Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets.
Although genome-wide association studies have implicated many individual loci in complex diseases, identifying the exact causal alleles and the cell types within which they act remains greatly challenging. To ultimately understand disease mechanism, researchers must carefully conceive functional studies in relevant pathogenic cell types to demonstrate the cellular impact of disease-associated genetic variants. This challenge is highlighted in autoimmune diseases, such as rheumatoid arthritis, where any of a broad range of immunological cell types might potentially be impacted by genetic variation to cause disease. To this end, we developed a statistical approach to identify potentially pathogenic cell types in autoimmune diseases by using a gene-expression data set of 223 murine-sorted immune cells from the Immunological Genome Consortium. We found enrichment of transitional B cell genes in systemic lupus erythematosus (p = 5.9 × 10(-6)) and epithelial-associated stimulated dendritic cell genes in Crohn disease (p = 1.6 × 10(-5)). Finally, we demonstrated enrichment of CD4+ effector memory T cell genes within rheumatoid arthritis loci (p < 10(-6)). To further validate the role of CD4+ effector memory T cells within rheumatoid arthritis, we identified 436 loci that were not yet known to be associated with the disease but that had a statistically suggestive association in a recent genome-wide association study (GWAS) meta-analysis (p(GWAS) < 0.001). Even among these putative loci, we noted a significant enrichment for genes specifically expressed in CD4+ effector memory T cells (p = 1.25 × 10(-4)). These cell types are primary candidates for future functional studies to reveal the role of risk alleles in autoimmunity. Our approach has application in other phenotypes, outside of autoimmunity, where many loci have been discovered and high-quality cell-type-specific gene expression is available.


Correction: Eight RGS and RGS-like Proteins Orchestrate Growth, Differentiation, and Pathogenicity of Magnaporthe oryzae.
[This corrects the article DOI: 10.1371/journal.ppat.1002450.].


Delayed speech development with facial asymmetry.
We report on four unrelated children with delayed speech development associated with mild facial asymmetry and transverse ear lobe creases. The combination of these features proved to be familial in one case. Our findings seem to confirm the existence of a syndrome described by Mehes [(1993) J Med Genet 30:76-77].


Regimented Phosphodiesterase Type 5 Inhibitor Use Reduces Emergency Department Visits for Recurrent Ischemic Priapism.
We evaluated the real-world effectiveness of regimented phosphodiesterase type 5 inhibitor dosing on recurrent ischemic priapism outcomes using emergency department visits as a proxy for therapeutic control of the disorder. We performed a retrospective chart review of patients with recurrent ischemic priapism who were started on regimented phosphodiesterase type 5 inhibitor therapy from May 2006 to January 2020. We compared the number of emergency department visits per month during a 6-month period before treatment, during treatment and after treatment discontinuation. We extracted and categorized priapism outcomes such as priapism frequency and duration. Of 216 patients identified with all cause priapism 114 were diagnosed with recurrent ischemic priapism and 42 were initiated on regimented phosphodiesterase type 5 inhibitor therapy. Treatment effectiveness was analyzed for 24 evaluable patients. Priapism etiology was idiopathic in 12 patients (50%), sickle cell disease in 11 (46%) and drug-induced in 1 (4%). The median length of regimented phosphodiesterase type 5 inhibitor use was 3 months (IQR 2-7). Treatment decreased emergency department visits per month by 4.4-fold (p <0.001), priapism duration tiers (p <0.001) and priapism frequency tiers (p <0.001). Of 24 patients 22 (92%) reported improvement in priapism outcomes, 9 of whom reported resolution of recurrent ischemic priapism episodes. A subgroup analysis of 17 patients with recurrent ischemic priapism relapse after treatment discontinuation showed a significant increase in priapism duration (p <0.001) and frequency (p <0.001) but no significant change in emergency department visits per month (p=0.91). Regimented phosphodiesterase type 5 inhibitor therapy was an impactful treatment in managing recurrent ischemic priapism according to objective and subjective parameters. This study provides further support for the use of regimented phosphodiesterase type 5 inhibitor dosing as a preventive strategy for recurrent ischemic priapism.


Direct and indirect in vivo stimulation of LAF-like production induced by acute nonspecific inflammatory processes.
Peritoneal macrophages harvested from animals undergoing an acute non-immunological inflammatory reaction induced by an injection of calcium pyrophosphate ( CaPP ) or dextran into the pleural cavity showed an enhanced level of production of a lymphocyte activating factor (LAF) like material. On the other hand, macrophages harvested from the site of inflammation did not show enhanced production of this activity when compared to macrophages derived from normal controls. This enhanced activity was observed for up to two/three days after initiation of the inflammatory reaction and was obtained in both the presence and absence of lipopolysaccharide (LPS) during in vitro cultivation. Thus these results demonstrate that the acute inflammatory reaction, initiated by a non-antigenic stimulus ( CaPP ), is able to stimulate macrophages remote from the inflammatory site to produce a factor which behaves like LAF in a standard LAF assay.


The benefit of early trabeculectomy versus conventional management in primary open angle glaucoma relative to severity of disease.
One hundred and sixteen patients with newly diagnosed primary open angle glaucoma were selected for a randomised, prospective, multicentre trial if the untreated intraocular pressure was over 25 mmHg and there was field loss characteristic of glaucoma. Conventional management of medical therapy followed by trabeculectomy in unsuccessful cases was compared with trabeculectomy at diagnosis followed where necessary by supplementary medical therapy. At a mean follow-up of 4.6 years there was no significant difference in visual acuity between the groups but the conventional management group had significantly greater loss of visual field which occurred during the unsuccessful attempt at medical control. The eyes which lost most visual field were those with least field loss at diagnosis and this paradox was attributed to a prolonged attempt at medical control in these eyes because they were thought to have a lower risk of visual field deterioration.


XXY male with X-linked dominant chondrodysplasia punctata (Happle syndrome)
Happle syndrome is an X-linked dominant disorder with presumed lethality in hemizygous males; familial occurrence is rare. We describe a family with Happle syndrome affecting individuals in 3 generations. A man in this family is the first known male patient with Happle syndrome. He is severely affected; this may be due to his 47,XXY karyotype.


Human biodistribution and dosimetry of [18F]nifene, an α4β2* nicotinic acetylcholine receptor PET tracer.
The α4β2* nicotinic acetylcholine receptor (nAChR) system is implicated in many neuropsychiatric pathologies. [18F]Nifene is a positron emission tomography (PET) ligand that has shown promise for in vivo imaging of the α4β2* nAChR system in preclinical models and humans. This work establishes the radiation burden associated with [18F]nifene PET scans in humans. Four human subjects (2M, 2F) underwent whole-body PET/CT scans to determine the human biodistribution of [18F]nifene. Source organs were identified and time-activity-curves (TACs) were extracted from the PET time-series. Dose estimates were calculated for each subject using OLINDA/EXM v1.1. [18F]Nifene was well tolerated by all subjects with no adverse events reported. The mean whole-body effective dose was 28.4±3.8 mSv/MBq without bladder voiding, and 22.6±1.9 mSv/MBq with hourly micturition. The urinary bladder radiation dose limited the maximum injected dose for a single scan to 278 MBq without urinary bladder voiding, and 519 MBq with hourly voiding. [18F]Nifene is a safe PET radioligand for imaging the α4β2* nAChR system in humans. This works presents human internal dosimetry for [18F]nifene in humans for the first time. These results facilitate safe development of future [18F]nifene studies to image the α4β2* nAChR system in humans.


Controlling the Energy-Transfer Processes in a Nanosized Molecular Upconverter to Tap into Luminescence Thermometry Application.
Photon upconversion (UC) in molecular species remains a highly sought-after property with vast potential applications in many fields. Until now, a few reports on molecular upconverters are limited to demonstrating upconversion. The low UC quantum yields (QY) and nuclearities hindered the application capabilities for molecular upconverters. To overcome these limitations, we report the use of a molecular cluster-aggregate (MCA) containing 20 lanthanide ions to target YbIII -TbIII -based cooperative UC. Upconversion quantum yield value of 1.04×10-4 %, among the highest value observed for a molecular cooperative UC, was attained for the {Gd11 Tb2 Yb7 } composition. Substitution of GdIII ions for EuIII centers opens a YbIII →TbIII →EuIII energy-transfer pathway, allowing the first proof-of-concept of potential application for molecular UC. This report on upconversion-based luminescence thermometry in a molecular species endorses further development of upconversion properties of nanoscale MCAs.


Portable comprehensive two-dimensional micro-gas chromatography using an integrated flow-restricted pneumatic modulator.
Two-dimensional (2D) gas chromatography (GC) provides enhanced vapor separation capabilities in contrast to conventional one-dimensional GC and is useful for the analysis of highly complex chemical samples. We developed a microfabricated flow-restricted pneumatic modulator (FRPM) for portable comprehensive 2D micro-GC (μGC), which enables rapid 2D injection and separation without compromising the 1D separation speed and eluent peak profiles. 2D injection characteristics such as injection peak width and peak height were fully characterized by using flow-through micro-photoionization detectors (μPIDs) at the FRPM inlet and outlet. A 2D injection peak width of ~25 ms could be achieved with a 2D/1D flow rate ratio over 10. The FRPM was further integrated with a 0.5-m long 2D μcolumn on the same chip, and its performance was characterized. Finally, we developed an automated portable comprehensive 2D μGC consisting of a 10 m OV-1 1D μcolumn, an integrated FRPM with a built-in 0.5 m polyethylene glycol 2D μcolumn, and two μPIDs. Rapid separation of 40 volatile organic compounds in ~5 min was demonstrated. A hybrid 2D contour plot was constructed by using both 1D and 2D chromatograms obtained with the two μPIDs at the end of the 1D and 2D μcolumns, which was enabled by the presence of the flow resistor in the FRPM.


