The prothrombin time/international normalized ratio (PT/INR) Line: derivation of local INR with commercial thromboplastins and coagulometers--two independent studies

The WHO scheme for prothrombin time (PT) standardization has been limited in application, because of its difficulties in implementation, particularly the need for mandatory manual PT testing and for local provision of thromboplastin international reference preparations (IRP).

Genomic analysis of non-splenic marginal zone lymphomas (MZL) indicates similarities between nodal and extranodal MZL and supports their derivation from memory B-cells

Three distinct categories of marginal zone lymphomas (MZLs) are currently recognized, principally based on their site of occurrence. They are thought to represent unique entities, but the relationship of one subtype with another is poorly understood. We investigated 17 non-splenic MZLs (seven nodal, 10 extranodal) by gene expression profiling to distinguish between subtypes and determine their cell of origin. Our findings suggest biological inter-relatedness of these entities despite occurrence at different locations and associations with possibly different aetiologies. Furthermore, the expression profiles of non-splenic MZL were similar to memory B cells.

Minimal assumption derivation of a weak Clauser-Horne inequality

According to Bell's theorem a large class of hidden-variable models obeying Bell's notion of local causality (LC) conflict with the predictions of quantum mechanics. Recently, a Bell-type theorem has been proven using a weaker notion of LC, yet assuming the existence of perfectly correlated event types. Here we present a similar Bell-type theorem without this latter assumption. The derived inequality differs from the Clauser-Horne inequality by some small correction terms, which render it less constraining.

Potentially avoidable 30-day hospital readmissions in medical patients: derivation and validation of a prediction model

IMPORTANCE Because effective interventions to reduce hospital readmissions are often expensive to implement, a score to predict potentially avoidable readmissions may help target the patients most likely to benefit. OBJECTIVE To derive and internally validate a prediction model for potentially avoidable 30-day hospital readmissions in medical patients using administrative and clinical data readily available prior to discharge. DESIGN Retrospective cohort study. SETTING Academic medical center in Boston, Massachusetts. PARTICIPANTS All patient discharges from any medical services between July 1, 2009, and June 30, 2010. MAIN OUTCOME MEASURES Potentially avoidable 30-day readmissions to 3 hospitals of the Partners HealthCare network were identified using a validated computerized algorithm based on administrative data (SQLape). A simple score was developed using multivariable logistic regression, with two-thirds of the sample randomly selected as the derivation cohort and one-third as the validation cohort. RESULTS Among 10 731 eligible discharges, 2398 discharges (22.3%) were followed by a 30-day readmission, of which 879 (8.5% of all discharges) were identified as potentially avoidable. The prediction score identified 7 independent factors, referred to as the HOSPITAL score: h emoglobin at discharge, discharge from an o ncology service, s odium level at discharge, p rocedure during the index admission, i ndex t ype of admission, number of a dmissions during the last 12 months, and l ength of stay. In the validation set, 26.7% of the patients were classified as high risk, with an estimated potentially avoidable readmission risk of 18.0% (observed, 18.2%). The HOSPITAL score had fair discriminatory power (C statistic, 0.71) and had good calibration. CONCLUSIONS AND RELEVANCE This simple prediction model identifies before discharge the risk of potentially avoidable 30-day readmission in medical patients. This score has potential to easily identify patients who may need more intensive transitional care interventions.

Rosette-forming glioneuronal tumor of the cerebellum in statu nascendi: an incidentally detected diminutive example indicates derivation from the internal granule cell layer

