Patient-related risks for nonadherence to antiretroviral therapy among HIV-infected youth in the United States: a study of prevalence and interactions.
Adherence continues to be a major barrier to successful treatment with highly active antiretroviral therapy (HAART) for HIV-infected individuals. HIV-infected adolescents and young adults face a lifetime of treatment with HAART. Often, individuals who struggle with adherence to HAART face multiple barriers that would therefore impact on the success of any single modality intervention. Thus, we conducted a cross-sectional, observational study to determine the prevalence of personal barriers to adherence and to identify associations between these barriers in HIV-infected subjects, 12 to 24. We studied the following personal barriers to adherence: mental health barriers, high/low self-efficacy and outcome expectancy, and the presence of specific structural barriers. There were 396 subjects infected after age 9 recruited from sites from the Adolescent Trials Network for HIV/AIDS Interventions or the Pediatric AIDS Clinical Trials Group. Of the 396 subjects, 148 (37.4%) self-identified as nonadherent. No significant differences were found between adherent and nonadherent subjects for the presence of mental health disorders. Adherence was significantly associated with all but one structural barrier. Both self-efficacy and outcome expectancy were higher among adherent versus nonadherent subjects (p < 0.0001). Grouping subjects according to low self-efficacy and outcome expectancy for adherence, adherence differed according to the presence or absence of mental health disorders and structural barriers (p < 0.0001). Our data suggest that adolescents have significant rates of non-adherence and face multiple personal barriers. Adherence interventions must address multiple barriers to have the maximum chance for positive effects.


Prognostic value of EEG in very premature newborns.
To evaluate the prognostic value of EEG regarding the psychomotor outcomes of very premature newborns. 76 premature infants <30 weeks gestation were enrolled between January 2001 and August 2004. They were examined at 4 and 9 months corrected ages, and at 18 months, 3-4 years and 5-6 years. EEGs performed in the neonatal period were analysed by two neurologists blind to the child's outcome. The mean follow-up was 5.6 years. 25 infants had normal neurological development and all EEGs were normal for 22 of these. 36 others had developmental disabilities (7 motor sequelae and 29 delayed psychomotor development). Of 187 EEGs, 43 were dysmature, 13 disorganised, 2 displayed electrical seizures without clinical manifestations and 15 showed other abnormal features. Dysmaturity was the predominant EEG pattern in newborns with severe or moderate sequelae and was persistent on several EEGs in 12 of these. In contrast, only three infants with normal development had a dysmature pattern on one EEG. All infants with a disorganised pattern had cognitive sequelae, and two had cerebral palsy. The sensitivity of EEG regarding psychomotor outcome was 83.3%, the specificity was 88% and the positive predictive value was 90.9%. Very preterm neonates remain at high risk of neurological sequelae and EEG is a sensitive method for assessing neuromotor and cognitive prognosis. A dysmature pattern was the predominant EEG characteristic in infants who developed severe or moderate impairment. Early postnatal tracing is useful but additional recordings are generally necessary to detect high-risk newborns.


Effect of insulin and plasma amino acid concentration on leucine metabolism in cirrhosis.
Clinically stable patients with cirrhosis demonstrate insulin resistance with regard to glucose metabolism. However, much less is known about the two major factors, insulin and plasma amino acid concentration, that regulate protein metabolism in cirrhotic patients. To examine this question, we performed paired euglycemic insulin clamp studies in combination with 14C-leucine and indirect calorimetry. In the first study insulin alone was infused, and the plasma amino acid concentration was allowed to decline. During the second study a balanced amino acid solution was infused with insulin to increase the total plasma amino acid concentration approximately twofold. Insulin-mediated glucose disposal (4.68 vs. 6.45 mg/kg-min, p less than 0.01) was significantly impaired by 30% in cirrhotic patients during both insulin clamp studies. In the postabsorptive state, cirrhotic patients manifested low plasma leucine (76 vs. 102 mumol/L) and alpha-ketoisocaproate (19 vs. 30 mumol/L) concentrations, but all parameters of leucine turnover were normal. When insulin alone was infused, the endogenous leucine flux (an index of protein degradation) declined similarly in cirrhotic patients (30.8 mumol/m2-min) and control (26.9) subjects, and this was accompanied by a similar decrease in plasma leucine concentration (31% vs. 33%). The decline in circulating leucine concentration was accompanied by a parallel decline in leucine oxidation (5.1 vs. 4.6 mumol/m2-min) and nonoxidative (28.9 vs. 26.0 mumol/m2-min) leucine disposal, which were of similar magnitude in cirrhotic patients and control subjects, respectively. In both cirrhotic patients and control subjects, combined hyperinsulinemia/hyperaminoacidemia elicited a similar stimulation of nonoxidative leucine disposal (an index of protein synthesis) and leucine oxidation while causing a greater suppression of endogenous leucine flux than observed with insulin alone. Thus the suppressive effect of insulin on protein degradation and the stimulatory effect of insulin/amino acid infusion on protein synthesis are not impaired in cirrhotic patients, demonstrating a clear-cut dissociation between the effects of insulin on protein and glucose metabolism.


Solid state nanofibers based on self-assemblies: from cleaving from self-assemblies to multilevel hierarchical constructs.
Self-assemblies and their hierarchies are useful to construct soft materials with structures at different length scales and to tune the materials properties for various functions. Here we address routes for solid nanofibers based on different forms of self-assemblies. On the other hand, we discuss rational "bottom-up" routes for multi-level hierarchical self-assembled constructs, with the aim of learning more about design principles for competing interactions and packing frustrations. Here we use the triblock copolypeptide poly(L-lysine)-b-poly(gamma-benzyl-L-glutamate)-b-poly(L-lysine) complexed with 2'-deoxyguanosine 5'-monophosphate. Supramolecular disks (G-quartets) stabilized by metal cations are formed and their columnar assembly leads to a packing frustration with the cylindrical packing of helical poly(gamma-benzyl-L-glutamate), which we suggest is important in controlling the lateral dimensions of the nanofibers. We foresee routes for functionalities by selecting different metal cations within the G-quartets. On the other hand, we discuss nanofibers that are cleaved from bulk self-assemblies in a "top-down" manner. After a short introduction based on cleaving nanofibers from diblock copolymeric self-assemblies, we focus on native cellulose nanofibers, as cleaved from plant cell wall fibers, which are expected to have feasible mechanical properties and to be templates for functional nanomaterials. Long nanofibers with 5-20 nm lateral dimensions can be cleaved within an aqueous medium to allow hydrogels and water can be removed to allow highly porous, lightweight, and flexible aerogels. We further describe inorganic/ organic hybrids as prepared by chemical vapour deposition and atomic layer deposition of the different nanofibers. We foresee functional materials by selecting inorganic coatings. Finally we briefly discuss how the organic template can be removed e.g., by thermal treatments to allow completely inorganic hollow nanofibrillar structures.


Finasteride-induced myalgia and HyperCKemia.
Finasteride is an antiandrogen, inhibits type II 5-alpha reductase (enzyme that converts testosterone to more potent form dihydrotestosterone), and is commonly used in the treatment of benign prostatic hyperplasia and male frontal baldness; however, it is not free from side effects, which include sexual dysfunction and, rarely, myopathy. We report a case of finasteride-associated myalgia and hyperCKemia and review similar cases reported in the literature. A 30-year-old man who had been taking finasteride 5 mg/d for 10 years to treat frontal baldness developed diffuse muscle aches associated with elevated creatine kinase level to 10,117 IU/L with neither weakness nor pigmenturia. His symptoms resolved and his creatine kinase level dropped down to 256 IU/L 3 weeks after finasteride discontinuation. Reversible myalgia associated with significant hyperCKemia is a possible adverse reaction of finasteride therapy.


Opioid switching from and to tapentadol extended release in cancer patients: conversion ratio with other opioids.
The aim of this exploratory study was to assess the conversion ratios between tapentadol and other opioids in patients requiring an opioid switching. A prospective study was carried out in a convenience sample of consecutive patients admitted to an acute palliative care unit and a home care unit for a period of 1 year. Patients who were switched from/to tapentadol were selected. The initial ratio between tapentadol and other opioids, expressed as oral morphine equivalents was 1:3.3. The subsequent doses were flexible and were changed to fit the patients' needs. Pain intensity and distress score were recorded until opioid doses were stable. In all, 37 patients were examined; 24 and 13 patients were switched from and to tapentadol, respectively. The most frequent sequences were tapentadol-morphine (18 patients) in one direction, and morphine-tapentadol (8 patients) in the other direction. In the sequence tapentadol-morphine and morphine-tapentadol, the mean final tapentadol-morphine ratios were 3.9:1 (SD 2.3), and 1:4.5 (SD 3.2), respectively, which did not differ significantly from the initial established conversion ratio. A minority of patients were switched from/to tapentadol to/from other opioids. Globally, the initial ratio did not change after switching took place. Data suggest that a conversion ratio between tapentadol and other opioids, expressed in oral morphine equivalents could be 1:3.3 in both direction, particularly in patients who are switched in conditions of equianalgesia. The limited number of patients prevents a definitive conclusion to be drawn, and data should be interpreted with caution, given the exploratory nature of the study and the question of the low number of patients should be addressed in future studies.


Diagnostic value of anti-human citrullinated fibrinogen ELISA and comparison with four other anti-citrullinated protein assays.
We studied the diagnostic performance of the anti-human citrullinated fibrinogen antibody (AhFibA) ELISA for rheumatoid arthritis (RA) in a consecutive cohort (population 1) and evaluated the agreement between the AhFibA ELISA and four other assays for anti-citrullinated protein/peptide antibodies (ACPAs) as well as rheumatoid factor in patients with longstanding RA (population 2). Population 1 consisted of 1024 patients with rheumatic symptoms; serum samples from these patients were sent to our laboratory for ACPA testing within the context of a diagnostic investigation for RA. Ninety-two of these patients were classified as having RA according to the American College of Rheumatology criteria and 463 were classified as non-RA patients. Population 2 consisted of 180 patients with longstanding RA and was used to assess agreement and correlations between five ACPA assays: anti-cyclic citrullinated peptide (CCP)1 and anti-CCP2 antibodies were detected using a commercially available ELISA, AhFibA using ELISA, and anti-PepA and anti-PepB antibodies using line immunoassay. Applying previously proposed cut-offs for AhFibA, we obtained a sensitivity of 60.9% and a specificity of 98.7% in population 1. Receiver operating characteristic curve analysis could not detect a significant difference in diagnostic performance between the AhFibA ELISA and anti-CCP2 assay. Performing a hierarchical nearest neighborhood cluster analysis of the five different ACPA assays in population 2, we identified two clusters: a cluster of anti-pepA, anti-pepB and anti-CCP1, and a cluster of AhFibA and anti-CCP2. In conclusion, we found that AhFibA and anti-CCP2 antibodies had similar diagnostic performance. However, disagreement between ACPA tests may occur.


