Spontaneous kicking in full-term and preterm infants with and without white matter disorder.
Early damage to white matter of the brain may have developmental consequences for prematurely born infants including the coordination of leg movements. Our perspective is that white matter damage initiates an ontogenetic course that may lead to movement dysfunction leading to disability. In this study, spontaneous kicking in the human infant is a "window" for evaluating the potential consequences of perinatal brain damage for sensori-motor coordination. We compare the intra-limb coordination patterns of 5-month-old premature infants with white matter damage (PTWMD) to a group of prematurely born infants without WMD (PT) and a group of full-term (FT) infants. The PT group demonstrates advanced kicking patterns in comparison to both the PTWMD and FT groups. The PTWMD group has less mature patterns than the FT group on some, but not all measures. The movement challenge for PTWMD infants may be in the transition from spontaneous kicking to movements with the legs that require decoupling of intralimb joints.


Laser cooling of trapped ytterbium ions with an ultraviolet diode laser.
We demonstrate an ultraviolet diode laser system for cooling of trapped ytterbium ions. The laser power and linewidth are comparable to those of previous systems based on resonant frequency doubling, but the system is simpler, more robust, and less expensive. We use the laser system to cool small numbers of ytterbium ions confined in a linear Paul trap. From the observed spectra, we deduce final temperatures of < 270 mK.


Premature formation of nucleolar channel systems indicates advanced endometrial maturation following controlled ovarian hyperstimulation.
Is there a shift in the timing of nucleolar channel system (NCS) formation following controlled ovarian hyperstimulation (COH)? NCSs appear prematurely following COH compared with natural cycles. During natural cycles, NCSs of endometrial epithelial cell (EEC) nuclei are exclusively present during the window of implantation and are uniformly distributed throughout the upper endometrial cavity. Prospective two-cohort study. Cohorts I and II each consisted of seven volunteers for the duration of three menstrual study cycles that were separated by at least one wash-out or rest cycle, between December 2008 and May 2012. Participants were recruited from a pool of healthy oocyte donors. Consecutive endometrial biopsies were obtained during the same luteal phase on cycle days (CD) 16, 20 and 26 for Cohort I, and on CD14, 22 and 24 for Cohort II, following random assignment to a natural cycle group, a COH cycle group (using a GnRH antagonist), or a COH cycle group receiving luteal phase hormonal supplementation (COH + S). The day of oocyte retrieval was designated CD14 in COH cycles and the day of the LH surge was designated CD13 in natural cycles. Prevalence of NCSs in the nuclei of EECs was quantified using indirect immunofluorescence with an antibody directed against a subset of related nuclear pore complex proteins that are major constituents of NCSs. Progesterone and estradiol levels were measured on the day of each endometrial biopsy. The natural cycle group exhibited peak NCS prevalence on CD20 [53.3%; interquartile range (IQR) 28.5-55.8], which rapidly declined on CD22 (11.8%; IQR 6.3-17.6), CD24 (2.5%; IQR 0.0-9.2) and CD26 (0.3%; IQR 0.0-3.5), and no NCSs on CD14 and 16 defining a short NCS window around CD20. In contrast, in COH and COH + S cycles, NCS prevalence was high already on CD16 (40.4%; IQR 22.6-53.4 and 35.6%; IQR 26.4-44.5, respectively; P = 0.001 compared with CD16 of the natural cycle group, Mann-Whitney), whereas no significant difference in NCS prevalence was detected on any of the other five CDs between the three groups (P > 0.05). The cohort size was small (n = 7) but was offset by the all-or-none presence of NCSs on CD16 in natural versus COH and COH + S cycles and the fact that each subject served as her own control. Premature appearance of NCSs and hence maturation of the endometrium following COH is consistent with previous studies based on histological dating but contradicts studies based on mRNA expression profiling, which reported a lag in endometrial maturation. However, this is the first study of this kind that is based on consecutive endometrial biopsies within the same cycle and that reports such clear-cut differences: no versus robust NCS presence on CD16. Our observation of advanced endometrial maturation following COH may contribute to the reduced implantation rates seen in fresh compared with frozen and donor IVF-embryo transfer cycles. Therefore, the NCS window could serve as a sensitive guide for timing of embryo transfer in frozen and donor cycles. The study was supported by the March of Dimes Birth Defects foundation (1-FY09-363 to U.T.M.); Ferring Pharmaceuticals, Parsippany, NJ; East Coast Fertility, Plainview, NY and the CMBG Training Program (T32 GM007491 to M.J.S.). We report no competing interests.


A model of comprehension in spina bifida meningomyelocele: meaning activation, integration, and revision.
Spina bifida meningomyelocele (SBM) is a neurodevelopmental disorder associated with adequate development of word reading and single word comprehension, but deficient text and discourse comprehension. Studies of comprehension in children with SBM are reviewed in relation to a comprehension model in which meanings are either activated from the surface code or constructed through resource-intensive integration and revision processes to form representations of the text base and models of the situation described by the text. Two new studies probed the construction of situation models in SBM. Experiment 1 tested the ability to build spatial and affective situation models from single sentences in 86 children with SBM (8 to 18 years of age) and 37 control children (8 to 16 years of age). Experiment 2 tested the ability to integrate across sentences to build spatial situation models in 15 children with SBM and 15 age-matched controls. Compared to age peers, children with SBM did not construct situation models that required integration of information across sentences, even though they could construct such models from single sentences. The data bear on the distinctive SBM neurocognitive profile, and more generally, on the significance of integration processes for the constructive aspects of language comprehension.