Rosette-forming glioneuronal tumor (RGNT) is a recently introduced, indolent neoplasm composed of diminutive circular aggregates of neurocytic-like cells on a noninfiltrative astrocytic background, typically located in the cerebellar midline The traded concept of RGNT being derived from site-specific periventricular precursors may be questioned in the face of extracerebellar examples as well as ones occurring in combination with other representatives of the glioneuronal family. We describe a hitherto not documented example of asymptomatic RGNT discovered during autopsy of a 74-year-old male. Located in the tuberal vermis, this lesion of 6 mm diameter consisted of several microscopic nests of what were felt to represent nascent stages of RGNT, all of them centered on the internal granular layer, and ranging from mucoid dehiscences thereof to fully evolved - if small - tumor foci. Molecular genetic analysis revealed a missense mutation in Exon 20 of the PIK3CA gene involving an A→G transition at Nucleotide 3140. On the other hand, neither codeletion of chromosomes 1p/19q nor pathogenic mutations of IDH1/2 were detected. By analogy with in situ paradigms in other organs, we propose that this tumor is likely to have arisen from the internal granular layer, rather than the plate of the 4th ventricle. A suggestive departure from the wholesale argument of "undifferentiated precursors", this finding also indirectly indicates that a subset of non-classical RGNTs - in particular extracerebellar examples, whose origin cannot be mechanistically accounted for by either of the above structures - may possibly reflect an instance of phenotypic convergence, rather than a lineage-restricted entity.

Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism.

RATIONALE Not all patients with acute pulmonary embolism (PE) have a high risk of an adverse short-term outcome. OBJECTIVES This prospective cohort study aimed to develop a multimarker prognostic model that accurately classifies normotensive patients with PE into low and high categories of risk of adverse medical outcomes. METHODS The study enrolled 848 outpatients from the PROTECT (PROgnosTic valuE of Computed Tomography) study (derivation cohort) and 529 patients from the Prognostic Factors for Pulmonary Embolism (PREP) study (validation cohort). Investigators assessed study participants for a 30-day complicated course, defined as death from any cause, hemodynamic collapse, and/or adjudicated recurrent PE. MEASUREMENTS AND MAIN RESULTS A complicated course occurred in 63 (7.4%) of the 848 normotensive patients with acute symptomatic PE in the derivation cohort and in 24 patients (4.5%) in the validation cohort. The final model included the simplified Pulmonary Embolism Severity Index, cardiac troponin I, brain natriuretic peptide, and lower limb ultrasound testing. The model performed similarly in the derivation (c-index of 0.75) and validation (c-index of 0.85) cohorts. The combination of the simplified Pulmonary Embolism Severity Index and brain natriuretic peptide testing showed a negative predictive value for a complicated course of 99.1 and 100% in the derivation and validation cohorts, respectively. The combination of all modalities had a positive predictive value for the prediction of a complicated course of 25.8% in the derivation cohort and 21.2% in the validation cohort. CONCLUSIONS For normotensive patients who have acute PE, we derived and validated a multimarker model that predicts all-cause mortality, hemodynamic collapse, and/or recurrent PE within the following 30 days.

Ventilation-perfusion ratio in perflubron during partial liquid ventilation

BACKGROUND: Functional magnetic resonance imaging (fMRI) of fluorine-19 allows for the mapping of oxygen partial pressure within perfluorocarbons in the alveolar space (Pao(2)). Theoretically, fMRI-detected Pao(2) can be combined with the Fick principle approach, i.e., a mass balance of oxygen uptake by ventilation and delivery by perfusion, to quantify the ventilation-perfusion ratio (Va/Q) of a lung region: The mixed venous blood and the inspiratory oxygen fraction, which are equal for all lung regions, are measured. In addition, the local expiratory oxygen fraction and the end capillary oxygen content, both of which may differ between the lung regions, are calculated using the fMRI-detected Pao(2). We investigated this approach by numerical simulations and applied it to quantify local Va/Q in the perfluorocarbons during partial liquid ventilation. METHODS: Numerical simulations were performed to analyze the sensitivity of the Va/Q calculation and to compare this approach with another one proposed by Rizi et al. in 2004 (Magn Reson Med 2004;52:65-72). Experimentally, the method was used during partial liquid ventilation in 7 anesthetized pigs. The Pao(2) distribution in intraalveolar perflubron was measured by fluorine-19 MRI. Respiratory gas fractions together with arterial and mixed venous blood samples were taken to quantify oxygen partial pressure and content. Using the Fick principle, the local Va/Q was estimated. The impact of gravity (nondependent versus dependent) of perflubron dose (10 vs 20 mL/kg body weight) and of inspired oxygen fraction (Fio(2)) (0.4-1.0) on Va/Q was examined. RESULTS: In numerical simulations, the Fick principle proved to be appropriate over the Va/Q range from 0.02 to 2.5. Va/Q values were in acceptable agreement with the method published by Rizi et al. In the experimental setting, low mean Va/Q values were found in perflubron (confidence interval [CI] 0.08-0.29 with 20 mL/kg perflubron). At this dose, Va/Q in the nondependent lung was higher (CI 0.18-0.39) than in the dependent lung regions (CI 0.06-0.16; P = 0.006; Student t test). Differences depending on Fio(2) or perflubron dose were, however, small. CONCLUSION: The results show that derivation of Va/Q from local Po(2) measurements using fMRI in perflubron is feasible. The low detected Va/Q suggests that oxygen transport into the perflubron-filled alveolar space is significantly restrained.