Models for the a subunits of the Thermus thermophilus V/A-ATPase and Saccharomyces cerevisiae V-ATPase enzymes by cryo-EM and evolutionary covariance.
Rotary ATPases couple ATP synthesis or hydrolysis to proton translocation across a membrane. However, understanding proton translocation has been hampered by a lack of structural information for the membrane-embedded a subunit. The V/A-ATPase from the eubacterium Thermus thermophilus is similar in structure to the eukaryotic V-ATPase but has a simpler subunit composition and functions in vivo to synthesize ATP rather than pump protons. We determined the T. thermophilus V/A-ATPase structure by cryo-EM at 6.4 Å resolution. Evolutionary covariance analysis allowed tracing of the a subunit sequence within the map, providing a complete model of the rotary ATPase. Comparing the membrane-embedded regions of the T. thermophilus V/A-ATPase and eukaryotic V-ATPase from Saccharomyces cerevisiae allowed identification of the α-helices that belong to the a subunit and revealed the existence of previously unknown subunits in the eukaryotic enzyme. Subsequent evolutionary covariance analysis enabled construction of a model of the a subunit in the S. cerevisae V-ATPase that explains numerous biochemical studies of that enzyme. Comparing the two a subunit structures determined here with a structure of the distantly related a subunit from the bovine F-type ATP synthase revealed a conserved pattern of residues, suggesting a common mechanism for proton transport in all rotary ATPases.


Beyond cue reactivity: blunted brain responses to pleasant stimuli predict long-term smoking abstinence.
Identifying addicts with higher risk of relapse would provide the opportunity to implement individualized interventions and increase cessation success rates. Unfortunately, the ability to predict the long-term success of drug cessation treatments continues to elude researchers. We tested whether brain responses to emotional and cigarette-related pictures were predictive of the ability to abstain from smoking. Smokers interested in quitting (n=180) participated in a smoking cessation clinical trial. Before the initiation of any treatment, we recorded event-related potentials (ERPs) evoked by emotional (both pleasant and unpleasant), neutral, and cigarette-related images. Cluster analysis was used to assign smokers to two groups based on the amplitude of the late positive potential (LPP) to the experimental stimuli. While both groups showed enhanced responses to cigarette-related cues, one group (n=81) also showed blunted brain responses to intrinsically pleasant stimuli. Smokers in the latter group were significantly less likely to be abstinent at 10, 12 and 24 weeks after their quit date. In conclusion, using ERPs, a direct measure of brain activity, we found that smokers with blunted brain responses to intrinsically pleasant stimuli had lower rates of long-term smoking abstinence. This response offers a new biomarker for identifying smokers at higher risk of relapse and for testing the efficacy of new interventions aimed at normalizing brain reward systems' responses to intrinsically pleasant stimuli.


Controversies in Microvascular Maxillofacial Reconstruction.
The effectiveness and reliability of microvascular reconstruction for large defects in the head and neck is no longer disputed. However, many controversies still persist in the ideal perioperative management of patients undergoing free tissue transfer. The optimal method of postoperative monitoring, the use of vasoconstrictors in the perioperative period, and the use of anticoagulants in the postoperative period remain topics of debate. This article offers recommendations on each of these controversies based on a review of the current literature.


Effect of perfluorochemical (PFC) emulsion on acute carbon monoxide poisoning in rats.
The effect of perfluorochemical (PFC) emulsion (25 w/v per cent of PFC concentration) on carbon monoxide poisoning was studied in rats exposed to 97 per cent O2 and three per cent CO. There was no significant difference in conversion rate of hemoglobin to carboxyhemoglobin (COHb) between PFC emulsion and saline groups. However, after re-exposure to pure oxygen, PFC emulsion group circulation reconverted to oxyhemoglobin (OXYHb) at a significantly faster rate than circulation in the control group. Survival time of rats was considerably affected by infusion of PFC emulsion and prolonged in proportion to increased injection dosage. Significant elevations in plasma glucose, lactate and aldolase levels and lactate/pyruvate ratio were found in the saline group and these levels remained well within normal range in the PFC emulsion group. These results indicate that PFC emulsion can function as an oxygen carrier in the presence of carbon monoxide and can deliver sufficient oxygen to peripheral tissues.


Effects of carrier agents on powder properties, stability of carotenoids, and encapsulation efficiency of goldenberry (Physalis peruviana L.) powder produced by co-current spray drying.
Maltodextrin, modified starch, inulin, alginate, gum arabic, and combinations thereof were used as carrier agents for spray drying of carotenoid-rich goldenberry (Physalis peruviana L.) juice and compared to cellobiose as an alternative carrier. Powders were analyzed with respect to particle size and morphology, yield, moisture content, cold water solubility, suspension stability, hygroscopicity, carotenoid encapsulation efficiency, and carotenoid retention during storage. A high initial carotenoid concentration after spray drying, a high encapsulation efficiency of 77.2%, and a slow carotenoid degradation kinetics favored the high carotenoid content of the cellobiose powder at the end of the storage. Cellobiose might protect the carotenoids from degradation processes by light exposure, high temperature, and oxygen due to a tighter particle crust and larger particle sizes. Therefore, cellobiose may be considered a potential carrier agent for the encapsulation of carotenoid-rich fruit juices.


Clinical and demographic features of minor salivary gland tumors: A collaborative study of 480 cases.
To describe the frequency, clinical, and demographic features of minor salivary gland tumors and possible associated factors. A cross-sectional study was conducted. Clinical and demographic data were collected from biopsy records of two oral pathology services. Chi-square test, Fisher's exact test, and descriptive statistical analysis were performed. A total of 480 (0.89%) minor salivary gland tumors were retrieved, 272 (56.7%) benign and 147 (30.7%) malignant. Sixty-one (12.6%) had no subtype specification. Most patients were women (307/64.0%), in sixth decade of life (80/16.7%), with a mean age of 45.32 years. Palate was the most common site (336/70.1%). Pleomorphic adenoma (PA; 245/51.1%), mucoepidermoid carcinoma (MEC; 70/14.6%), and adenoid cystic carcinoma (ACC; 43/8.9%) were the most frequent tumors. Symptomatic case, recurrence, and tobacco use were associated with malignancy (p < 0.05). PA and MEC were more frequent in palate (p < 0.05). No association between the three most frequent histological types and gender or age group was observed (p > 0.05). This represents one of the largest exclusive series of minor salivary gland tumors in Brazil and worldwide. PA, MEC, and ACC were the most frequent tumors. Clinical and demographic data are similar from Brazilian studies or from other countries.


Development and Evaluation of an Integrated Outpatient Infusion Care Model for the Treatment of Pediatric Headache.
Care for pediatric patients with headache often occurs in high-cost settings such as emergency departments (EDs) and inpatient settings. Outpatient infusion centers have the potential to reduce care costs for pediatric headache management. In this quality improvement study, we describe our experience in creating the capacity to support an integrated outpatient pediatric headache infusion care model through an infusion center. We compare costs of receiving headache treatment in this model with those in the emergency and inpatient settings. Because dihydroergotamine (DHE) is a costly infusion, encounters at which DHE was administered were analyzed separately. We track the number of ED visits and inpatient admissions for headache using run charts. As a balancing measure, we compare treatment efficacy between the infusion care model and the inpatient setting. The mean percentage increase in cost of receiving headache treatment in the inpatient setting with DHE was 61% (confidence interval [CI]: 30-99%), and that without DHE was 582% (CI: 299-1068%) compared with receiving equivalent treatments in the infusion center. The mean percentage increase in cost of receiving headache treatment in the ED was 30% (CI: -15 to 100%) compared with equivalent treatment in the infusion center. After the intervention, ED visits and inpatient admissions for headache decreased. The mean change in head pain was similar across care settings. Our findings demonstrate that developing an integrated ambulatory care model with infusion capacity for refractory pediatric headache is feasible, and our early outcomes suggest this may have a favorable impact on the overall value of care for this population.


[Value of modern diagnostic technics in rupture of the spleen].
Personal experience is reported of the latest instrumental techniques used to diagnose ruptures of the spleen following a closed abdominal trauma. Particular interest was taken in patients with unclear clinical symptoms who were given a series of surgical and/or non-surgical tests in order to diagnose ruptured spleen in the asymptomatic phase. Tests analysed included: peritoneal injection-douche, laparoscopy, angiography, scintiphotography, echography and CAT scanning.


Distribution of PNS myelin proteins and membrane enzymes in fractions isolated by continuous gradient zonal centrifugation.
Myelin was purified from adult rabbit sciatic nerve by two procedures: discontinuous gradient centrifugation and continuous gradient zonal centrifugation. Two fractions were obtained from the discontinuous gradient. The fraction floating on 0.32 M sucrose and the fraction recovered from the 0.32/0.85 M sucrose interface showed typical myelin membranes by electron microscopy and typical myelin proteins by gel electrophoresis. The specific activity of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) decreased from the top to the bottom of the discontinuous gradient. The myelin separated by zonal centrifugation on a continuous sucrose gradient showed three distinct peaks (on monitoring optical density) at 0.10, 0.30 and 0.57 M sucrose. The latter peak yielded 92% of the material applied. The two minor peaks of low density exhibited high CNP and acetylcholinesterase (AChE) activities but the specific activity of both enzymes increased markedly at the heavy end of the gradient. The zonal fractions showed typical myelin proteins in all fractions by polyacrylamide gel electrophoresis but with important quantitative differences. These results indicate that PNS myelin shows significant heterogeneity.


An ultrasensitive method for detecting mutations from short and rare cell-free DNA.
Circulating tumor DNA (ctDNA) was short and rare, making the detection performance of the current targeted sequencing methods unsatisfying. We developed the One-PrimER Amplification (OPERA) system and examined its performance in detecting mutations of low variant allelic frequency (VAF) in various samples with short-sized DNA fragments. In cell line-derived samples containing sonication-sheared DNA fragments with 50-150 bp, OPERA was capable of detecting mutations as low as 0.0025% VAF, while CAPP-Seq only detected mutations of >0.03% VAF. Both single nucleotide variant and insertion/deletion can be detected by OPERA. In synthetic fragments as short as 80 bp with low VAF (0.03%-0.1%), the detection sensitivity of OPERA was significantly higher compared to that of droplet digital polymerase chain reaction. The error rate was 5.9×10-5 errors per base after de-duplication in plasma samples collected from healthy volunteers. By suppressing "single-strand errors", the error rate can be further lowered by >5 folds in EGFR T790M hotspot. In plasma samples collected from lung cancer patients, OPERA detected mutations in 57.1% stage I patients with 100% specificity and achieved a sensitivity of 30.0% in patients with tumor volume of less than 1 cm3. OPERA can effectively detect mutations in rare and highly-fragmented DNA.