Nutil: A Pre- and Post-processing Toolbox for Histological Rodent Brain Section Images.
With recent technological advances in microscopy and image acquisition of tissue sections, further developments of tools are required for viewing, transforming, and analyzing the ever-increasing amounts of high-resolution data produced. In the field of neuroscience, histological images of whole rodent brain sections are commonly used for investigating brain connections as well as cellular and molecular organization in the normal and diseased brain, but present a problem for the typical neuroscientist with no or limited programming experience in terms of the pre- and post-processing steps needed for analysis. To meet this need we have designed Nutil, an open access and stand-alone executable software that enables automated transformations, post-processing, and analyses of 2D section images using multi-core processing (OpenMP). The software is written in C++ for efficiency, and provides the user with a clean and easy graphical user interface for specifying the input and output parameters. Nutil currently contains four separate tools: (1) A transformation toolchain named "Transform" that allows for rotation, mirroring and scaling, resizing, and renaming of very large tiled tiff images. (2) "TiffCreator" enables the generation of tiled TIFF images from other image formats such as PNG and JPEG. (3) A "Resize" tool completes the preprocessing toolset and allows downscaling of PNG and JPEG images with output in PNG format. (4) The fourth tool is a post-processing method called "Quantifier" that enables the quantification of segmented objects in the context of regions defined by brain atlas maps generated with the QuickNII software based on a 3D reference atlas (mouse or rat). The output consists of a set of report files, point cloud coordinate files for visualization in reference atlas space, and reference atlas images superimposed with color-coded objects. The Nutil software is made available by the Human Brain Project (https://www.humanbrainproject.eu) at https://www.nitrc.org/projects/nutil/.


Presynaptic depression of synaptic transmission mediated by activation of metabotropic glutamate receptors in rat neocortex.
Conventional intracellular recordings were obtained from layer II-III neurons in adult rat neocortical brain slices. Excitatory and inhibitory (I) postsynaptic potentials (PSPs) were evoked prior to and during bath application of agonists and antagonists of metabotropic glutamate receptors (mGluRs). In the presence of the selective mGluR agonist 1S,3R-1-aminocyclopentane-1,3- dicarboxylic acid (1S,3R-ACPD; 5-200 microM), both excitatory and inhibitory components of the evoked PSPs were reversibly reduced. PSPs were significantly, but less effectively, decreased by L-2-amino-4-phosphonobutyric acid. Exposure to putative mGluR antagonists, alpha-methyl-4-carboxyphenylglycine or L-2-amino-3-phosphonopropionic acid, did not inhibit the 1S,3R-ACPD-mediated effect. In the presence of 6,7-dinitroquinoxaline-2,3-dione and D-2-amino-5-phosphonovaleric acid, 1S,3R-ACPD reversibly depressed directly evoked neocortical IPSPs; however, quisqualic acid (1-10 microM) did not mimic this effect. Analysis of spontaneous PSPs and paired-pulse facilitation indicated a presynaptic locus of action for 1S,3R-ACPD at mGluRs. These findings indicate that a specific mGluR subtype(s) may modulate both excitatory and inhibitory synaptic transmission in the adult rat neocortex via a presynaptic reduction of transmitter release.


A tale of three next generation sequencing platforms: comparison of Ion Torrent, Pacific Biosciences and Illumina MiSeq sequencers.
Next generation sequencing (NGS) technology has revolutionized genomic and genetic research. The pace of change in this area is rapid with three major new sequencing platforms having been released in 2011: Ion Torrent's PGM, Pacific Biosciences' RS and the Illumina MiSeq. Here we compare the results obtained with those platforms to the performance of the Illumina HiSeq, the current market leader. In order to compare these platforms, and get sufficient coverage depth to allow meaningful analysis, we have sequenced a set of 4 microbial genomes with mean GC content ranging from 19.3 to 67.7%. Together, these represent a comprehensive range of genome content. Here we report our analysis of that sequence data in terms of coverage distribution, bias, GC distribution, variant detection and accuracy. Sequence generated by Ion Torrent, MiSeq and Pacific Biosciences technologies displays near perfect coverage behaviour on GC-rich, neutral and moderately AT-rich genomes, but a profound bias was observed upon sequencing the extremely AT-rich genome of Plasmodium falciparum on the PGM, resulting in no coverage for approximately 30% of the genome. We analysed the ability to call variants from each platform and found that we could call slightly more variants from Ion Torrent data compared to MiSeq data, but at the expense of a higher false positive rate. Variant calling from Pacific Biosciences data was possible but higher coverage depth was required. Context specific errors were observed in both PGM and MiSeq data, but not in that from the Pacific Biosciences platform. All three fast turnaround sequencers evaluated here were able to generate usable sequence. However there are key differences between the quality of that data and the applications it will support.


Retinal Vascular Signs and Cerebrovascular Diseases.
Cerebrovascular disease (CeVD), including stroke, is a leading cause of death globally. The retina is an extension of the cerebrum, sharing embryological and vascular pathways. The association between different retinal signs and CeVD has been extensively evaluated. In this review, we summarize recent studies which have examined this association. We searched 6 databases through July 2019 for studies evaluating the link between retinal vascular signs and diseases with CeVD. CeVD was classified into 2 groups: clinical CeVD (including clinical stroke, silent cerebral infarction, cerebral hemorrhage, and stroke mortality), and sub-clinical CeVD (including MRI-defined lacunar infarct and white matter lesions [WMLs]). Retinal vascular signs were classified into 3 groups: classic hypertensive retinopathy (including retinal microaneurysms, retinal microhemorrhage, focal/generalized arteriolar narrowing, cotton-wool spots, and arteriovenous nicking), clinical retinal diseases (including diabetic retinopathy [DR], age-related macular degeneration [AMD], retinal vein occlusion, retinal artery occlusion [RAO], and retinal emboli), and retinal vascular imaging measures (including retinal vessel diameter and geometry). We also examined emerging retinal vascular imaging measures and the use of artificial intelligence (AI) deep learning (DL) techniques. Hypertensive retinopathy signs were consistently associated with clinical CeVD and subclinical CeVD subtypes including subclinical cerebral large artery infarction, lacunar infarction, and WMLs. Some clinical retinal diseases such as DR, retinal arterial and venous occlusion, and transient monocular vision loss are consistently associated with clinical CeVD. There is an increased risk of recurrent stroke immediately after RAO. Less consistent associations are seen with AMD. Retinal vascular imaging using computer assisted, semi-automated software to measure retinal vascular caliber and other parameters (tortuosity, fractal dimension, and branching angle) has shown strong associations to clinical and subclinical CeVD. Other new retinal vascular imaging techniques (dynamic retinal vessel analysis, adaptive optics, and optical coherence tomography angiography) are emerging technologies in this field. Application of AI-DL is expected to detect subclinical retinal changes and discrete retinal features in predicting systemic conditions including CeVD. There is extensive and increasing evidence that a range of retinal vascular signs and disease are closely linked to CeVD, including subclinical and clinical CeVD. New technology including AI-DL will allow further translation to clinical utilization.


