ARID5B genetic polymorphisms contribute to racial disparities in the incidence and treatment outcome of childhood acute lymphoblastic leukemia.
Recent genome-wide screens have identified genetic variations in ARID5B associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). We sought to determine the contribution of ARID5B single nucleotide polymorphisms (SNPs) to racial disparities in ALL susceptibility and treatment outcome. We compared the association between ARID5B SNP genotype and ALL susceptibility in whites (> 95% European genetic ancestry; 978 cases and 1,046 controls) versus in Hispanics (> 10% Native American ancestry; 330 cases and 541 controls). We determined the relationships between ARID5B SNP genotype and ALL relapse risk in 1,605 children treated on the Children's Oncology Group (COG) P9904/9905 clinical trials. Among 49 ARID5B SNPs interrogated, 10 were significantly associated with ALL susceptibility in both whites and Hispanics (P < .05), with risk alleles consistently more frequent in Hispanics than in whites. rs10821936 exhibited the most significant association in both races (P = 8.4 × 10(-20) in whites; P = 1 × 10(-6) in Hispanics), and genotype at this SNP was highly correlated with local Native American genetic ancestry (P = 1.8 × 10(-8)). Multivariate analyses in Hispanics identified an additional SNP associated with ALL susceptibility independent of rs10821936. Eight ARID5B SNPs were associated with both ALL susceptibility and relapse hazard; the alleles related to higher ALL incidence were always linked to poorer treatment outcome and were more frequent in Hispanics. ARID5B polymorphisms are important determinants of childhood ALL susceptibility and treatment outcome, and they contribute to racial disparities in this disease.


Expression of the G-CSF receptor in monocytic cells is sufficient to mediate hematopoietic progenitor mobilization by G-CSF in mice.
Granulocyte colony-stimulating factor (G-CSF), the prototypical mobilizing cytokine, induces hematopoietic stem and progenitor cell (HSPC) mobilization from the bone marrow in a cell-nonautonomous fashion. This process is mediated, in part, through suppression of osteoblasts and disruption of CXCR4/CXCL12 signaling. The cellular targets of G-CSF that initiate the mobilization cascade have not been identified. We use mixed G-CSF receptor (G-CSFR)-deficient bone marrow chimeras to show that G-CSF-induced mobilization of HSPCs correlates poorly with the number of wild-type neutrophils. We generated transgenic mice in which expression of the G-CSFR is restricted to cells of the monocytic lineage. G-CSF-induced HSPC mobilization, osteoblast suppression, and inhibition of CXCL12 expression in the bone marrow of these transgenic mice are intact, demonstrating that G-CSFR signals in monocytic cells are sufficient to induce HSPC mobilization. Moreover, G-CSF treatment of wild-type mice is associated with marked loss of monocytic cells in the bone marrow. Finally, we show that bone marrow macrophages produce factors that support the growth and/or survival of osteoblasts in vitro. Together, these data suggest a model in which G-CSFR signals in bone marrow monocytic cells inhibit the production of trophic factors required for osteoblast lineage cell maintenance, ultimately leading to HSPC mobilization.


The contribution of a pharmacy admissions service to patient care.
The aim of this study was to determine the impact of two specialised admissions pharmacists on an acute medical admissions ward. For a one-week period, contributions made to the medical post-take ward round (PTWR), the number of drug histories taken and interventions made as a result, and the availability of medication needed on discharge were documented. An average of 1.1 contributions per patient were made on the PTWR; a large proportion of these concerned therapeutic choice. Pharmacists also intervened to stop medication due to adverse drug reactions in 12% (n=10) of contributions. Fifty-two drug histories were checked by a pharmacist, resulting in 61 interventions (1.1 interventions per patient). The majority of interventions resulted from the unintentional omission of a regular medication (65%, n=39). Only 24% (n=29) of items needed on discharge had to be dispensed in pharmacy and 33% (n=41) were available as patients' own drugs.


Activated sludge process monitoring through in situ near-infrared spectral analysis.
The application of near infrared (NIR) spectroscopy for industrial process monitoring is achieving increasing importance over the last twenty years. In fact, the real time monitoring capacity of NIR spectroscopy is a very important feature for process monitoring, prediction and control as it allows a fast evaluation of the state of the process. However, the application of NIR spectroscopy in wastewater treatment processes is still to be explored. Although some applications of the technique for wastewater monitoring have been reported in the literature, there is still a need for more investigation related with applications, limitations and advantages of the technique when compared with other methods. An activated sludge reactor for aerobic treatment of a complex medium was monitored in situ with a NIR transflectance probe and traditional chemical parameters analysed off-line. NIR spectrophotometric data measured at the feed, reactor and settler were coupled to principal component analysis (PCA) to infer about the ability of this monitoring system to detect changes in the feed influent. The analysis of the score plots resulting from PCA permitted to identify the moments at which the perturbations occurred and to follow the consequent instability induced in the reactor till the day where the system is recuperated. The promising results obtained, suggest the interest in more detailed studies on the feasibility of NIR spectroscopy as an alternative method for monitoring and control of wastewater treatment processes.


Meningioma and systemic lupus erythematosus: a matter of pure coincidence?
To describe three cases of meningioma observed in a large cohort of 546 patients with systemic lupus erythematosus (SLE) followed at our Department in the last 15 years. We identified three cases of meningioma among 181 patients with SLE who underwent a brain magnetic resonance imaging (MRI) during their disease course (prevalence 1.65%). All three SLE cases were women with a disease onset at 47-, 18- and 42 -years-old, respectively. All patients presented neuropsychiatric (NP) symptoms and had an incidental finding of a meningioma at brain MRI. One patient presented simultaneously a breast cancer. Only one patient had the surgical removal of the mass without improvement of her symptoms while in the other two patients, the removal was not indicated. The association between meningioma and SLE may be a pure coincidence. However, it draws our attention because its detection may represent a confounding factor in the setting of a NPSLE patient.


Decreased frequency of somatic hypermutation and impaired affinity maturation but intact germinal center formation in mice expressing antisense RNA to DNA polymerase zeta.
To examine a role of DNA polymerase zeta in somatic hypermutation, we generated transgenic mice that express antisense RNA to a portion of mouse REV3, the gene encoding this polymerase. These mice express high levels of antisense RNA, significantly reducing the levels of endogenous mouse REV3 transcript. Following immunization to a hapten-protein complex, transgenic mice mounted vigorous Ab responses, accomplished the switch to IgG, and formed numerous germinal centers. However, in most transgenic animals, the generation of high affinity Abs was delayed. In addition, accumulation of somatic mutations in the V(H) genes of memory B cells from transgenic mice was decreased, particularly among those that generate amino acid replacements that enhance affinity of the B cell receptor to the hapten. These data implicate DNA polymerase zeta, a nonreplicative polymerase, in the process of affinity maturation, possibly through a role in somatic hypermutation, clonal selection, or both.


Theory and optimization of lens ducts.
Lens ducts are simple optical devices that have found application in the coupling of pump radiation from extended two-dimensional semiconductor laser diode arrays into solid-state laser gain media. The operation of these devices relies on the combined effects of lensing at their curved input surface and channeling by total internal reflection off their canted planar sides, to contain and couple semiconductor diode laser light efficiently to the input face of a solid-state laser crystal or glass. The lens duct provides a robust method for amplifying the irradiance of laser diode array pump sources and has made possible a scalable diode end-pumping architecture that offers the opportunity to expand significantly the number of ions and transitions that can be practically engaged in diode-pumped solid-state laser systems. An analytic model that describes the transfer efficiency of lens ducts and aids in the optimization of their design is presented.


Risk assessment for yellow Fever in Western and north-Western provinces of zambia.
North-Western and Western provinces of Zambia were reclassified as low-risk areas for yellow fever (YF). However, the current potential for YF transmission in these areas is unclear. To determine the current potential risk of YF infection. A cross sectional study was conducted in North-Western and Western provinces of Zambia. Samples were tested for both YF virus-specific IgG and IgM antibodies by the ELISA and YF virus confirmation was done using Plaque Reduction Neutralization Test. The samples were also tested for IgG and IgM antibodies against other flaviviruses. Out of the 3625 respondents who participated in the survey, 46.7% were males and 9.4% were aged less than 5 years. Overall, 58.1% of the participants slept under an impregnated insecticide-treated net and 20.6% reported indoor residual spraying of insecticides. A total of 616 (17.0%) samples were presumptive YF positive. The prevalence for YF was 0.3% for long-term infection and 0.2% for recent YF infection. None of the YF confirmed cases had received YF vaccine. Prevalence rates for other flaviviruses were 149 (4.1%) for Dengue, 370 (10.2%) for West Nile and 217 (6.0%) for Zika. There is evidence of past and recent infection of YF in both provinces. Hence, they are at a low risk for YF infection. Yellow fever vaccination should be included in the EPI program in the two provinces and strengthen surveillance with laboratory confirmation.


Continuous Monitoring of Patient Mobility for 18 Months Using Inertial Sensors following Traumatic Knee Injury: A Case Study.
Continuous patient activity monitoring during rehabilitation, enabled by digital technologies, will allow the objective capture of real-world mobility and aligning treatment to each individual's recovery trajectory in real time. To explore the feasibility and added value of such approaches, we present a case study of a 36-year-old male participant monitored continuously for activity levels and gait parameters using a waist-worn inertial sensor following a tibial plateau fracture on the right side, sustained as a result of a high-energy trauma during a sporting accident. During rehabilitation, data were collected for a period of 553 days, with > 80% daytime compliance, until the participant returned to near full mobility. The participant completed a daily diary with the annotation of major events (falls, near falls, cycling periods, or physiotherapy sessions) and key dates in the patient's recovery, including medical interventions, transitioning off crutches, and returning to work. We demonstrate the feasibility of collecting, storing, and mining of continuous digital mobility data and show that such data can detect changes in mobility and provide insights into long-term rehabilitation. We make both raw data and annotations available as a resource with the aspiration that further methods and insights will be built on this initial exploration of added value and continue to demonstrate that continuous monitoring can be deployed to aid rehabilitation.