Interfascicular Anatomy of the Motor Branch of the Ulnar Nerve: A Cadaveric Study.
The motor branch of the ulnar nerve contains fascicles that innervate the intrinsic musculature of the hand. This cadaveric study aimed to describe the organization and consistency of the internal topography of the motor branch of the ulnar nerve. Five fresh-frozen cadaveric specimens with an average age of 74 years (range, 65-88 years) were dissected. The ulnar nerve was exposed and transfixed to the underlying tissues to maintain its orientation throughout the dissection. The dorsal cutaneous branch (DCB) and the volar sensory branch were identified and reflected to expose the motor branch. The fascicles to the first dorsal interosseus (FDI), flexor pollicis brevis, and abductor digiti minimi (ADM) were identified. Internal neurolysis was performed distal to proximal to identify the interfascicular arrangement of these fascicles within the motor branch. The organization of these fascicles was noted, and the branch points of the DCB, FDI, and ADM were measured relative to the pisiform using a handheld electronic caliper. The internal topography of the motor branch was consistent among all specimens. Proximal to the pisiform, the arrangement from radial to ulnar was as follows: volar sensory branch, flexor pollicis brevis, FDI/intrinsic muscles, ADM, and DCB. The position of these branches remained consistent as the deep motor branch curved radially within the palm and traveled to the terminal musculature. The locations of the average branch points of the FDI, ADM, and DCB with respect to the pisiform were as follows: FDI, 4.6 cm distal (range, 4.1-4.9 cm), 4.5 cm radial (range, 4.1-4.9 cm); ADM, 0.65 cm distal (range, 0.3-1.1 cm), 0.7 cm radial (range, 0.3-1.1 cm), DCB, 7.7 cm proximal (range, 4.2-10.1 cm), and 0.4 cm ulnar (range, 0.3-0.8 cm). The internal topography of the ulnar nerve motor branch was consistent among the specimens studied. The topography of the motor branches was maintained as the motor branch turns radially within the palm. This study provides further understanding of the internal topography of the ulnar nerve motor branch at the wrist level.


Using high-resolution LiDAR-derived canopy structure and topography to characterise hibernaculum locations of the hazel dormouse.
The hazel dormouse is predominantly an arboreal species that moves down to the ground to hibernate in the autumn in temperate parts of its distributional ranges at locations not yet well understood. The main objective of this study is to test whether environmental characteristics surrounding hazel dormouse hibernacula can be identified using high-resolution remote sensing and data collected in situ. To achieve this, remotely sensed variables, including canopy height and cover, topographic slope, sky view, solar radiation and cold air drainage, were modelled around 83 dormouse hibernacula in England (n = 62) and the Netherlands (n = 21), and environmental characteristics that may be favoured by pre-hibernating dormice were identified. Data on leaf litter depth, temperature, canopy cover and distance to the nearest tree were collected in situ and analysed at hibernaculum locations in England. The findings indicated that remotely sensed data were effective in identifying attributes surrounding the locations of dormouse hibernacula and when compared to in situ information, provided more conclusive results. This study suggests that remotely sensed topographic slope, canopy height and sky view have an influence on hazel dormice choosing suitable locations to hibernate; whilst in situ data suggested that average daily mean temperature at the hibernaculum may also have an effect. Remote sensing proved capable of identifying localised environmental characteristics in the wider landscape that may be important for hibernating dormice. This study proposes that this method can provide a novel progression from habitat modelling to conservation management for the hazel dormouse, as well as other species using habitats where topography and vegetation structure influence fine-resolution favourability.


Neuropsychological performance in medicated vs. unmedicated patients with obsessive-compulsive disorder.
To date, there have been no formal investigations of neuropsychological performance in patients with obsessive-compulsive disorder (OCD) taking psychotropic medications. The purpose of this study was to determine whether medicated and unmedicated patients with OCD demonstrate differences in neuropsychological functioning. Fifty-two patients with a primary DSM-IV diagnosis of OCD participated in the study; 28 were taking serotonin reuptake inhibitors (SRIs), and 24 were treatment-naïve (n=8) or had finished a washout period prior to their inclusion in other studies (n=16). The groups were well matched with regard to demographic and clinical variables, including symptom severity. Each group was administered a comprehensive neuropsychological battery to assess general intelligence, attention, verbal and non-verbal working memory, declarative and procedural learning, visuo-constructive skills, and executive functions. SRI-medicated did not differ from SRI-free patients on any neuropsychological measure. Benzodiazepines seemed to improve the patients' functioning on a semantic verbal fluency test. In addition, there were significant interactions between SRIs and benzodiazepines on the perseverative errors of the Wisconsin Card Sorting Test and on reaction times. SRI-medicated patients with OCD are able to perform on cognitive functioning tests at a comparable level with that of SRI-free patients, and these results have positive implications for OCD patients who respond to SRIs. The interactions between SRIs and benzodiazepines and their effect on cognition in OCD are likely to be complex and deserve further study.


Facile one-step synthesis of graphene oxide/polyhedral oligomeric silsesquioxane composite-coated fiber for high-efficiency solid-phase microextraction of polycyclic musks.
Efficient fabrication of excellent fiber coatings for high-performance solid-phase microextraction (SPME) is interesting. Here, a high-efficiency synthesis strategy on graphene oxide/polyhedral oligomeric silsesquioxane (GO/POSS) composite-coated fiber was exploited via an ultra-fast UV polymerization in one step, and applied to excellent SPME of polycyclic musks (PCMs). Using methacryloxy siloxane-grafted GO and POSS-methacryl substituted (POSS-MA) as functional monomers, a facile and direct UV polymerization of multiple reactions including alkenyl radical reaction and thiol-ene click chemistry was fulfilled on thiol-pretreated fiber in only 5 min without tedious process. Characteristics such as morphology, FT-IR, XPS, BET and TG of fiber coating were studied in detail, as well as the SPME performance. Attributing to the rigid stereo conformation of POSS and large conjugate plane of GO-based nanosheet, the significant surface area, high hydrophobicity and intrinsic π-π interactions were adopted in fiber coating. In comparison of commercial SPME fibers, POSS-based or GO-based SPME fibers, a superior extraction performance towards PCMs was achieved with GO/POSS-coated fiber. High-efficiency extraction of PCMs was gained with prominent enrichment factors and the sensitive detection limits of PCMs were of 0.04-0.12 ng/L. In particular, the extraction efficiency was robust and still maintained a high level above 93% for PCMs even after 150 cycle's applications. Good recoveries of PCMs reached 86.6%-102.1% and 86.7%-101.3% in river water and cosmetic samples, respectively. It lights an attractive approach to efficiently fabricating robust GO/POSS-coated fiber for high-performance SPME of PCMs.


Population variation alters aggression-associated oxytocin and vasopressin expressions in brains of Brandt's voles in field conditions.
Density-dependent change in aggressive behavior contributes to the population regulation of many small rodents, but the underlying neurological mechanisms have not been examined in field conditions. We hypothesized that crowding stress and aggression-associated oxytocin (OT) and arginine vasopressin (AVP) in specific regions of the brain may be closely related to aggressive behaviors and population changes of small rodents. We analyzed the association of OT and AVP expression, aggressive behavior, and population density of Brandt's voles in 24 large semi-natural enclosures (0.48 ha each) in Inner Mongolia grassland. We tested the effects of population density on the OT/AVP system and aggressive behavior by experimentally manipulating populations of Brandt's voles in the grassland enclosures. High density was positively and significantly associated with more aggressive behavior, and increased expression of mRNA and protein of AVP and its receptor, but decreased expression of mRNA and protein of OT and its receptor in specific brain regions of the voles. Our study suggests that changes in OT/AVP expression are likely a result of the increased psychosocial stress that these voles experience during overcrowding, and thus the OT/AVP system can be used as indicators of density-dependent stressors in Brandt's voles.


NADH and NADPH peroxidases as antioxidant defense mechanisms in intestinal sulfate-reducing bacteria.
Animal and human feces typically include intestinal sulfate-reducing bacteria (SRB). Hydrogen sulfide and acetate are the end products of their dissimilatory sulfate reduction and may create a synergistic effect. Here, we report NADH and NADPH peroxidase activities from intestinal SRB Desulfomicrobium orale and Desulfovibrio piger. We sought to compare enzymatic activities under the influence of various temperature and pH regimes, as well as to carry out kinetic analyses of enzymatic reaction rates, maximum amounts of the reaction product, reaction times, maximum rates of the enzyme reactions, and Michaelis constants in cell-free extracts of intestinal SRB, D. piger Vib-7, and D. orale Rod-9, collected from exponential and stationary growth phases. The optimal temperature (35 °C) and pH (7.0) for both enzyme's activity were determined. The difference in trends of Michaelis constants (Km) during exponential and stationary phases are noticeable between D. piger Vib-7 and D. orale Rod-9; D. orale Rod-9 showed much higher Km (the exception is NADH peroxidase of D. piger Vib-7: 1.42 ± 0.11 mM) during the both monitored phases. Studies of the NADH and NADPH peroxidases-as putative antioxidant defense systems of intestinal SRB and detailed data on the kinetic properties of this enzyme, as expressed by the decomposition of hydrogen peroxide-could be important for clarifying evolutionary mechanisms of antioxidant defense systems, their etiological role in the process of dissimilatory sulfate reduction, and their possible role in the development of bowel diseases.


A study of ancient pottery by means of X-ray fluorescence spectroscopy, multivariate statistics and mineralogical analysis.
Energy-dispersive X-ray fluorescence spectroscopy was used to determine the composition of 64 potsherds from the Hellenistic settlement of Orraon, in northwestern Greece. Data classification by principal components analysis revealed four distinct groups of pottery, pointing to different local production practices rather than different provenance. The interpretation of statistical grouping was corroborated by a complementary X-ray diffraction analysis. Compositional and mineralogical data, combined with archaeological and materials' science criteria, allowed addressing various aspects of pottery making, such as selection of raw clays, tempers and firing conditions.


Application of Bayesian regression with singular value decomposition method in association studies for sequence data.
Genetic association studies usually involve a large number of single-nucleotide polymorphisms (SNPs) (k) and a relative small sample size (n), which produces the situation that k is much greater than n. Because conventional statistical approaches are unable to deal with multiple SNPs simultaneously when k is much greater than n, single-SNP association studies have been used to identify genes involved in a disease's pathophysiology, which causes a multiple testing problem. To evaluate the contribution of multiple SNPs simultaneously to disease traits when k is much greater than n, we developed the Bayesian regression with singular value decomposition (BRSVD) method. The method reduces the dimension of the design matrix from k to n by applying singular value decomposition to the design matrix. We evaluated the model using a Markov chain Monte Carlo simulation with Gibbs sampler constructed from the posterior densities driven by conjugate prior densities. Permutation was incorporated to generate empirical p-values. We applied the BRSVD method to the sequence data provided by Genetic Analysis Workshop 17 and found that the BRSVD method is a practical method that can be used to analyze sequence data in comparison to the single-SNP association test and the penalized regression method.