Factors affecting establishment success of the endangered Caribbean cactus Harrisia portoricensis (Cactaceae).
Early plant stages may be the most vulnerable within the life cycle of plants especially in arid ecosystems. Interference from exotic species may exacerbate this condition. We evaluated germination, seedling survival and growth in the endangered Caribbean cactus Harrisia portoricensis, as a function of sunlight exposure (i.e., growing under open and shaded areas), different shade providers (i.e., growing under two native shrubs and one exotic grass species), two levels of predation (i.e., exclusion and non-exclusion) and variable microenvironmental conditions (i.e., temperature, PAR, humidity). Field experiments demonstrated that suitable conditions for germination and establishment of H. portoricensis seedling are optimal in shaded areas beneath the canopy of established species, but experiments also demonstrated that the identity of the shade provider can have a significant influence on the outcome of these processes. Harrisia portoricensis seedlings had higher probabilities of survival and grew better (i.e., larger diameters) when they were transplanted beneath the canopy of native shrubs, than beneath the exotic grass species, where temperature and solar radiation values were on average much higher than those obtained under the canopies of native shrubs. We also detected that exclusion from potential predators did not increase seedling survival. Our combined results for H. portoricensis suggested that the modification of microenvironmental conditions by the exotic grass may lower the probability of recruitment and establishment of this endangered cactus species.


Community-based care coordination: practical applications for childhood asthma.
Care coordination programs have been used to address chronic illnesses, including childhood asthma, but primarily via practice-based models. An alternative approach employs community-based care coordinators who bridge gaps between families, health care providers, and support services. Merck Childhood Asthma Network, Inc. (MCAN) sites developed community-based care coordination approaches for childhood asthma. Using a community-based care coordination logic model, programs at each site are described along with program operational statistics. Four sites used three to four community health workers (CHWs) to provide care coordination, whereas one site used five school-based asthma nurses. This school-based site had the highest caseload (82.5 per year), but program duration was 3 months with 4 calls or visits. Other sites averaged fewer cases (35 to 61 per CHW per year), but families received more (7 to 17) calls or visits over a year. Retention was 43% to 93% at 6 months and 24% to 75% at 12 months. Pre-post cross-site data document changes in asthma management behaviors and outcomes. After program participation, 93% to 100% of caregivers had confidence in controlling their child's asthma, 85% to 92% had taken steps to reduce triggers, 69% to 100% had obtained an asthma action plan, and 46% to 100% of those with moderate to severe asthma reported appropriate use of controller medication. Emergency department visits for asthma decreased by 36% to 63%, and asthma-related hospitalizations declined by 26% to 78%. More than three fourths had fewer school absences. In conclusion, MCAN community-based care coordination programs improved management behaviors and decreased morbidity across all sites.


Associations between sleep quality and anxiety and depression symptoms in a sample of young adult twins and siblings.
Little is known about the aetiology of the links between sleep disturbance and anxiety and depression symptoms. The aim of this study was to estimate genetic and environmental influences on these associations. Questionnaires were completed by 1556 young adults from twin and sibling pairs (61.5% female). Sleep disturbance was moderately correlated with symptoms of anxiety (r=.39) and depression (r=.50). There was substantial overlap between genes influencing sleep disturbance and those influencing symptoms of anxiety (rA=.58) and depression (rA=.68). Overall, the associations between sleep and symptoms of both anxiety and depression were mainly due to genes (explaining 74% and 58% of the covariances respectively), with the remainder due to nonshared environmental factors. Moderate phenotypic and genetic correlations between the phenotypes support the view that sleep disturbance is related to the presence of various psychiatric difficulties, but also warrants independent consideration and treatment.


Assessing Medical Students' Tobacco Dependence Treatment Skills Using a Detailed Behavioral Checklist.
CONSTRUCT: This article describes the development and implementation of an assessment intended to provide objective scores that would be valid indications of medical students' abilities to counsel patients about tobacco dependence. Assessing medical students' advanced communication skills, particularly in the context of providing tobacco-dependence treatment, consistently and accurately is challenging; doing so across multiple medical schools is even more difficult. Ten medical schools implemented a tobacco-dependence treatment case as part of an Objective Structured Clinical Examination for 3rd-year medical students. A 33-item checklist with detailed criteria and examples was developed for scoring students' performances. Trained coders viewed and coded 660 videotaped encounters; approximately 10% also were coded by the coding supervisor to check accuracy. Average time required to code an encounter was approximately 31 minutes; accuracy (i.e., agreement with the gold standard coder) was excellent. Overall, students performed an average of 1 in 4 of the 33 behaviors included on the checklist, and only 1 in 10 discussed setting a quit date. Most students (almost 9 in 10) asked how much the patient smoked in a day, and just over 7 in 10 informed the patient that the cough was due to smoking. The authors developed and implemented a rigorous assessment that will be used to evaluate medical students' tobacco-dependence treatment skills. Operationalizing the specific counseling behaviors, training coders to accurately capture students' performances using a structured checklist, and conducting the coding all required substantial time commitments but will provide confidence in the objectivity of the assessment results. In addition, this assessment can be used to provide formative information on medical students' tobacco-dependence treatment skills and to tailor ongoing training for medical students in this area.


Efficacy and safety of regorafenib in patients with metastatic and/or unresectable GI stromal tumor after failure of imatinib and sunitinib: a multicenter phase II trial.
Metastatic GI stromal tumor (GIST) is a life-threatening disease with no therapy of proven efficacy after failure of imatinib and sunitinib. Regorafenib is a structurally unique inhibitor of multiple cancer-associated kinases, including KIT and platelet-derived growth factor receptor (PDGFR), with broad-spectrum anticancer activity in preclinical and early-phase trials. Because KIT and PDGFR-α remain drivers of GIST after resistance to imatinib and sunitinib, we performed a multicenter single-stage phase II trial of regorafenib in patients with advanced GIST after failure of at least imatinib and sunitinib. Patients received regorafenib orally, 160 mg daily, on days 1 to 21 of a 28-day cycle. Disease assessment was performed every two cycles per RECIST 1.1. Primary end point was clinical benefit rate (CBR), defined as objective responses (ie, complete or partial response [PR] as well as stable disease [SD] ≥ 16 weeks). Serial tumor biopsies were obtained from consenting patients whenever possible. From February to December 2010, 34 patients were enrolled at four US centers. As of July 28, 2011, 33 patients had received at least two cycles of regorafenib (range, two to 17 cycles). CBR was 79% (95% CI, 61% to 91%). Four patients achieved PR, and 22 exhibited SD ≥ 16 weeks. Median progression-free survival was 10.0 months. The most common grade 3 toxicities were hypertension and hand-foot-skin reaction. Regorafenib has significant activity in patients with advanced GIST after failure of both imatinib and sunitinib. A phase III trial of regorafenib versus placebo is ongoing to define more fully the safety and efficacy of regorafenib in this setting.