Defining reference sequences for Nocardia species by similarity and clustering analyses of 16S rRNA gene sequence data.
The intra- and inter-species genetic diversity of bacteria and the absence of 'reference', or the most representative, sequences of individual species present a significant challenge for sequence-based identification. The aims of this study were to determine the utility, and compare the performance of several clustering and classification algorithms to identify the species of 364 sequences of 16S rRNA gene with a defined species in GenBank, and 110 sequences of 16S rRNA gene with no defined species, all within the genus Nocardia. A total of 364 16S rRNA gene sequences of Nocardia species were studied. In addition, 110 16S rRNA gene sequences assigned only to the Nocardia genus level at the time of submission to GenBank were used for machine learning classification experiments. Different clustering algorithms were compared with a novel algorithm or the linear mapping (LM) of the distance matrix. Principal Components Analysis was used for the dimensionality reduction and visualization. The LM algorithm achieved the highest performance and classified the set of 364 16S rRNA sequences into 80 clusters, the majority of which (83.52%) corresponded with the original species. The most representative 16S rRNA sequences for individual Nocardia species have been identified as 'centroids' in respective clusters from which the distances to all other sequences were minimized; 110 16S rRNA gene sequences with identifications recorded only at the genus level were classified using machine learning methods. Simple kNN machine learning demonstrated the highest performance and classified Nocardia species sequences with an accuracy of 92.7% and a mean frequency of 0.578. The identification of centroids of 16S rRNA gene sequence clusters using novel distance matrix clustering enables the identification of the most representative sequences for each individual species of Nocardia and allows the quantitation of inter- and intra-species variability.


Doppler flowmeter-assessed circadian rhythms in neonatal cardiac function, family history, and intrauterine growth retardation.
This study examines the circadian variation of aortic blood flow velocity, acceleration, and distance of stroke, assessed every 4 hours for 24 hours by Doppler ultrasound in 88 human newborns. Groups 1 and 2 involve neonates with a negative family history of high blood pressure or myocardial infarction monitored during the first day or between the second and tenth days postpartum, respectively; groups 3 to 6 are 2- to 10-day-old babies with a positive family history of high blood pressure (group 3) or of myocardial infarction (group 4) or with a negative family history and intrauterine growth retardation (group 5) or born prematurely (group 6). Cosinor analyses demonstrate a circadian rhythm for all variables in groups 2 and 5 (p < 0.001), with overall high values occurring around 17:40. In group 2, a circadian rhythm remains demonstrable in boys and girls considered separately, and mostly so in arbitrary subgroups of different sizes, with only slight differences in rhythm parameters among them. These results show that, with relatively small samples, reproducible circadian rhythms of cardiac function can be detected shortly after birth in neonates with a negative family history of high blood pressure or myocardial infarction.


Loss of pollen-specific phospholipase NOT LIKE DAD triggers gynogenesis in maize.
Gynogenesis is an asexual mode of reproduction common to animals and plants, in which stimuli from the sperm cell trigger the development of the unfertilized egg cell into a haploid embryo. Fine mapping restricted a major maize QTL (quantitative trait locus) responsible for the aptitude of inducer lines to trigger gynogenesis to a zone containing a single gene NOT LIKE DAD (NLD) coding for a patatin-like phospholipase A. In all surveyed inducer lines, NLD carries a 4-bp insertion leading to a predicted truncated protein. This frameshift mutation is responsible for haploid induction because complementation with wild-type NLD abolishes the haploid induction capacity. Activity of the NLD promoter is restricted to mature pollen and pollen tube. The translational NLD::citrine fusion protein likely localizes to the sperm cell plasma membrane. In Arabidopsis roots, the truncated protein is no longer localized to the plasma membrane, contrary to the wild-type NLD protein. In conclusion, an intact pollen-specific phospholipase is required for successful sexual reproduction and its targeted disruption may allow establishing powerful haploid breeding tools in numerous crops.


An arbitrary-spectrum spatial visual stimulator for vision research.
Visual neuroscientists require accurate control of visual stimulation. However, few stimulator solutions simultaneously offer high spatio-temporal resolution and free control over the spectra of the light sources, because they rely on off-the-shelf technology developed for human trichromatic vision. Importantly, consumer displays fail to drive UV-shifted short wavelength-sensitive photoreceptors, which strongly contribute to visual behaviour in many animals, including mice, zebrafish and fruit flies. Moreover, many non-mammalian species feature more than three spectral photoreceptor types. Here, we present a flexible, spatial visual stimulator with up to six arbitrary spectrum chromatic channels. It combines a standard digital light processing engine with open source hard- and software that can be easily adapted to the experimentalist's needs. We demonstrate the capability of this general visual stimulator experimentally in the in vitro mouse retinal whole-mount and the in vivo zebrafish. With this work, we intend to start a community effort of sharing and developing a common stimulator design for vision research.


The Impact of Hospitalists on Value-Based Purchasing Program Scores.
As part of the provisions of the 2010 Affordable Care Act, the Centers for Medicare & Medicaid Services adjusts payments made to hospitals through its Hospital Value-Based Purchasing (HVBP) program. In light of the increasing aim to improve efficiency, healthcare organizations are exploring innovative strategies for care delivery, including the use of hospitalists. Supporters of the hospitalist model suggest use of these specialists offers several advantages over the traditional model of physician care in the inpatient setting, including improved coordination, reduced costs, and improved quality indicator scores. This study explores the effect of hospitalists on hospitals' scores in the four domains of the fiscal year 2016 HVBP program: clinical process of care, patient experience of care (PEOC), outcome, and efficiency. Data from the 2015 HVBP database, the 2015 Medicare Final Rule Standardizing File, and the 2015 American Hospital Association database were used for the analysis. The study used multivariate regression analysis in Stata 12. Results from this study suggest that hospitals employing a higher percentage of hospitalists see related improvement in their overall total performance score. In light of improvements within the PEOC, outcome, and efficiency scores, it would appear that hospitalists are primarily providing linking services, which helps provide better coordination of care that is otherwise lacking in more traditionally fragmented approaches to care.


Connecting thermal physiology and latitudinal niche partitioning in marine Synechococcus.
Marine Synechococcus cyanobacteria constitute a monophyletic group that displays a wide latitudinal distribution, ranging from the equator to the polar fronts. Whether these organisms are all physiologically adapted to stand a large temperature gradient or stenotherms with narrow growth temperature ranges has so far remained unexplored. We submitted a panel of six strains, isolated along a gradient of latitude in the North Atlantic Ocean, to long- and short-term variations of temperature. Upon a downward shift of temperature, the strains showed strikingly distinct resistance, seemingly related to their latitude of isolation, with tropical strains collapsing while northern strains were capable of growing. This behaviour was associated to differential photosynthetic performances. In the tropical strains, the rapid photosystem II inactivation and the decrease of the antioxydant β-carotene relative to chl a suggested a strong induction of oxidative stress. These different responses were related to the thermal preferenda of the strains. The northern strains could grow at 10 °C while the other strains preferred higher temperatures. In addition, we pointed out a correspondence between strain isolation temperature and phylogeny. In particular, clades I and IV laboratory strains were all collected in the coldest waters of the distribution area of marine Synechococus. We, however, show that clade I Synechococcus exhibit different levels of adaptation, which apparently reflect their location on the latitudinal temperature gradient. This study reveals the existence of lineages of marine Synechococcus physiologically specialised in different thermal niches, therefore suggesting the existence of temperature ecotypes within the marine Synechococcus radiation.


Gyrotaxis in a steady vortical flow.
We show that gyrotactic motility within a steady vortical flow leads to tightly clustered aggregations of microorganisms. Two dimensionless numbers, characterizing the relative swimming speed and stability against overturning by vorticity, govern the coupling between motility and flow. Exploration of parameter space reveals a striking array of patchiness regimes. Aggregations are found to form within a few overturning time scales, suggesting that vortical flows might be capable of efficiently separating species with different motility characteristics.


De novo design of a tumor-penetrating peptide.
Poor penetration of antitumor drugs into the extravascular tumor tissue is often a major factor limiting the efficacy of cancer treatments. Our group has recently described a strategy to enhance tumor penetration of chemotherapeutic drugs through use of iRGD peptide (CRGDK/RGPDC). This peptide comprises two sequence motifs: RGD, which binds to αvβ3/5 integrins on tumor endothelia and tumor cells, and a cryptic CendR motif (R/KXXR/K-OH). Once integrin binding has brought iRGD to the tumor, the peptide is proteolytically cleaved to expose the cryptic CendR motif. The truncated peptide loses affinity for its primary receptor and binds to neuropilin-1, activating a tissue penetration pathway that delivers the peptide along with attached or co-administered payload into the tumor mass. Here, we describe the design of a new tumor-penetrating peptide based on the current knowledge of homing sequences and internalizing receptors. The tumor-homing motif in the new peptide is the NGR sequence, which binds to endothelial CD13. The NGR sequence was placed in the context of a CendR motif (RNGR), and this sequence was embedded in the iRGD framework. The resulting peptide (CRNGRGPDC, iNGR) homed to tumor vessels and penetrated into tumor tissue more effectively than the standard NGR peptide. iNGR induced greater tumor penetration of coupled nanoparticles and co-administered compounds than NGR. Doxorubicin given together with iNGR was significantly more efficacious than the drug alone. These results show that a tumor-specific, tissue-penetrating peptide can be constructed from known sequence elements. This principle may be useful in designing tissue-penetrating peptides for other diseases.