Fermentation and dry fractionation increase bioactivity of cloudberry (Rubus chamaemorus).
Phenolic composition and bioactivity of cloudberry was modified by bioprocessing, and highly bioactive fractions were produced by dry fractionation of the press cake. During fermentation polymeric ellagitannins were partly degraded into ellagic acid derivatives. Phenolic compounds were differentially distributed in seed coarse and fine fractions after dry fractionation process. Tannins concentrated in fine fraction, and flavonol derivatives were mainly found in coarse fraction. Ellagic acid derivatives were equally distributed between the dry fractions. Fermentation and dry fractionation increased statistically significantly anti-adhesion and anti-inflammatory activity of cloudberry. The seed fine fraction showed significant inhibition of P fimbria-mediated haemagglutination assay of uropathogenic Escherichia coli. The seed coarse fraction significantly reduced NO and IL-6 production and iNOS expression in activated macrophages. Fermentation did not affect antimicrobial activity, but slight increase in activity was detected in dry fractions. The results indicate the potential of cloudberry in pharma or health food applications.


Exposure to etoxazole induces mitochondria-mediated apoptosis in porcine trophectoderm and uterine luminal epithelial cells.
Etoxazole is an organofluorine insecticide widely used in agriculture. Exposure to insecticides is a serious environmental problem owing to their cytotoxic effects in humans and animals. Reproductive toxicity of various organofluorine insecticides have been shown in previous studies. However, few studies have evaluated the toxicity of etoxazole in mammals. We aimed to examine the toxic effects of etoxazole in porcine trophectoderm (pTr) and uterine luminal epithelial (pLE) cells. To estimate the effects of etoxazole, we conducted assays after treatment with multiple concentration of etoxazole (0, 2, 4, 6 and 9 μM) to pTr and pLE cells for 0-72 h. Etoxazole decreased the cell proliferation, viability, and migration of pTr and pLE cells. Further, etoxazole induced apoptosis via cell cycle arrest and disruption of mitochondrial membrane potential. We also found that pro-apoptotic proteins and endoplasmic reticulum (ER) stress-response proteins were activated in response to etoxazole. Finally, we observed that etoxazole altered the PI3K/AKT and MAPK signaling pathways and the mRNA expression of genes associated with implantation. Collectively, these results suggest that etoxazole disrupts normal cellular physiology and might cause early implantation failure.


Stimulation of phosphoinositide hydrolysis by glyceraldehyde-3-phosphate in electroporated HIT-T15 cells.
HIT-T15 cells labeled with myo-[3H] inositol were permeabilized by electroporation and subsequently stimulated with various glycolytic intermediates in the presence of 20 mM LiCl in a buffer mimicking cytosolic ionic composition. Of the various glycolytic intermediates tested, only D-glyceraldehyde-3-phosphate (G3-P) stimulated the formation of labeled inositol phosphates. The half-maximal response to G3-P occurred at a concentration of 0.75 mM. Formation of inositol phosphates in electroporated cells was also observed in response to GTP. G3-P further potentiated the formation of inositol phosphates in response to GTP, however, the interaction between G3-P and GTP was additive rather than synergistic, indicating that G3-P stimulates phosphoinositide hydrolysis in a manner different than the receptor mediated GTP-dependent activation of phospholipase C. The potentiation of the GTP response by G3-P did not appear to involve inhibition of the GTPase activity of a phosphoinositide-specific G protein, since G3-P also potentiated the formation of inositol phosphates in response to GTP-gamma-S or NaF in a nearly additive manner.


Leptin as a marker of training stress in highly trained male rowers?
The purpose of this study was to investigate the potentially important role leptin may play during training monitoring in athletes. Twelve highly trained male rowers underwent a 3-week period of maximally increased training stress followed by a 2-week tapering period. Fasting blood was sampled after a rest day. Subjects also performed a maximal 2000-m rowing ergometer test before and after 3 weeks of heavy training, and after 2 weeks of tapering. Blood samples were obtained before, immediately after and after 30 min of recovery. Leptin concentrations were measured in duplicate by radioimmunoassay. Mean training time was about 100% higher during the heavy training period (17.5 h x week(-1)) compared to the tapering period (8.9 h x week(-1)). The 3-week heavy training period induced a significant reduction ( P<0.05) in the fasting leptin concentration [from 2.5 (0.4) to 1.5 (0.4) ng x ml(-1)]. Fasting plasma leptin was significantly increased by the end of the 2-week tapering period [2.0 (0.4) ng x ml(-1)] but remained significantly lower compared to the pretraining value. Leptin levels were also significantly decreased only after the 2000-m rowing ergometer test performed at the end of the heavy training period. No differences in leptin concentrations were observed after other performance tests compared to their respective baseline values. In addition, fasting leptin concentration was significantly related to the weekly training time ( r=-0.45; P=0.006). In conclusion, it appears that leptin is sensitive to the rapid and pronounced changes in training volume. A greater training time is associated with a lower leptin concentration in highly trained male rowers. It is suggested that it may be possible to direct typical rowing training by monitoring leptin status.


Clarifying the composition of the ATP consumption factors required for maintaining ion homeostasis in mouse rod photoreceptors.
To date, no effective treatment has been established for photoreceptor loss due to energy imbalances, but numerous therapeutic approaches have reported some success in slowing photoreceptor degeneration by downregulating energy demand. However, the detailed mechanisms remain unclear. This study aimed to clarify the composition of ATP consumption factors in photoreceptors in darkness and in light. We introduced mathematical formulas for ionic current activities combined with a phototransduction model to form a new mathematical model for estimating the energy expenditure of each ionic current. The proposed model included various ionic currents identified in mouse rods using a gene expression database incorporating an available electrophysiological recording of each specific gene. ATP was mainly consumed by Na+/K+-ATPase and plasma membrane Ca2+-ATPase pumps to remove excess Na+ and Ca2+. The rod consumed 7 [Formula: see text] 107 molecules of ATP s-1, where 65% was used to remove ions from the cyclic nucleotide-gated channel and 20% from the hyperpolarization-activated current in darkness. Increased light intensity raised the energy requirements of the complex phototransduction cascade mechanisms. Nevertheless, the overall energy consumption was less than that in darkness due to the significant reduction in ATPase activities, where the hyperpolarization-activated current proportion increased to 83%. A better understanding of energy demand/supply may provide an effective tool for investigating retinal pathophysiological changes and analyzing novel therapeutic treatments related to the energy consumption of photoreceptors.


Microfilaraemia, serum antibody and development of clinical disease in microfilaraemic subjects infected with Wuchereria bancrofti and treated with diethylcarbamazine citrate.
A seroepidemiological survey of bancroftian filariasis was carried out in 2 townships in Sri Lanka with the objectives of determining the microfilaraemia rates, dependence on age and sex, susceptibility to re-infection, effect of diethylcarbamazine therapy on serum antibodies to microfilarial surface antigens, and the predictive value of the indirect fluorescent antibody test. The mean microfilaraemia rate was 5.4%. Microfilaraemia was not sex-dependent but a marginally elevated incidence was seen in the 6-35 year age groups. In up to 58% of the microfilaraemic patients who had been treated for microfilaraemia previously, a second phase of microfilaraemia was seen 2-7 years after treatment. This was unlikely to have been due to incomplete parasite elimination. Antibodies to microfilarial surface were found in 24-35% of microfilaraemic patients and in 14-63% of amicrofilaraemic symptomatic subjects. Serum anti-microfilarial surface antibody levels did not alter with chemotherapy with diethylcarbamazine citrate. The findings of follow-up investigations of microfilaraemic subjects were compatible with the notion that microfilaraemia does not necessarily lead to clinical disease.


Cloning and characterization of a novel regulator of G protein signalling in human platelets.
In an effort to understand the modulation of G protein-coupled receptor (GPCR)-mediated signalling in platelets, we sought to identify which regulators of G protein signalling proteins (RGSs) are present in human platelets. Using degenerate oligonucleotides, we performed RT-PCR with human platelet and megakaryocytic cell line RNA. In addition to confirming the presence of several known RGS transcripts, we found a novel RGS domain-containing transcript in platelet RNA. Northern blot analysis of multiple human tissues indicates that this transcript is most abundantly expressed in platelets compared to other tissues examined. Full-length cloning of this novel RGS, which we now term RGS18, demonstrates that this transcript is predicted to encode a 235-amino acid protein that is most closely related to RGS5 (46% identity) and that has approximately 30-40% identity to other RGS proteins. RGS18 is expressed in platelet, leukocyte, and megakaryocyte cell lines and binds to endogenous Galphai1, Galphai2, Galphai3, and Galphaq but not Galphaz, Galphas or Galpha12 in vitro.


Analysis of solvent residues in pharmaceutical bulk drugs by wall-coated open tubular gas chromatography.
A simple general method for the determination of solvent residues in drugs is described. The procedure is based on wide-bore wall coated open tubular (WCOT) gas chromatographic analysis of bulk drug solutions. The use of wide-bore WCOT columns with chemically crosslinked methyl silicone stationary phases offers improvements in specificity and sensitivity over earlier packed-column methods. The factors that influence method accuracy are discussed, including a consideration of instrumental and matrix contributions to the linearity and bias of the method. Some problems with interferences peculiar to benzyl alcohol are reported.


Effects of stimulating hip and trunk muscles on seated stability, posture, and reach after spinal cord injury.
To determine the stimulated strength of the paralyzed gluteal and paraspinal muscles and their effects on the seated function of individuals with paralysis. Case series with subjects acting as their own concurrent controls. Hospital-based clinical biomechanics laboratory. Users (N=8) of implanted neuroprostheses for lower extremity function with low-cervical or thoracic level injuries. Dynamometry and digital motion capture both with and without stimulation to the hip and trunk muscles. Isometric trunk extension moment at 0°, 15°, and 30° of flexion; seated stability in terms of simulated isokinetic rowing; pelvic tilt, shoulder height, loaded and unloaded bimanual reaching to different heights, and subjective ratings of difficulty during unsupported sitting. Stimulation produced significant increases in mean trunk extension moment (9.2±9.5Nm, P<.001) and rowing force (27.4±23.1N, P<.012) over baseline volitional values. Similarly, stimulation induced positive changes in average pelvic tilt (16.7±15.7°) and shoulder height (2.2±2.5cm) during quiet sitting and bimanual reaching, and increased mean reach distance (5.5±6.6cm) over all subjects, target heights, and loading conditions. Subjects consistently rated tasks with stimulation easier than voluntary effort alone. In spite of considerable intersubject variability, stabilizing the paralyzed trunk with electrical stimulation can positively impact seated posture, extend forward reach, and allow exertion of larger forces on objects in the environment.