Monoamine oxidase inhibitors l-deprenyl and clorgyline protect nonmalignant human cells from ionising radiation and chemotherapy toxicity.
l-Deprenyl (R-(-)-deprenyl, selegiline) is an inhibitor of monoamine oxidase-B (MAO-B) that is known to protect nerve cells from a variety of chemical and physical insults. As apoptosis is a common mechanism of radiation-induced cell death, the effect of l-deprenyl on the survival of cultured cells and tissue explants was studied following exposure to gamma radiation. The results obtained were compared with the effects of the less-selective MAO-B inhibitor pargyline and the MAO-A inhibitor clorgyline. l-Deprenyl at a concentration of 10(-9) M protected the nontumorigenic cell line (HaCaT) and normal human urothelial explants from the effects of cobalt-60 gamma radiation, but did not protect tumorigenic human cell lines HaCaT-ras, HPV-transfected human keratinocytes (HPV-G cells), or PC3. Human bladder carcinoma explants were not protected. Clorgyline showed a smaller protective effect of normal cells, whereas pargyline had no effect. Radiation-induced delayed effects (genomic instability measured as delayed cell death) were prevented in normal cells by l-deprenyl but, interestingly, deprenyl appeared to increase the amount of delayed death in the tumorigenic cell lines. Studies using l-deprenyl prior to the exposure of nonmalignant cells to cisplatin showed that cell death due to this agent was also reduced. Treatment of cultures of nontumorigenic cells with l-deprenyl or clorgyline significantly increased the levels of the protein Bcl-2 following irradiation, but there was no such effect on the already-elevated levels of this protein in the tumour samples. Since the Bcl-2 has been shown to be an inhibitor of apoptosis or programmed cell death, this would imply that the protective effects of l-deprenyl and clorgyline involve activation of antiapoptotic pathways within the normal cell. This hypothesis is supported by data showing reduced levels of apoptosis in HaCAT cells and in normal bladder explant cultures following treatment with l-deprenyl.


Lightweight genome viewer: portable software for browsing genomics data in its chromosomal context.
Lightweight genome viewer (lwgv) is a web-based tool for visualization of sequence annotations in their chromosomal context. It performs most of the functions of larger genome browsers, while relying on standard flat-file formats and bypassing the database needs of most visualization tools. Visualization as an aide to discovery requires display of novel data in conjunction with static annotations in their chromosomal context. With database-based systems, displaying dynamic results requires temporary tables that need to be tracked for removal. lwgv simplifies the visualization of user-generated results on a local computer. The dynamic results of these analyses are written to transient files, which can import static content from a more permanent file. lwgv is currently used in many different applications, from whole genome browsers to single-gene RNAi design visualization, demonstrating its applicability in a large variety of contexts and scales. lwgv provides a lightweight alternative to large genome browsers for visualizing biological annotations and dynamic analyses in their chromosomal context. It is particularly suited for applications ranging from short sequences to medium-sized genomes when the creation and maintenance of a large software and database infrastructure is not necessary or desired.


Preferential impact of pregnancy-associated plasma protein-A deficiency on visceral fat in mice on high-fat diet.
Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of pregnancy-associated plasma protein-A (PAPP-A), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice. PAPP-A mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific PAPP-A expression in fat accumulation, wild-type (WT) and PAPP-A knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and PAPP-A KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of PAPP-A KO compared with WT mice. After 20 wk on HFD, phosphorylation of AKT, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in PAPP-A KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of PAPP-A KO mice. These data establish fat depot-specific expression of PAPP-A and indicate preferential impact of PAPP-A deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities.


A randomized, controlled pragmatic trial of telephonic medication therapy management to reduce hospitalization in home health patients.
To evaluate the effectiveness of a telephonic medication therapy management (MTM) service on reducing hospitalizations among home health patients. Forty randomly selected, geographically diverse home health care centers in the United States. Two-stage, randomized, controlled trial with 60-day follow-up. All Medicare- insured home health care patients were eligible to participate. Twenty-eight consecutive patients within each care center were recruited and randomized to usual care or MTM intervention. The MTM intervention consisted of the following: (1) initial phone call by a pharmacy technician to verify active medications; (2) pharmacist-provided medication regimen review by telephone; and (3) follow-up pharmacist phone calls at day seven and as needed for 30 days. The primary outcome was 60-day all-cause hospitalization. Data were collected from in-home nursing assessments using the OASIS-C. Multivariate logistic regression modeled the effect of the MTM intervention on the probability of hospitalization while adjusting for patients' baseline risk of hospitalization, number of medications taken daily, and other OASIS-C data elements. A total of 895 patients (intervention n = 415, control n = 480) were block-randomized to the intervention or usual care. There was no significant difference in the 60-day probability of hospitalization between the MTM intervention and control groups (Adjusted OR: 1.26, 95 percent CI: 0.89-1.77, p = .19). For patients within the lowest baseline risk quartile (n = 232), the intervention group was three times more likely to remain out of the hospital at 60 days (Adjusted OR: 3.79, 95 percent CI: 1.35-10.57, p = .01) compared to the usual care group. This MTM intervention may not be effective for all home health patients; however, for those patients with the lowest-risk profile, the MTM intervention prevented patients from being hospitalized at 60 days.