Factors predictive of inaccurate determination of horizontal extent of intestinal-type early gastric cancers during endoscopic submucosal dissection: a retrospective analysis.
Certain tumor characteristics may pose challenges when endoscopically determining the horizontal extent of early gastric cancers (EGC). In the present study, clinicopathological features related to inaccurate endoscopic evaluation of horizontal extent of intestinal-type EGC were analyzed. We analyzed 431 lesions with intestinal-type EGC treated by endoscopic submucosal dissection (ESD) at our hospital. We focused on whether pretreatment demarcation was accurate by comparing positional relationships between marking dots and tumor edges in resected specimens, and factors related to inaccurate evaluation were analyzed. Gender, age, tumor size, location, circumference, depth, ulceration, macroscopic type, presence of a flat (0-IIb) component, predominant histological type, mixture of diffuse-type adenocarcinoma, mixed histology, and use of magnification endoscopy with narrow band imaging were analyzed. Reasons for inaccurate evaluation were also investigated by re-examining endoscopic images and prepared histological slides. Rate of inaccurate evaluation of horizontal extent was 7.4% (32/431 lesions). Multivariate analysis revealed the following significant independent variables contributing to inaccurate endoscopic evaluation: presence of a flat component, large size, and predominant histological findings of moderately differentiated adenocarcinoma. Re-examination of prepared histological slides of inaccurately evaluated cases revealed a marginal flat spreading area in 28 of the 32 lesions (87.5%). In 14 of the 32 lesions (43.8%), tumor margins were composed of moderately differentiated adenocarcinoma. For lesions with a flat component, large lesions, and moderately differentiated adenocarcinoma, determination of the horizontal extent can be challenging in EGC indicated for ESD, even with the best available endoscopic tools.


Metastases to the breast: a review of 33 cases.
The aim of the study was to show the clinical and radiological manifestations of metastases to the breast (MB). From 1987 to 2006, 33 patients with MB were diagnosed at our institution. Their clinical and radiological features were retrospectively evaluated. Of the 33 cases, 31 presented as a palpable breast lump. On mammography, their findings were classified as follows: well-circumscribed masses (11 cases), ill-circumscribed masses (five), focal asymmetric densities (one) and inflammatory skin changes (six). Mammograms were normal in six cases (all of them showed dense breast tissue). Four CT scans showed two well-circumscribed masses and two ill-circumscribed masses. Ultrasonography was available in 18 cases: hypoechoic lesions (15 cases) were more frequent than hyperechoic (one) or isoechoic lesions (two). The appearance on magnetic resonance was similar to primary breast cancer (one case). The most common primary tumours causing MB were haematological malignancies (nine cases) and melanomas (seven). Metastases to the breast showed a wide range of mammographic and ultrasonographic appearances, resembling both benign and malignant lesions. Any patient who presents with a breast lump with a history of cancer should undergo a core-needle biopsy in order to determine the histology of the lump.


Versatile, cell and chip friendly method to gel alginate in microfluidic devices.
Alginate is used extensively in microfluidic devices to produce discrete beads or fibres at the microscale. Such structures may be used to encapsulate sensitive cargoes such as cells and biomolecules. On chip gelation of alginate represents a significant challenge since gelling kinetics or physicochemical conditions are not biocompatible. Here we present a new method that offers a hitherto unprecedented level of control over the gelling kinetics and pH applied to the encapsulation of a variety of cells in both bead and fibre geometries. This versatile approach proved straightforward to adjust to achieve appropriate solution conditions required for implementation in microfluidic devices and resulted in highly reliable device operation and very high viability of several different encapsulated cell types for prolonged periods. We believe this method offers a paradigm shift in alginate gelling technology for application in microfluidics.


The Biokinetic Spectrum for Temperature.
We identify and describe the distribution of temperature-dependent specific growth rates for life on Earth, which we term the biokinetic spectrum for temperature. The spectrum has the potential to provide for more robust modeling in thermal ecology since any conclusions derived from it will be based on observed data rather than using theoretical assumptions. It may also provide constraints for systems biology model predictions and provide insights in physiology. The spectrum has a Δ-shape with a sharp peak at around 42°C. At higher temperatures up to 60°C there was a gap of attenuated growth rates. We found another peak at 67°C and a steady decline in maximum rates thereafter. By using Bayesian quantile regression to summarise and explore the data we were able to conclude that the gap represented an actual biological transition between mesophiles and thermophiles that we term the Mesophile-Thermophile Gap (MTG). We have not identified any organism that grows above the maximum rate of the spectrum. We used a thermodynamic model to recover the Δ-shape, suggesting that the growth rate limits arise from a trade-off between activity and stability of proteins. The spectrum provides underpinning principles that will find utility in models concerned with the thermal responses of biological processes.


Automatic extraction of forward stroke volume using dynamic PET/CT: a dual-tracer and dual-scanner validation in patients with heart valve disease.
The aim of this study was to develop and validate an automated method for extracting forward stroke volume (FSV) using indicator dilution theory directly from dynamic positron emission tomography (PET) studies for two different tracers and scanners. 35 subjects underwent a dynamic (11)C-acetate PET scan on a Siemens Biograph TruePoint-64 PET/CT (scanner I). In addition, 10 subjects underwent both dynamic (15)O-water PET and (11)C-acetate PET scans on a GE Discovery-ST PET/CT (scanner II). The left ventricular (LV)-aortic time-activity curve (TAC) was extracted automatically from PET data using cluster analysis. The first-pass peak was isolated by automatic extrapolation of the downslope of the TAC. FSV was calculated as the injected dose divided by the product of heart rate and the area under the curve of the first-pass peak. Gold standard FSV was measured using phase-contrast cardiovascular magnetic resonance (CMR). FSVPET correlated highly with FSVCMR (r = 0.87, slope = 0.90 for scanner I, r = 0.87, slope = 1.65, and r = 0.85, slope = 1.69 for scanner II for (15)O-water and (11)C-acetate, respectively) although a systematic bias was observed for both scanners (p < 0.001 for all). FSV based on (11)C-acetate and (15)O-water correlated highly (r = 0.99, slope = 1.03) with no significant difference between FSV estimates (p = 0.14). FSV can be obtained automatically using dynamic PET/CT and cluster analysis. Results are almost identical for (11)C-acetate and (15)O-water. A scanner-dependent bias was observed, and a scanner calibration factor is required for multi-scanner studies. Generalization of the method to other tracers and scanners requires further validation.


How New Caledonian crows solve novel foraging problems and what it means for cumulative culture.
New Caledonian crows make and use tools, and tool types vary over geographic landscapes. Social learning may explain the variation in tool design, but it is unknown to what degree social learning accounts for the maintenance of these designs. Indeed, little is known about the mechanisms these crows use to obtain information from others, despite the question's importance in understanding whether tool behavior is transmitted via social, genetic, or environmental means. For social transmission to account for tool-type variation, copying must utilize a mechanism that is action specific (e.g., pushing left vs. right) as well as context specific (e.g., pushing a particular object vs. any object). To determine whether crows can copy a demonstrator's actions as well as the contexts in which they occur, we conducted a diffusion experiment using a novel foraging task. We used a nontool task to eliminate any confounds introduced by individual differences in their prior tool experience. Two groups had demonstrators (trained in isolation on different options of a four-option task, including a two-action option) and one group did not. We found that crows socially learn about context: After observers see a demonstrator interact with the task, they are more likely to interact with the same parts of the task. In contrast, observers did not copy the demonstrator's specific actions. Our results suggest it is unlikely that observing tool-making behavior transmits tool types. We suggest it is possible that tool types are transmitted when crows copy the physical form of the tools they encounter.


Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis.
: We conducted a pooled analysis of two phase III trials, RV-MM-EMN-441 and EMN01, to compare maintenance with lenalidomide-prednisone vs. lenalidomide in newly diagnosed transplant-eligible and -ineligible myeloma patients. Primary endpoints were progression-free survival, progression-free survival 2 and overall survival with both regimens. A secondary aim was to evaluate the impact of duration of maintenance on overall survival and on outcome after relapse. A total of 625 patients (lenalidomide-prednisone arm, n = 315; lenalidomide arm, n = 310) were analyzed. The median follow-up was 58 months. Median progression-free survival (25 vs. 19 months; p = 0.08), progression-free survival 2 (56 vs. 49 months; p = 0.9) and overall survival (73 months vs. NR; p = 0.08) were not significantly different between the two arms. Toxicity profiles of lenalidomide-prednisone and lenalidomide were similar, with the exception of neutropenia that was higher in the lenalidomide arm (grade ≥ 3: 9% vs. 19%, p < 0.001), without an increase in the rate of infections. Overall survival (median NR vs. 49 months, p < 0.001), progression-free survival from relapse (median 35 vs. 24 months, p = 0.004) and overall survival from relapse (median not reached vs. 41 months, p = 0.002) were significantly longer in patients continuing maintenance for ≥2 years. We showed that the addition of prednisone at 25 or 50 mg every other day (eod) to lenalidomide maintenance did not induce any significant advantage.


Application of a membrane bioreactor system for opto-electronic industrial wastewater treatment--a pilot study.
The membrane bioreactor (MBR) system has become more and more attractive in the field of wastewater treatment. It is particularly attractive in situations where long solids retention times are required, such as nitrifying bacteria, and physical retention is critical to achieving more efficiency for biological degradation of pollutants. Although it is a new technology, the MBR process has been applied to industrial wastewater treatment for only the past decade. The opto-electronic industry, developed very fast over the past decade in the world, is a high technological manufacturing industry. The treatment of the opto-electronic industrial wastewater containing a significant quantity of organic nitrogen compounds, with a ratio over 95% in organic nitrogen (Org-N) to total nitrogen (T-N), is very difficult to meet the discharge limits. The purpose of this research is mainly to discuss the treatment capacity of high-strength organic nitrogen wastewater, and to investigate the capabilities of the MBR process. A 2 m3/day capacity MBR pilot plant consisting of anoxic and aerobic tanks and a membrane bioreactor was installed for evaluation. The operation was continued for 130 days. Over the whole experimental period, a satisfactory organic removal performance was achieved. The COD could be removed with an average of over 94.5%. For TOC and BOD5, the average removal efficiencies were 96.3 and 97.6%, respectively. The nitrification and denitrification were also successfully achieved. The effluent did not contain any suspended solids. Only a small concentration of ammonia nitrogen was found in the effluent. The stable effluent quality and satisfactory removal performance mentioned above were ensured by the efficient interception performance of the membrane device incorporated within the biological reactor. The MBR system shows promise as a means of treating very high organic nitrogen wastewater without dilution. The effluent of TKN, NOx-N and COD can fall below 20 mg/L, 30 mg/L and 50 mg/L.