A two-part, single-arm, multicentre, phase I study of zanubrutinib, a selective Bruton tyrosine kinase inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies.
This single-arm, multicentre, phase I study is the first study of zanubrutinib, a potent, specific, irreversible Bruton tyrosine kinase (BTK) inhibitor, in Chinese patients with relapsed/refractory B-cell malignancies. The objectives were to evaluate safety and preliminary anti-tumour activity. Forty-four patients received zanubrutinib 320 mg once daily (QD) (n = 10) or 160 mg twice daily (BID) (n = 34) until disease progression or unacceptable toxicity. 29.5% of patients received zanubrutinib for at least two years. The most common adverse event (AE) and the most common grade 3 or higher AE was neutrophil count decreased (54.5% and 25.0% respectively). Two patients (4.5%) discontinued treatment due to AEs and one treatment-emergent AE led to death. All haemorrhagic events were grade 1-2 (except for one non-serious grade 3 purpura). No second primary malignancies, tumour lysis syndrome, or atrial fibrillation/flutter occurred. The overall response rate was 52.3% (complete response rate, 18.2%). Patients with all cancer subtypes benefited from treatment. BTK C481S/R or L528W mutations were found in zanubrutinib-progressive patients. The safety/efficacy profiles of patients treated with 320 mg QD and 160 mg BID were comparable and similar daily area under the curve (AUC) was achieved. Overall, zanubrutinib was well tolerated and either of these two regimens is clinically practical. Registered at ClinicalTrials.gov (NCT03189524, on 16 June 2017, https://clinicaltrials.gov/ct2/show/NCT03189524).


Examining body image discrepancies and perceived weight status in adult Japanese women.
This study examined potential differences and similarities between attitudes about body shape and eating behaviors in Japan versus America. Discrepancies between various body ideals (e.g., own versus ideal; Japanese versus American) and perceived weight status were examined in a sample of adult Japanese women. Forty-five adult Japanese women rated various body ideals using the Stunkard Body Shape Questionnaire. They also answered questions about their perceived body weight and completed the Eating Disorders Inventory (EDI-2). Participants rated the ideal body shape for Japanese women to be significantly thinner than for American women. Body image discrepancy predicted drive for thinness and bulimic symptoms as measured by the EDI-2. Furthermore, there was an interaction between perfectionism and perceived overweight status, such that among participants high on perceived weight status, perfectionism predicted greater bulimic symptomology. The relative importance of the internalization of the Western beauty ideal to the rise of eating disorders in Japan is discussed. Similarities between the findings of this study and studies conducted on American samples are highlighted, and areas for future research are proposed.


Asynchronous (segmental early) relaxation of the left ventricle.
Segmental early relaxation, a form of left ventricular asynchrony, refers to lengthening of a myocardial segment before mitral valve opening. This phenomenon may occur in normal and diseased hearts; when it is seen in a diseased ventricle it may occur in either the abnormally contracting segment or the normal segment. Experimental data indicate that altered loading conditions, especially nonuniform distribution of load or functional inhomogeneities (as may occur with regional ischemia), or both, may result in asynchronous relaxation of the left ventricle.


[Extrapulmonary respiratory sounds in newborns: classification and iconographic contribution].
The extra-pulmonary stridors of the newborn represent a frequent and difficult diagnosis pathology for the radiologists and the neonatologist. After an introduction about the most important anatomical dates, A. reviews the reasons of the neonatologic stridor, and emphasizes the vascular congenital anomalies, most important for a early differential diagnosis. Concluding, are reported radiologic findings of this shifty pathology.


Clinical epidemiology of vancomycin-resistant Enterococcus gallinarum and Enterococcus casseliflavus bloodstream infections.
This study aimed to evaluate the clinical outcomes of vancomycin-resistant enterococcal bloodstream infections (VRE BSI) caused by Enterococcus gallinarum or Enterococcus casseliflavus. Variables associated with treatment failure were determined and treatment options were compared. This was a national retrospective study of hospitalised Veterans Affairs patients with non-faecium, non-faecalis VRE BSI. The primary outcome was treatment failure, defined as a composite of: (i) 30-day all-cause mortality; (ii) microbiological failure; and (iii) 30-day VRE BSI recurrence. Stepwise Poisson regression was conducted to determine variables associated with treatment failure. In total, 48 patients were included, with 29 cases (60.4%) caused by E. gallinarum and 19 cases (39.6%) caused by E. casseliflavus. Among these cases, 20 (41.7%) were treated with an anti-VRE agent (linezolid or daptomycin) and 28 (58.3%) were treated with an anti-enterococcal β-lactam. Overall, 30-day mortality was 10.4% (5/48) and composite treatment failure was 39.6% (19/48). In multivariate analysis, treatment with an anti-enterococcal β-lactam was associated with increased treatment failure in comparison with anti-VRE therapy (adjusted risk ratio = 1.73, 95% confidence interval 1.06-4.97; P = 0.031). Overall, treatment with linezolid or daptomycin for vancomycin-resistant E. gallinarum or E. casseliflavus BSI resulted in improved clinical outcomes in comparison with anti-enterococcal β-lactam treatment.


Effect of defoliation upon root growth, phosphate absorption and respiration in nutrient-limited tundra graminoids.
Moderate experimental defoliation stimulated root respiration and phosphate absorption in two tundra graminoids, Eriophorum vaginatum and Carex aquatilis, growing under nutrient-limited field conditions in northern Alaska. The increase in phosphate absorption rate following defoliation of Eriophorum was associated with a decrease in root phosphate and available carbohydrate contents per unit root length but a constant root nitrogen content. Only after four repeated defoliations did phosphate absorption rate decrease below control levels. We suggest that the stimulation of root respiration and phosphate absorption immediately following defoliation resulted from lowered root phosphorus status as nutrient reserves were reallocated to support shoot regrowth. Root growth was affected more severely by defoliation than was root activity. Two or more defoliations reduced root elongation, initiation and weight per unit length, but root mortality increased only after four defoliations. Carex aquatilis, a species with large belowground biomass, was less sensitive to defoliation than Eriophorum. Phosphate absorption rate increased only after four defoliations in this species, and root elongation, initiation and mortality were affected only by the most severe clipping regimes. Responses of plants to repeated defoliation over two growing seasons were consistent with results of short-term studies.


Exploiting replication gaps for cancer therapy.
Defects in DNA double-strand break repair are thought to render BRCA1 or BRCA2 (BRCA) mutant tumors selectively sensitive to PARP inhibitors (PARPis). Challenging this framework, BRCA and PARP1 share functions in DNA synthesis on the lagging strand. Thus, BRCA deficiency or "BRCAness" could reflect an inherent lagging strand problem that is vulnerable to drugs such as PARPi that also target the lagging strand, a combination that generates a toxic accumulation of replication gaps.


Axon guidance effect of classical morphogens Shh and BMP7 in the hypothalamo-pituitary system.
Hypothalamus plays a key role in homeostasis, and functions of the hypothalamus depend on the accurate trajectory of hypothalamic neuroendocrine axons. Thus, understanding the guidance of hypothalamic neuroendocrine axons is crucial for knowing how hypothalamus works. Previous studies suggest FGF10 deriving from the medial ventral midline of the hypothalamus plays an important role in axon guidance of the developing hypothalamus. Here we show that Shh and BMP7, which are from the anterior and posterior hypothalamic ventral midline respectively, together repel hypothalamic axons towards the medial ventral midline.


A randomized comparison of methylene blue-directed biopsy versus conventional four-quadrant biopsy for the detection of intestinal metaplasia and dysplasia in patients with long-segment Barrett's esophagus.
Methylene blue (MB) selectively stains specialized intestinal metaplasia (SIM) and may assist in surveying a columnar-lined esophagus for Barrett's esophagus associated dysplasia. This is a prospective, randomized crossover study comparing 4-quadrant random biopsies (4QB) versus MB-directed biopsies for the detection of SIM and dysplasia in 48 patients with long segment Barrett's esophagus (LSBE). Patients randomly underwent two endoscopies over a 4-wk time period with either 4QB or MB-directed biopsies as their first or second exam. Our aim was to correlate stain intensity with histology. The sensitivity of MB for SIM and dysplasia was 75.2% and 83.1%, respectively. The yield of 4QB for identifying nondysplasia SIM was 57.6% (523/917) and for dysplasia was 12% (111/917). Dark staining was significantly associated with histologic grade (P < 0.007). The final diagnosis was correct in 43 (90%) patients using MB and in 45 (94%) using 4QB. The 4QB technique missed dysplasia in 3 of 21 patients while MB biopsies missed dysplasia in 5 of 21 patients. The discordance between the two techniques was not significant (P= 0.727, McNemar's test). The mean number of biopsies taken during 4QB was 18.92 +/- 6.36 and with MB was 9.23 +/- 2.89 (P < 0.001). MB requires significantly fewer biopsies than 4QB to evaluate for SIM and dysplasia. Dark staining correlates more with HGD than LGD in our experience. While MB is not more accurate than 4QB, MB may help to define areas to target for biopsy during surveillance endoscopy in patients with LSBE.


Making the most of learning in the operating theatre: student strategies and curricular initiatives.
Students in medical programmes around the world are required to attend with their patient in the operating theatre, yet little is known about this area of medical education. Most of the published literature on the operating theatre is normative in character, written from the perspective of the surgeon as teacher. This paper, in contrast, reports the student's perspective as learner. It is an interpretive case study conducted in the department of surgery at an Australian university. Research approaches were combined in a multi-method strategy which included in-depth interviews with students and surgeons, observations in operating theatres, group interviews and a student survey. The aim was to understand the student's experience of the theatre as a learning environment, with a view to improving teaching and learning in this setting. The operating theatre is a challenging place in which to learn. The challenges are conceptualized in this paper around three key domains: the challenge posed by the physical environment and the emotional impact of surgery as work; the challenge of the educational task, and the challenge of managing the social relations of work in the operating theatre. Students who report finding the operating theatre a useful experience are those who adopt active strategies to successfully manage their learning across the three domains. The paper describes curricular initiatives that have been introduced in a department of surgery to help more students make the most of their learning in theatres, and goes on to discuss the wider implications of the findings for surgical education beyond this case study.