Measurements of Humidity in the Atmosphere and Validation Experiments MOHAVE-2009; overview of campaign operations and results

The Measurements of Humidity in the Atmosphere and Validation Experiment (MOHAVE) 2009 campaign took place on 11–27 October 2009 at the JPL Table Mountain Facility in California (TMF). The main objectives of the campaign were to (1) validate the water vapor measurements of several instruments, including, three Raman lidars, two microwave radiometers, two Fourier-Transform spectrometers, and two GPS receivers (column water), (2) cover water vapor measurements from the ground to the mesopause without gaps, and (3) study upper tropospheric humidity variability at timescales varying from a few minutes to several days. A total of 58 radiosondes and 20 Frost-Point hygrometer sondes were launched. Two types of radiosondes were used during the campaign. Non negligible differences in the readings between the two radiosonde types used (Vaisala RS92 and InterMet iMet-1) made a small, but measurable impact on the derivation of water vapor mixing ratio by the Frost-Point hygrometers. As observed in previous campaigns, the RS92 humidity measurements remained within 5% of the Frost-point in the lower and mid-troposphere, but were too dry in the upper troposphere. Over 270 h of water vapor measurements from three Raman lidars (JPL and GSFC) were compared to RS92, CFH, and NOAA-FPH. The JPL lidar profiles reached 20 km when integrated all night, and 15 km when integrated for 1 h. Excellent agreement between this lidar and the frost-point hygrometers was found throughout the measurement range, with only a 3% (0.3 ppmv) mean wet bias for the lidar in the upper troposphere and lower stratosphere (UTLS). The other two lidars provided satisfactory results in the lower and mid-troposphere (2–5% wet bias over the range 3–10 km), but suffered from contamination by fluorescence (wet bias ranging from 5 to 50% between 10 km and 15 km), preventing their use as an independent measurement in the UTLS. The comparison between all available stratospheric sounders allowed to identify only the largest biases, in particular a 10% dry bias of the Water Vapor Millimeter-wave Spectrometer compared to the Aura-Microwave Limb Sounder. No other large, or at least statistically significant, biases could be observed. Total Precipitable Water (TPW) measurements from six different co-located instruments were available. Several retrieval groups provided their own TPW retrievals, resulting in the comparison of 10 different datasets. Agreement within 7% (0.7 mm) was found between all datasets. Such good agreement illustrates the maturity of these measurements and raises confidence levels for their use as an alternate or complementary source of calibration for the Raman lidars. Tropospheric and stratospheric ozone and temperature measurements were also available during the campaign. The water vapor and ozone lidar measurements, together with the advected potential vorticity results from the high-resolution transport model MIMOSA, allowed the identification and study of a deep stratospheric intrusion over TMF. These observations demonstrated the lidar strong potential for future long-term monitoring of water vapor in the UTLS.

Genuine cross-correlations: Which surrogate based measure reproduces analytical results best?