Genital ulcer severity score and genital health quality of life in Behçet's disease.
Behçet's Disease (BD) is a chronic auto-inflammatory, multisystem relapsing/remitting disorder of unknown aetiology. Oro-genital ulceration is a key feature of the disease and has a major impact on the patients' quality of life. Other clinical manifestations include ocular inflammation, rheumatologic and skin involvement, while CNS and vascular complications can lead to considerable morbidity. The availability of a valid monitoring tool for BD activity is crucial in evaluating the impact of the disease on daily life activity. The aims of this study were to validate a novel tool for monitoring genital ulceration severity in BD and to assess the impact of genital ulcers on the Genital Health Quality of Life (GHQoL). Genital Ulcer Severity Score (GUSS) was developed using six genital ulcer characteristics: number, size, duration, ulcer-free period, pain and site. A total of 207 BD patients were examined, (137 females: mean age ± SD: 39.83 ± 13.42 and 70 males: mean age ± SD: 39.98 ± 11.95) from the multidisciplinary Behçet's Centre of Excellence at Barts Health NHS Trust. GUSS was used in conjunction with Behçet's Disease Current Activity Form (BDCAF). The over-all score of GUSS showed a strong correlation with all genital ulcer characteristics, and the strongest correlation was with the pain domain (r = 0.936; P < 0.0001). Ulcer average size and ulcer pain were the major predicting factors in GUSS (β = 0.284; β = 0.275) respectively, and P-values were significant. Multivariate regression analysis indicated that the ulcer pain, size and site are the main ulcer characteristics having an influence on the GHQoL (R(2): 0.600; P < 0.0001). This study established the practicality of GUSS as a severity monitoring tool for BD genital ulcers and validated its use in 207 patients. Genital ulcers of BD have a considerable impact on the patients GHQoL.


Psychosocial Scores and Jaw Muscle Activity in Women.
To test whether women with temporomandibular disorder (TMD)-related pain showed higher psychosocial scores and higher awake- and sleep-time jaw muscle activities (characterized by duty factors) compared to pain-free controls and whether psychosocial scores and the jaw muscle duty factors were associated. Subjects gave informed consent to participate. The Diagnostic Criteria for TMD (DC/TMD) were used for diagnosis of TMD pain, and 31 and 36 women were included in the TMD-related pain and control groups, respectively. DC/TMD Axis II instruments were used to determine psychosocial scores. Subjects self-recorded masseter and anterior temporalis electromyography (EMG) over 3 days and 3 nights. The duty factor (time of muscle activity/total recording time [%]) was quantified using subject-specific EMG/bite-force calibration via data recorded in the laboratory. Group differences (α = .05) were assessed for psychosocial scores and duty factors using chi-square and two-sample t tests. Linear regression assessed whether psychosocial scores were associated with duty factors. Average duty factors were ≤ 2.4% for awake and sleep times in both muscles, and between-group comparisons showed no significant differences. For physical symptom scores, there were significantly fewer TMD-related pain subjects in the normal category and significantly more in the moderate-severe category (all P < .01) compared to controls. Subjects with elevated compared to normal psychosocial scores showed significantly higher jaw muscle duty factors by ≥ 1.5-fold. A significantly larger proportion of TMD-related pain subjects compared to control subjects had moderate-severe physical symptom scores. Awake- and sleep-time jaw muscle duty factors were not different between groups and were generally low among all subjects. Additionally, higher than normal psychosocial scores were associated with significantly more low-magnitude jaw muscle activity.


Partial purification and characterisation of an inhibitor of hepatocyte proliferation derived from nonparenchymal cells after partial hepatectomy.
We have investigated the influences that nonparenchymal cells from regenerating rat liver exert on hepatocyte proliferation. When primary adult rat hepatocytes isolated from resting liver were co-cultured with nonparenchymal cells (NPCs) from resting liver of a different syngeneic animal, the proliferative response of hepatocytes to epidermal growth factor (EGF) was unaffected by the presence of NPCs. In the presence of NPCs taken from livers that had undergone partial hepatectomy 24 hours before (regen-NPCs), the response of hepatocytes from resting liver to EGF, TGF-alpha, and hepatocyte growth factor (HGF) was markedly inhibited. Inhibitory activity was not dependent on cell-to-cell contact, and conditioned-medium from regen-NPCs, but not normal NPCs, inhibited EGF-induced hepatocyte DNA synthesis by approximately 50%. After concentration by gel chromatography and lyophilisation, inhibition was 98%. The inhibitory activity migrated on SDS-PAGE gel electrophoresis with an apparent molecular weight of 14 to 17 kDa and was trypsin-sensitive but relatively heat-stable. The effects of blocking antibodies established that it was not TGF-beta 1, IL1-beta, or IL6. Investigations of regen-NPCs taken at different time points demonstrated that inhibitory activity was released into conditioned medium of cells harvested at 24 and 48 hours after partial hepatectomy, but not 10 or 72 hours. This powerful inhibitor of hepatocyte response to proliferogens is released by cultures of NPCs with a time course suggesting that it may be involved in terminating the surge of hepatocyte replication induced by partial hepatectomy.


A genetic register for von Hippel-Lindau disease.
A genetic register for von Hippel-Lindau disease was set up in the north west of England in 1990. Population statistics, clinical features, age at onset, and survival of 83 people affected with von Hippel-Lindau (VHL) disease were studied. In addition, the effectiveness of the screening programme used and the occurrence of central nervous system haemangioblastomas in the general population were examined. The diagnostic point prevalence of heterozygotes in the North Western Region was 1 center dot 18/100 000 (1/85 000) people, with an estimated birth incidence of 2 center dot 20/100 000 (1/45 500) live births. The mutation rate was estimated directly to be 1 center dot 4 x 10(-6)/gene/generation (1/714 200). The mean age at onset of first symptoms was 26 center dot 25 years, with cerebellar haemangioblastoma being the most common presenting manifestation (34 center dot 9% of cases). The mean age at diagnosis of VHL disease was 30 center dot 87 years. Overall, 50 patients (60 center dot 2%) developed a cerebellar haemangioblastoma, 34 (41 center dot 0%) a retinal angioma, 21 (25 center dot 3%) a renal cell carcinoma, 12 (14 center dot 5%) a spinal haemangioblastoma, and 12 (14 center dot 5%) a phaeochromocytoma. Mean age at diagnosis of renal cell carcinoma (38 center dot 9 years) was significantly higher than that for cerebellar haemangioblastoma (30 center dot 0 years) and retinal angioma (21.1 years). Mean age at death was 40 center dot 9 years with cerebellar haemangioblastoma being the most common cause (47 center dot 7% of deaths). A total of 65 VHL manifestations were diagnosed asymptomatically following appropriate clinical and radiological screening tests, and failure to detect manifestations of VHL disease in spite of appropriate screening occurred on only two occasions. The use of DNA linkage analysis and direct mutation testing reduced the personal risk of carrying the VHL gene to below 1% in 14 people. In addition to the 83 clinically affected subjects, three obligate carriers who were considered to be lesion free in spite of extensive screening tests were identified. Fourteen percent of all CNS haemangioblastomas on the regionally based Cancer Registry were found to occur as part of VHL disease, but investigations for VHL in apparently sporadic disease appeared to be limited.


Autologous stromal vascular fraction therapy for rheumatoid arthritis: rationale and clinical safety.
Advancements in rheumatoid arthritis (RA) treatment protocols and introduction of targeted biological therapies have markedly improved patient outcomes, despite this, up to 50% of patients still fail to achieve a significant clinical response. In veterinary medicine, stem cell therapy in the form of autologous stromal vascular fraction (SVF) is an accepted therapeutic modality for degenerative conditions with 80% improvement and no serious treatment associated adverse events reported. Clinical translation of SVF therapy relies on confirmation of veterinary findings in targeted patient populations. Here we describe the rationale and preclinical data supporting the use of autologous SVF in treatment of RA, as well as provide 1, 3, 6, and 13 month safety outcomes in 13 RA patients treated with this approach.


Linkage disequilibrium in natural and experimental populations of Drosophila melanogaster.
We have studied linkage disequilibrium in Drosophila melanogaster in two samples from a wild population and in four large laboratory populations derived from the wild samples. We have assayed four polymorphic enzyme loci, fairly closely linked in the third chromosome: Sod Est-6, Pgm, and Odh. The assay method used allows us to identify the allele associations separately in each of the two homologous chromosomes from each male sampled. We have detected significant linkage disequilibrium between two loci in 16.7% of the cases in the wild samples and in 27.8% of the cases in the experimental populations, considerably more than would be expected by chance alone. We have also found three-locus disequilibria in more instances than would be expected by chance. Some disequilibria present in the wild samples disappear in the experimental populations derived from them, but new ones appear over the generations. The effective population sizes required to generate the observed disequilibria by randomness range from 40 to more than 60,000 individuals in the natural population, depending on which locus pair is considered, and from 100 to more than 60,000 in the experimental populations. These population sizes are unrealistic; the fact that different locus-pairs yield disparate estimates within the same population argues against the likelihood that the disequilibria may have arisen as a consequence of population bottlenecks. Migration, or population mixing, cannot be excluded as the process generating the disequilibria in the wild samples, but can in the experimental populations. We conclude that linkage disequilibrium in these populations is most likely due to natural selection acting on the allozymes, or on loci very tightly linked to them.


