Quality of referrals for lower extremity ultrasonography and computed tomography pulmonary angiography and associations with positive findings of venous thromboembolism.

INTRODUCTION: The referral is the basis for radiologists' assessment of modality, protocol and urgency, and insufficient information may threaten patient safety. The aim of this study was to assess the completeness of referrals for lower extremity venous duplex ultrasonography (LEVDUS) and computed tomography pulmonary angiography (CTPA), and to investigate associations between the provided clinical information including risk factors, symptoms and lab results in the referrals and positive findings of deep vein thrombosis (DVT) and pulmonary embolism (PE), respectively. METHODS: Referrals for LEVDUS (801) and CTPA (800) performed from 2016 to 2019 were obtained. Three categories of clinical information from the referrals were recorded: symptoms, risk factors and laboratory results, as well as positive imaging findings of venous thromboembolism (VTE). Referral completeness was rated from zero to three according to how many categories of clinical information the referral provided. RESULTS: Information from all three clinical information categories was provided in 15% and 25% of referrals for LEVDUS and CTPA, respectively, while 2% and 10% of referrals did not contain any clinical information. Symptoms were provided most often (85% for LEVDUS and 94% for CTPA). Provided information about risk factors was significantly associated with positive findings for LEVDUS, (p = 0.02) and CTPA (p < 0.001). CONCLUSION: A great majority of referrals failed to provide one or more categories of clinical information. Risk factors were associated with a positive finding of VTE on LEVDUS and CTPA. IMPLICATIONS FOR PRACTICE: Improving clinical information in referrals may improve justification, patient safety and quality of radiology services.

Study of the N=32 and N=34 Shell Gap for Ti and V by the First High-Precision Multireflection Time-of-Flight Mass Measurements at BigRIPS-SLOWRI.

The atomic masses of ^{55}Sc, ^{56,58}Ti, and ^{56-59}V have been determined using the high-precision multireflection time-of-flight technique. The radioisotopes have been produced at RIKEN's Radioactive Isotope Beam Factory (RIBF) and delivered to the novel designed gas cell and multireflection system, which has been recently commissioned downstream of the ZeroDegree spectrometer following the BigRIPS separator. For ^{56,58}Ti and ^{56-59}V, the mass uncertainties have been reduced down to the order of 10 keV, shedding new light on the N=34 shell effect in Ti and V isotopes by the first high-precision mass measurements of the critical species ^{58}Ti and ^{59}V. With the new precision achieved, we reveal the nonexistence of the N=34 empirical two-neutron shell gaps for Ti and V, and the enhanced energy gap above the occupied νp_{3/2} orbit is identified as a feature unique to Ca. We perform new Monte Carlo shell model calculations including the νd_{5/2} and νg_{9/2} orbits and compare the results with conventional shell model calculations, which exclude the νg_{9/2} and the νd_{5/2} orbits. The comparison indicates that the shell gap reduction in Ti is related to a partial occupation of the higher orbitals for the outer two valence neutrons at N=34.

MiniBioReactor Array (MBRA) in vitro gut model: a reliable system to study microbiota-dependent response to antibiotic treatment.

Background: Antimicrobial drugs are mostly studied for their impact on emergence of bacterial antibiotic resistance, but their impact on the gut microbiota is also of tremendous interest. In vitro gut models are important tools to study such complex drug-microbiota interactions in humans. Methods: The MiniBioReactor Array (MBRA) in vitro microbiota system; a single-stage continuous flow culture model, hosted in an anaerobic chamber; was used to evaluate the impact of three concentrations of a third-generation cephalosporin (ceftriaxone) on faecal microbiota from two healthy donors (treatment versus control: three replicates per condition). We conducted 16S microbiome profiling and analysed microbial richness, diversity and taxonomic changes. ß-Lactamase activities were evaluated and correlated with the effects observed in the MBRA in vitro system. Results: The MBRA preserved each donor's specificities, and differences between the donors were maintained through time. Before treatment, all faecal cultures belonging to the same donor were comparable in composition, richness, and diversity. Treatment with ceftriaxone was associated with a decrease in α-diversity, and an increase in ß-diversity index, in a concentration-dependent manner. The maximum effect on diversity was observed after 72 h of treatment. Importantly, one donor had a stronger microbiota ß-lactamase activity that was associated with a reduced impact of ceftriaxone on microbiota composition. Conclusions: MBRA can reliably mimic the intestinal microbiota and its modifications under antibiotic selective pressure. The impact of the treatment was donor- and concentration-dependent. We hypothesize these results could be explained, at least in part, by the differences in ß-lactamase activity of the microbiota itself. Our results support the relevance and promise of the MBRA system to study drug-microbiota interactions.