Limited angle tomography for transmission X-ray microscopy using deep learning.
In transmission X-ray microscopy (TXM) systems, the rotation of a scanned sample might be restricted to a limited angular range to avoid collision with other system parts or high attenuation at certain tilting angles. Image reconstruction from such limited angle data suffers from artifacts because of missing data. In this work, deep learning is applied to limited angle reconstruction in TXMs for the first time. With the challenge to obtain sufficient real data for training, training a deep neural network from synthetic data is investigated. In particular, U-Net, the state-of-the-art neural network in biomedical imaging, is trained from synthetic ellipsoid data and multi-category data to reduce artifacts in filtered back-projection (FBP) reconstruction images. The proposed method is evaluated on synthetic data and real scanned chlorella data in 100° limited angle tomography. For synthetic test data, U-Net significantly reduces the root-mean-square error (RMSE) from 2.55 × 10-3 µm-1 in the FBP reconstruction to 1.21 × 10-3 µm-1 in the U-Net reconstruction and also improves the structural similarity (SSIM) index from 0.625 to 0.920. With penalized weighted least-square denoising of measured projections, the RMSE and SSIM are further improved to 1.16 × 10-3 µm-1 and 0.932, respectively. For real test data, the proposed method remarkably improves the 3D visualization of the subcellular structures in the chlorella cell, which indicates its important value for nanoscale imaging in biology, nanoscience and materials science.


A mismatch of planning and achieved tibial plateau angle in cranial closing wedge surgery: An in silico and clinical evaluation of 100 cases.
(1) To determine whether Oxley's modified cranial closing wedge osteotomy (CCWO) results in a tibial plateau angle (TPA) of 5° in silico, (2) compare in silico to clinical postoperative TPA and (3) determine the impact of ostectomy distalization in silico. Cross-sectional retrospective radiographic in silico study. A total of 100 stifle radiographs; 90 dogs (small ≤25 kg = 84; large >25 kg = 16). Tibial plateau angles were measured preoperatively (TPAPre ), after in silico planning (TPAPlan ), and postoperatively (TPAPost ). Virtual ostectomies were evaluated for plate fit. Postoperative ostectomy position was measured. Virtual ostectomies were performed 5/7.5/10/15 mm from the patellar tendon insertion in 10 dogs from each preoperative TPA category (≤20°/21-25°/ 26-30°/31-35°/>35°). Comparisons for TPAPre , TPAPost , and TPAPlan were made between small and large dogs, and the outcome to the target 5° between TPA categories and ostectomy positions. Mean ± SD TPAPre was 28.6 ± 6.2° and higher in small than large dogs. Mean TPAPlan was 7.6 ± 2.7°. Plate fit was appropriate in all. In silico, TPAs were greater than 5° except for cases with TPAPre > 35°. Median TPAPost was 5.5° (-4-21) and was higher in small (7°) than large (4.5°) dogs. Postoperative ostectomy position was more distal than Oxley's guidelines. When distalized >7.5 mm in silico, the magnitude of under-correction increased. Oxley's modified CCWO did not result in TPA of 5° in most cases. Ostectomy distalization exacerbated under-correction. Current guidelines should be modified to achieve 5° TPA postoperatively.


60 YEARS OF POMC: Transcriptional and epigenetic regulation of POMC gene expression.
Expression of the pro-opiomelanocortin (POMC) gene integrates numerous inputs that reflect the developmental history of POMC-expressing cells of the pituitary and hypothalamus, as well as their critical role in the endocrine system. These inputs are integrated at specific regulatory sequences within the promoter and pituitary or hypothalamic enhancers of the POMC locus. Investigations of developmental mechanisms and transcription factors (TFs) responsible for pituitary activation of POMC transcription led to the discovery of the Pitx factors that have critical roles in pituitary development and striking patterning functions in embryonic development. Terminal differentiation of the two pituitary POMC lineages, the corticotrophs and melanotrophs, is controlled by Tpit; mutations of the human TPIT gene cause isolated adrenocorticotrophic hormone deficiency. Intermediate lobe and melanotroph identity is provided by the pioneer TF Pax7 that remodels chromatin to reveal a new repertoire of enhancers for Tpit action. Many signaling pathways regulate POMC transcription including activation by hypothalamic corticotrophin-releasing hormone acting through the orphan nuclear receptors of the Nur family and feedback repression by glucocorticoids and their glucocorticoid receptor. TFs of the basic helix-loop-helix, Smad, Stat, Etv, and nuclear factor-B families also mediate signals for control of POMC transcription. Whereas most of these regulatory processes are conserved in different species, there are also notable differences between specific targets for regulation of the human compared with mouse POMC genes.


Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model.
Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver.


Integration of non-invasive functional assessments with anatomical risk stratification in complex coronary artery disease: the non-invasive functional SYNTAX score.
Since the early days of coronary angiography, the extension and severity of coronary artery disease (CAD) have been used for risk stratification. The SYNTAX score objectively characterizes CAD in patients with multivessel disease. Furthermore, recalculating the SYNTAX score by the incorporation of the functional component coronary stenosis (i.e., FFR) increases the discrimination for the risk of adverse events. The calculation of the SYNTAX score derived from non-invasive modalities such as coronary computed tomography angiography (CTA) has emerged as a mean to obtain the SYNTAX score before invasive cardiac catheterization. Likewise, the computation of the non-invasive fractional flow reserve CT (FFRCT) allows for the calculation of the non-invasive functional SYNTAX score. Ultimately, the combination of anatomical and functional evaluations with clinical factors further refines the identification of patients at risk and provides a recommendation for the Heart Team regarding the treatment strategy (i.e., PCI or CABG) based on the predicted 4-year mortality. The purpose of this review is to describe the integration of a novel non-invasive functional coronary assessment with the angiographic risk score in patients with multivessel CAD.


Detection of Drugs in Nails: Three Year Experience.
Nails (fingernails and toenails) are made of keratin. As the nail grows, substances incorporate into the keratin fibers where they can be detected 3-6 months after use. Samples are collected by clipping of 2-3 mm of nail from all fingers (100 mg). We present drug testing results from 10,349 nail samples collected from high-risk cases during a 3-year period of time. Samples were analyzed by validated analytical methods. The initial testing was performed mostly using enzyme-linked immunosorbent assay, but by liquid chromatography-tandem mass spectrometry (LC-MS-MS) as well. Presumptive positive samples were subjected to confirmatory testing with sample preparation procedures including washing, pulverizing, digestion and extraction optimized for each drug class. The total of 7,799 samples was analyzed for amphetamines. The concentrations ranged from 40 to 572,865 pg/mg (median, 100-3,687) for all amphetamine analytes. Amphetamine and methamphetamine were present in 14% of the samples, 22 samples were positive for 3,4-methylenedioxymethamphetamine (0.3%), 7 for methylenedioxyamphetamine (0.09%) and 4 for 3,4-methylenedioxy-N-ethylamphetamine (0.05%). Cocaine and related analytes were found in 5% samples (7,787 total), and the concentration range was 20-265,063 pg/mg (median 84-1,768). Opioids overall ranged from 40 to 118,229 pg/mg (median 123-830). The most prevalent opioid was oxycodone (15.1%) and hydrocodone (11.4%) compared with 1.0-3.6% for the others, including morphine, codeine, hydromorphone, methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine and oxymorphone. Carboxy-Δ-9-tetrahydrocannabinol positivity rate was 18.1% (0.04-262 pg/mg, median 6.41). Out of 3,039 samples, 756 were positive (24.9%) for ethyl glucuronide (20-3,754 pg/mg, median 88). Other drugs found in nails included barbiturates, benzodiazepines, ketamine, meperidine, tramadol, zolpidem, propoxyphene, naltrexone and buprenorphine. Nail analyses have become a reliable way of determining the long-term use and abuse of drugs. Extraction techniques are simple and produce accurate and precise results. Sensitive analytical instrumentation, mainly LC-MS-MS, allows for detection of femtogram (10(-15) g) quantities of substances in nails. Samples were from a high-risk population, therefore the extraordinary positivity rate was observed.


Lights and Shadows: A Comprehensive Survey on Cooperative and Precoding Schemes to Overcome LOS Blockage and Interference in Indoor VLC.
Visible light communications (VLC) have received significant attention as a way of moving part of the saturated indoor wireless traffic to the wide and unregulated visible optical spectrum. Nowadays, VLC are considered as a suitable technology, for several applications such as high-rate data transmission, supporting internet of things communications or positioning. The signal processing originally derived from radio-frequency (RF) systems such as cooperative or precoding schemes can be applied to VLC. However, its implementation is not straightforward. Furthermore, unlike RF transmission, VLC present a predominant line-of-sight link, although a weak non-LoS component may appear due to the reflection of the light on walls, floor, ceiling and nearby objects. Blocking effects may compromise the performance of the aforementioned transmission schemes. There exist several surveys in the literature focused on VLC and its applications, but the management of the shadowing and interference in VLC requires a comprehensive study. To fill this gap, this work introduces the implementation of cooperative and precoding schemes to VLC, while remarking their benefits and drawbacks for overcoming the shadowing effects. After that, the combination of both cooperative and precoding schemes is analyzed as a way of providing resilient VLC networks. Finally, we propose several open issues that the cooperative and precoding schemes must face in order to provide satisfactory VLC performance in indoor scenarios.