The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field.
The vertebrate heart arises from the fusion of bilateral regions of anterior mesoderm to form a linear heart tube. Recent studies in mouse and chick have demonstrated that a second cardiac progenitor population, known as the anterior or secondary heart field, is progressively added to the heart at the time of cardiac looping. While it is clear that this second field contributes to the myocardium, its precise boundaries, other lineages derived from this population, and its contributions to the postnatal heart remain unclear. In this study, we used regulatory elements from the mouse mef2c gene to direct the expression of Cre recombinase exclusively in the anterior heart field and its derivatives in transgenic mice. By crossing these mice, termed mef2c-AHF-Cre, to Cre-dependent lacZ reporter mice, we generated a fate map of the embryonic, fetal, and postnatal heart. These studies show that the endothelial and myocardial components of the outflow tract, right ventricle, and ventricular septum are derivatives of mef2c-AHF-Cre expressing cells within the anterior heart field and its derivatives. These studies also show that the atria, epicardium, coronary vessels, and the majority of outflow tract smooth muscle are not derived from this anterior heart field population. Furthermore, a transgene marker specific for the anterior heart field is expressed in the common ventricular chamber in mef2c mutant mice, suggesting that the cardiac looping defect in these mice is not due to a failure in anterior heart field addition to the heart. Finally, the Cre transgenic mice described here will be a crucial tool for conditional gene inactivation exclusively in the anterior heart field and its derivatives.


A three-state model for the photo-Fries rearrangement.
A three-state model for the photo-Fries rearrangement (PFR) is proposed based on multiconfigurational calculations. It provides a comprehensive mechanistic picture of all steps of the reaction, from the photoabsorption to the final tautomerization. The three states participating in the PFR are an aromatic 1ππ*, which absorbs the radiation; a pre-dissociative 1nπ*, which transfers the energy to the dissociative region; and a 1πσ*, along which dissociation occurs. The transfer from 1ππ* to 1nπ* involves pyramidalization of the carbonyl carbon, while transfer from 1nπ* to 1πσ* takes place through CO stretching. Different products are available after a conical intersection with the ground state. Among them is a recombined radical intermediate, which can yield ortho-PFR products after an intramolecular 1,3-H tunneling. The three-state model is developed for phenyl acetate, the basic prototype for the PFR, and it reconciles the theory with a series of observations from time-resolved spectroscopy. It also delivers a rational way to optimize PFR yields, since, as shown for four different systems, diverse substituents can change the energetic order of the 1ππ* and 1nπ* states, preventing or enhancing the PFR.


Evaluation of the effects of long-term storage of bovine ear notch samples on the ability of 2 diagnostic assays to identify calves persistently infected with bovine viral diarrhoea virus.
Research aimed at optimising diagnostic laboratory procedures is central to the development of effective bovine viral diarrhoea virus (BVDV) control programmes. BVDV is a single-stranded RNA virus that crosses the placenta to infect foetuses, resulting in reproductive losses due to foetal death or persistently infected calves that die early in life. Persistently infected animals are widely accepted to be the primary reservoir of BVDV and the largest source of infection. This poses important challenges to overall animal/herd health and can cause major losses to the cattle industry. Long-term storage of bovine ear notch samples from calves persistently infected with BVDV may adversely affect the ability of diagnostic assays to detect the virus efficiently. In order to test this hypothesis, ear notch samples from 7 animals were divided into 2 groups. One set was subjected to prompt formalin fixation and the other set stored either as fresh samples without preservatives at -2 degrees C, or soaked overnight in phosphate buffered saline followed by freezing of the supernatant fluid at -2 degrees C. Frozen ear notches and ear notch supernatant yielded positive results with an antigen-capture, enzyme linked immunosorbent assay (AC-ELISA) for the duration of the study (6 months) and optical density (OD) values remained significantly within range. There was no significant difference between storing fresh ear notch samples or PBS at -2 degrees C. However, positive immunohistochemistry (IHC) staining on formalin fixed ear notches started to fade between Day 17 and Day 29 when stored at room temperature. It was concluded that fresh ear notches could safely be stored at -2 degrees C for a period of 6 months prior to testing for BVD viral antigens.


"Acute chest syndrome" in adults with sickle cell anemia. Microbiology, treatment, and prevention.
Fifty-two episodes of fever, chest pain, increased leukocytosis, and pulmonary infiltrate ("acute chest syndrome") were studied in 28 adults with sickle cell anemia. Possible bacterial pathogens were identified in sputum cultures from less than half of the episodes; no pneumococci were found, and Staphylocococcus aureus was the only bacterium associated with a longer illness than that seen when only normal flora were recovered. Much disease diagnosed as "pneumonia" in adults with sickle cell anemia is probably pulmonary infarction. Many of these patients will recover with no more than modest supportive care; if antibiotics are used they should be directed against S aureus (and possibly Hemophilus species). Pneumococcal polysaccharide vaccine has great potential for preventing life-threatening infection in children with sickle cell anemia, but may not change the incidence or severity of the acute chest syndrome in adults.


Lymphatic filariasis control in Tanga Region, Tanzania: status after eight rounds of mass drug administration.
Lymphatic filariasis (LF) control started in Tanga Region of Tanzania in 2004, with annual ivermectin/albendazole mass drug administration (MDA). Since then, the current project has monitored the effect in communities and schools in rural areas of Tanga District. In 2013, after 8 rounds of MDA, spot check surveys were added in the other 7 districts of Tanga Region, to assess the regional LF status. LF vector and transmission surveillance, and human cross sectional surveys in communities and schools, continued in Tanga District as previously reported. In each of the other 7 districts, 2-3 spot check sites were selected and about 200 schoolchildren were examined for circulating filarial antigens (CFA). At 1-2 of the sites in each district, additional about 200 community volunteers were examined for CFA and chronic LF disease, and the CFA positives were re-examined for microfilariae (mf). The downward trend in LF transmission and human infection previously reported for Tanga District continued, with prevalences after MDA 8 reaching 15.5% and 3.5% for CFA and mf in communities (decrease by 75.5% and 89.6% from baseline) and 2.3% for CFA in schoolchildren (decrease by 90.9% from baseline). Surprisingly, the prevalence of chronic LF morbidity after MDA 8 was less than half of baseline records. No infective vector mosquitoes were detected after MDA 7. Spot checks in the other districts after MDA 8 showed relatively high LF burdens in the coastal districts. LF burdens gradually decreased when moving to districts further inland and with higher altitudes. LF was still widespread in many parts of Tanga Region after MDA 8, in particular in the coastal areas. This calls for intensified control, which should include increased MDA treatment coverage, strengthening of bed net usage, and more male focus in LF health information dissemination. The low LF burdens observed in some inland districts suggest that MDA in these could be stepped down to provide more resources for upscale of control in the coastal areas. Monitoring should continue to guide the programme to ensure that the current major achievements will ultimately lead to successful LF elimination.


