm)(3), images without phase retrieval showed higher spatial resolution (6.7mm(-1) at 10% MTF) than corresponding images with phase retrieval (2.5mm(-1)). Phase retrieval produced a reduction of the noise level and an increase of the CNR by more than one order of magnitude, compared to raw phase-contrast images. Microcalcifications with a diameter down to 130µm could be detected in both types of images. CONCLUSIONS: The investigation on test objects indicates that breast CT with a monochromatic SR source is technically feasible in terms of spatial resolution, image noise and contrast, for in vivo 3D imaging with a dose comparable to that of two-view mammography. Images obtained with the phase retrieval algorithm showed the best performance in the trade-off between spatial resolution and image noise.

Towards breast tomography with synchrotron radiation at Elettra: first images.

The aim of the SYRMA-CT collaboration is to set-up the first clinical trial of phase-contrast breast CT with synchrotron radiation (SR). In order to combine high image quality and low delivered dose a number of innovative elements are merged: a CdTe single photon counting detector, state-of-the-art CT reconstruction and phase retrieval algorithms. To facilitate an accurate exam optimization, a Monte Carlo model was developed for dose calculation using GEANT4. In this study, high isotropic spatial resolution (120 µm)(3) CT scans of objects with dimensions and attenuation similar to a human breast were acquired, delivering mean glandular doses in the range of those delivered in clinical breast CT (5-25 mGy). Due to the spatial coherence of the SR beam and the long distance between sample and detector, the images contain, not only absorption, but also phase information from the samples. The application of a phase-retrieval procedure increases the contrast-to-noise ratio of the tomographic images, while the contrast remains almost constant. After applying the simultaneous algebraic reconstruction technique to low-dose phase-retrieved data sets (about 5 mGy) with a reduced number of projections, the spatial resolution was found to be equal to filtered back projection utilizing a four fold higher dose, while the contrast-to-noise ratio was reduced by 30%. These first results indicate the feasibility of clinical breast CT with SR.

Opportunities to improve antimicrobial use in paediatric intensive care units: a nationwide survey in Spain.

Improving antimicrobial use is a complex process that requires an accurate assessment of ongoing problems and barriers. Paediatric intensive care units (PICU) have seldom been assessed from this perspective. Two Internet-based, self-administered surveys were conducted nationwide in Spain between January and February 2014. The first survey aimed to assess those characteristics of Spanish PICUs that could influence antimicrobial prescribing or antimicrobial stewardship. The second survey targeted Spanish PICU physicians and pursued to assess their attitudes and perceptions regarding antimicrobial resistance and antimicrobial use. Information about 29/39 contacted PICUs was obtained. A total of 114/206 (55.3%) paediatric intensivists responded. PICUs were heterogeneous regarding years since foundation, number of beds, type of patients admitted and staffing. Only 11 (37.9%) PICUs had available e-prescribing systems. Procalcitonin was available in 24 (89.1%) PICUs, but there were no procalcitonin-based protocols in 14 (60.9%) of them. Half of surveyed PICUs had implemented antimicrobial stewardship activities. Ninety-eight of the 114 PICU physicians (86%) who participated considered that antimicrobial resistance was a significantly relevant problem for their daily and that improving antimicrobial use in their PICU should be a priority (103; 90.4%). The main perceived problems regarding antimicrobial use were the excessive use of antimicrobials in patients with nonconfirmed infections and excessive use of broad-spectrum antimicrobials. The most valued antimicrobial stewardship interventions were the implementation of protocols to guide antimicrobial therapy. Spanish PICU doctors are aware of the relevance of the problem of antimicrobial resistance and the need to improve antimicrobial use. Targeted interventions should take into account their difficulties and preferences when feasible.

Cisplatin plus paclitaxel and maintenance of bevacizumab on tumour progression, dissemination, and survival of ovarian carcinoma xenograft models.