First Application of Mass Measurements with the Rare-RI Ring Reveals the Solar r-Process Abundance Trend at A=122 and A=123.

The Rare-RI Ring (R3) is a recently commissioned cyclotronlike storage ring mass spectrometer dedicated to mass measurements of exotic nuclei far from stability at Radioactive Isotope Beam Factory (RIBF) in RIKEN. The first application of mass measurement using the R3 mass spectrometer at RIBF is reported. Rare isotopes produced at RIBF-^{127}Sn, ^{126}In, ^{125}Cd, ^{124}Ag, ^{123}Pd-were injected in R3. Masses of ^{126}In, ^{125}Cd, and ^{123}Pd were measured whereby the mass uncertainty of ^{123}Pd was improved. This is the first reported measurement with a new storage ring mass spectrometry technique realized at a heavy-ion cyclotron and employing individual injection of the preidentified rare nuclei. The latter is essential for the future mass measurements of the rarest isotopes produced at RIBF. The impact of the new ^{123}Pd result on the solar r-process abundances in a neutron star merger event is investigated by performing reaction network calculations of 20 trajectories with varying electron fraction Y_{e}. It is found that the neutron capture cross section on ^{123}Pd increases by a factor of 2.2 and ß-delayed neutron emission probability, P_{1 n}, of ^{123}Rh increases by 14%. The neutron capture cross section on ^{122}Pd decreases by a factor of 2.6 leading to pileup of material at A=122, thus reproducing the trend of the solar r-process abundances. The trend of the two-neutron separation energies (S_{2n}) was investigated for the Pd isotopic chain. The new mass measurement with improved uncertainty excludes large changes of the S_{2n} value at N=77. Such large increase of the S_{2n} values before N=82 was proposed as an alternative to the quenching of the N=82 shell gap to reproduce r-process abundances in the mass region of A=112-124.

Deciphering the immune microenvironment of a tissue by digital imaging and cognition network.

Evidence has highlighted the importance of immune cells in various gut disorders. Both the quantification and localization of these cells are essential to the understanding of the complex mechanisms implicated in these pathologies. Even if quantification can be assessed (e.g., by flow cytometry), simultaneous cell localization and quantification of whole tissues remains technically challenging. Here, we describe the use of a computer learning-based algorithm created in the Tissue Studio interface that allows for a semi-automated, robust and rapid quantitative analysis of immunofluorescence staining on whole colon sections according to their distribution in different tissue areas. Indeed, this algorithm was validated to characterize gut immune microenvironment. Its application to the preclinical colon cancer APCMin/+ mouse model is illustrated by the simultaneous counting of total leucocytes and T cell subpopulations, in the colonic mucosa, lymphoid follicles and tumors. Moreover, we quantify T cells in lymphoid follicles for which quantification is not possible with classical methods. Thus, this algorithm is a new and robust preclinical research tool, for investigating immune contexture exemplified by T cells but it is also applicable to other immune cells such as other myeloid and lymphoid populations or other cellular phenomenon along mouse gut.

Plumbing neutron stars to new depths with the binding energy of the exotic nuclide 82Zn.

Modeling the composition of neutron-star crusts depends strongly on binding energies of neutron-rich nuclides near the N = 50 and N = 82 shell closures. Using a recent development of time-of-flight mass spectrometry for on-line purification of radioactive ion beams to access more exotic species, we have determined for the first time the mass of (82)Zn with the ISOLTRAP setup at the ISOLDE-CERN facility. With a robust neutron-star model based on nuclear energy-density-functional theory, we solve the general relativistic Tolman-Oppenheimer-Volkoff equations and calculate the neutron-star crust composition based on the new experimental mass. The composition profile is not only altered but now constrained by experimental data deeper into the crust than before.