An analytical formulation of isotope fractionation due to self-shielding.
Isotope fractionation due to photochemical self-shielding is believed to be responsible for the enrichment of inner solar system planetary materials in the rare isotopes of carbon, nitrogen, and oxygen relative to the Sun. Self-shielding may also contribute to sulfur isotope mass-independent fractionation in modern atmospheric sulfates, although its role in the early Earth atmosphere has not yet been convincingly established. Here, I present an analytical formulation of isotopic photodissociation rate coefficients that describe self-shielding isotope signatures for 3 and 4-isotope systems broadly representative of O and S isotopes. The analytic equations are derived for idealized molecular spectra, making an analytic formulation tractable. The idealized spectra characterize key features of actual isotopologue spectra, particularly for CO and SO2, but are applicable to many small molecules and their isotopologues. The analytic expressions are convenient for evaluating the magnitude of isotope effects without having to pursue involved numerical solutions. More importantly, the analytic expressions illustrate the origin of particular isotope signatures, such as the previously unexplained large mass-dependent fractionation associated with photodissociation of optically-thick SO2. The formulation presented here elucidates the origin of some of these important isotopic fractionation processes.


Emerging trends for radioimmunotherapy in solid tumors.
Due to its ability to target both known and occult lesions, radioimmunotherapy (RIT) is an attractive therapeutic modality for solid tumors. Poor tumor uptake and undesirable pharmacokinetics, however, have precluded the administration of radioimmunoconjugates at therapeutically relevant doses thereby limiting the clinical utility of RIT. In solid tumors, efficacy of RIT is further compromised by heterogeneities in blood flow, tumor stroma, expression of target antigens and radioresistance. As a result significant efforts have been invested toward developing strategies to overcome these impediments. Further, there is an emerging interest in exploiting short-range, high energy α-particle emitting radionuclides for the eradication of minimal residual and micrometastatic disease. As a result several modalities for localized therapy and models of minimal disease have been developed for preclinical evaluation. This review provides a brief update on the recent efforts toward improving the efficacy of RIT for solid tumors, and development of RIT strategies for minimal disease associated with solid tumors. Further, some of promising approaches to improve tumor targeting, which showed promise in the past, but have now been ignored are also discussed.


Disparities in human papillomavirus (HPV) vaccine initiation and completion based on sexual orientation among women in the United States.
We compared HPV vaccine initiation and completion of heterosexual with lesbian and bisexual (LB) women. We aggregated National Health and Nutrition Examination Survey data from 2009 to 2016 for 3,017 women aged 18 to 34 y in the United States. HPV vaccine initiation was defined as reported receipt of ≥1 dose of the vaccine and completion as receipt of the three recommended doses. Weighted percentages and multivariable logistic regression models were used to examine differences in HPV vaccine initiation and completion between heterosexual and LB women. Approximately 12% of respondents self-identified as LB women. Overall, a higher percentage of respondents (26%) had initiated the HPV vaccine than completed the three vaccine doses (17%). In the bivariate analysis, LB women had higher initiation ([35% of LB women versus 25% heterosexual]; p = .0012) and completion rates ([24% of LB women versus 17% heterosexual]; p = .0052) than heterosexual women. After adjusting for covariates, compared to heterosexual women, LB women were 60% (aOR = 1.60, 95% CI: 1.16-2.19) more likely to initiate and 63% (aOR = 1.63, 95% CI: 1.12-2.37) more likely to complete the HPV vaccine. Although LB women had higher likelihood of HPV vaccine initiation and completion compared with heterosexual women, their HPV vaccine uptake was well below the Healthy People 2020 target (80%). Understanding differences in the drivers of vaccine uptake in the LB population may inform strategies that would further increase HPV vaccine uptake toward achieving the 80% completion target.


Detection of normal plantar fascia thickness in adults via the ultrasonographic method.
Heel pain is a prevalent concern in orthopedic clinics, and there are numerous pathologic abnormalities that can cause heel pain. Plantar fasciitis is the most common cause of heel pain, and the plantar fascia thickens in this process. It has been found that thickening to greater than 4 mm in ultrasonographic measurements can be accepted as meaningful in diagnoses. Herein, we aimed to measure normal plantar fascia thickness in adults using ultrasonography. We used ultrasonography to measure the plantar fascia thickness of 156 healthy adults in both feet between April 1, 2011, and June 30, 2011. These adults had no previous heel pain. The 156 participants comprised 88 women (56.4%) and 68 men (43.6%) (mean age, 37.9 years; range, 18-65 years). The weight, height, and body mass index of the participants were recorded, and statistical analyses were conducted. The mean ± SD (range) plantar fascia thickness measurements for subgroups of the sample were as follows: 3.284 ± 0.56 mm (2.4-5.1 mm) for male right feet, 3.3 ± 0.55 mm (2.5-5.0 mm) for male left feet, 2.842 ± 0.42 mm (1.8-4.1 mm) for female right feet, and 2.8 ± 0.44 mm (1.8-4.3 mm) for female left feet. The overall mean ± SD (range) thickness for the right foot was 3.035 ± 0.53 mm (1.8-5.1 mm) and for the left foot was 3.053 ± 0.54 mm (1.8-5.0 mm). There was a statistically significant and positive correlation between plantar fascia thickness and participant age, weight, height, and body mass index. The plantar fascia thickness of adults without heel pain was measured to be less than 4 mm in most participants (~92%). There was no statistically significant difference between the thickness of the right and left foot plantar fascia.


Distributions of Virus-Like Particles and Prokaryotes within Microenvironments.
Microbial interactions are important for ecosystem function, but occur at the microscale and so are difficult to observe. Previous studies in marine systems have shown significant shifts in microbial community abundance and composition over scales of micrometres to centimetres. This study investigates the microscale abundance distributions of virus-like particles (VLPs) and prokaryotes in the lower reaches of a river to determine the extent to which microscale microbial patchiness exists in freshwater systems. Here we report local hotspots surrounded by gradients that reach a maximum 80 and 107 fold change in abundance over 0.9 cm for prokaryotic and VLP subpopulations. Changes in prokaryotic and VLP hotspots were tightly coupled. There were no gradients at tens of centimetres across the boundary layers, which is consistent with strong mixing and turbulence-driven aggregation found in river systems. Quantification of the patchiness shows a marked asymmetry with patches 10 times greater than background common, but depletions being rare or absent in most samples. This consistent asymmetry suggests that coldspots depleted by grazing and lysis are rapidly mixed to background concentrations, while the prevalence of hotspots indicates persistence against disruption. The hotspot to coldspot relative abundance may be useful for understanding microbial river dynamics. The patchiness indicates that the mean- field approach of bulk phase sampling misses the microbially relevant community variation and may underestimate the concentrations of these important microbial groups.


The relationship between the efficacy of epidural anesthesia and the concentration of lidocaine in cerebrospinal fluid.
Addition of bicarbonate to local anesthetics improves the efficacy of epidural anesthesia. We evaluated whether the addition of bicarbonate to lidocaine enhanced pain threshold in cesarean section. We speculated that bicarbonate would increase the concentration of lidocaine in cerebrospinal fluid (CSF). To examine this possibility, we evaluated the relationship between the lidocaine concentration in the CSF and the pain threshold. Twenty eight full-term parturients undergoing cesarean section under epidural anesthesia at L2-3 were divided into two groups: the first group (lidocaine group) received 17 mL of 2% lidocaine-epinephrine (1:200,000) and the second group (lidocaine-bicarbonate group) received the same concentration of lidocaine-epinephrine supplemented bicarbonate. Twenty min after administration of local anesthetics, we collected 1 mL samples of the CSF. The pain threshold after the repeated electrical stimulation was used to assess sensory blockade at the L2, S1, and S3 dermatomes. Demographic data were comparable between the groups. There were no differences in the pain threshold at all dermatomes and the lidocaine concentration between the groups. There was a significant correlation between the pain threshold and the lidocaine concentration at the combined S1 and S3 dermatomes in the lidocaine-bicarbonate group. We find neither bicarbonate caused a significant difference in the efficacy of epidural anesthesia nor it caused an increase of lidocaine concentration in the CSF. The result that we found a significant correlation between the lidocaine concentration in the CSF and the pain threshold at the sacral region in the lidocaine bicarbonate group suggests that, bicarbonate enhances the efficacy of anesthesia at outside of spinal canal.


Understanding the super-spreading events of SARS in Singapore.
It has been noted that SARS transmission is characterised by a few super-spreading events (SSEs) giving rise to a disproportionate number of secondary cases. Clinical and environmental features surrounding the index cases involved were compared with cases in non- SSEs. Data on 231 cases of probable SARS admitted to Tan Tock Seng Hospital (TTSH) were used. Index cases directly causing 10 or more secondary cases were classified as having been involved in SSEs; all others were defined as non-SSEs. Only 5 cases were involved in SSEs; all 5 were isolated on day 5 of illness or later, and spent at least a brief period in a non-isolation ward; in contrast, amongst the 226 non-SSE cases, only 40.7% and 4.0% were isolated late and admitted to non-isolation wards respectively, and only 3.1% had both these environmental features present; the differences were highly significant (P = 0.012, P <0.001 and P <0.001 by Fisher's Exact test). When compared to 7 non-SSE cases with delayed isolation and an admission to non-isolation wards, SSEs were more likely to have co-morbid disease or require ICU care at time of isolation (P = 0.045 for both factors). SSEs were likely due to a conglomeration of environmental factors of delayed isolation and admission to a non-isolation ward, coupled with severe disease stage at time of isolation.