Natural DNA mixtures generated in fraternal twins in utero.
Analysis of multiple genetic loci using short tandem repeats (STR) is widely used in human identity testing because the extensive polymorphism at these loci allows for a high degree of discrimination among individuals. We recently received a forensic case that included several pieces of evidence and reference blood samples. Upon initial testing, one of the suspects had a DNA profile that included three alleles at four of the nine loci tested (vWA, FGA, TH01, and D5S818). At each locus, two of the alleles appeared to be "major" alleles with a third "minor" allele present. The profile appeared to be a mixture of two people. Contamination of this first reference sample was suspected and a second, unopened blood specimen was requested from this individual. The DNA profile from this second reference specimen was identical to that of the original specimen at each locus. One of the evidence samples also displayed an identical mixed DNA profile matching that of the reference specimens mentioned above. The relative peak heights of the two "major" and one "minor" allele remained constant in all three samples. Additional background information revealed that the suspect had not received a bone marrow transplant or blood transfusion. However, it was disclosed that this individual is a fraternal (dizygotic) twin. We hypothesize that an exchange of blood cells between the fetuses occurred in utero and that the additional alleles present in these reference samples are derived from cells contributed by his twin sibling. No additional specimens from the suspect or his twin could be obtained for confirmation, and our hypothesis remains untested. Forensic scientists should be aware of this possibility when faced with a DNA profile in which extra alleles at multiple loci are detected.


Reduced bone breakage and increased bone strength in free range laying hens fed omega-3 polyunsaturated fatty acid supplemented diets.
The omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) are the immediate precursors to a number of important mediators of immunity, inflammation and bone function, with products of omega-6 generally thought to promote inflammation and favour bone resorption. Western diets generally provide a 10 to 20-fold deficit in omega-3 PUFAs compared with omega-6, and this is thought to have contributed to the marked rise in incidence of disorders of modern human societies, such as heart disease, colitis and perhaps osteoporosis. Many of our food production animals, fed on grains rich in omega-6, are also exposed to a dietary deficit in omega-3, with perhaps similar health consequences. Bone fragility due to osteoporotic changes in laying hens is a major economic and welfare problem, with our recent estimates of breakage rates indicating up to 95% of free range hens suffer breaks during lay. Free range hens housed in full scale commercial systems were provided diets supplemented with omega-3 alpha linolenic acid, and the skeletal benefits were investigated by comparison to standard diets rich in omega-6. There was a significant 40-60% reduction in keel bone breakage rate, and a corresponding reduction in breakage severity in the omega-3 supplemented hens. There was significantly greater bone density and bone mineral content, alongside increases in total bone and trabecular volumes. The mechanical properties of the omega-3 supplemented hens were improved, with strength, energy to break and stiffness demonstrating significant increases. Alkaline phosphatase (an osteoblast marker) and tartrate-resistant acid phosphatase (an osteoclast marker) both showed significant increases with the omega-3 diets, indicating enhanced bone turnover. This was corroborated by the significantly lower levels of the mature collagen crosslinks, hydroxylysyl pyridinoline, lysyl pyridinoline and histidinohydroxy-lysinonorleucine, with a corresponding significant shift in the mature:immature crosslink ratio. The improved skeletal health in laying hens corresponds to as many as 68million fewer hens suffering keel fractures in the EU each year. The biomechanical and biochemical evidence suggests that increased bone turnover has enhanced the bone mechanical properties, and that this may suggest potential benefits for human osteoporosis.


Evaluating The Impact of Risk Factors on Birth Weight and Gestational Age: A Multilevel Joint Modeling Approach.
Abnormalities in birth weight and gestational age cause several adverse maternal and infant outcomes. Our study aims to determine the potential factors that affect birth weight and gestational age, and their association. We conducted this cross-sectional study of 4415 pregnant women in Tehran, Iran, from July 6-21, 2015. Joint multilevel multiple logistic regression was used in the analysis with demographic and obstetrical variables at the first level, and the hospitals at the second level. We observed the following prevalence rates: preterm (5.5%), term (94%), and postterm (0.5%). Low birth weight (LBW) had a prevalence rate of 4.8%, whereas the prevalence rate for normal weight was 92.4, and 2.8% for macrosomia. Compared to term, older mother's age [odds ratio (OR)=1.04, 95% confidence interval (CI): 1.02-1.07], preeclampsia (OR=4.14, 95% CI: 2.71-6.31), multiple pregnancy (OR=18.04, 95% CI: 9.75- 33.38), and use of assisted reproductive technology (ART) (OR=2.47, 95% CI: 1.64-33.73) were associated with preterm birth. Better socioeconomic status (SES) was responsible for decreased odds for postterm birth compared to term birth (OR=0.53, 95% CI: 0.37-0.74). Cases with higher maternal body mass index (BMI) were 1.02 times more likely for macrosomia (95% CI: 1.01-1.04), and male infant sex (OR=1.78, 95% CI: 1.21-2.60). LBW was related to multiparity (OR=0.59, 95% CI: 0.42-0.82), multiple pregnancy (OR=17.35, 95% CI: 9.73-30.94), and preeclampsia (OR=3.36, 95% CI: 2.15-5.24). Maternal age, SES, preeclampsia, multiple pregnancy, ART, higher maternal BMI, parity, and male infant sex were determined to be predictive variables for birth weight and gestational age after taking into consideration their association by using a joint multilevel multiple logistic regression model.


A trial of permethrin-treated bed nets in the prevention of malaria in Gambian children.
A trial was undertaken in a rural area of The Gambia to investigate the impact of permethrin-treated bed nets on malaria. Two groups of children, matched for age, sex, and malaria exposure, were followed through the rainy season of 1985 for illness and febrile episodes. One group of 205 children slept under permethrin-treated bed nets (0.5 g/m2); 184 children who slept under placebo-treated nets formed the control group. At the end of the rains the children were examined for splenomegaly and blood samples were taken for determination of packed cell volume (PCV) and parasitaemia. Permethrin treatment of bed nets was well accepted and was without side-effects. Children who slept under treated nets had significantly fewer episodes of clinical malaria than control children. However, at the end of the rains there was no significant difference in the prevalence of splenomegaly or parasitaemia or in the mean PCV between the groups. It is suggested that permethrin treatment of nets may have a greater effect on the duration of probing by mosquitoes for a blood meal than on the number of bites received.


Global Public Perceptions of Genomic Data Sharing: What Shapes the Willingness to Donate DNA and Health Data?
Analyzing genomic data across populations is central to understanding the role of genetic factors in health and disease. Successful data sharing relies on public support, which requires attention to whether people around the world are willing to donate their data that are then subsequently shared with others for research. However, studies of such public perceptions are geographically limited and do not enable comparison. This paper presents results from a very large public survey on attitudes toward genomic data sharing. Data from 36,268 individuals across 22 countries (gathered in 15 languages) are presented. In general, publics across the world do not appear to be aware of, nor familiar with, the concepts of DNA, genetics, and genomics. Willingness to donate one's DNA and health data for research is relatively low, and trust in the process of data's being shared with multiple users (e.g., doctors, researchers, governments) is also low. Participants were most willing to donate DNA or health information for research when the recipient was specified as a medical doctor and least willing to donate when the recipient was a for-profit researcher. Those who were familiar with genetics and who were trusting of the users asking for data were more likely to be willing to donate. However, less than half of participants trusted more than one potential user of data, although this varied across countries. Genetic information was not uniformly seen as different from other forms of health information, but there was an association between seeing genetic information as special in some way compared to other health data and increased willingness to donate. The global perspective provided by our "Your DNA, Your Say" study is valuable for informing the development of international policy and practice for sharing genomic data. It highlights that the research community not only needs to be worthy of trust by the public, but also urgent steps need to be taken to authentically communicate why genomic research is necessary and how data donation, and subsequent sharing, is integral to this.


Treatment-Related Adverse Events of Chimeric Antigen Receptor T-Cell (CAR T) in Clinical Trials: A Systematic Review and Meta-Analysis.
Chimeric antigen receptors T (CAR-T) cell therapy of cancer is a rapidly evolving field. It has been shown to be remarkably effective in cases of hematological malignancies, and its approval by the FDA has significantly increased the enthusiasm for wide clinical usage and development of novel CAR-T therapies. However, it has also challenged physicians and investigators to recognize and deal with treatment-associated toxicities. A total of 2592 patients were included from 84 eligible studies that were systematically searched and reviewed from the databases of PubMed, de, the American Society of Hematology and the Cochrane Library. The meta-analysis and subgroup analysis by a Bayesian logistic regression model were used to evaluate the incidences of therapy-related toxicities such as cytokine release syndrome (CRS) and neurological symptoms (NS), and the differences between different targets and cancer types were analyzed. The pooled all-grade CRS rate and grade ≥ 3 CRS rate was 77% and 29%, respectively, with a significantly higher incidence in the hematologic malignancies (all-grade: 81%; grade ≥ 3: 29%) than in solid tumors (all-grade: 37%; grade ≥ 3: 19%). The pooled estimate NS rate from the individual studies were 40% for all-grade and 28% for grade ≥ 3. It was also higher in the hematologic subgroup than in the solid tumors group. The subgroup analysis by cancer type showed that higher incidences of grade ≥ 3 CRS were observed in anti-CD19 CAR-T therapy for ALL and NHL, anti-BCMA CAR-T for MM, and anti-CEA CAR-T for solid tumors, which were between 24-36%, while higher incidences of grade ≥ 3 NS were mainly observed in CD19-ALL/NHL (23-37%) and BCMA-MM (12%). Importantly, subgroup analysis on anti-CD19 CAR-T studies showed that young patients (vs. adult patients), allologous T cell origin (vs. autologous origin), gamma retrovirus vector, and higher doses of CAR-T cells were associated with high-grade CRS. On the other hand, the patients with NHL (vs ALL), administered with higher dose of CAR-T, and adult patients (vs. young patients) had an increased incidence of grade ≥ 3 NS events. This study offers a comprehensive summary of treatment-related toxicity and will guide future clinical trials and therapeutic designs investigating CAR T cell therapy.