Q value and half-lives for the double-ß-decay nuclide 110Pd.

The 110Pd double-ß decay Q value was measured with the Penning-trap mass spectrometer ISOLTRAP to be Q=2017.85(64) keV. This value shifted by 14 keV compared with the literature value and is 17 times more precise, resulting in new phase-space factors for the two-neutrino and neutrinoless decay modes. In addition a new set of the relevant matrix elements has been calculated. The expected half-life of the two-neutrino mode was reevaluated as 1.5(6)×10(20) yr. With its high natural abundance, the new results reveal 110Pd to be an excellent candidate for double-ß decay studies.

Critical-point boundary for the nuclear quantum phase transition near A=100 from mass measurements of (96,97)Kr.

Mass measurements of (96,97)Kr using the ISOLTRAP Penning-trap spectrometer at CERN-ISOLDE are reported, extending the mass surface beyond N=60 for Z=36. These new results show behavior in sharp contrast to the heavier neighbors where a sudden and intense deformation is present. We interpret this as the establishment of a nuclear quantum phase transition critical-point boundary. The new masses confirm findings from nuclear mean-square charge-radius measurements up to N=60 but are at variance with conclusions from recent gamma-ray spectroscopy.

Measurement of melatonin in alcoholic and hot water extracts of Tanacetum parthenium, Tripleurospermum disciforme and Viola odorata.

BACKGROUND AND THE PURPOSE OF THE STUDY: Melatonin has recently been found in several plant tissues. Some reports show that the majority of the herbs containing the high level of melatonin have been used traditionally to treat neurological disorders or diseases associated with the generation of free radicals. Current study was undertaken to screen some medicinal plant species with historical evidence of efficacy in the treatment of neurological and antioxidant deficiency related disorders for their melatonin content. The melatonin content of boiled and alcoholic extracts were also compared. METHODS: In this study, three medicinal herbs, Tanacetum parthenium (L.) Schultz. Bip. (Asteraceae), Tripleurospermum disciforme (C.A.Mey) Schultz. Bip. (Asteraceae) and Viola odorata (L.) (Violaceae) were analyzed using high performance liquid chromatography with ultraviolet detector (HPLC-UV), enzyme linked immunosorbent assay (ELISA) and thin layer chromatography (TLC). RESULTS: Melatonin content in the dry plant powders differed with different assay methods (p < 0.001). For example, the melatonin content in T. disciforme was determined as 3.073 µg/g and 2.906 µg/g by the HPLC and the ELISA methods, respectively. MAJOR CONCLUSION: The results demonstrated that a hydroalcoholic solution could extract more melatonin from flowers of the herbs than hot water (p < 0.001). The presence of melatonin in these plant tissues may provide some explanation for the anecdotal evidence of their physiological effects in humans.

Discovery of 229Rn and the structure of the heaviest Rn and Ra isotopes from Penning-trap mass measurements.

The masses of the neutron-rich radon isotopes {223-229}Rn have been determined for the first time, using the ISOLTRAP setup at CERN ISOLDE. In addition, this experiment marks the first discovery of a new nuclide, 229Rn, by Penning-trap mass measurement. The new, high-accuracy data allow a fine examination of the mass surface, via the valence-nucleon interaction deltaV{pn}. The results reveal intriguing behavior, possibly reflecting either a N=134 subshell closure or an octupolar deformation in this region.

Intramuscular plasmid DNA electrotransfer: biodistribution and degradation.