All-Inorganic Halide Perovskites as Potential Thermoelectric Materials: Dynamic Cation off-Centering Induces Ultralow Thermal Conductivity.
Halide perovskites are anticipated to impact next generation high performance solar cells because of their extraordinary charge transport and optoelectronic properties. However, their thermal transport behavior has received limited attention. In this work, we studied the thermal transport and thermoelectric properties of the CsSnBr3-xIx perovskites. We find a strong correlation between lattice dynamics and an ultralow thermal conductivity for series CsSnBr3-xIx reaching 0.32 Wm-1K-1 at 550 K. The CsSnBr3-xIx also possess a decent Seebeck coefficient and controllable electrical transport properties. The crystallography data and theoretical calculations suggest the Cs atom deviates from its ideal cuboctahedral geometry imposed by the perovskite cage and behaves as a heavy atom rattling oscillator. This off-center tendency of Cs, together with the distortion of SnX6 (X = Br or I) octahedra, produces a highly dynamic and disordered structure in CsSnBr3-xIx, which gives rise to a very low Debye temperature and phonon velocity. Moreover, the low temperature heat capacity data suggests strong coupling between the low frequency optical phonons and heat carrying acoustical phonons. This induces strong phonon resonance scattering that induces the ultralow lattice thermal conductivity of CsSnBr3-xIx.


Skeletal muscle-on-a-chip: an in vitro model to evaluate tissue formation and injury.
Engineered skeletal muscle tissues can be used for in vitro studies that require physiologically relevant models of native tissues. Herein, we describe the development of a three-dimensional (3D) skeletal muscle tissue that recapitulates the architectural and structural complexities of muscle within a microfluidic device. Using a 3D photo-patterning approach, we spatially confined a cell-laden gelatin network around two bio-inert hydrogel pillars, which induce uniaxial alignment of the cells and serve as anchoring sites for the encapsulated cells and muscle tissues as they form and mature. We have characterized the tissue morphology and strain profile during differentiation of the cells and skeletal muscle tissue formation by using a combination of fluorescence microscopy and computational tools. The time-dependent strain profile suggests the existence of individual cells within the gelatin matrix, which differentiated to form a multinucleated skeletal muscle tissue bundle as a function of culture time. We have also developed a method to calculate the passive tension generated by the engineered muscle tissue bundles suspended between two pillars. Finally, as a proof-of-concept we have examined the applicability of the skeletal muscle-on-chip system as a screening platform and in vitro muscle injury model. We studied the dose-dependent effect of cardiotoxin on the engineered muscle tissue architecture and its subsequent effect on the passive tension. This simple yet effective tool can be appealing for studies that necessitate the analysis of skeletal muscle structure and function, including preclinical drug discovery and development.


Cost-effectiveness of a community-based physical activity programme for adults (Be Active) in the UK: an economic analysis within a natural experiment.
To determine the cost-effectiveness of a physical activity programme (Be Active) aimed at city-dwelling adults living in Birmingham, UK. Very little is known about the cost-effectiveness of public health programmes to improve city-wide physical activity rates. This paper presents a cost-effectiveness analysis that compares a physical activity intervention (Be Active) with no intervention (usual care) using an economic model to quantify the reduction in disease risk over a lifetime. Metabolic equivalent minutes achieved per week, quality-adjusted life years (QALYs) gained and healthcare costs were all included as the main outcome measures in the model. A cost-benefit analysis was also conducted using 'willingness-to-pay' as a measure of value. Under base-case assumptions-that is, assuming that the benefits of increased physical activity are sustained over 5 years, participation in the Be Active programme increased quality-adjusted life expectancy by 0.06 years, at an expected discounted cost of £3552, and thus the cost-effectiveness of Be Active is £400 per QALY. When the start-up costs of the programme are removed from the economic model, the cost-effectiveness is further improved to £16 per QALY. The societal value placed on the Be Active programme was greater than the operation cost therefore the Be Active physical activity intervention results in a net benefit to society. Participation in Be Active appeared to be cost-effective and cost-beneficial. These results support the use of Be Active as part of a public health programme to improve physical activity levels within the Birmingham-wide population.


Differential expression of nuclear lamin proteins during chicken development.
By immunocytochemistry, quantitative immunoblotting, and two-dimensional gel electrophoresis, we have analyzed the distribution of nuclear lamin proteins during chicken embryonic development. Whereas no qualitative differences in the patterns of expression of lamins A, B1, and B2 were observed during gametogenesis in either the female or the male germ line, profound changes in the composition of the nuclear lamina occurred during the development of somatic tissues. Most unexpectedly, early chicken embryos were found to contain little if any lamin A, although they contained substantial amounts of lamins B1 and B2. During embryonic development, lamin A became increasingly prominent, whereas the amounts of lamin B1 decreased in many tissues. Interestingly, the extent and the developmental timing of these changes displayed pronounced tissue-specific variations. Lamin B2 was expressed in fairly constant amounts in all cell types investigated (except for pachytene-stage germ cells). These results have implications for the purported functional specializations of individual lamin proteins. In addition, they suggest that alterations in the composition of the nuclear lamina may be important for the establishment of cell- or tissue-specific differences in nuclear architecture.