Chromone linked nitrone derivative induces the expression of iNOS2 and Th1 cytokines but reduces the Th2 response in experimental visceral leishmaniasis.
In our previous work we have shown that the novel synthetic chromone derivative could effectively inhibit the Leishmania donovani replication in vitro and in vivo with less cytotoxicity on murine splenocytes. The aim of the present study is to explore the possible mechanism of anti-leishmanial effect of C-(6-methyl-4-oxo-4H-1-benzopyran-3-yl)-N-(p-tolyl) nitrone (designated as NP1) in vitro and in vivo in experimental visceral leishmaniasis caused by L. donovani. The cytotoxic effect of this derivative was studied in murine peritoneal macrophages by MTT method. NP1 at a dose of 17.06 μM showed 50% inhibition on L. donovani promastigotes but found less cytotoxic to the RAW 264.7 cells. Even the higher concentration of IC50 (up to four fold) did not exert much cytotoxic effect on RAW 264.7. Interestingly, NP1 at lower concentration (8.53 μM) could inhibit 50% of intracellular amastigotes in murine peritoneal macrophages. L. donovani is known to exert its pathogenic effects mainly by the suppression of NO generation and subversion of the cellular inflammatory responses in the macrophages. NP1 was found to induce a potent host-protective immune response by enhancing NO generation and iNOS2 expression at mRNA level and by up-regulating proinflammatory cytokines such as IL-12 and IFN-γ and limiting the expression of IL-10 in vivo. The NO dependent killing was further confirmed in iNOS(-/-) mice compared to wild type. In agreement with the fact, induced synthesis of IL-12 and IFN-γ and associated down-regulation of IL-10 by the treatment of NP1 clearly indicated the possibility of novel strategy of drug development against Leishmania infection.


Characterization of ovulatory capacity development in the dominant follicle of dromedary camels (Camelus dromedarius).
The acquisition of ovulatory capacity in the growing dominant follicle (DF) of dromedary camels was examined in the current study. Ovulation occurred in response to hCG (1500 IU) in 27.3%, 58.3% or 100% of camels with follicles of 9, 10 or 11 mm diameter, respectively. A high dose of hCG (4500 IU) resulted in ovulation of 77.8% and 100% of camels with follicles of 9 and 10mm, respectively. In naturally mated animals, ovulation occurred in 36.4% and 92.8% of camels with 10 and 11 mm follicles, respectively.


The safety, efficacy, and cost-effectiveness of intraoperative cell salvage in metastatic spine tumor surgery.
Metastatic spine tumor surgery (MSTS) is associated with substantial blood loss, therefore leading to high morbidity and mortality. Although intraoperative cell salvage with leukocyte depletion filter (IOCS-LDF) has been studied as an effective means of reducing blood loss in other surgical settings, including the spine, no study has yet analyzed the efficacy of reinfusion of salvaged blood in reducing the need for allogenic blood transfusion in patients who have had surgery for MSTS. This study aimed to analyze the efficacy, safety, and cost-effectiveness of using IOCS-LDF in MSTS. This is a retrospective controlled study. A total of 176 patients undergoing MSTS were included in the study. All patients undergoing MSTS at a single center between February 2010 and December 2014 were included in the study. The primary outcome measure was the use of autologous blood transfusion. Secondary outcome measures included hospital stay, survival time, complications, and procedural costs. The key predictor variable was whether IOCS-LDF was used during surgery. Logistic and linear regression analyses were conducted by controlling variables such as tumor type, number of diseased vertebrae, approach, number and site of stabilized segments, operation time, preoperative anemia, American Society of Anesthesiologists (ASA) grade, age, gender, and body mass index (BMI). No funding was obtained and there are no conflicts of interest to be declared. Data included 63 cases (IOCS-LDF) and 113 controls (non-IOCS-LDF). Intraoperative cell salvage with LDF utilization was substantively and significantly associated with a lower likelihood of allogenic blood transfusion (OR=0.407, p=.03). Intraoperative cell salvage with LDF was cost neutral (p=.88). Average hospital stay was 3.76 days shorter among IOCS-LDF patients (p=.03). Patient survival and complication rates were comparable in both groups. We have demonstrated that the use of IOCS-LDF in MSTS reduces the need for postoperative allogenic blood transfusion while maintaining satisfactory postoperative hemoglobin. We recommend routine use of IOCS-LDF in MSTS for its safety, efficacy, and potential cost benefit.


Tissue-specific identification of multi-omics features for pan-cancer drug response prediction.
Current statistical models for drug response prediction and biomarker identification fall short in leveraging the shared and unique information from various cancer tissues and multi-omics profiles. We developed mix-lasso model that introduces an additional sample group penalty term to capture tissue-specific effects of features on pan-cancer response prediction. The mix-lasso model takes into account both the similarity between drug responses (i.e., multi-task learning), and the heterogeneity between multi-omics data (multi-modal learning). When applied to large-scale pharmacogenomics dataset from Cancer Therapeutics Response Portal, mix-lasso enabled accurate drug response predictions and identification of tissue-specific predictive features in the presence of various degrees of missing data, drug-drug correlations, and high-dimensional and correlated genomic and molecular features that often hinder the use of statistical approaches in drug response modeling. Compared to tree lasso model, mix-lasso identified a smaller number of tissue-specific features, hence making the model more interpretable and stable for drug discovery applications.


Observations on the removal of microaggregates from stored blood by centrifugation and filtration through a standard 170 micron transfusion filter.
The effect of centrifugation (5 minutes, 6900 X g) on the amount and particle size of blood microaggregates was studied in order to assess whether centrifugation and filtration by a standard (170 micron) transfusion set filter could be used for aggregate removal instead of microfiltration. Aggregates were quantitated using a method based on nylon screens with graded pore sizes. At the beginning of storage, centrifugation increased the particle size of aggregates only slightly. In 7-day-old blood, aggregates capable of passing a 160 micron screen amounted to 308 +/- 107 (SD) mg of debris protein per liter of blood before and 55 +/- 26 (SD) mg of protein (n = 10) after centrifugation. In 14-day-old blood centrifugation increased the size of aggregates even more effectively: 311 +/- 81 (SD) before and 29 +/- 14 (SD) mg of protein following centrifugation. Microaggregates can thus be removed effectively by the centrifugation and filtration method from blood stored for more than 1 week. A standard transfusion set filter can be used instead of a micropore filter.


Type II collagen C2C epitope in human synovial fluid and serum after knee injury--associations with molecular and structural markers of injury.
Investigate in a cross-sectional study time-dependent changes of synovial fluid type II collagen epitope C2C concentrations after knee injury and correlate to other joint injury biomarkers. Synovial fluid samples were aspirated between 0 days and 7 years after injury (n = 235). Serum was collected from 71 of the knee injured patients. Synovial fluid from 8 knee-healthy subjects was used as reference. C2C was quantified by immunoassay and structural injury was determined from magnetic resonance images (MRI) of the injured knee acquired 1-38 days after injury (n = 98). Additional joint injury biomarker results were from earlier investigations of the same samples. Synovial fluid C2C concentrations were higher in injured knees than in knees of reference subjects from 1 day up to 7 years after injury. C2C concentrations in synovial fluid and serum were correlated (r = 0.403, P < 0.001). In synovial fluid from subjects early after injury (0-33 days), C2C concentrations were correlated with cross-linked C-telopeptide of type II collagen (r = 0.444, P = 0.003), ARGS-aggrecan (r = 0.337, P < 0.001), osteocalcin (r = 0.345, P < 0.001), osteopontin (r = 0.371, P < 0.001) and IL-8 (r = -0.385, P < 0.001), but not with structural joint injury as visualized on MRI. The increased levels of synovial fluid C2C after injury, together with the associations seen with several other injury-related biomarkers, suggest that an acute knee injury is associated with an immediate and sustained local degradation of type II collagen.


Cytokines secreted by bone-metastatic breast cancer cells alter the expression pattern of f-actin and reduce focal adhesion plaques in osteoblasts through PI3K.
Breast cancer frequently metastasizes to bone, resulting in osteolytic lesions. These lesions, formed by activated osteoclasts, cause pain, an increased susceptibility to fractures, and hypercalcemia. It has been shown that breast cancer cells communicate with osteoblasts and subsequently stimulate osteoclast activity; however, little research has focused on understanding the interaction between breast cancer cells and osteoblasts. We recently reported that conditioned medium from MDA-MB-231 breast cancer cells inhibited the differentiation of MC3T3-E1 osteoblasts through the secretion of transforming growth factor beta (TGFbeta). In addition, the breast cancer conditioned medium altered MC3T3-E1 morphology, the pattern of actin stress fibers, and reduced focal adhesion plaques. In the current study, we identified the mechanism used by MDA-MB-231 cells to cause these effects. When MC3T3-E1 osteoblasts were cultured with MDA-MB-231 conditioned medium preincubated with neutralizing antibodies to platelet derived growth factor (PDGF), insulin-like growth factorII (IGFII), and TGFbeta, focal adhesion plaques and actin stress fiber formation were restored. These cytokines were further found to signal through PI3Kinase and Rac. In conclusion, TGFbeta, PDGF, and IGFII might be good therapeutic targets for treating breast cancer-induced osteolytic lesions.


Congenital intrahepatic portosystemic shunt.
The authors report a congenital intrahepatic portosystemic shunt detected by angiography in a young patient with acute onset of hyperammoniemia and hepatic encephalopathy.


A comparison between mobile and stationary gas chromatography-mass spectrometry devices for analysis of complex volatile profiles.
On-site analysis of volatile organic compounds (VOCs) with miniaturized gas chromatography-mass spectrometry (GC-MS) systems is a very rapidly developing field of application. While, on the one hand, major technological advances are improving the availability of these systems on the market, on the other hand, systematic studies to assess the performance of such instruments are still lacking. To fill this gap, we compared three portable GC-MS devices to a state-of-the-art benchtop (stationary) system for analysis of a standard mixture of 18 VOCs. We systematically compared analytical parameters such as the sensitivity and similarity of the signal response pattern and the quality of the obtained mass spectra. We found that the investigated mobile instruments (i) showed different response profiles with a generally lower number of identified analytes. Also, (ii) mass spectral reproducibility (% relative standard deviation (RSD) of the relative abundance of selective fragments) was generally worse in the mobile devices (mean RSD for all targeted fragments ~9.7% vs. ~3.5% in the stationary system). Furthermore, mobile devices (iii) showed a poorer mass spectral similarity to commercial reference library spectra (>20% deviation of fragment ion relative intensity vs. ~10% in the stationary GC-MS), suggesting a less reliable identification of analytes by library search. Indeed, (iv) the performance was better with higher-mass and/or more abundant fragments, which should be considered to improve the results of library searches for substance identification. Finally, (v) the estimation of the signal-to-noise ratio (S/N) in mobile instruments as a measure of sensitivity revealed a significantly lower performance compared to the benchtop lab equipment (with a ratio among medians of ~8 times lower). Overall, our study reveals not only a poor signal-to-noise ratio and poor reproducibility of the data obtained from mobile instruments, but also unfavorable results with respect to a reliable identification of substances when they are applied for complex mixtures of volatiles.