We have studied radiolabelled plasmid DNA biodistribution and degradation in the muscle at different times after injection, with or without electrotransfer using previously defined conditions. Radiolabelled plasmid progressively left the muscle and was degraded as soon as 5 min after plasmid injection, with or without electrotransfer. Autoradiography showed that the major part of injected radioactivity was detected in the interfibrilar space of a large proportion of the muscle. Large zones of accumulation of radioactivity, which seems to be contained in some fibres (more than 20 microm), were identified as soon as 5 min after electrotransfer. Such structures were never observed on slices of non-electrotransferred muscles. However, these structures were not frequent and probably lesional. The surprising fact is that despite the amount of intact plasmid having been greatly reduced between 5 min and 3 h after injection, the level of transfection remains unchanged whether electric pulses were delivered 20 s or 3 h after injection. Such a behavior was similarly observed when injecting 0.3, 3 or 30 microg of plasmid DNA. Moreover, the transfection level was correlated to the amount of plasmid DNA injected. These results suggest that as soon as it is injected, plasmid DNA is proportionally partitioned between at least two compartments. While a major part of plasmid DNA is rapidly cleared and degraded, the electrotransferable pool of plasmid DNA represents a very small part of the amount injected and belongs to another compartment where it is protected from endogenous DNAses.

Postprandial metabolic profiles following meals and snacks eaten during simulated night and day shift work.

Shift workers are known to have an increased risk of developing cardiovascular disease (CVD) compared with day workers. An important factor contributing to this increased risk could be the increased incidence of postprandial metabolic risk factors for CVD among shift workers, as a consequence of the maladaptation of endogenous circadian rhythms to abrupt changes in shift times. We have previously shown that both simulated and real shift workers showed relatively impaired glucose and lipid tolerance if a single test meal was consumed between 00:00-02:00 h (night shift) compared with 12:00-14:00 h (day shift). The objective of the present study was to extend these observations to compare the cumulative metabolic effect of consecutive snacks/meals, as might normally be consumed throughout a period of night or day shift work. In a randomized crossover study, eight healthy nonobese men (20-33 yrs, BMI 20-25kg/m2) consumed a combination of two meals and a snack on two occasions following a standardized prestudy meal, simulating night and day shift working (total energy 2500 kcal: 40% fat, 50% carbohydrate, 10% protein). Meals were consumed at 01:00/ 13:00 h and 07:00/19:00h, and the snack at 04:00/16:00 h. Blood was taken after an overnight fast, and for 8 h following the first meal on each occasion, for the measurement of glucose, insulin, triacylglycerol (TAG), and nonesterified fatty acids (NEFA). RM-ANOVA (factors time and shift) showed a significant effect of shift for plasma TAG, with higher levels on simulated night compared to day shift (p < 0.05). There was a trend toward an effect of shift for plasma glucose, with higher plasma glucose at night (p = 0.08), and there was a time-shift interaction for plasma insulin levels (p < 0.01). NEFA levels were unaffected by shift. Inspection of the area under the plasma response curve (AUC) following each meal and snack revealed that the differences in lipid tolerance occurred throughout the study, with greatest differences occurring following the mid-shift snack. In contrast, glucose tolerance was relatively impaired following the first night-time meal, with no differences observed following the second meal. Plasma insulin levels were significantly lower following the first meal (p < 0.05), but significantly higher following the second meal (p < 0.01) on the simulated night shift. These findings confirm our previous observations of raised postprandial TAG and glucose at night, and show that sequential meal ingestion has a more pronounced effect on subsequent lipid than carbohydrate tolerance.

Partial prevention of cisplatin-induced neuropathy by electroporation-mediated nonviral gene transfer.

Cisplatin-induced sensory peripheral neuropathy is the dose-limiting factor for cisplatin chemotherapy. We describe the preventive effect of NT-3 delivery, using direct gene transfer into muscle by in vivo electroporation in a mouse model of cisplatin-induced neuropathy. Cisplatin-induced neuropathy was produced by weekly injections of cisplatin (five injections). Two doses of plasmid DNA encoding murine NT-3 (pCMVNT-3) were tested (5 and 50 microg/animal/injection). Cisplatin-treated mice were given two intramuscular injections. The first injection of pCMVNT-3 was given 2 days before the first injection of cisplatin and the second injection 2 weeks later. Six weeks after the start of the experiment, measurement of NT-3 levels (ELISA) demonstrated significant levels both in muscle and plasma. We observed a smaller cisplatin-related increase in the latency of the sensory nerve action potential of the caudal nerve in pCMVNT-3-treated mice than in controls (p < 0.0001). Mean sensory distal latencies were not different between the 5- and 50- microg/animal/injection groups. Treatment with gene therapy induced only a slight muscle toxicity and no general side effects. Therefore, neurotrophic factor delivery by direct gene transfer into muscle by electroporation is of potential benefit in the prevention of cisplatin-induced neuropathy and of peripheral neuropathies in general.