The analysis of short segments of noise-contaminated, multivariate real world data constitutes a challenge. In this paper we compare several techniques of analysis, which are supposed to correctly extract the amount of genuine cross-correlations from a multivariate data set. In order to test for the quality of their performance we derive time series from a linear test model, which allows the analytical derivation of genuine correlations. We compare the numerical estimates of the four measures with the analytical results for different correlation pattern. In the bivariate case all but one measure performs similarly well. However, in the multivariate case measures based on the eigenvalues of the equal-time cross-correlation matrix do not extract exclusively information about the amount of genuine correlations, but they rather reflect the spatial organization of the correlation pattern. This may lead to failures when interpreting the numerical results as illustrated by an application to three electroencephalographic recordings of three patients suffering from pharmacoresistent epilepsy.

Alteration of host cell phenotype by Theileria annulata and Theileria parva: mining for manipulators in the parasite genomes

The apicomplexan parasites Theileria annulata and Theileria parva cause severe lymphoproliferative disorders in cattle. Disease pathogenesis is linked to the ability of the parasite to transform the infected host cell (leukocyte) and induce uncontrolled proliferation. It is known that transformation involves parasite dependent perturbation of leukocyte signal transduction pathways that regulate apoptosis, division and gene expression, and there is evidence for the translocation of Theileria DNA binding proteins to the host cell nucleus. However, the parasite factors responsible for the inhibition of host cell apoptosis, or induction of host cell proliferation are unknown. The recent derivation of the complete genome sequence for both T. annulata and T. parva has provided a wealth of information that can be searched to identify molecules with the potential to subvert host cell regulatory pathways. This review summarizes current knowledge of the mechanisms used by Theileria parasites to transform the host cell, and highlights recent work that has mined the Theileria genomes to identify candidate manipulators of host cell phenotype.

Surplus embryos in Switzerland in 2003: legislation and availability of human embryos for research

Legislation influences the availability of embryos for research. The law in Switzerland, and in some other European countries, is restrictive concerning medically assisted reproduction and stem cell research. Swiss law prohibits the creation of embryos for research purposes. It permits the derivation of human embryonic stem cells for research from surplus embryos but prohibits research with intact surplus embryos and embryo donation to other couples. Swiss law defines all embryos generated during a reproductive cycle and not used for reproduction as surplus embryos. The aim of this study was to evaluate the surplus embryos generated in Switzerland in 2003. A detailed questionnaire was sent to all registered IVF units in Switzerland (n = 22). 11727 embryos were generated during 2003. Of these, 93.5% were transferred into the uterus and 0.4% were cryopreserved. The remaining 6.1% (n = 711) became surplus. Of these, 2.7% were transferred intravaginally and the rest discarded due to poor quality (1.6%), development arrest (1.5%), renunciation by the couple (0.2%) or for other reasons (0.1%). The number of surplus embryos in Switzerland in 2003 was evaluated. Most surplus embryos became so during a therapeutic cycle. The restrictive legal regulation decreases the availability of human embryos for research.

Geriatric Pain Measure short form: development and initial evaluation

OBJECTIVES: To develop and evaluate a short form of the 24-item Geriatric Pain Measure (GPM) for use in community-dwelling older adults. DESIGN: Derivation and validation of a 12-item version of the GPM in a European and an independent U.S. sample of community-dwelling older adults. SETTING: Three community-dwelling sites in London, United Kingdom; Hamburg, Germany; Solothurn, Switzerland; and two ambulatory geriatrics clinics in Los Angeles, California. PARTICIPANTS: European sample: 1,059 community-dwelling older persons from three sites (London, UK; Hamburg, Germany; Solothurn, Switzerland); validation sample: 50 persons from Los Angeles, California, ambulatory geriatric clinics. MEASUREMENTS: Multidimensional questionnaire including self-reported demographic and clinical information. RESULTS: Based on item-to-total scale correlations in the European sample, 11 of 24 GPM items were selected for inclusion in the short form. One additional item (pain-related sleep problems) was included based on clinical relevance. In the validation sample, the Cronbach alpha of GPM-12 was 0.92 (individual subscale range 0.77-0.92), and the Pearson correlation coefficient (r) between GPM-12 and the original GPM was 0.98. The correlation between the GPM-12 and the McGill Pain Questionnaire was 0.63 (P<.001), similar to the correlation between the original GPM and the McGill Pain Questionnaire (Pearson r=0.63; P<.001). Exploratory factor analysis indicated that the GPM-12 covers three subfactors (pain intensity, pain with ambulation, disengagement because of pain). CONCLUSION: The GPM-12 demonstrated good validity and reliability in these European and U.S. populations of older adults. Despite its brevity, the GPM-12 captures the multidimensional nature of pain in three subscales. The self-administered GPM-12 may be useful in the clinical assessment process and management of pain and in pain-related research in older persons.