A precarious rite of passage in postreform China: heroin use among Nuosu youths on the move.
This article employs the rite of passage concept to analyze why and how heroin use and a subsequent HIV/AIDS epidemic have taken hold among minority Nuosu (Yi) young men in Southwest China. It juxtaposes structural inequalities and sociocultural particularities in social suffering among Nuosu youths as they attempt to create meaningful lives in China's market reform era. Since the 1980s, young Nuosu have ventured out to Han-dominant cities in search of fun and opportunities. This movement has become a new foray into manhood and inadvertently set up their encounter with heroin and the subsequent introduction of HIV into their hometowns. The article is based on my 20-month ethnographic fieldwork in Limu, a mountainous Nuosu community in Liangshan Yi Autonomous Prefecture, Sichuan Province, between 2002 and 2009.


Screening and Whole-Genome Sequencing of Two Streptomyces Species from the Rhizosphere Soil of Peony Reveal Their Characteristics as Plant Growth-Promoting Rhizobacteria.
Two bacteria, Streptomyces albireticuli MDJK11 and S. alboflavus MDJK44, which are potential plant growth-promoting rhizobacteria against pathogenic fungi were isolated from the rhizosphere soil of peony in Shandong, China. Their biological characteristics and complete genome sequences were reported in this study. The total genome size of MDJK11 was only 8.14 Mb with 6,550 protein-coding genes and a high GC content of 72.8 mol%. The MDJK44 genome comprises a 9.62 Mb chromosome with 72.1 mol% GC content, 7,285 protein-coding genes, and two plasmids. Some gene sequences in these two genomes were analyzed to be heterologously obtained by horizontal transfer. Gene or gene cluster candidates responding to secondary metabolites production, antimicrobial activities, and plant growth-promoting capacities were also analyzed in this paper. The genomic information and biological characteristics will facilitate the understanding and application of S. albireticuli and S. alboflavus species as biocontrol agents in future agriculture.


Regression tree analysis of ecological momentary assessment data.
An increasingly popular form of data collection in health psychology research is Ecological Momentary Assessment (EMA); that is, using diaries or smartphones to collect intensive longitudinal data. This method is increasingly applied to the study of relationships between state-based aspects of individuals' functioning and health outcomes (e.g., binge eating, alcohol use). Analysis of such data is challenging and regression tree modelling (RTM) may be a useful alternative to multilevel modelling for investigating the association between a set of explanatory variables and a continuous outcome. Furthermore, RTM outputs 'decision trees' that could be used by health practitioners to guide assessment and tailor intervention. In contrast to regression, RTM is able to easily accommodate many complex, higher-order interactions between predictor variables (without the need to create explicit interaction terms). These benefits make the technique useful for those interested in monitoring and intervening upon health and psychological outcomes (e.g., mood, eating behaviour, risky alcohol use, and treatment adherence). Using real data, this paper demonstrates both the benefits and limitations of RTM and how to extend these models to accommodate analysis of nested data; that is, data that arise from EMA where repeated observations are nested within individuals.


Improving recruitment in clinical trials: why eligible participants decline.
There is a need to explore why protocol-eligible subjects refuse participation in clinical trials. Without a clear understanding, participation by representative populations will be an ongoing obstacle to recruitment. This descriptive research study analyzes frequency data regarding a sample of 965 individuals who, despite being eligible for studies with the National Institute of Mental Health intramural program, declined research participation. Overall, responses regarding reasons for declining fell into the following five categories: a result of specific protocol issues; inconvenience; for other reasons not mentioned; financial reasons; and, lastly, decided to participate elsewhere. The results of this study identify common factors which suggest there are steps that investigators can take to better accommodate the needs of the public and, consequently, improve research participation.


MicroRNA expression and regulation in mouse uterus during embryo implantation.
MicroRNAs (miRNAs) are 21-24-nucleotide non-coding RNAs found in diverse organisms. Although hundreds of miRNAs have been cloned or predicted, only very few miRNAs have been functionally characterized. Embryo implantation is a crucial step in mammalian reproduction. Many genes have been shown to be significantly changed in mouse uterus during embryo implantation. However, miRNA expression profiles in the mouse uterus between implantation sites and inter-implantation sites are still unknown. In this study, miRNA microarray was used to examine differential expression of miRNAs in the mouse uterus between implantation sites and inter-implantation sites. Compared with inter-implantation sites, there were 8 up-regulated miR-NAs at implantation sites, which were confirmed by both Northern blot and in situ hybridization. miR-21 was highly expressed in the subluminal stromal cells at implantation sites on day 5 of pregnancy. Because miR-21 was not detected in mouse uterus during pseudopregnancy and under delayed implantation, miR-21 expression at implantation sites was regulated by active blastocysts. Furthermore, we showed that Reck was the target gene of miR-21. Our data suggest that miR-21 may play a key role during embryo implantation.


High-density transcriptional initiation signals underline genomic islands in bacteria.
Genomic islands (GIs), frequently associated with the pathogenicity of bacteria and having a substantial influence on bacterial evolution, are groups of "alien" elements which probably undergo special temporal-spatial regulation in the host genome. Are there particular hallmark transcriptional signals for these "exotic" regions? We here explore the potential transcriptional signals that underline the GIs beyond the conventional views on basic sequence composition, such as codon usage and GC property bias. It showed that there is a significant enrichment of the transcription start positions (TSPs) in the GI regions compared to the whole genome of Salmonella enterica and Escherichia coli. There was up to a four-fold increase for the 70% GIs, implying high-density TSPs profile can potentially differentiate the GI regions. Based on this feature, we developed a new sliding window method GIST, Genomic-island Identification by Signals of Transcription, to identify these regions. Subsequently, we compared the known GI-associated features of the GIs detected by GIST and by the existing method Islandviewer to those of the whole genome. Our method demonstrates high sensitivity in detecting GIs harboring genes with biased GI-like function, preferred subcellular localization, skewed GC property, shorter gene length and biased "non-optimal" codon usage. The special transcriptional signals discovered here may contribute to the coordinate expression regulation of foreign genes. Finally, by using GIST, we detected many interesting GIs in the 2011 German E. coli O104:H4 outbreak strain TY-2482, including the microcin H47 system and gene cluster ycgXEFZ-ymgABC that activates the production of biofilm matrix. The aforesaid findings highlight the power of GIST to predict GIs with distinct intrinsic features to the genome. The heterogeneity of cumulative TSPs profiles may not only be a better identity for "alien" regions, but also provide hints to the special evolutionary course and transcriptional regulation of GI regions.


Cloning, expression, and characterization of human cytosolic aminopeptidase P: a single manganese(II)-dependent enzyme.
The mammalian bradykinin-degrading enzyme aminopeptidase P (AP-P; E. C. 18.104.22.168) is a metal-dependent enzyme and is a member of the peptidase clan MG. AP-P exists as membrane-bound and cytosolic forms, which represent distinct gene products. A partially truncated clone encoding the cytosolic form was obtained from a human pancreatic cDNA library and the 5' region containing the initiating Met was obtained by 5' rapid accumulation of cDNA ends (RACE). The open reading frame encodes a protein of 623 amino acids with a calculated molecular mass of 69,886 Da. The full-length cDNA with a C-terminal hexahistidine tag was expressed in Escherichia coli and COS-1 cells and migrated on SDS-PAGE with a molecular mass of 71 kDa. The expressed cytosolic AP-P hydrolyzed the X-Pro bond of bradykinin and substance P but did not hydrolyze Gly-Pro-hydroxyPro. Hydrolysis of bradykinin was inhibited by 1,10-phenanthroline and by the specific inhibitor of the membrane-bound form of mammalian AP-P, apstatin. Inductively coupled plasma atomic emission spectroscopy of AP-P expressed in E. coli revealed the presence of 1 mol of manganese/mol of protein and insignificant amounts of cobalt, iron, and zinc. The enzymatic activity of AP-P was promoted in the presence of Mn(II), and this activation was increased further by the addition of glutathione. The only other metal ion to cause slight activation of the enzyme was Co(II), with Ca(II), Cu(II), Mg(II), Ni(II), and Zn(II) all being inhibitory. Removal of the metal ion from the protein was achieved by treatment with 1,10-phenanthroline. The metal-free enzyme was reactivated by the addition of Mn(II) and, partially, by Fe(II). Neither Co(II) nor Zn(II) reactivated the metal-free enzyme. On the basis of these data we propose that human cytosolic AP-P is a single metal ion-dependent enzyme and that manganese is most likely the metal ion used in vivo.


Reprogramming of the antimycin NRPS-PKS assembly lines inspired by gene evolution.
Reprogramming of the NRPS/PKS assembly line is an attractive method for the production of new bioactive molecules. However, it is usually hampered by the loss of intimate domain/module interactions required for the precise control of chain transfer and elongation reactions. In this study, we first establish heterologous expression systems of the unique antimycin-type cyclic depsipeptides: JBIR-06 (tri-lactone) and neoantimycin (tetra-lactone), and engineer their biosyntheses by taking advantage of bioinformatic analyses and evolutionary insights. As a result, we successfully accomplish three manipulations: (i) ring contraction of neoantimycin (from tetra-lactone to tri-lactone), (ii) ring expansion of JBIR-06 (from tri-lactone to tetra-lactone), and (iii) alkyl chain diversification of JBIR-06 by the incorporation of various alkylmalonyl-CoA extender units, to generate a set of unnatural derivatives in practical yields. This study presents a useful strategy for engineering NRPS-PKS module enzymes, based on nature's diversification of the domain and module organizations.