EBF1-JAK2 inhibits the PAX5 function through physical interaction with PAX5 and kinase activity.
Gene aberrations of B-cell regulators and growth signal components such as the JAK-STAT pathway are frequently found in B-cell acute lymphoblastic leukemia (B-ALL). EBF1 is a B-cell regulator that regulates the expression of PAX5 and co-operates with PAX5 to regulate B-cell differentiation. Here, we analyzed the function of the fusion protein of EBF1 and JAK2, EBF1-JAK2 (E-J). E-J caused constitutive activation of JAK-STAT and MAPK pathways and induced autonomous cell growth in a cytokine-dependent cell line. E-J did not affect the transcriptional activity of EBF1 but inhibited that of PAX5. Both the physical interaction of E-J with PAX5 and kinase activity of E-J were required for E-J to inhibit PAX5 function, although the detailed mechanism of inhibition remains unclear. Importantly, gene set enrichment analysis using the results of our previous RNA-seq data of 323 primary BCR-ABL1-negative ALL samples demonstrated repression of the transcriptional target genes of PAX5 in E-J-positive ALL cells, which suggests that E-J also inhibited PAX5 function in ALL cells. Our results shed new light on the mechanisms of differentiation block by kinase fusion proteins.


Long term results of polytetrafluoroethylene in above knee femoropopliteal bypass for critical ischaemia.
Ninety-six consecutive above-knee femoropopliteal bypasses, using polytetrafluoroethylene (PTFE) preferentially, were performed for limb-threatening ischaemia. Cumulative primary graft patency was 68 per cent, 49 per cent and 36 per cent and limb salvage 93 per cent, 85 per cent and 75 per cent at 1, 3 and 5 yr respectively. As a result of poor long term survival (51 per cent at 5 yr), and the healing of remedial lesions before graft occlusion, 68 patients (72 per cent) required no further intervention. Eighteen secondary bypasses were undertaken, 12 using ipsilateral saphenous vein. In this group of elderly patients with poor life expectancy, where a limited operation is desirable, the use of PTFE provided excellent limb salvage with low morbidity. Although we can no longer justify our continued use of PTFE in every case of critical ischaemia because of its inferior patency to autogenous vein, we continue to use it preferentially in patients whose lifespan is likely to be short and in cases where a remedial lesion is present.


[Construction of standardized and programmed multi-level medical rescue system: 26-year experience review and prospect of Tianjin Trauma Emergency Center].
With the rapid development of modern society, high energy injury has greatly increase as compared with the past, and the number of trauma patients seeking medical treatments has risen year by year. Trauma emergency medicine has become the reflection of the service level and medical quality of medical institutions, as well as the hospital administrators' attention and concern to this discipline. This paper aims to elaborate the status and role of emergent medicine of trauma in the development of hospitals, to review the significant experience in the construction and reform of Tianjin Trauma Emergence Center, and put forward the prospect of future disciplines and center construction in combination with the practice.


Systemic humoral factors participating in the course of spinal cord injury.
Systemic humoral factors have been studied in traumatic, chronic and acute spinal cord injured patients. Antibodies specific to nervous system autoantigens were detected in a majority of the sera obtained from these patients, at different periods after injury. Limited in vitro sprouting of dorsal root ganglia in chicken embryos was observed in the presence of serum from these patients. The possible association between growth inhibiting factors and the presence of antibodies against nervous tissue autoantigens is discussed.


Giant Warthin's Tumour of the Parotid Gland: A Rare Case Report.
Warthin's tumour was first adequately described in 1929 by an American pathologist, Aldred Scott Warthin. It is synonymous with papillary cystadenoma lymphomatosum (PCL), cystadenolymphoma or adenolymphoma. Giant salivary gland tumours are usually pleomorphic adenomas. The average size of Warthin's tumour is reported to be about 2-4 cm. In the current fascinating case, an enormous disfiguring salivary gland tumour was reported which turned out to be Warthin's tumour on histopathology, which is probably the largest PCL reported till date.


Starting parenting in isolation a qualitative user-initiated study of parents' experiences with hospitalization in Neonatal Intensive Care units during the COVID-19 pandemic.
Worldwide, strict infection control measures including visitation regulations were implemented due to the COVID-19 pandemic at Neonatal Intensive Care Units (NICUs). These regulations gave restricted access for parents to their hospitalized infants. The consequence was limited ability to involve in the care of their infants. At Oslo University Hospital entry to NICU was denied to all except healthy mothers in March 2020. The absolute access ban for fathers lasted for 10 weeks. The aim of this study was to explore parental experiences with an infant hospitalized in the NICU during this absolute visitation ban period. We invited post discharge all parents of surviving infants that had been hospitalized for at least 14 days to participate. They were interviewed during autumn 2020 using an explorative semi-structured interview approach. Data were analyzed via inductive thematic analysis. Nine mothers and four fathers participated. The COVID-19 regulations strongly impacted the parent's experiences of their stay. The fathers' limited access felt life-impacting. Parents struggled to become a family and raised their voices to be heard. Not being able to experience parenthood together led to emotional loneliness. The fathers struggled to learn how to care for their infant. The regulations might lead to a postponed attachment. On the other hand, of positive aspect the parents got some quietness. Being hospitalized during this first wave was experienced as exceptional and made parents seeking alliances by other parents. Social media was used to keep in contact with the outside world. The regulations had strong negative impact on parental experiences during the NICU hospitalization. The restriction to fathers' access to the NICU acted as a significant obstacle to early infant-father bonding and led to loneliness and isolation by the mothers. Thus, these COVID-19 measures might have had adverse consequences for families.


Bioavailability of tryptophan in selected foods by rat growth assay.
Tryptophan bioavailabilities were estimated in 16 protein sources using 10 day rat growth assays with casein as the reference protein. Growth responses of rats fed test food diets were compared to growth responses of rats fed basal diets with graded levels of tryptophan ranging from 50 to 100 mg of tryptophan/100 g diet. Estimates of tryptophan availabilities were 85-100% for all products except whole wheat cereal (73%) and pinto beans (59%). Results of a previous study on lysine availability indicated that poor response to pinto beans was due either to poor digestibility or to the presence of some unidentified growth inhibitor.


Carbonised red mud--a new water treatment product made from a waste material.
Proposals to use red mud, the waste produced by the extraction of alumina from bauxite ore in the Bayer process, as a material for treatment of heavy metal-contaminated water are limited by its inherent alkalinity and variability. Attempts to lower its pH have been largely unreliable. However, an alternative strategy is carbonisation of red mud by catalytic hydrocarbon cracking, which results in a magnetic material of greater surface area. The efficacy of this material has been compared with that of the untreated parent red mud and acidified red mud for the sorption of CrO(4)(2-), Cu(2+) and Pb(2+). Carbonised red mud does not remove CrO(4)(2-) from solution, but shows enhancement of Cu(2+) and Pb(2+) removal. There is an approximate ten-fold increase in removal of Cu(2+) and Pb(2+) by carbonised red mud compared with acidified red mud.


Autocrine TGF-beta signaling is required for the GDNF/CNTF-induced neuronal differentiation of adrenal chromaffin tsAM5D cells expressing temperature-sensitive SV40 T-antigen.
We recently established adrenal medullary cell line tsAM5D, which was immortalized by use of a temperature-sensitive mutant of the oncogene simian virus 40 large T-antigen. In the present study, when co-treated with glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF), tsAM5D cells proliferated at the permissive temperature (33 degrees C) for the T-antigen expression and differentiated into neuron-like cells at the nonpermissive temperature (39 degrees C). Interestingly, in GDNF/CNTF-treated cultures, the addition of pan-specific transforming growth factor (TGF)-beta-neutralizing antibody did not affect the cell proliferation at 33 degrees C, but significantly reduced the survival of neuronally differentiated cells at 39 degrees C. Using real-time RT-PCR for analysis of GDNF/CNTF-treated cells, we found that the expression of mRNAs for TGF-beta1, TGF-beta2, and TGF-beta3 was up-regulated by the temperature shift. These results suggest that autocrine TGF-beta signaling is necessary for the survival of GDNF/CNTF-differentiated tsAM5D cells upon the temperature shift.


Varian Halcyon dosimetric comparison for multiarc VMAT prostate and head-and-neck cancers.
The Varian Halcyon linear accelerator is designed for faster treatment time and fewer treatment errors than conventional linear accelerators. Its increased gantry speed (4 rpm), dose rate (800 MU/min), and leaf speed (5 cm/s) reduce treatment time. The 2 multileaf collimator banks of 1 cm leaf width could cause planning difficulties, but utilizing many arcs could address this challenge. While 3 or more arcs are often avoided due to the increased treatment time, the Halcyon can deliver 5 arcs in under 3 minutes. For prostate and head-and-neck, we hypothesized plan quality would increase with increasing arcs without compromising treatment time. Fifteen prostate and fifteen head-and-neck previously treated patients were replanned to 78 and 66 Gy, respectively. A total of 150 volumetric modulated arc therapy (VMAT) plans, ranging from 1 to 5 arcs, were created to compare organ-at-risk (OAR) sparing, target coverage, homogeneity, and hotspot volume. Plans were normalized to the prescribed dose of 98% and 95% of the primary target volume for prostate and head-and-neck, respectively. All prostate 4-arc and 5-arc plans met MD Anderson Cancer Center (MDACC) constraints, while 86.7%, 20%, and 6.7% of the 1-arc, 2-arc, and 3-arc plans did not meet constraints, respectively. As the number of arcs increased, all OAR maximum doses decreased. All head-and-neck 5-arc plans met MDACC constraints, while 73.3%, 26.7%, 13.3%, and 6.7% of the 1-arc, 2-arc, 3-arc, and 4-arc plans did not meet constraints, respectively. The contralateral parotid mean dose and the spinal cord maximum dose decreased with increasing arcs. Homogeneity and conformity indices decreased when increasing from 1 to 5 arcs for both prostate and head-and-neck. Overall, homogeneity and conformity indices and OAR doses improved when using three or more arcs. Therefore, using at least 3 arcs for VMAT plans on the Halcyon will increase plan quality without compromising treatment time.