Anti-Aβ drug candidates in clinical trials and plasmonic nanoparticle-based drug-screen for Alzheimer's disease.
Alzheimer's disease (AD) is the most common cause of neurodegenerative disorder in elderly people, and has become a social problem in aging societies globally. Amyloid-β (Aβ) aggregates (i.e., Aβ fibrils and plaques) present in the brains of AD patients are hallmarks of AD. Although various promising anti-Aβ drugs have been tested in pre-clinical and randomized controlled trials, the trial results have not yet been translated into clinical practice due to increasing time and cost of drug development. Recent investigations have addressed how the formation of Aβ aggregates is influenced by the surface of gold nanoparticles (AuNPs) to obtain a detailed understanding of the in vivo process of amyloid formation. Particularly, AuNPs catalytically provide nucleation sites to accelerate the formation of Aβ aggregates. Moreover, AuNPs have great potential as a sensing tool due to their optical property. Employing this dual function (i.e., catalytic and optical property), AuNP-based colorimetry is highlighted as a simple and innovative method for monitoring the efficacy of anti-Aβ reagents. In this review, we briefly survey important developments and designs of anti-Aβ drugs. The significance and perspectives of AuNP-based drug-screening in pharmacologic research are also discussed.


A study on biomedical researchers' perspectives on public engagement in Southeast Asia.
Introduction: Public engagement is increasingly promoted in the scientific community. Although there are studies about researchers' perspectives on public engagement, these are predominantly from Global North settings and there is little data from the context of Southeast Asia. The Oxford University Clinical Research Unit (OUCRU) is a clinical and public health research programme with sites in Vietnam, Nepal and Indonesia. There is a dedicated public engagement team, and it is recognised as an important part of the research process. Methods: Through this study we explored the views and needs of local researchers with regards to practicing public engagement. We obtained opinions of 70 researchers through an online survey with both open-ended and closed-ended questions. Results: Most researchers perceived public engagement as improving public science literacy, rather than supporting public participation in science and research. While the participants largely see public engagement as a necessary practice, they experienced four main barriers to taking part in public engagement: time, lack of capacity, lack of support and personal perceptions. Most participants indicated they had somewhat to low confidence to communicate about science to the public. Experience, skill and knowledge, and personal preference emerged as factors that influence their perceived confidence for science communication. In our analysis, experience appeared to be the main factor contributing to researchers' high confidence. Recommendations: We recommended to support researchers by not only providing them with training for skills and knowledge, but also with opportunities to conduct public engagement, and a range of methods to suit their personal styles of communicating. It is also evident that more support is needed to build an enabling institutional environment that gives researchers professional recognition for their engagement work. This study, while modest in its scope, has informed our approach to supporting researcher-led engagement, and may guide other institutes wishing to improve this.


Methods Matter: Methods for Sampling Microplastic and Other Anthropogenic Particles and Their Implications for Monitoring and Ecological Risk Assessment.
To inform mitigation strategies and understand how microplastics affect wildlife, research is focused on understanding the sources, pathways, and occurrence of microplastics in the environment and in wildlife. Microplastics research entails counting and characterizing microplastics in nature, which is a labor-intensive process, particularly given the range of particle sizes and morphologies present within this diverse class of contaminants. Thus, it is crucial to determine appropriate sampling methods that best capture the types and quantities of microplastics relevant to inform the questions and objectives at hand. It is also critical to follow protocols with strict quality assurance and quality control (QA/QC) measures so that results reflect accurate estimates of microplastic contamination. Here, we assess different sampling procedures and QA/QC strategies to inform best practices for future environmental monitoring and assessments of exposure. We compare microplastic abundance and characteristics in surface-water samples collected using different methods (i.e., manta and bulk water) at the same sites, as well as duplicate samples for each method taken at the same site and approximate time. Samples were collected from 9 sampling sites within San Francisco Bay, California, USA, using 3 different sampling methods: 1) manta trawl (manta), 2) 1-L grab (grab), and 3) 10-L bulk water filtered in situ (pump). Bulk water sampling methods (both grab and pump) captured more microplastics within the smaller size range (<335 µm), most of which were fibers. Manta samples captured a greater diversity of morphologies but underestimated smaller-sized particles. Inspection of pump samples revealed high numbers of particles from procedural contamination, stressing the need for robust QA/QC, including sampling and analyzing laboratory blanks, field blanks, and duplicates. Choosing the appropriate sampling method, combined with rigorous, standardized QA/QC practices, is essential for the future of microplastics research in marine and freshwater ecosystems. Integr Environ Assess Manag 2021;17:282-291. © 2020 SETAC.


MitoNEET is a uniquely folded 2Fe 2S outer mitochondrial membrane protein stabilized by pioglitazone.
Iron-sulfur (Fe-S) proteins are key players in vital processes involving energy homeostasis and metabolism from the simplest to most complex organisms. We report a 1.5 A x-ray crystal structure of the first identified outer mitochondrial membrane Fe-S protein, mitoNEET. Two protomers intertwine to form a unique dimeric structure that constitutes a new fold to not only the approximately 650 reported Fe-S protein structures but also to all known proteins. We name this motif the NEET fold. The protomers form a two-domain structure: a beta-cap domain and a cluster-binding domain that coordinates two acid-labile 2Fe-2S clusters. Binding of pioglitazone, an insulin-sensitizing thiazolidinedione used in the treatment of type 2 diabetes, stabilizes the protein against 2Fe-2S cluster release. The biophysical properties of mitoNEET suggest that it may participate in a redox-sensitive signaling and/or in Fe-S cluster transfer.


Contact sensitivity in the mouse. IV. The role of lymphocytes and macrophages in passive transfer and the mechanism of their interaction.
Contact sensitivity skin reactions were produced in mice by immunization with 2-phenyl-4-ethoxymethylene oxazolone (oxazolone) and detected by the increase in ear thickness after challenging the ears with 2% oxazolone. These skin reactions can be transferred from immunized donors to irradiated recipients by peritoneal exudate cells induced by thioglycollate. The peritoneal exudate cells were separated into purified macrophage and purified lymphocyte populations. Both cell populations transferred skin reactions. However, their time course was different. The reactions produced by lymphocytes were greater at 24 hr than at 12 hr while the reactions produced by macrophages declined slightly between 12 and 24 hr. The working hypothesis was formed that the peritoneal lymphocytes conveyed a factor (presumptive cytophilic antibody) to peritoneal macrophages which enabled them to transfer ear reactions. Experiment showed that peritoneal and lymph node lymphocytes from sensitized donors within a Millipore chamber conveyed a factor to macrophages outside the chamber which enabled them to transfer ear reactions. In contrast, peritoneal macrophages (from sensitized donors) within the chamber and peritoneal lymphocytes outside the chamber were inactive. These findings suggested that there are three modes of immunological tissue damage: hypersensitivity mediated by lymphocytes (classical delayed hypersensitivity), hypersensitivity mediated by circulating antibody (classical immediate type hypersensitivity), and hypersensitivity mediated by macrophages which have passively acquired a factor (macrophage-mediated hypersensitivity).


Haloperidol affects coupling between QT and RR intervals in guinea pig isolated heart.
Prolonged QT interval is an independent risk factor for development of ventricular arrhythmias. Haloperidol is one of the drugs inducing QT prolongation. Previous studies showed that haloperidol affects not only QT duration but also heart rate (RR interval). The present work focused on relationship between QT and RR and its changes under acute and chronic haloperidol administration. The study included 14 male guinea pigs divided into control and haloperidol-treated group. After 21-days administration of haloperidol or vehiculum, electrograms in isolated hearts were recorded. QT/RR and dQT/dRR coupling were calculated. Chronic haloperidol administration significantly decreases the coupling between QT and RR. Acute haloperidol exposure significantly decreases the dQT/dRR coupling in both treated and untreated guinea pig hearts. Flatter QT/RR relationship reveals a lack of QT adaptation to increased heart rate. It should be emphasized that in such situation ECG recording will not show significant QT prolongation evaluated according to clinical rules. However, if QT interval does not adapt to increased heart rate sufficiently, the risk of ventricular arrhythmias may be increased despite practically normal QT interval length. The results are supported by findings in biochemical analyses, which proved eligibility of the used model.


GENIES: gene network inference engine based on supervised analysis.
Gene network inference engine based on supervised analysis (GENIES) is a web server to predict unknown part of gene network from various types of genome-wide data in the framework of supervised network inference. The originality of GENIES lies in the construction of a predictive model using partially known network information and in the integration of heterogeneous data with kernel methods. The GENIES server accepts any 'profiles' of genes or proteins (e.g. gene expression profiles, protein subcellular localization profiles and phylogenetic profiles) or pre-calculated gene-gene similarity matrices (or 'kernels') in the tab-delimited file format. As a training data set to learn a predictive model, the users can choose either known molecular network information in the KEGG PATHWAY database or their own gene network data. The user can also select an algorithm of supervised network inference, choose various parameters in the method, and control the weights of heterogeneous data integration. The server provides the list of newly predicted gene pairs, maps the predicted gene pairs onto the associated pathway diagrams in KEGG PATHWAY and indicates candidate genes for missing enzymes in organism-specific metabolic pathways. GENIES (http://www.genome.jp/tools/genies/) is publicly available as one of the genome analysis tools in GenomeNet.


Pulmonary Kaposi's sarcoma in Africa.
A study was carried out to identify the main clinical radiological and bronchoscopic features of HIV related Kaposi's sarcoma of the lung in African patients. Forty seven HIV positive patients with epidemic Kaposi's sarcoma who had clinical or radiological respiratory changes were investigated by simple lung function tests and fibreoptic bronchoscopy. The most common respiratory symptoms in the 47 patients were persistent cough in 42, haemoptysis in 23, and breathlessness in 38. A restrictive spirometric pattern was most common. The mean (SD) forced expiratory volume in one second (FEV1) was 1.88 (0.62) 1 with a forced vital capacity (FVC) of 2.66 (0.87) 1 and a FEV1/FVC% of 73.2 (7.5). On the chest radiograph 26 patients had diffuse reticulonodular shadows, 11 focal nodular shadows, seven a pleural effusion, and one a substantial increase in vascular markings; in two the radiograph was normal. At bronchoscopy characteristic discrete lesions were easily visible in 37 patients and were often bright red. Multiple nodules were seen in 11, flat or early plaque lesions in 12 (14 had both), proximal flat lesions and diffuse infiltration in three, diffuse infiltration alone in four, and masses in two; one had normal appearances at bronchoscopy. One patient had Pneumocystis carinii and two had a single bacterial pathogen cultured from the bronchoalveolar lavage fluid. Only two of 29 bronchoscopic biopsies showed classical histological Kaposi's sarcoma. After cytotoxic treatment 20 patients have died, with an overall median survival of 70 days. In this African population symptomatic pulmonary Kaposi's sarcoma was common, with lesions seen in all but one patient at bronchoscopy. Coexistent infection was uncommon. Prognosis was poor despite treatment.