Increased risk of atrial fibrillation in patients with coeliac disease: a nationwide cohort study.
Inflammatory markers are established risk factors for atrial fibrillation (AF), but the role of autoimmune diseases is unknown. The aim of the study was to examine the association between coeliac disease (CD) and AF in a large cohort of patients with biopsy-verified CD. We identified 28,637 patients with CD through biopsy reports (defined as Marsh 3: villous atrophy) from all pathology departments (n = 28) in Sweden. Biopsies had been performed between 1969 and 2008. Age- and sex-matched reference individuals (n = 141,731) were identified from the Swedish Total Population Register. Data on AF were obtained from the Swedish Hospital Discharge Register, the Hospital Outpatient Register, and the Cause of Death Register. Hazard ratios (HRs) for AF were estimated using Cox regression. In the CD cohort, 941 individuals developed AF (vs. 2918 reference individuals) during a median follow-up of 9 years. The corresponding adjusted HR for AF was 1.34 (95% CI = 1.24-1.44). The absolute risk of AF in CD was 321 of 100,000 person-years, with an excess risk of 81 of 100,000. A prior AF diagnosis was also associated with an increased risk of subsequent CD (odds ratio = 1.45, 95% CI = 1.31-1.62). Atrial fibrillation is more common both before and after CD diagnosis in patients with CD though the excess risk is small. Potential explanations for the increased risk of AF in CD include chronic inflammation and shared risk factors, but ascertainment bias may also have contributed. Coeliac disease affects 1-2% of the Western population. Our results indicate that patients with coeliac disease, verified by intestinal biopsy, are at increased risk of atrial fibrillation. This observation is consistent with previous findings that elevation of inflammatory markers predicts atrial fibrillation. Additional studies are needed to clarify the mechanistic link between atrial fibrillation and autoimmune diseases such as coeliac disease.


Transition state mimetics of the Plasmodium export element are potent inhibitors of Plasmepsin V from P. falciparum and P. vivax.
Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; RxL↓xE/Q/D) in the parasite's endoplasmic reticulum. Here, we generated transition state mimetics of the native PEXEL substrate that potently inhibit PMV isolated from Plasmodium falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics was completely dependent on the presence of P1 Leu and P3 Arg. Treatment of P. falciparum-infected erythrocytes with a set of optimized mimetics impaired PEXEL processing and killed the parasites. The striking effect of the compounds provides a clearer understanding of the accessibility of the PMV active site and reaffirms the enzyme as an attractive target for the design of future antimalarials.


Costs of stroke and stroke services: Determinants of patient costs and a comparison of costs of regular care and care organised in stroke services.
BACKGROUND: Stroke is a major cause of death and long-term disability in Western societies and constitutes a major claim on health care budgets. Organising stroke care in a stroke service has recently been demonstrated to result in better health effects for patients. This paper discusses patient costs after stroke and compares costs between regular and stroke service care. METHODS: Costs were calculated within the framework of the evaluation of three experiments with stroke services in the Netherlands. Cost calculations are base on medical consumption data and actual costs. RESULTS: 598 patients were consecutively admitted to hospital after stroke. The average total costs of care per patient for the 6 month follow-up are estimated at 16,000. Costs are dominated by institutional and accommodation costs. Patients who die after stroke incur less costs. For patients that survive the acute phase, the most important determinants of costs are disability status and having a partner - as they influence patients' stroke careers. These determinants also interact. The most efficient stroke service experiment was most successful in co-ordinating patient flow from hospital to (nursing) home, through capacity planning and efficient discharge procedures. In this region the costs of stroke service care are the same as for regular stroke care. The other experiments suffered from waiting lists for nursing homes and home care, leading to "blocked beds" in hospitals and nursing homes and higher costs of care. Costs of co-ordination are estimated at about 3% of total costs of care. CONCLUSION: This paper demonstrates that by organising care for stroke patients in a stroke service, better health effects can be achieved with the same budget. In addition, it provides insight in need, predisposing and enabling factors that determine costs of care after stroke.


Comparison of home and away-from-home physical activity using accelerometers and cellular network-based tracking devices.
Measuring physical at home and away from home is essential for assessing health and well-being, and could help design interventions to increase physical activity. Here, we describe how physical activity at home and away from home can be quantified by combining information from cellular network-based tracking devices and accelerometers. Thirty-five working adults wore a cellular network-based tracking device and an accelerometer for 6 consecutive days and logged their travel away from home. Performance of the tracking device was determined using the travel log for reference. Tracking device and accelerometer data were merged to compare physical activity at home and away from home. The tracking device detected 98.6% of all away-from-home excursions, accurately measured time away from home and demonstrated few prolonged signal drop-out periods. Most physical activity took place away from home on weekdays, but not on weekends. Subjects were more physically active per unit of time while away from home, particularly on weekends. Cellular network-based tracking devices represent an alternative to global positioning systems for tracking location, and provide information easily integrated with accelerometers to determine where physical activity takes place. Promoting greater time spent away from home may increase physical activity.


Cleaning the air and improving health with hydrogen fuel-cell vehicles.
Converting all U.S. onroad vehicles to hydrogen fuel-cell vehicles (HFCVs) may improve air quality, health, and climate significantly, whether the hydrogen is produced by steam reforming of natural gas, wind electrolysis, or coal gasification. Most benefits would result from eliminating current vehicle exhaust. Wind and natural gas HFCVs offer the greatest potential health benefits and could save 3700 to 6400 U.S. lives annually. Wind HFCVs should benefit climate most. An all-HFCV fleet would hardly affect tropospheric water vapor concentrations. Conversion to coal HFCVs may improve health but would damage climate more than fossil/electric hybrids. The real cost of hydrogen from wind electrolysis may be below that of U.S. gasoline.


Personalized Cardiac Computational Models: From Clinical Data to Simulation of Infarct-Related Ventricular Tachycardia.
In the chronic stage of myocardial infarction, a significant number of patients develop life-threatening ventricular tachycardias (VT) due to the arrhythmogenic nature of the remodeled myocardium. Radiofrequency ablation (RFA) is a common procedure to isolate reentry pathways across the infarct scar that are responsible for VT. Unfortunately, this strategy show relatively low success rates; up to 50% of patients experience recurrent VT after the procedure. In the last decade, intensive research in the field of computational cardiac electrophysiology (EP) has demonstrated the ability of three-dimensional (3D) cardiac computational models to perform in-silico EP studies. However, the personalization and modeling of certain key components remain challenging, particularly in the case of the infarct border zone (BZ). In this study, we used a clinical dataset from a patient with a history of infarct-related VT to build an image-based 3D ventricular model aimed at computational simulation of cardiac EP, including detailed patient-specific cardiac anatomy and infarct scar geometry. We modeled the BZ in eight different ways by combining the presence or absence of electrical remodeling with four different levels of image-based patchy fibrosis (0, 10, 20, and 30%). A 3D torso model was also constructed to compute the ECG. Patient-specific sinus activation patterns were simulated and validated against the patient's ECG. Subsequently, the pacing protocol used to induce reentrant VTs in the EP laboratory was reproduced in-silico. The clinical VT was induced with different versions of the model and from different pacing points, thus identifying the slow conducting channel responsible for such VT. Finally, the real patient's ECG recorded during VT episodes was used to validate our simulation results and to assess different strategies to model the BZ. Our study showed that reduced conduction velocities and heterogeneity in action potential duration in the BZ are the main factors in promoting reentrant activity. Either electrical remodeling or fibrosis in a degree of at least 30% in the BZ were required to initiate VT. Moreover, this proof-of-concept study confirms the feasibility of developing 3D computational models for cardiac EP able to reproduce cardiac activation in sinus rhythm and during VT, using exclusively non-invasive clinical data.


Early Pregnancy Cardiovascular Health and Subclinical Atherosclerosis.
Background Assessing and optimizing cardiovascular health (CVH) early in life, such as in pregnancy, could lead to a longer lifetime spent in better CVH and reduce the risk of cardiovascular disease. This might especially benefit women with a hypertensive disorder of pregnancy (HDP) who are more likely to develop atherosclerosis and cardiovascular disease. We hypothesized that CVH in pregnancy is related to later life CVH and carotid intima-media thickness (CIMT), and that these associations differ between women with a normotensive pregnancy and women with an HDP. Methods and Results This study was conducted within the prospective population-based Generation R Study. CVH in pregnancy was based on 5 metrics (blood pressure, total-cholesterol, glucose, smoking, and body mass index). Postpartum CVH additionally included physical activity and diet scores, according to the American Heart Association classification. Postpartum CVH and CIMT were measured 10 years after pregnancy. Results were analyzed for women with a normotensive pregnancy and those with an HDP. Women with a normotensive pregnancy (n=1786) and women with an HDP (n=138) were evaluated from early pregnancy until 10 years postpartum. Better CVH in early pregnancy was associated with a smaller CIMT and better postpartum CVH in all women, especially in those with an HDP (CIMT: -9.82 μm [95% CI: -17.98, -1.67]). Conclusions Already in pregnancy, better CVH is associated with a smaller CIMT and better CVH 10 years postpartum, especially in women with an HDP. As pregnancy is an incentive for women to improve lifestyle, assessing CVH in pregnancy might help improve postpartum CVH and reduce cardiovascular disease risk.


Electroclinical history of a five-year-old girl with GRIN1-related early-onset epileptic encephalopathy: a video-case study.
De novo mutations in the GRIN1 gene have been recently reported as the molecular cause of a broad-spectrum early-onset neurological phenotype. Here, we describe a five-year-old girl with an early-onset epileptic encephalopathy associated with an infantile hyperkinetic movement disorder and oculomotor abnormalities. Whole-exome sequencing identified a novel p.Met641Leu de novo variant in the GRIN1 gene as the cause of the phenotype. In silico analysis suggested that the p.Met641Leu variant would alter the gating property of the ion channel, with the involved methionine residue facing towards the ion pore. Long-term systematic video-EEG allowed us to report on the electroclinical history and, specifically, on the semiology of the hyperkinetic movement disorder and oculomotor abnormalities resembling oculogyric crises in our patient. Our findings and a review of the recent literature reinforce the notion of GRIN1-encephalopathy as a recognizable neurological phenotype that should be suspected in early-onset epilepsy associated with hyperkinetic movement disorders. [Published with video sequence on www.epilepticdisorders.com].