New approaches to measuring the performance of programs that generate differential diagnoses using ROC curves and other metrics.

INTRODUCTION: Evaluation of computer programs which generate multiple diagnoses can be hampered by a lack of effective, well recognized performance metrics. We have developed a method to calculate mean sensitivity and specificity for multiple diagnoses and generate ROC curves. METHODS: Data came from a clinical evaluation of the Heart Disease Program (HDP). Sensitivity, specificity, positive and negative predictive value (PPV, NPV) were calculated for each diagnosis type in the study. A weighted mean of overall sensitivity and specificity was derived and used to create an ROC curve. Alternative metrics Comprehensiveness and Relevance were calculated for each case and compared to the other measures. RESULTS: Weighted mean sensitivity closely matched Comprehensiveness and mean PPV matched Relevance. Plotting the Physician's sensitivity and specificity on the ROC curve showed that their discrimination was similar to the HDP but sensitivity was significantly lower. CONCLUSIONS: These metrics give a clear picture of a program's diagnostic performance and allow straightforward comparison between different programs and different studies.

Nonsurgical closure of a patent foramen ovale in a patient with carcinoid heart disease and severe hypoxia from interatrial shunting.

We report the percutaneous transcatheter closure of a patent foramen ovale using an Amplatzer septal occluder in a rare patient with carcinoid heart disease involving both the right and left heart who presented with severe hypoxemia secondary to intra-atrial shunting. We believe this is the first report of this technique being utilized in a patient with carcinoid heart disease and it may represent an alternative to surgical closure in these patients at high risk for surgical complications.

Minicircle: an improved DNA molecule for in vitro and in vivo gene transfer.

Minicircles are a new form of supercoiled DNA molecule for nonviral gene transfer which have neither bacterial origin of replication nor antibiotic resistance marker. They are thus smaller and potentially safer than the standard plasmids currently used in gene therapy. They were obtained in E. coli by att site-specific recombination mediated by the phage lambda integrase, which was used to excise the expression cassette from the unwanted plasmid sequences. We produced two minicircles containing the luciferase or beta-galactosidase gene under the control of the strong human cytomegalovirus immediate-early enhancer/promoter. Comparing maximal differences, these minicircles gave 2.5 to 5.5 times more reporter gene activity than the unrecombined plasmid in the NIH3T3 cell line and rabbit smooth muscle cells. Moreover, injection in vivo into mouse cranial tibial muscle, or human head and neck carcinoma grafted in nude mice resulted in 13 to 50 times more reporter gene expression with minicircles than with the unrecombined plasmid or larger plasmids. Histological analysis in muscle showed there were more transfected myofibers with minicircles than with unrecombined plasmid.

Differential diagnoses of the heart disease program have better sensitivity than resident physicians.

We describe a prospective clinical evaluation of a computer program to assist with the diagnosis of heart disease. The Heart Disease Program (HDP) is a large diagnostic program covering most areas of heart disease and some related areas of general medicine. The program's output is a set of differential diagnoses with explanations and it can be deployed in a clinical setting using a web interface. A framework for assessing the complex diagnostic summaries generated by the HDP was developed and the program's diagnostic accuracy in a clinical setting was assessed. The diagnoses used for comparison came from the physician entering the case, a "gold standard" assigned by review of patient charts and investigations, and the opinions of expert cardiologists. The data collection, methods of comparison, example analyses and results on 114 cases are presented here. The HDP had a significantly higher sensitivity for both the gold standard (60%) and the cardiologist's diagnoses (58%) than the physicians did (39%, 34%). These findings were consistent in the 2 collection cohorts and for the more serious diagnoses alone. The significance of these findings and the many challenges in comparing these different diagnoses and minimizing bias are discussed.