BACKGROUND: Bevacizumab is being incorporated as first-line therapy with standard-of-care chemotherapy on epithelial ovarian carcinoma (EOC). We investigated bevacizumab combined with chemotherapy on tumour progression and mouse survival in EOC xenograft models. METHODS: Bevacizumab was administered concomitantly with cisplatin plus paclitaxel (DDP+PTX), continued after induction (maintenance) or started after chemotherapy. The effect on tumour progression was monitored by bioluminescence imaging (BLI) (1A9-luc xenograft). Tumour dissemination into the peritoneal organs and ascites formation (HOC22 xenograft) was evaluated by histological analysis at the end of treatment (interim) and at euthanasia (survival). The effects on overall survival (OS) were investigated in both EOC models. RESULTS: Bevacizumab with PTX+DDP delayed tumour progression in mice bearing EOC xenografts. OS was significantly extended, with complete responses, by bevacizumab continued after stopping chemotherapy in the HOC22 xenograft. Bevacizumab alone inhibited ascites formation, with only limited effect on tumour burden, but combined with PTX+DDP reduced ascites and metastases. Bevacizumab started after induction with PTX+DDP and maintained was equally effective on tumour progression and survival on 1A9-luc xenograft. CONCLUSION: Bevacizumab combined with chemotherapy not only affected tumour progression, but when administered as maintenance regimen significantly prolonged survival, reducing ascites, and tumour dissemination. We believe our findings are consistent with the clinical results and shed light on the potential effects of this kind of treatment on tumour progression.

Nuevas estrategias de monitorización hemodinámica con el monitor PiCCO / New strategies of hemodynamic monitoring using the PiCCO monitor

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Relevance of biofilms in pediatric tonsillar disease.

In this investigation, we study the relation between chronic inflammation of the tonsils, clinical features, and the presence of biofilms in the crypts in patients presenting with obstructive hypertrophy and recurrent upper airway pathology. Thirty-six patients who needed to undergo a tonsillectomy for obstructive reasons (aged 1 to 6 years), among which none of them had taken any antibiotics 30 days prior to surgery, were included. Samples were examined with hematoxylin-eosin and Gram staining, fluorescent microscopy, and confocal laser microscopy. The predominance of symptoms were those related to obstructive pathology rather than infection (p < 0.01). All patients had tonsillar hypertrophy (grade III or IV), but an association with adenoids hypertrophy was detected in 66.66% of cases (p < 0.05). 77.28% of tonsils presented biofilms in their crypts, but hypertrophy and tonsillar follicle number were not related to the presence or absence of biofilms. Here, we demonstrated that symptoms like harsh raucous sound, tonsillar and adenoids hypertrophy, apnea, and cervical adenopathies are clearly related to the presence of biofilm in tonsils. Our results allow us to propose that biofilms are involved in the pathogenesis of tonsils and adenoids hypertrophy. The prevention of biofilms formation should be focused in the early stages, attempting to restrain bacterial attachment to the respiratory mucosa.

Quantitative phase retrieval with picosecond X-ray pulses from the ATF Inverse Compton Scattering source.

Quantitative phase retrieval is experimentally demonstrated using the Inverse Compton Scattering X-ray source available at the Accelerator Test Facility (ATF) in the Brookhaven National Laboratory. Phase-contrast images are collected using in-line geometry, with a single X-ray pulse of approximate duration of one picosecond. The projected thickness of homogeneous samples of various polymers is recovered quantitatively from the time-averaged intensity of transmitted X-rays. The data are in good agreement with the expectations showing that ATF Inverse Compton Scattering source is suitable for performing phase-sensitive quantitative X-ray imaging on the picosecond scale. The method shows promise for quantitative imaging of fast dynamic phenomena.

¿Qué hay de nuevo en el tratamiento del SDRA? / What is new in the treatment of ARDS?

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Insuficiencia respiratoria aguda en el niño / Acute respiratory failure in the child

La insuficiencia respiratoria, hipoxia con o sin hipercapnia, es un síndrome frecuente en niños. Su diagnóstico y tratamiento es más sencillo cuando se conoce la fisiopatología. Los procesos implicados en la oxigenación tisular y en la eliminación de dióxido de carbono son la ventilación, la perfusión y la difusión. Alteraciones en cualquiera de estos procesos pueden desencadenar insuficiencia respiratoria. Las manifestaciones clínicas de la insuficiencia respiratoria son muy variadas y la morbi-mortalidad en niños ha disminuido con el desarrollo de nuevas técnicas ventiladoras, tratamientos farmacológicos adyuvantes y ECMO (AU)

Respiratory failure, hypoxia with or without hipercapnia, is common in infants and children. The knowledge of the underlying abnormal physiology facilitates the diagnosis and therapy. A variety of processes including ventilation, perfusion and diffusion are involved in tissue oxygenation and carbon dioxide removal. Abnormalities in any of these mechanisms can lead to respiratory failure. The spectrum of clinical findings I highly variable. Efforts to decrease morbidity and mortality have fuelled investigations into innovative methods of ventilation, ventilation techniques, pharmacotherapeutic adjuncts and extracorporeal life support modalities (AU)