F-box-directed CRL complex assembly and regulation by the CSN and CAND1.
The COP9 signalosome (CSN) is thought to maintain the stability of cullin-RING ubiquitin ligases (CRL) by limiting the autocatalytic destruction of substrate adapters such as F box proteins (FBPs). CAND1, a protein associated with unneddylated CUL1, was proposed to assist in this role in an as yet unclear fashion. We found that only a subset of Schizosaccharomyces pombe FBPs, which feature a critical F box proline that promotes their interaction with CUL1, required CSN for stability. Unlike the CRL3 adaptor Btb3p, none of the CSN-sensitive FBPs were affected by deletion of ubp12. Contrary to current models, CAND1 does not control adaptor stability but maintains the cellular balance of CRL1 complexes by preventing rare FBPs from being outcompeted for binding to CUL1 by more ample adapters. These findings were integrated into a refined model of CRL control in which substrate availability toggles CRLs between independent CSN and CAND1 cycles.


Structural analysis of metal sites in proteins: non-heme iron sites as a case study.
In metalloproteins, the protein environment modulates metal properties to achieve the required goal, which can be protein stabilization or function. The analysis of metal sites at the atomic level of detail provided by protein structures can thus be of benefit in functional and evolutionary studies of proteins. In this work, we propose a structural bioinformatics approach to the study of metalloproteins based on structural templates of metal sites that include the PDB coordinates of protein residues forming the first and the second coordination sphere of the metal. We have applied this approach to non-heme iron sites, which have been analyzed at various levels. Templates of sites located in different protein domains have been compared, showing that similar sites can be found in unrelated proteins as the result of convergent evolution. Templates of sites located in proteins of a large superfamily have been compared, showing possible mechanisms of divergent evolution of proteins to achieve different functions. Furthermore, template comparisons have been used to predict the function of uncharacterized proteins, showing that similarity searches focused on metal sites can be advantageously combined with typical whole-domain comparisons. Structural templates of metal sites, finally, may constitute the basis for a systematic classification of metalloproteins in databases.


Concepts in clinical scholarship. Research literature in occupational therapy, 2001-2005.
One method to determine trends in occupational therapy research is to survey the literature published in occupational therapy journals. This study describes the types and topics of articles published in five prominent occupational therapy journals over a 5-year span. Feature articles published between 2001 and 2005 were analyzed to determine the types of articles and research and subject areas. The percentage of research articles published between 2001 and 2005 increased from 65% to 78% of all articles published and is higher than previous reports. More than 70% of the research articles used designs that substantially contribute to the evidence base for occupational therapy (defined by Kielhofner, Hammel, Finlayson, Helfrich, & Taylor [2004] as correlational-comparison, experimental, qualitative, and meta-analysis). Of the research articles, 60% addressed pediatric, physical disability, and rehabilitation topics. The 5-year period showed a trend of increasing frequency of geriatric and pediatric topics in research reports. Scholars should emphasize research designs that build the evidence for occupational therapy approaches and practices and focus on research topics of highest value to society.


Stressful Life Events and Predictors of Post-traumatic Growth among High-Risk Early Emerging Adults.
Stressful life events (SLEs) may elicit positive psychosocial change among youth, referred to as Post-traumatic Growth (PTG). We assessed types of SLEs experienced, degree to which participants reported PTG, and variables predicting PTG across 24 months among a sample of high risk, ethnically diverse early emerging adults. Participants were recruited from alternative high schools (n = 564; mean age=16.8; 65% Hispanic). Multi-level regression models were constructed to examine the impact of environmental (SLE quantity, severity) and personal factors (hedonic ability, perceived stress, developmental stage, future time orientation) on a composite score of PTG. The majority of participants reported positive changes resulted from their most life-altering SLE of the past two years. Predictors of PTG included fewer SLEs, less general stress, having a future time perspective, and greater identification with the developmental stage of Emerging Adulthood. Findings suggest intervention targets to foster positive adaptation among early emerging adults who experience frequent SLEs.


The role of key features in predator recognition by untrained birds.
The most important role in the recognition and categorization of predators (as well as other animals) is usually attributed to so-called key features. Under laboratory conditions, we tested the role of yellow eyes (specific for the genus Accipiter in European raptors) and hooked beak (common for all European birds of prey) in the recognition of the sparrowhawk (Accipiter nisus) by untrained great tits (Parus major) caught in the wild. Using wooden dummies, we interchanged either one of these potential key features or the body of the sparrowhawk (predator) and domestic pigeon (harmless bird). The tested tits showed three types of behaviour in the presence of the dummies: fear, interest without fear, and lack of interest. Eye interchange lowered fear of the sparrowhawk, but did not cause fear of the pigeon. Beak interchange did not lower fear of the sparrowhawk. Eye interchange caused increased interest in both species. Thus, a specific sparrowhawk feature is necessary for correct sparrowhawk dummy recognition but a general raptor feature is not. On the other hand, a specific sparrowhawk feature on a pigeon dummy is not enough to prompt sparrowhawk recognition. Thus, key features play an important, but not exclusive, role in predator recognition. An increased interest in some of the modified dummies implies that the tits have a general concept of a sparrowhawk. The individual variability in behaviour of tits is discussed.


Regional differences in treatment for osteoporosis. The Global Longitudinal Study of Osteoporosis in Women (GLOW).
To determine if important geographic differences exist in treatment rates for osteoporosis and whether this variation can be explained by regional variation in risk factors. The Global Longitudinal Study of Osteoporosis in Women is an observational study of women ≥55 years sampled from primary care practices in 10 countries. Self-administered questionnaires were used to collect data on patient characteristics, risk factors for fracture, previous fractures, anti-osteoporosis medication, and health status. Among 58,009 women, current anti-osteoporosis medication use was lowest in Northern Europe (16%) and highest in U.S.A. and Australia (32%). Between 48% (U.S.A., Southern Europe) and 68% (Northern Europe) of women aged ≥65 years with a history of spine or hip fracture since age 45 were untreated. Among women with osteoporosis, the percentage of treated cases was lowest in Europe (45-52% versus 62-65% elsewhere). Women with osteopenia and no other risk factors were treated with anti-osteoporosis medication most frequently in U.S.A. (31%) and Canada (31%), and least frequently in Southern Europe (12%), Northern Europe (13%), and Australia (16%). After adjusting for risk factors, U.S. women were threefold as likely to be treated with anti-osteoporosis medication as Northern European women (odds ratio 2.8; 95% confidence interval 2.5-3.1) and 1.5 times as likely to be treated as Southern European women (1.5, 1.4-1.6). Up to half of women reporting previous hip or spine fracture did not receive treatment. The likelihood of being treated for osteoporosis differed between regions, and cannot be explained by variation in risk factors. Many women at risk of fracture do not receive prophylaxis.


Construction and characterization of a DNA library from mouse chromosomes 19 purified by flow cytometry.
In spite of the constant development concerning physical mapping of eukaryotic genomes, the mouse chromosome 19 remains poorly characterized. In order to improve the possibilities for studying this chromosome, we have constructed a chromosome-specific EcoRI DNA fragment library from mouse chromosomes 19 sorted by flow cytometry. The resulting library contains about 3 X 10(4) recombinant clones. The identified inserts range in size from about 0.2-10 kb, with a 4 kb average size and with no observable redundancy. The purity of the library has been analyzed by flow-blot. For that purpose, chromosomes from 2 cell lines, 1 with a normal karyotype and 1 with translocated chromosome 19, were sorted on nylon filters and hybridized with 9 clones of the library. Results show that 5 clones out of the 9 clearly originate from sorted chromosomes 19 and 3 and are likely to be derived from its DNA, thus indicating that the library of chromosome 19 is of high purity.


Impact of the center on graft failure after liver transplantation.
The hospital at which liver transplantation (LT) is performed has a substantial impact on post-LT outcomes. Center-specific outcome data are closely monitored not only by the centers themselves but also by patients and government regulatory agencies. However, the true magnitude of this center effect, apart from the effects of the region and donor service area (DSA) as well as recipient and donor determinants of graft survival, has not been examined. We analyzed data submitted to the Organ Procurement and Transplantation Network for all adult (age ≥ 18 years) primary LT recipients (2005-2008). Using a mixed effects, proportional hazards regression analysis, we modeled graft failure within 1 year after LT on the basis of center (de-identified), region, DSA, and donor and recipient characteristics. At 115 unique centers, 14,654 recipients underwent transplantation. Rates of graft loss within a year varied from 5.9% for the lowest quartile of centers to 20.2% for the highest quartile. Gauged by a comparison of the 75th and 25th percentiles of the data, the magnitude of the center effect on graft survival (1.49-fold change) was similar to that of the recipient Model for End-Stage Liver Disease (MELD) score (1.47) and the donor risk index (DRI; 1.45). The center effect was similar across the DRI and MELD score quartiles and was not associated with a center's annual LT volume. After stratification by region and DSA, the magnitude of the center effect, though decreased, remained significant and substantial (1.30-fold interquartile difference). In conclusion, the LT center is a significant predictor of graft failure that is independent of region and DSA as well as donor and recipient characteristics.