Inhibitory effect of β-escin on Zika virus infection through the interruption of viral binding, replication, and stability.
β-Escin is a mixture of triterpenoid saponins extracted from horse chestnut seeds that have diverse pharmacological activities, including anti-inflammation, anti-edematous, venotonic, and antiviral effects. In the clinical setting, β-escin is primarily used to treat venous insufficiency and blunt trauma injuries. The anti-Zika virus (ZIKV) activity of β-escin has not been explored. This study investigated the antiviral efficacy of β-escin on ZIKV and dengue virus (DENV) in vitro and then elucidated the underlying mechanism. The inhibitory effects of β-escin on viral RNA synthesis, protein levels, and infection ability were determined using qRT-PCR, Western blotting, and immunofluorescence assays, respectively. To further characterize how β-escin interferes with the viral life cycle, the time-of-addition experiment was performed. An inactivation assay was performed to determine whether β-escin affects ZIKV virion stability. To broaden these findings, the antiviral effects of β-escin on different DENV serotypes were assessed using dose-inhibition and time-of-addition assays. The results showed that β-escin exhibits anti-ZIKV activity by decreasing viral RNA levels, protein expression, progeny yield, and virion stability. β-Escin inhibited ZIKV infection by disrupting viral binding and replication. Furthermore, β-escin demonstrated antiviral activities against four DENV serotypes in a Vero cell model and prophylactic protection against ZIKV and DENV infections.


Application of solid phase aggregation of coated erythrocytes technique for detection of rinderpest antigen.
A solid phase aggregation of coated erythrocytes (SPACE) technique was standardized and used for the detection of rinderpest antigen in 129 samples of 9 visceral organs; from 50 clinical samples such as gum scraping, tongue scraping, faeces, urine, nasal swabs; blood from 18 rinderpest infected cattle and 2 field samples. The comparative sensitivity of SPACE, reverse phase passive haemagglutination and counter-immuno-electrophoresis tests was found to be 86.8, 84.5 and 79.8%, respectively.


Contact X-ray therapy for rectal cancer: experience in Centre Antoine-Lacassagne, Nice, 2002-2006.
To report the results of using contact X-ray (CXR), which has been used in the Centre-Lacassagne since 2002 for rectal cancer. A total of 44 patients were treated between 2002 and 2006 using four distinct clinical approaches. Patients with Stage T1N0 tumors were treated with transanal local excision (TLE) and adjuvant CXR (45 Gy in three fractions) (n = 7). The 11 inoperable (or who had refused surgery) patients with Stage T2-T3 disease were treated with CXR plus external beam radiotherapy (EBRT). Those with Stage T3N0-N2 tumors were treated with preoperative CXR plus EBRT (with or without concurrent chemotherapy) followed by surgery (n = 21). Finally, the patients with Stage T2 disease were treated with CXR plus EBRT followed by TLE (n = 5). The median follow-up was 25 months. In the 7 patients who underwent TLE first, no local failure was observed, and their anorectal function was good. Of the 11 inoperable patients who underwent CXR plus EBRT alone, 10 achieved local control. In the third group (preoperative CXR plus EBRT), anterior resection was performed in 16 of 21 patients. Complete sterilization of the operative specimen was seen in 4 cases (19%). No local recurrence occurred. Finally, of the 5 patients treated with CXR plus EBRT followed by TLE, a complete or near complete clinical response was observed in all. TLE with a R0 resection margin was performed in all cases. The rectum was preserved with good function in all 5 patients. These early results have confirmed that CXR combined with surgery (or alone with EBRT) can play a major role in the conservative and curative treatment of rectal cancer.


A comprehensive regulatory framework to address the unmet need for new antibacterial treatments.
To bring new antibacterial drugs to the market is challenging because discovery of new agents is difficult, two large trials per indication are needed in accordance with traditional regulatory requirements, and the economic reward is limited if the use of new antibiotics is constrained. These challenges have resulted in an alarmingly thin antibiotic pipeline, despite the rapid and continued growth in the need for new drugs. Approaches that balance the quantity of data needed for registration with the unmet medical need would encourage work in this area. Therefore, a tiered regulatory framework that allows either disease-based or pathogen-based label indications is proposed, with label wording that promotes the most appropriate use of new agents. Such a framework is within the bounds of present regulatory approaches, is amenable to international harmonisation, and would be a welcome step towards the facilitation of a robust and sustainable discovery and development infrastructure.


Long-term outcomes and prognostic factors of pulmonary metastasectomy for osteosarcoma and soft tissue sarcoma.
The prognostic factors of pulmonary metastasectomy in patients with osteosarcoma and soft tissue sarcoma remain controversial. The purpose of our analysis was to explore the prognostic factors and outcomes of patients with osteosarcoma and soft tissue sarcoma who underwent pulmonary metastasectomy at our institution. We reviewed the data of 44 patients who underwent resection of pulmonary metastases from 1996 to 2016 at our institution. The Kaplan-Meier method, log-rank test and multivariate Cox hazard model were used for comparison and survival analyses. There was no perioperative mortality. The median post-metastasectomy overall survival was 24.8 months, and the 5-year overall survival rate of all patients was 43.5%. The 5-year survival rate of the patients who underwent repeat thoracotomies was 60.0%. Incomplete resection, a largest tumor size > 2 cm and a disease-free interval < 12 months were associated with poor survival in multivariate analyses. Among eight patients, who underwent repeat pulmonary resection, two remain alive with no evidence of disease. These patients had the longest DFI and DFI-2 (time from first pulmonary metastasectomy to the diagnosis of recurrent pulmonary metastasis), respectively. The survival of patients with a relatively long disease-free interval, small tumor size and complete resection was favorable following the treatment of osteosarcoma and soft tissue sarcoma with pulmonary metastasectomy. Repeat pulmonary metastasectomies also provide favorable prognosis in select patients.


Identification of potent inhibitors of Plasmodium falciparum plasmepsin II from an encoded statine combinatorial library.
An encoded 13,020-member combinatorial library was synthesized containing a statine core. Evaluation of this library with plasmepsin II, an aspartyl protease required for hemoglobin metabolism in the malaria parasite, led to the identification of potent and selective inhibitors as well as novel structure-activity relationships.


Mixed-method assessment of caregiver feeding practices in early care and education centres during COVID-19.
The COVID-19 pandemic changed early care and education (ECE) mealtimes. Feeding practices that support children's emerging autonomy may support children's healthy eating, but it is unknown whether and how COVID-19 changed feeding practices. This paper describes caregiver feeding practices in ECE centres in Florida during COVID-19. A mixed-methods design was used to understand mealtime feeding practices. Survey and interview questions were developed based on the Trust Model. More than 7000 surveys were sent to ECE centres. Analysis included descriptive statistics for survey data and thematic analysis for interview data. This statewide study included teachers in all licensed and license-exempt ECE centres. Four hundred and thirty-one teachers completed a survey, and twenty-nine participated in follow-up interviews. Surveys showed most teachers engaged in autonomy-supportive behaviours, such as letting children eat until they were finished (90 %). The most common controlling behaviour was praising children for cleaning their plates (70 %). The most common responses about changes to mealtimes were keeping physical distance and serving healthy food. Interview themes were Autonomy Support, Controlling Feeding Practices, Interactions are the Same, Interactions are Different, Physical Distancing and Healthy Eating. Mealtimes are a central part of the day for young children and teachers in ECE environments. COVID-19 continues to influence ECE routines as behaviour change remains the primary method of reducing the risk of COVID-19 in the absence of a vaccine for young children. Understanding teachers' practices and perspectives is important for reducing the risk of COVID-19 and supporting children's autonomy and healthy eating.


Context-dependent memory in a meaningful environment for medical education: in the classroom and at the bedside.
Learning-in-context is a much-discussed topic in medical education. Information is said to be better recalled when the learning environment resembles the later retrieval environment. Godden and Baddeley (1975) showed that divers recalled words better when the recall condition matched the original learning environment, i.e. underwater or on land. Though it is unclear whether the findings can be generalized for medical education, medical educators regularly refer to them. We replicated the Godden and Baddeley study in ecologically more valid conditions for medical education and extended it with meaningful subject matter (namely, a patient case description). Sixty-three clerks were randomized over four conditions, contrasting a clinical (bedside) with an educational (classroom) environment as both learning and recall conditions. Students were asked to recall a list of words and a patient case in the same environment or in the opposite environment as where they learned it. We failed to find a significant same-context advantage for free recall of the list of words and the patient case propositions. However, there does appear to be a slight tendency towards better recall of the case description when learning took place in the clinical environment. In medical education, the context, if conceived as physical surroundings, does not seem to contribute to a same-context advantage. One should be cautious in generalizing the findings of Godden and Baddeley. However, different forms of 'context' other than the physical one used in the Godden and Baddeley study may well enhance learning effects in medical education.


Distribution-abundance relationship for passerines breeding in Tunisian oases: test of the sampling hypothesis.
The positive relationship between local abundance and distribution of species is a widely recognized pattern in community ecology. However, it has been suggested that this relationship can simply be an artefact of sampling because locally rare species are less detectable then locally abundant ones, and hence their distribution can easily be underestimated. Here, we use count data to investigate the relationship between distribution and abundance of passerines breeding in a sample of oases from southern Tunisia, and we provide a test of the sampling artefact hypothesis. In particular, we checked for a difference in detection probability between localized and widespread species, and we tested if increasing the sampling effort affects the significance of the relationship. A significant positive relationship between the average local abundance of passerine species and the proportion of occupied oases was found. The use of a capture-recapture approach allowed us to estimate and to compare the detection probabilities of localized and widespread species subsets. We found that localized species were locally less detectable than widespread species, which is consistent with the main assumption of the sampling artefact hypothesis. However, increasing the detection probability of species by conducting more counts did not affect the significance of the relationship, which did not give support to the sampling artefact hypothesis. Our work implies that sampling contributed to the distribution-abundance relationship we found, but that it is unlikely that such a relationship could entirely be explained by an artefact of sampling. It also underlines the insight that can be gained by using probabilistic approaches of estimating species number and detection probability when attempting to disentangle sampling from ecological effects in community ecology studies.