Calcium Phosphate as a Key Material for Socially Responsible Tissue Engineering.
Socially responsible technologies are designed while taking into consideration the socioeconomic, geopolitical and environmental limitations of regions in which they will be implemented. In the medical context, this involves making therapeutic platforms more accessible and affordable to patients in poor regions of the world wherein a given disease is endemic. This often necessitates going against the reigning trend of making therapeutic nanoparticles ever more structurally complex and expensive. However, studies aimed at simplifying materials and formulations while maintaining the functionality and therapeutic response of their more complex counterparts seldom provoke a significant interest in the scientific community. In this review we demonstrate that such compositional simplifications are meaningful when it comes to the design of a solution for osteomyelitis, a disease that is in its natural, non-postoperative form particularly prevalent in the underdeveloped parts of the world wherein poverty, poor sanitary conditions, and chronically compromised defense lines of the immune system are the norm. We show that calcium phosphate nanoparticles, which are inexpensive to make, could be chemically designed to possess the same functionality as a hypothetic mixture additionally composed of: (a) a bone growth factor; (b) an antibiotic for prophylactic or anti-infective purposes; (c) a bisphosphonate as an antiresorptive compound; (d) a viral vector to enable the intracellular delivery of therapeutics; (e) a luminescent dye; (f) a radiographic component; (g) an imaging contrast agent; (h) a magnetic domain; and (i) polymers as viscous components enabling the injectability of the material and acting as carriers for the sustained release of a drug. In particular, calcium phosphates could: (a) produce tunable drug release profiles; (b) take the form of viscous and injectable, self-setting pastes; (c) be naturally osteo-inductive and inhibitory for osteoclastogenesis; (d) intracellularly deliver bioactive compounds; (e) accommodate an array of functional ions; (f) be processed into macroporous constructs for tissue engineering; and (g) be naturally antimicrobial. All in all, we see in calcium phosphates the presence of a protean nature whose therapeutic potentials have been barely tapped into.


Bacterial communities associated with the lichen symbiosis.
Lichens are commonly described as a mutualistic symbiosis between fungi and "algae" (Chlorophyta or Cyanobacteria); however, they also have internal bacterial communities. Recent research suggests that lichen-associated microbes are an integral component of lichen thalli and that the classical view of this symbiotic relationship should be expanded to include bacteria. However, we still have a limited understanding of the phylogenetic structure of these communities and their variability across lichen species. To address these knowledge gaps, we used bar-coded pyrosequencing to survey the bacterial communities associated with lichens. Bacterial sequences obtained from four lichen species at multiple locations on rock outcrops suggested that each lichen species harbored a distinct community and that all communities were dominated by Alphaproteobacteria. Across all samples, we recovered numerous bacterial phylotypes that were closely related to sequences isolated from lichens in prior investigations, including those from a lichen-associated Rhizobiales lineage (LAR1; putative N(2) fixers). LAR1-related phylotypes were relatively abundant and were found in all four lichen species, and many sequences closely related to other known N(2) fixers (e.g., Azospirillum, Bradyrhizobium, and Frankia) were recovered. Our findings confirm the presence of highly structured bacterial communities within lichens and provide additional evidence that these bacteria may serve distinct functional roles within lichen symbioses.


Efficacy and safety of alpha-lipoic acid supplementation in the treatment of symptomatic diabetic neuropathy.
The purpose of this article is to review current evidence available for alpha-lipoic acid (ALA) and its ability to improve symptoms of peripheral diabetic neuropathy (PDN). This article searched MEDLINE from 1966 to November 2005 to identify clinical trials that supplemented ALA to individuals with type 1 or type 2 diabetes and positive sensory symptoms of PDN. Clinical trials to be included in this review met specific criteria of randomization, double masking, and placebo-controlled design. The search results produced 5 clinical trials that met the prerequisites for this review. ALA appears to improve neuropathic symptoms and deficits when administered via parenteral supplementation over a 3-week period. Oral treatment with ALA appears to have more conflicting data whether it improves sensory symptoms or just neuropathic deficits alone. An oral regimen of ALA and optimal length of treatment remains unclear. Both parenteral and up to a 2-year time period of oral supplementation of ALA appears to be safe without affecting glycemic control. Based on these results, ALA should be considered as a treatment option for patients with PDN. When discussing supplementation with patients, it is important to discuss potential side effects; vitamin, mineral, and drug interactions; and current evidence available regarding efficacy.


Expression of TAP1 by human trophoblast.
Successful placentation in the human is dependent on the trophoblast evading recognition and destruction by the maternal immune system. However, invasive cytotrophoblast express HLA-G which may be able to present peptide to T cells. Transporter proteins are essential for peptide presentation and major histocompatibility complex (MHC) class I assembly. We have determined their expression by trophoblast in relation to HLA-G, using immunohistochemistry. Anti-transporter protein antibody (TAP1) labeling closely paralleled that of MHC class I, but the intensity of its expression was much greater on the HLA-G+ extravillous cytotrophoblast than any other fetal or maternal tissue in the first trimester and at term. This suggests that the extravillous cytotrophoblast are very actively assembling MHC class I antigens with peptides. However, expression of MHC class I by the cytotrophoblast was not correspondingly elevated. This pattern could result from HLA-G being shed from the surface of the trophoblast, a process which may play a central role in protecting the fetus from maternal immune attack.


Molecular analysis of T cell receptor (Ti) variable region (V) gene expression. Evidence that a single Ti beta V gene family can be used in formation of V domains on phenotypically and functionally diverse T cell populations.
We examine the rules governing Ti beta variable (V) gene segment usage in the formation of T cell antigen-MHC receptors in diverse regulatory and effector T lymphoid subpopulations. To this end, a single Ti beta V gene family and its products were analyzed. A monoclonal antibody, termed anti-Ti3A, which was shown to be reactive with an epitope encoded by members of the REX cell line Ti beta V gene family, and which was expressed on 2% of human T lymphocytes was used in selection of clones from unprimed peripheral T lymphocytes. Both T4+, as well as T8+ T cell clones with inducer, suppressor, and/or cytotoxic function were defined. Southern analysis, isoelectric focusing and two-dimensional peptide mapping indicated that individual members of the REX V gene family were linked to different Ti beta diversity and/or joining and constant region segments. Moreover, the Ti alpha chains of such clones were distinct. These results imply that Ti beta V gene usage is not restricted to any functionally or phenotypically defined T cell subsets, and there is presumably little, if any, restriction on the mechanisms that generate combinational, junctional or chain association-mediated diversity.