Preparedness and Response to Pediatric COVID-19 in European Emergency Departments: A Survey of the REPEM and PERUKI Networks.
We aim to describe the variability and identify gaps in preparedness and response to the coronavirus disease 2019 pandemic in European emergency departments (EDs) caring for children. A cross-sectional point-prevalence survey was developed and disseminated through the pediatric emergency medicine research networks for Europe (Research in European Pediatric Emergency Medicine) and the United Kingdom and Ireland (Paediatric Emergency Research in the United Kingdom and Ireland). We aimed to include 10 EDs for countries with greater than 20 million inhabitants and 5 EDs for less populated countries, unless the number of eligible EDs was less than 5. ED directors or their delegates completed the survey between March 20 and 21 to report practice at that time. We used descriptive statistics to analyze data. Overall, 102 centers from 18 countries (86% response rate) completed the survey: 34% did not have an ED contingency plan for pandemics and 36% had never had simulations for such events. Wide variation on personal protective equipment (PPE) items was shown for recommended PPE use at pretriage and for patient assessment, with 62% of centers experiencing shortage in one or more PPE items, most frequently FFP2 and N95 masks. Only 17% of EDs had negative-pressure isolation rooms. Coronavirus disease 2019-positive ED staff was reported in 25% of centers. We found variation and identified gaps in preparedness and response to the coronavirus disease 2019 epidemic across European referral EDs for children. A lack in early availability of a documented contingency plan, provision of simulation training, appropriate use of PPE, and appropriate isolation facilities emerged as gaps that should be optimized to improve preparedness and inform responses to future pandemics.


Prevalence of asthma in Jordan: comparison between Bedouins and urban schoolchildren using the International Study of Asthma and Allergies in Childhood phase III protocol.
The aim of this cross-sectional study was to compare the prevalence of asthma and its symptoms in children aged 6-7 years and 13-14 years in an urban (Amman city) area and among Bedouins in northern Jordan. The number of students included in both studied groups was 9108. This study is part of the International Study of Asthma and Allergies in Childhood (ISAAC), phase III. The response rate was 84% for urban schoolchildren compared with 68% among Bedouin schoolchildren. There was no statistical significance in prevalence of asthma diagnosed by a physician between the Amman city group and Bedouins (8.8% versus 9.5%). Wheeze induced by exercise and night cough was significantly common in schoolchildren aged 13-14 years compared with primary schoolchildren (18.5 and 25.3% versus 11.1 and 22.6%; p < 0.001). Wheezing ever and sleep disturbances were significantly more common in male subjects (27.5%, p < 0.01, and 12.2%, p < 0.001, respectively). Primary schoolchildren aged 6-7 years had significant wheezing ever (27.2%) compared with older children (25.1%; p < 0.05). Bedouin children had significant exercise-induced wheeze (16.4%) compared with children in Amman city (13.1%, p < 0.001), but the latter had significant prevalence of night cough (25%) compared with the Bedouin group (22.6%; p < 0.01). In conclusion, this study shows that asthma is moderately common in Jordan. There was no difference in prevalence of asthma diagnosed by a physician between an urbanized region and Bedouins having low socioeconomic status. Asthma was common in male children, which is similar to other reports elsewhere. There is a twofold increase in the prevalence of asthma in Jordan in the last 10 years.


Role of IGF1R in Breast Cancer Subtypes, Stemness, and Lineage Differentiation.
Insulin-like growth factor (IGF) signaling is fundamental for growth and survival. A large body of evidence (laboratory, epidemiological, and clinical) implicates the exploitation of this pathway in cancer. Up to 50% of breast tumors express the activated form of the type 1 insulin-like growth factor receptor (IGF1R). Breast cancers are categorized into subtypes based upon hormone and ERRB2 receptor expression and/or gene expression profiling. Even though IGF1R influences tumorigenic phenotypes and drug resistance across all breast cancer subtypes, it has specific expression and function in each. In some subtypes, IGF1R levels correlate with a favorable prognosis, while in others it is associated with recurrence and poor prognosis, suggesting different actions based upon cellular and molecular contexts. In this review, we examine IGF1R expression and function as it relates to breast cancer subtype and therapy-acquired resistance. Additionally, we discuss the role of IGF1R in stem cell maintenance and lineage differentiation and how these cell fate influences may alter the differentiation potential and cellular composition of breast tumors.


Playing to an audience: the social environment influences aggression and victory displays.
Animal behaviour studies have begun to incorporate the influence of the social environment, providing new opportunities for studying signal strategies and evolution. We examined how the presence and sex of an audience influenced aggression and victory display behaviour in field-captured and laboratory-reared field crickets (Gryllus veletis). Audience type, rearing environment and their interaction were important predictors in all model sets. Thus, audience type may impose different costs and benefits for competing males depending on whether they are socially experienced or not. Our results suggest that field-captured winners, in particular, dynamically adjust their contest behaviour to potentially gain a reproductive benefit via female eavesdropping and may deter future aggression from rivals by advertising their aggressiveness and victories.


Mutations in the SAC1 gene suppress defects in yeast Golgi and yeast actin function.
The budding mode of Saccharomyces cerevisiae cell growth demands that a high degree of secretory polarity be established and directed toward the emerging bud. We report here our demonstration that mutations in SAC1, a gene identified by virtue of its allele-specific genetic interactions with yeast actin defects, were also capable of suppressing sec14 lethalities associated with yeast Golgi defects. Moreover, these sac1 suppressor properties also extended to sec6 and sec9 secretory vesicle defects. The genetic data are consistent with the notion that SAC1p modulates both secretory pathway and actin cytoskeleton function. On this basis, we suggest that SAC1p may represent one aspect of the mechanism whereby secretory and cytoskeletal activities are coordinated, so that proper spatial regulation of secretion might be achieved.


The effect of genotype on response thresholds to sucrose and foraging behavior of honey bees (Apis mellifera L.).
Honey bee foragers were tested for their proboscis extension response (PER) to water and varying solutions of sucrose. Returning pollen and nectar foragers were collected at the entrance of a colony and were assayed in the laboratory. Pollen foragers had a significantly higher probability of responding to water and to lower concentrations of sucrose. Bees derived from artificially selected high- and low-pollen-hoarding strains were also tested using the proboscis extension assay. Returning foragers were captured and tested for PERs0 to 30% sucrose. Results demonstrated a genotypic effect on PERs of returnining foragers. The PERs of departing high- and low-strain foragers were consistent with those of returning foragers. The PERs were related to nectar and water reward perception of foragers. High strain bees were more likely to return with loads of water and lower concentrations of sucrose than foragers from low pollen strain. Low-strain bees were more likely to return empty. We identified a previously mapped genomic region that contains a variable quantitative trait locus that appears to influence sucrose response thresholds. These studies demonstrate a gene-brain-behavior pathway that can be altered as a consequence of colony-level selection for quantities of stored food.


[Three-dimensional orthotopic tissue reconstruction with a free, prefabricated high-density porous polyethylene implant flap].
We investigated the appropriateness of the implant to be used in free-tissue transfers in a rabbit model in which a full-thickness skin graft was wrapped around a prefabricated high-density porous polyethylene implant. In ten New Zealand white rabbits, high-density porous polyethylene implants (Medpor), 10x15x3 mm in size, were bilaterally placed and anchored underneath the superficial inferior epigastric artery and vein pedicle under anesthesia. The flaps were prefabricated through vascular induction. Eight weeks later, the flaps were wrapped by a full-thickness postauricular skin graft, following orthotopic transplantation. Two weeks after grafting, full-thickness biopsy samples were obtained from the distal one-third of the implants and stained with hematoxylin-eosin and Masson trichrome for histologic examination. Graft compliance was observed in all the implants. Histologic sections showed rich fibro-neovascular tissue, neovascularization, and development of connective tissue cells. There were very few polymorphonuclear cells. No signs of inflammation were observed. Prefabrication of the high-density porous polyethylene implant under the superficial inferior epigastric artery and vein results in sufficient conditions for its use in free transfers.


Azastilbenes: a cut-off to p38 MAPK inhibitors.
Inhibitors with vicinal 4-fluorophenyl/4-pyridine rings on a five- or six-membered heterocyclic ring are known to inhibit the p38 mitogen-activated protein kinase (MAPK), which is a potential target for rheumatoid arthritis and several different types of cancer. Several substituted azastilbene-based compounds with vicinal 4-fluorophenyl/4-pyridine rings were designed using computational docking, synthesized, and evaluated in a cell-free radiometric p38α assay. The biochemical evaluation shows that the best inhibition (down to 110 nM) is achieved for azastilbene-based compounds having an isopropylamine substituent in the 2-position of the pyridine ring. The inhibition of p38 signaling in human breast cancer cells was observed for two of the compounds.


Inhibition of Salmonella enterica by plant-associated pseudomonads in vitro and on sprouting alfalfa seed.
Foodborne illness due to the consumption of contaminated raw or lightly cooked sprouts is a continuing food safety concern. In this study, we tested several plant-associated pseudomonads for their ability to inhibit the growth of Salmonella enterica both in vitro and in situ. An agar spot bioassay method was used with three different media. Only Pseudomonas fluorescens 2-79 produced clear zones of inhibition when tested against five serovars of S. enterica, and activity was dependent on media type and serovar. The antibiosis by derivative strains of P. fluorescens 2-79 defective in the production of phenazine-1-carboxylic acid and fluorescent siderophore was not reduced, indicating that these known antimicrobial metabolites were not responsible for the inhibition observed in our studies. However, mutants defective in the regulatory gene gacS (global antibiotic and cyanide control) were severely reduced in inhibitory activity. In tryptic soy broth, the control cultures of a cocktail of S. enterica strains reached approximately 10 log CFU/ml by 24 h but, when coinoculated with P. fluorescens 2-79, reached only approximately 5 log CFU/ml. The addition of P. fluorescens 2-79 to the seed soak water prior to the germination of alfalfa seed previously inoculated with a cocktail of S. enterica strains led to an average reduction of 5 log CFU/g at 6 days of sprouting without an adverse effect on sprout yield or appearance. Time course studies indicated that S. enterica outgrowth was controlled on days 1 through 6 of sprouting. Competitive exclusion as a potential food safety intervention for seed sprouts merits further study.