The paradox of chronic neuroinflammation, systemic immune suppression, autoimmunity after traumatic chronic spinal cord injury.
During the transition from acute to chronic stages of recovery after spinal cord injury (SCI), there is an evolving state of immunologic dysfunction that exacerbates the problems associated with the more clinically obvious neurologic deficits. Since injury directly affects cells embedded within the "immune privileged/specialized" milieu of the spinal cord, maladaptive or inefficient responses are likely to occur. Collectively, these responses qualify as part of the continuum of "SCI disease" and are important therapeutic targets to improve neural repair and neurological outcome. Generic immune suppressive therapies have been largely unsuccessful, mostly because inflammation and immunity exert both beneficial (plasticity enhancing) and detrimental (e.g. glia- and neurodegenerative; secondary damage) effects and these functions change over time. Moreover, "compartimentalized" investigations, limited to only intraspinal inflammation and associated cellular or molecular changes in the spinal cord, neglect the reality that the structure and function of the CNS are influenced by systemic immune challenges and that the immune system is 'hardwired' into the nervous system. Here, we consider this interplay during the progression from acute to chronic SCI. Specifically, we survey impaired/non-resolving intraspinal inflammation and the paradox of systemic inflammatory responses in the context of ongoing chronic immune suppression and autoimmunity. The concepts of systemic inflammatory response syndrome (SIRS), compensatory anti-inflammatory response syndrome (CARS) and "neurogenic" spinal cord injury-induced immune depression syndrome (SCI-IDS) are discussed as determinants of impaired "host-defense" and trauma-induced autoimmunity.


The association between genetic risk score and blood pressure is modified by coffee consumption: Gene-diet interaction analysis in a population-based study.
Recent genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that are associated with high blood pressure (BP). However, whether coffee consumption interacts with the genetic variants related to BP is yet unclear. Thus, this study aimed to investigate whether the association between genetic risk core (GRS) and blood pressure was modified by usual coffee consumption. Data were from the 'Health Survey of São Paulo' a cross-sectional population-based survey, among 533 participants aged 20 years or older. Coffee consumption was estimated by two 24-h dietary recalls and categorized into <1, 1-3, and >3 cups/day. The GRS was calculated based on SNPs in previous GWAS [CYP1A1/CYP1A2 (rs2470893, rs2472297); CPLX3/ULK3 (rs6495122); MTHFR (rs17367504)]. Multiple logistic regression analysis were performed to estimate the associations between GRS with high BP, and both, high systolic BP (SBP) and diastolic BP (DBP); and the multiplicative interaction term between the GRS and coffee consumption were tested by including in the models. Higher GRS independently contributed to higher probability of elevated BP, SBP and DBP in this population (OR = 1.85, 95%CI = 1.19-2.87; OR = 2.30, 95%CI = 1.32-4.01 and OR = 1.66, 95%CI = 1.10-2.51; respectively). Moreover, there were a significant interaction effects for coffee consumption and GRS on the high BP, SBP and DBP. Individuals with higher BP increasing alleles in the GRS had a significantly high BP (OR = 5.09, 95%CI = 1.32-19.7), and both elevated SBP and DBP (OR = 2.14, 95%CI = 1.12-4.11; OR = 3.54, 95%CI = 1.17-10.75), among those with high coffee consumption (>3 cups coffee/day). Consumption of coffee could interact with genetic predisposition in relation to BP. Thus, the GRS for high BP is modified by coffee consumption. Individuals with greater GRS appeared to have high BP associated with higher coffee consumption, highlighting the particular importance to reduce coffee intake in individuals genetically predisposed to this cardiovascular disease risk factor.


Fluctuating selection strength and intense male competition underlie variation and exaggeration of a water strider's male weapon.
Sexually selected traits can reach high degrees of phenotypic expression and variation under directional selection. A growing number of studies suggest that such selection can vary in space, time and form within and between populations. However, the impact of these fluctuations on sexual trait evolution is poorly understood. In the water strider Microvelia longipes, males display striking trait exaggeration and phenotypic variation manifested as extreme differences in the rear leg length. To study the origin and maintenance of this exaggerated trait, we conducted comparative behavioural, morphometric and reaction norm experiments in a selection of Microvelia species. We uncovered differences both in the mating behaviour and the degree of sexual dimorphism across these species. Interestingly, M. longipes evolved a specific mating behaviour where males compete for egg-laying sites, consisting of small floating objects, to intercept and copulate with gravid females. Through male-male competition assays, we demonstrated that male rear legs are used as weapons to dominate egg-laying sites and that intense competition is associated with the evolution of rear leg length exaggeration. Field observations revealed rapid fluctuation in M. longipes habitat stability and the abundance of egg-laying sites. Paternity tests using genetic markers demonstrated that small males could only fertilize about 5% of the eggs when egg-laying sites are limiting, whereas this proportion increased to about 20% when egg-laying sites become abundant. Furthermore, diet manipulation and artificial selection experiments also showed that the exaggerated leg length in M. longipes males is influenced by both genetic and nutritional factors. Collectively, our results highlight how fluctuation in the strength of directional sexual selection, through changes in the intensity of male competition, can drive the exaggeration and phenotypic variation in this weapon trait.


Rapid Mast Cell Generation from Gata2 Reporter Pluripotent Stem Cells.
Mast cells are tissue-resident immune cells. Their overgrowth/overactivation results in a range of common distressing, sometimes life-threatening disorders, including asthma, psoriasis, anaphylaxis, and mastocytosis. Currently, drug discovery is hampered by use of cancer-derived mast cell lines or primary cells. Cell lines provide low numbers of mature mast cells and are not representative of in vivo mast cells. Mast cell generation from blood/bone marrow gives poor reproducibility, requiring 8-12 weeks of culture. Here we report a method for the rapid/robust production of mast cells from pluripotent stem cells (PSCs). An advantageous Gata2Venus reporter enriches mast cells and progenitors as they differentiate from PSCs. Highly proliferative mouse mast cells and progenitors emerge after 2 weeks. This method is applicable for rapid human mast cell generation, and could enable the production of sufficient numbers of physiologically relevant human mast cells from patient induced PSCs for the study of mast cell-associated disorders and drug discovery.


Pituitary control of growth in the neonatal rat: effects of neonatal hypophysectomy on somatic and organ growth, serum insulin-like growth factors (IGF)-I and -II levels, and expression of IGF binding proteins.
The neonatal period is a time of transition between pituitary-independent fetal growth and the pituitary-dependent growth seen in older mammals. To evaluate pituitary-dependent neonatal growth, Wistar rats were hypophysectomized (Hx) on postnatal day 6. Nineteen days post-Hx, body weight and tail length were inhibited 48% and 34%, respectively, compared with sham-Hx controls. Organ weights determined on days 10, 15, 20, 25, and 30 revealed three patterns of pituitary-dependence: 1) pituitary-independent growth in the brain and lung; 2) moderate pituitary-dependent growth in the heart, liver, kidney, and intestine; and 3) marked pituitary-dependent growth in the adrenals, spleen, and testes. Both serum insulin-like growth factor (IGF)-I and -II levels fell significantly in Hx pups by 54 h after Hx (P = 0.0005), and Northern analysis on day 15 showed a significant decrease in liver messenger RNA (mRNA) for IGF-II. Analysis of the major IGF binding proteins (BPs) was performed by Western ligand blots. Hx performed on day 6 resulted in a linear decrease in the amount of the 22k BP from day 10 to day 30. In contrast, the major neonatal BP (IGFBP-2, a 29.5k molecule) showed a biphasic response to neonatal Hx. On postnatal day 10, 4 days after Hx, a significant decrease in IGFBP-2 occurred, which persisted through day 15; by postnatal day 20 and continuing through postnatal day 30, the amount of IGFBP-2 in the serum dramatically increased. The 40 to 50k fraction of IGFBP-3 first appeared in significant quantities by postnatal day 20, and after Hx dropped to 10% of sham-control values. Similarly, Northern analysis on day 15 demonstrated a significant decrease in liver, but not brain, mRNA for IGFBP-2 after Hx, whereas on postnatal day 25, liver mRNA for IGFBP-2 was increased in Hx pups compared with sham controls. We conclude that the pituitary gland exerts significant but selective effects on neonatal growth, with the notable exception of brain growth. Serum levels of both IGF-I and IGF-II, as well as their BPs, are pituitary dependent in the neonatal period. Pituitary-dependent neonatal growth thus appears to be mediated by IGF and modulated by IGF-binding proteins. On the other hand, that portion of the persistent growth in the neonatal Hx rat that is independent of the pituitary-IGF axis may be a good model for investigation of fetal growth.


De novo emergence of obsessive-compulsive symptoms with atypical antipsychotics in asian patients with schizophrenia or schizoaffective disorder: a retrospective, cross-sectional study.
The objective of our study was to establish the incidence of de novo emergence of obsessive-compulsive symptoms (OCS) in patients taking atypical antipsychotics in an Asian population. Outpatients with schizophrenia or schizo-affective disorder (DSM-IV criteria) who were prescribed any of the 4 atypical antipsychotics approved by the U.S. Food and Drug Administration at the time of the study (clozapine, olanzapine, risperidone, and quetiapine) during a 2-month period (April through May) in 2003 at a tertiary psychiatric hospital were identified. Demographic information was gathered, and the Yale-Brown Obsessive Compulsive Symptom Checklist and the Yale-Brown Obsessive Compulsive Scale (YBOCS) were used for assessment by an independent rater who was blinded to the patients' treatment. Three hundred three patients met the entry criteria and consented to participate in the study. These subjects included 180 women and 123 men. The mean age was 41 years (range, 21-76 years), and the outpatients were predominantly of Chinese ethnicity (86%). Obsessive-compulsive symptoms emerged de novo in 9 of the 303 patients (3.0%); 2 of the 9 patients were taking clozapine, 4 were taking olanzapine, and 3 were taking risperidone. This study highlights the need for clinical awareness of the possible occurrence or exacerbation of OCS with atypical antipsychotics. It also highlights the need for careful assessment and mental state examination of these patients and the need to educate the patient on the possibility of these side effects.