Risk prediction of fever in neutropenia in children with cancer: a step towards individually tailored supportive therapy?

BACKGROUND: Fever in severe chemotherapy-induced neutropenia (FN) is the most frequent manifestation of a potentially lethal complication of current intensive chemotherapy regimens. This study aimed at establishing models predicting the risk of FN, and of FN with bacteremia, in pediatric cancer patients. METHODS: In a single-centre cohort study, characteristics potentially associated with FN and episodes of FN were retrospectively extracted from charts. Poisson regression accounting for chemotherapy exposure time was used for analysis. Prediction models were constructed based on a derivation set of two thirds of observations, and validated based on the remaining third of observations. RESULTS: In 360 pediatric cancer patients diagnosed and treated for a cumulative chemotherapy exposure time of 424 years, 629 FN were recorded (1.48 FN per patient per year, 95% confidence interval (CI), 1.37-1.61), 145 of them with bacteremia (23% of FN; 0.34; 0.29-0.40). More intensive chemotherapy, shorter time since diagnosis, bone marrow involvement, central venous access device (CVAD), and prior FN were significantly and independently associated with a higher risk to develop both FN and FN with bacteremia. The prediction models explained more than 30% of the respective risks. CONCLUSIONS: The two models predicting FN and FN with bacteremia were based on five easily accessible clinical variables. Before clinical application, they need to be validated by prospective studies.

Visual and spectral analysis of sleep EEG in acute hemispheric stroke

BACKGROUND: Reports on the effects of focal hemispheric damage on sleep EEG are rare and contradictory. PATIENTS AND METHODS: Twenty patients (mean age +/- SD 53 +/- 14 years) with a first acute hemispheric stroke and no sleep apnea were studied. Stroke severity [National Institute of Health Stroke Scale (NIHSS)], volume (diffusion-weighted brain MRI), and short-term outcome (Rankin score) were assessed. Within the first 8 days after stroke onset, 1-3 sleep EEG recordings per patient were performed. Sleep scoring and spectral analysis were based on the central derivation of the healthy hemisphere. Data were compared with those of 10 age-matched and gender-matched hospitalized controls with no brain damage and no sleep apnea. RESULTS: Stroke patients had higher amounts of wakefulness after sleep onset (112 +/- 53 min vs. 60 +/- 38 min, p < 0.05) and a lower sleep efficiency (76 +/- 10% vs. 86 +/- 8%, p < 0.05) than controls. Time spent in slow-wave sleep (SWS) and rapid eye movement (REM) sleep and total sleep time were lower in stroke patients, but differences were not significant. A positive correlation was found between the amount of SWS and stroke volume (r = 0.79). The slow-wave activity (SWA) ratio NREM sleep/wakefulness was lower in patients than in controls (p < 0.05), and correlated with NIHSS (r = -0.47). CONCLUSION: Acute hemispheric stroke is accompanied by alterations of sleep EEG over the healthy hemisphere that correlate with stroke volume and outcome. The increased SWA during wakefulness and SWS over the healthy hemisphere contralaterally to large strokes may reflect neuronal hypometabolism induced transhemispherically (diaschisis).