Three-dimensional architecture of the mesangial matrix--comparison of the intact and acellular glomerulus.
The three-dimensional ultrastructure of the rat mesangial matrix was studied in acellular rat renal cortex in comparison with intact cortex by scanning electron microscopy (SEM). The mesangial region was covered with fenestrated endothelial cells and was not identified in untreated specimens by SEM. Acellular renal cortex was obtained by perfusion with 4 mM EDTA, 3% Triton X-100, 0.0025% deoxyribonuclease in 1 M NaCl and 4% sodium deoxycholate. Transmission electron microscopy revealed that the glomerular basement membrane (GBM) and mesangial matrix maintained their respective shape and did not collapse even after removal of the cellular components. By SEM, the mesangial matrix appeared as fenestrated septa with oval or round stomata between the glomerular capillaries. The diameter of the stomata was 601 +/- 290 nm. The diameter of the fibrils forming the stomata was 177 +/- 80 nm. These fenestrated structures of the mesangial matrix appear to be useful in supporting glomerular tufts, in stretching and retracting mesangial cells and in passing macromolecules from the capillary lumen into the mesangium.


Kidney transplantation in mice using left and right kidney grafts.
Mouse kidney transplantation is a powerful tool for scientific research. The conventional method uses only the left donor kidney for grafting because of shorter renal vessels on the right side. We developed a new technique of harvesting both left and right kidneys from one donor mouse, and separately transplanted them into two recipients. Forty-six kidney grafts (23 left, 23 right kidneys) were transplanted to 46 recipient mice. Life-supporting kidney transplantation (in which both recipient kidneys were removed) was performed in 12 recipients (six of each group). Cold ischemia times were considerably longer for the second kidney graft (2.5-3 versus 1 h), which resulted in reduced graft function at early time points. However, the 14 d survival rate was comparable with 80% for right and 70% for left kidney grafts. Recipient animals were sacrificed between 1 and 6 wk after transplantation. Histologic examination of surviving grafts showed intact renal parenchyma, whereas total necrosis was usually seen in failed grafts. The causes of graft failure were thrombosis of the renal artery, narrow outflow of the renal vein, and fistula of the ureter. In a subgroup of animals, specific staining for apoptosis was performed. A tendency for a higher rate of apoptosis was seen at 1 wk compared with 6 wk post-transplant, but no correlation with cold ischemia time was found. We report a new microsurgical technique of mouse kidney transplantation using both right and left donor kidneys as grafts for two recipient mice. Right kidney grafts showed equal survival compared with left kidney grafts. Thus, this technique reduces overall operating time and costs for microsurgery experiments.


Characterization of neuromyelitis optica and neuromyelitis optica spectrum disorder patients with a late onset.
Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.


1,25 Dihydroxyvitamin D3 Enhances the Antifibroid Effects of Ulipristal Acetate in Human Uterine Fibroids.
Both European and American trials showed superior effect of ulipristal acetate (UPA) to placebo. However, the latter, which included black patients with known higher vitaminD3 deficiency risk, showed lower rate of amenorrhea responders and insignificant uterine fibroid (UF) size reduction. Our objective is to investigate whether adding vitamin D3 to UPA can enhance UPA potency on UF phenotype in vitro. We screened the antiproliferative effect of different (UPA/vitaminD3) combinations on UF cell proliferation using dimethylthiazolyl diphenyltetrazolium bromide assay. Cells then were treated with UPA 100 nM in the presence or absence of vitamin D3 100 nM, and expression level of several markers related to proliferation, apoptosis, fibrosis, inflammation, and angiogenesis was measured on RNA or at protein level using quantitative real-time polymerase chain reaction, Western blot, immunofluorescence, or multiplex enzyme-linked immunosorbent assay techniques. Significant dose- and time-dependent growth inhibitory effects of UPA/vitamin D3 combinations were observed compared to untreated cells at 2 and 4 days (P < .05). Importantly, vitamin D3/UPA combination significantly reduced cell proliferation as compared to UPA at 2, 4, 6, and 8 days (P < .05). Combination treatment significantly decreased protein expression of proliferation markers Ki-67, PCNA, and CyclinD1 by more than 50% compared to UPA (P < .05) along with a significant increase in apoptosis induction. Combination treatment resulted in a 2-fold decrease in protein levels of extracellular matrix markers collagen-1 and fibronectin besides pro-fibrogenic cytokine transforming growth factor β3 (P < .05). Moreover, it significantly decreased the production of pro-inflammatory cytokines interleukins 6, 8, 1α, and 1β compared to UPA (P < .05). Combination of vitamin D3 with UPA exhibits additional and orchestrated anti-UF effects, therefore might offer a more favorable clinical option.


Jishengella endophytica gen. nov., sp. nov., a new member of the family Micromonosporaceae.
A novel endophytic actinomycete, designated strain 202201(T), was isolated from an Acanthus illicifolius root collected from the mangrove reserve zone in Hainan Province, China. Phylogenetic analysis based on 16S rRNA gene sequences suggested that strain 202201(T) fell within the family Micromonosporaceae. The strain formed an extensively branched substrate mycelium, which carried uneven warty-surfaced spores. Cell walls of strain 202201(T) contained meso-diaminopimelic acid and xylose, mannose, arabinose, ribose and glucose were detected as whole-cell sugars. The acyl type of the cell-wall polysaccharides was glycolyl. The major menaquinones were MK-9(H(4)), MK-9(H(6)), MK-9(H(8)) and MK-10(H(4)). The polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol mannoside and phosphatidylserine. The major cellular fatty acids were 10-methyl-C(17 : 0), iso-C(15 : 0), iso-C(16 : 0) and C(17 : 1)ω8c. The DNA G+C content was 72.3 mol%. On the basis of the morphological and chemotaxonomic characteristics, phylogenetic analysis and characteristic patterns of 16S rRNA gene signature nucleotides, strain 202201(T) ( = CGMCC 4.5597(T ) = DSM 45430(T)) represents a novel species of a new genus within the family Micromonosporaceae, for which the name Jishengella endophytica gen. nov., sp. nov. is proposed.


Benralizumab for the Prevention of COPD Exacerbations.
The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known. In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. <220 per cubic millimeter]) who had frequent exacerbations despite receiving guideline-based inhaled treatment. Patients were randomly assigned to receive benralizumab (30 or 100 mg in GALATHEA; 10, 30, or 100 mg in TERRANOVA) every 8 weeks (every 4 weeks for the first three doses) or placebo. The primary end point was the treatment effect of benralizumab, measured as the annualized COPD exacerbation rate ratio (benralizumab vs. placebo) at week 56 in patients with baseline blood eosinophil counts of 220 per cubic millimeter or greater. Safety was also assessed. In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo. Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).


Predictors and Outcomes of Crossover to Surgery from Physical Therapy for Meniscal Tear and Osteoarthritis: A Randomized Trial Comparing Physical Therapy and Surgery.
Arthroscopic partial meniscectomy (APM) combined with physical therapy (PT) have yielded pain relief similar to that provided by PT alone in randomized trials of subjects with a degenerative meniscal tear. However, many patients randomized to PT received APM before assessment of the primary outcome. We sought to identify factors associated with crossing over to APM and to compare pain relief between patients who had crossed over to APM and those who had been randomized to APM. We used data from the MeTeOR (Meniscal Tear in Osteoarthritis Research) Trial of APM with PT versus PT alone in subjects ≥45 years old who had mild-to-moderate osteoarthritis and a degenerative meniscal tear. We assessed independent predictors of crossover to APM among those randomized to PT. We also compared pain relief at 6 months among those randomized to PT who crossed over to APM, those who did not cross over, and those originally randomized to APM. One hundred and sixty-four subjects were randomized to and received APM and 177 were randomized to PT, of whom 48 (27%) crossed over to receive APM in the first 140 days after randomization. In multivariate analyses, factors associated with a higher likelihood of crossing over to APM among those who had originally been randomized to PT included a baseline Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) Pain Score of ≥40 (risk ratio [RR] = 1.99; 95% confidence interval [CI] = 1.00, 3.93) and symptom duration of <1 year (RR = 1.74; 95% CI = 0.98, 3.08). Eighty-one percent of subjects who crossed over to APM and 82% of those randomized to APM had an improvement of ≥10 points in their pain score at 6 months, as did 73% of those who were randomized to and received only PT. Subjects who crossed over to APM had presented with a shorter symptom duration and greater baseline pain than those who did not cross over from PT. Subjects who crossed over had rates of surgical success similar to those of the patients who had been randomized to surgery. Our findings also suggest that an initial course of rigorous PT prior to APM may not compromise surgical outcome. Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.


Social patterning of telephone health-advice for diarrhoea and vomiting: analysis of 24 million telehealth calls in England.
Gastrointestinal (GI) infections are common and most people do not see a physician. There is conflicting evidence of the impact of socioeconomic status (SES) on risk of GI infections. We assessed the relationship between SES and GI calls to two National Health Service (NHS) telephone advice services in England. Over 24 million calls to NHS Direct (2010-13) and NHS 111 (2013-15) were extracted from Public Health England (PHE) syndromic surveillance systems. The relationship between SES and GI calls was assessed using generalised linear models (GLM). Adjusting for rurality and age-sex interactions, in NHS Direct, children in disadvantaged areas were at lower risk of GI calls; in NHS 111 there was a higher risk of GI calls in disadvantaged areas for all ages (0-4 years RR 1.27, 95% CI 1.25-1.29; 5-9 years RR 1.43, 95% CI 1.36-1.51; 10-14 years RR 1.36, 95% CI 1.26-1.41; 15-19 years RR 1.59, 95% CI 1.52-1.67; 20-59 years RR 1.50, 95% CI 1.47-1.53, 60 years and over RR 1.12, 95% CI 1.09-1.14). Disadvantaged areas had higher risk of GI calls in NHS 111. This may relate to differences in exposure or vulnerability to GI infections, or propensity to call about GI infections.