Three Centuries of Synchronous Forest Defoliator Outbreaks in Western North America.
Insect outbreaks often occur synchronously across large spatial scales, but the long-term temporal stability of the phenomenon and the mechanisms behind it are not well understood. In this study, I use a widespread lepidopteran defoliator native to western North America-the western spruce budworm-as a case study to explore patterns of and potential causes for synchronous population fluctuations. Analyses of synchrony are typically severely limited by the short historical records available for many species. To overcome this limitation, I compiled multi-century dendrochronological reconstructions of western spruce budworm outbreaks from across much of the species' range. This allowed me to analyze synchrony at a sub-continental spatial scale over the last three centuries. I found statistically significant synchrony among regional outbreak records up to 2,000 km apart and identified numerous outbreak periods that occurred synchronously across much of the species' range. I quantified spatial and temporal associations between climate and synchronous outbreak periods using paleoclimate reconstructions. The spatial patterns of outbreak histories and climate records were remarkably similar, with higher similarity in outbreak histories apparent between regions with more similar climate conditions. Synchronous outbreaks typically occurred during periods of average or above average moisture availability preceded by periods of low moisture availability. My results suggest that climatic variability has played a key role in synchronizing western spruce budworm population fluctuations in disjunct forests across western North America for at least the last three centuries. Widespread synchrony appears to be a natural part of this species' population dynamics, though synchronous outbreaks have occurred more frequently during the 20th century than during prior centuries. This study uses a novel combination of statistical methods and dendrochronological data to provide analyses of this species' population dynamics with an unprecedented combination of spatial extent and temporal depth.


ACR Appropriateness Criteria® rib fractures.
Rib fracture is the most common thoracic injury, present in 10% of all traumatic injuries and almost 40% of patients who sustain severe nonpenetrating trauma. Although rib fractures can produce significant morbidity, the diagnosis of associated complications (such as pneumothorax, hemothorax, pulmonary contusion, atelectasis, flail chest, cardiovascular injury, and injuries to solid and hollow abdominal organs) may have a more significant clinical impact. When isolated, rib fractures have a relatively low morbidity and mortality, and failure to detect isolated rib fractures does not necessarily alter patient management or outcome in uncomplicated cases. A standard posteroanterior chest radiograph should be the initial, and often the only, imaging test required in patients with suspected rib fracture after minor trauma. Detailed radiographs of the ribs rarely add additional information that would change treatment, and, although other imaging tests (eg, computed tomography, bone scan) have increased sensitivity for detection of rib fractures, there are little data to support their use. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review process include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.


A randomised controlled trial to compare the effectiveness of ice-packs and Epifoam with cooling maternity gel pads at alleviating postnatal perineal trauma.
To evaluate the effectiveness of standard regimes (ice packs and Epifoam) at relieving perineal trauma and compare these with a new cooling device (maternity gel pad). A randomised controlled trial involving three treatment groups. The women were free to choose the time of initial application (within four hours after delivery) in all treatment groups and the number of subsequent treatments up to 48 hours after suturing. A midwifery unit in the north of England and then continued in the women's own homes. 120 women who had undergone an instrumental delivery and had a 48 hours post-delivery stay in a postnatal ward. The ordinal scale of none, mild, moderate and severe was used to determine the levels of perineal oedema and bruising at initial assessment (less than 4 hours), 24 hours and at 48 hours, by use of a newly developed visual evaluating tool. Self-assessed pain was recorded using a 10-point visual analogue scale within four hours, at 24 hours, 48 hours, and finally at five days after suturing. Women's opinions as to the effectiveness of their treatment was rated by use of a 5-point scale describing the categories; poor, fair, good, very good and excellent. A high proportion of women had some perineal oedema at initial assessment. A statistically significant difference in the proportion of women with oedema was found between treatment groups at 48 hours (p = 0.01), which was in favour of the maternity gel pad group. This was particularly noticeable for women with initial levels of mild oedema (p = 0.017). Localised treatment with the gel pad caused a significant decrease in reported pain at 48 hours in women who initially demonstrated moderate or severe pain (p = 0.048). A significant increase in the proportion of women with some bruising was seen across all treatment groups from initial assessment, through 24 hours to 48 hours (p < 0.0005). The bruising was significantly less in the gel-pad group in women who initially had no bruising (p = 0.021). There was no statistically significant effect of treatment at other initial levels of severity for oedema, bruising or pain at 24 hours, 48 hours and five days (for pain). Women in the gel-pad group rated the effectiveness of their localised treatment to be significantly higher than women in the other two treatment groups (p < 0.0005). This trial demonstrated that a high proportion of women experience perineal oedema, bruising and pain following an instrumental delivery, which continues for at least five days for perineal pain, despite oral analgesia. Maternity gel pads, which were specially designed to cool the perineal region, were more effective in alleviating perineal trauma when compared with hospital standard regimens and were more highly rated by women.


Trans-spectral absorption and scattering of electromagnetic radiation by diesel soot.
The mass density normalized absorption and total scattering coefficients have been measured using in situ techniques at selected wavelengths from the visible to approximately 1 cm for soot generated by the open combustion of diesel fuel. Particle morphologies are complex although similar to those of soots of other hydrocarbons and methods of generation. An ellipsoidal model has been applied as an approximation to the often multiconnected, chainlike aerosol and then compared with the measured results. The experimental results show an approximate (lambda)(-1) dependence over more than five decades of wavelength data. There is only general agreement with the simplified calculations in this feature as well as in the magnitude.


Model-based evaluation of similarity in pharmacokinetics of two formulations of the blood-derived plasma product c1 esterase inhibitor.
A novel formulation of C1 esterase inhibitor concentrate, a plasma product used in the treatment of hereditary angioedema (HAE), was studied in a clinical trial for similarity in pharmacokinetics (PK) compared with the reference product. Direct trial data were limited given the availability of patients, and therefore a modeling approach was used to study similarity. Type I error of the study was evaluated using simulations based on retrospective data. A population PK modeling analysis was performed on data from the trial. Analysis of variance was carried out on results of a noncompartmental PK analysis (NCA) of the clinical data. Simulations showed that type I error was inflated to 62% (P < .05) when bioequivalence criteria (confidence intervals within 80%-125%) were adhered to strictly. In the clinical trial, 13 HAE patients were evaluable. The population PK analysis showed no significant differences in PK parameters, whereas confidence intervals for all parameters were within 80% to 125%. The relative differences in area under the curve, incremental recovery, and mean residence time estimated using NCA were all close to 1. The novel formulation showed similar PK characteristics to the original formulation. The model-based approach showed that strict criteria for PK comparison could not be applied in this analysis.


Protective role of reactive astrocytes in brain ischemia.
Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP(-/-)Vim(-/-) mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP(-/-)Vim(-/-) than in wild-type (WT) mice; GFAP(-/-), Vim(-/-) and WT mice had the same infarct volume. Endothelin B receptor (ET(B)R) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP(-/-)Vim(-/-) astrocytes. In WT astrocytes, ET(B)R colocalized extensively with bundles of IFs. GFAP(-/-)Vim(-/-) astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP(-/-)Vim(-/-) than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ET(B)R-mediated control of gap junctions, and PAI-1 expression.


The chronic impact of work on suicides and under-utilization of psychiatric and psychosocial services.
Work-related stress appears to be a contributing factor in the lives of employed people who kill themselves, particularly during economic downturns. However, few studies have compared them with working community controls who may be experiencing similar strains, in order to explore the role of mental disorders in these deaths and the implication of such strains on their service use pattern. We hypothesized that both work stress and mental illness were associated with suicides, and that mental illness served as the mediator between work stress and suicide. Based on the Behavioral Model, we also assumed work stress associated with their use of services. A sample of 175 employed individuals (suicides=63; controls=112) drawn from a psychological autopsy (PA) dataset was examined based on demographics and socioeconomic factors, psychiatric diagnoses and use of services, psychosocial factors, and life events. A mediator analysis was conducted to examine the impact of work on suicides. Suicides generally had depression and anxiety, debts, higher impulsivity and poorer social support in comparison to controls. Chronic impact from work, which was fully mediated by psychiatric illness, was found higher among those suicides that did not seek contact with clinical service providers. PA is a post-hoc cross-sectional comparison method which does not allow causal analyses. It is important to develop new approaches for engaging vulnerable individuals in the workplace before they become suicidal, as their depression and social isolation can serve to cut them off from help when they are most in need. Occupational mental health programs should be made available for employees and their families.


Two-dimensional ammonium distribution in sediment pore waters using a new colorimetric diffusive equilibration in thin-film technique.
This study presents a new gel based technique to describe the pore water ammonium distribution through the sediment-water interface in two dimensions at a millimeter scale. The technique is an adaptation of the classical colorimetric method based on the Berthelot's reaction. After the thin film of the gel probe was equilibrated by diffusion either in standard solutions or in pore waters, a colorimetric reagent gel was set on the gel probe, allowing development of the characteristic green color. A flatbed scanner and subsequent densitometry image analysis allowed to determine the concentration distribution of ammonium. The gel probe was tested in the laboratory for two media, deionized water and seawater, within the range 0-3000 μM in NH4 +. Detection limit is about 20 μM and accuracy about ±25 μM. The field validation was realized in a tidal mudflat of the French Atlantic coast by comparison with conventional pore water extraction and colorimetric analysis. The large range of concentrations and its applicability in continental and marine sediments suggest a wide range of applications of the technique for a reasonable cost.