Reasoning requirements for diagnosis of heart disease.

Over the past dozen years, the Heart Disease Program (HDP) has been developed to assist physicians in reasoning about cardiovascular disorders. Driven by several evaluations, the inference mechanism has progressed from a logic based model, to a Bayesian Probability Network (BPN) and finally a pseudo-Bayesian network with temporal and severity reasoning. Though aspects of cardiovascular reasoning are handled well by BPNs, temporal reasoning, homeostatic feedback mechanisms and effects of disease severities require additional inference strategies. This article discusses how these reasoning problems are handled, and deals with closely linked issues in building the user interface to collect detailed cardiovascular data and provide clear explanations of diagnoses.

Maturation of fetal human neural xenografts in the adult rat brain.

Transplantation of human fetal neural cells has been used for several years as a treatment for Parkinson's disease. These therapeutic trials were based on a large number of rat allografts studies, and the species to species extrapolation appeared valid in many respects. One major difference between neurons of various species, however, is their rate of maturation; indeed, human neurons have been proven to grow much more slowly than rat neurons. This has been studied mostly, up to now, at the light microscope level. In an attempt to determine the fine structural correlates of this protracted development and to detail the schedule of morphogenesis and synaptogenesis, human fetal brain stem tissue (at 8 weeks of gestation) was transplanted into a previously lesioned brain area of immunosuppressed adult rats. Transplants, which were allowed to develop for 15 days to 3 months, were analyzed using the electron microscope. At 15 days, small cells containing a large nucleus were surrounded by wide extracellular spaces. At 1 month, grafted neurons displayed a thin rim of cytoplasm and few thin processes. At 2 months, extracellular spaces tended to diminish. Thin processes formed bundles and large processes extended from enlarged neurons. Major changes were observed at 3 months survival as the neuropile filled up with cells and processes and synaptogenesis began. Comparison with a similar ultrastructural study of thalamic rat allografts shows that human cells develop following a pattern similar to that in rat cells but that the duration of each maturation step is largely extended.

Ontogeny of human striatal DARPP-32 neurons in fetuses and following xenografting to the adult rat brain.

After a number of reports indicating positive clinical outcome of intrastriatal transplantation of fetal ventral mesencephalic tissue into patients with Parkinson's disease, the time may have come to consider the possibility of using this technique to treat patients with Huntington's disease. On the basis of the available literature, the Network of European CNS Transplantation and Restoration has established a program aiming at defining the optimal conditions for such clinical trials. The present study, conducted within this framework, pursued the goal of providing information concerning the period of striatal neuronal ontogeny in humans, taking into account the technical and legal requirements imposed by the clinical procedure of neural transplantation using human tissue. On this basis, it aimed at establishing a reliable dissecting method for the intrastriatal grafting of human fetal striatal neurons. The ontogeny of medium-spiny neurons within the developing striatum was first studied in a series of human fetal brains, 5 to 10 weeks postconception, using immunocytochemical detection of DARPP-32. Immunoreactive neurons were observed in fetuses at 7 weeks of age and older. They were mostly localized in clusters, packed in the lateral ganglionic eminence. Over a 2-week-long period, DARPP-32 neurons increased in number. Their morphology remained poorly differentiated, however, with small cell bodies, few branched dendrites, and variable intensity of immunostaining. Based on these findings, selective dissection of the lateral ganglionic eminence was carried out. This tissue was stereotaxically implanted into the striatum of immunosuppressed adult rats previously lesioned. Two months postgrafting, DARPP-32 neurons were observed as discrete patches, embedded within areas of essentially DARPP-32-negative tissue. Up to 2 months after grafting, neurons remained poorly differentiated in general, with only a few neurons exhibiting a dense immunoreactivity and long processes. These results indicate that striatal DARPP-32-immunoreactive neurons are present in the lateral ganglionic eminence in fetuses as soon as 7 weeks postconception. The striatal tissue can be dissected out and successfully transplanted. Within the grafts, neuronal differentiation appears to be a very long process, suggesting that many months might be necessary for these neurons to become functionally integrated into an adult host brain.