The effects of a multiyear universal social-emotional learning program: The role of student and school characteristics.
This article examines the impact of a universal social-emotional learning program, the Fast Track PATHS (Promoting Alternative Thinking Strategies) curriculum and teacher consultation, embedded within the Fast Track selective prevention model. The longitudinal analysis involved 2,937 children of multiple ethnicities who remained in the same intervention or control schools for Grades 1, 2, and 3. The study involved a clustered randomized controlled trial involving sets of schools randomized within 3 U.S. locations. Measures assessed teacher and peer reports of aggression, hyperactive-disruptive behaviors, and social competence. Beginning in first grade and through 3 successive years, teachers received training and support and implemented the PATHS curriculum in their classrooms. The study examined the main effects of intervention as well as how outcomes were affected by characteristics of the child (baseline level of problem behavior, gender) and by the school environment (student poverty). Modest positive effects of sustained program exposure included reduced aggression and increased prosocial behavior (according to both teacher and peer report) and improved academic engagement (according to teacher report). Peer report effects were moderated by gender, with significant effects only for boys. Most intervention effects were moderated by school environment, with effects stronger in less disadvantaged schools, and effects on aggression were larger in students who showed higher baseline levels of aggression. A major implication of the findings is that well-implemented multiyear social-emotional learning programs can have significant and meaningful preventive effects on the population-level rates of aggression, social competence, and academic engagement in the elementary school years.


Nonoisotopic assay for the presynaptic choline transporter reveals capacity for allosteric modulation of choline uptake.
Current therapies to enhance CNS cholinergic function rely primarily on extracellular acetylcholinesterase (AChE) inhibition, a pharmacotherapeutic strategy that produces dose-limiting side effects. The Na(+)-dependent, high-affinity choline transporter (CHT) is an unexplored target for cholinergic medication development. Although functional at the plasma membrane, CHT at steady-state is localized to synaptic vesicles such that vesicular fusion can support a biosynthetic response to neuronal excitation. To identify allosteric potentiators of CHT activity, we mapped endocytic sequences in the C-terminus of human CHT, identifying transporter mutants that exhibit significantly increased transport function. A stable HEK-293 cell line was generated from one of these mutants (CHT LV-AA) and used to establish a high-throughput screen (HTS) compatible assay based on the electrogenic nature of the transporter. We established that the addition of choline to these cells, at concentrations appropriate for high-affinity choline transport at presynaptic terminals, generates a hemicholinium-3 (HC-3)-sensitive, membrane depolarization that can be used for the screening of CHT inhibitors and activators. Using this assay, we discovered that staurosporine increased CHT LV-AA choline uptake activity, an effect mediated by a decrease in choline K(M) with no change in V(max). As staurosporine did not change surface levels of CHT, nor inhibit HC-3 binding, we propose that its action is directly or indirectly allosteric in nature. Surprisingly, staurosporine reduced choline-induced membrane depolarization, suggesting that increased substrate coupling to ion gradients, arising at the expense of nonstoichiometric ion flow, accompanies a shift of CHT to a higher-affinity state. Our findings provide a new approach for the identification of CHT modulators that is compatible with high-throughput screening approaches and presents a novel model by which small molecules can enhance substrate flux through enhanced gradient coupling.


Increased breadth and depth of cytotoxic T lymphocytes responses against HIV-1-B Nef by inclusion of epitope variant sequences.
Different vaccine approaches cope with HIV-1 diversity, ranging from centralized(1-4) to variability-encompassing(5-7) antigens. For all these strategies, a concern remains: how does HIV-1 diversity impact epitope recognition by the immune system? We studied the relationship between HIV-1 diversity and CD8(+) T Lymphocytes (CTL) targeting of HIV-1 subtype B Nef using 944 peptides (10-mers overlapping by nine amino acids (AA)) that corresponded to consensus peptides and their most common variants in the HIV-1-B virus population. IFN-γ ELISpot assays were performed using freshly isolated PBMC from 26 HIV-1-infected persons. Three hundred and fifty peptides elicited a response in at least one individual. Individuals targeted a median of 7 discrete regions. Overall, 33% of responses were directed against viral variants but not elicited against consensus-based test peptides. However, there was no significant relationship between the frequency of a 10-mer in the viral population and either its frequency of recognition (Spearman's correlation coefficient ρ = 0.24) or the magnitude of the responses (ρ = 0.16). We found that peptides with a single mutation compared to the consensus were likely to be recognized (especially if the change was conservative) and to elicit responses of similar magnitude as the consensus peptide. Our results indicate that cross-reactivity between rare and frequent variants is likely to play a role in the expansion of CTL responses, and that maximizing antigenic diversity in a vaccine may increase the breadth and depth of CTL responses. However, since there are few obvious preferred pathways to virologic escape, the diversity that may be required to block all potential escape pathways may be too large for a realistic vaccine to accommodate. Furthermore, since peptides were not recognized based on their frequency in the population, it remains unclear by which mechanisms variability-inclusive antigens (i.e., constructs enriched with frequent variants) expand CTL recognition.


Effectiveness of strategies for the management and/or prevention of hypothermia within the adult perioperative environment.
Inadvertent hypothermia is common in patients undergoing surgical procedures with a reported prevalence of perioperative hypothermia ranging from 50% to 90%. Hypothermia within the perioperative environment may have many undesired physiological effects that are associated with postoperative morbidity. There are different options for treating and/or preventing hypothermia within the adult perioperative environment, which include active and passive warming methods. This systematic review was undertaken to provide comprehensive evidence on the most effective strategies for prevention and management of inadvertent hypothermia in the perioperative environment. The objective of this review was to identify the most effective methods for the treatment and/or preventions of hypothermia in intraoperative or postoperative patients. Adult patients ≥ 18 years of age, who underwent any type of surgery were included in this review. Types of interventions included were any type of linen or cover, aluminium foil wraps, forced-air warming devices, radiant warming devices and fluid warming devices. This review considered all identified prospective studies that used a clearly described process for randomisation, and/or included a control group. The primary outcome of interest was change in core body temperature. Two independent reviewers assessed methodological validity of papers selected for retrieval and any disagreements were resolved through discussion. Nineteen studies with a combined 1451 patients who underwent different surgical procedures were included in this review. Meta-analysis was not possible. Forced-air warming in pregnant women scheduled for caesarean delivery under regional anaesthesia prevented maternal and foetal hypothermia. Intravenous and irrigating fluids warmed (38-40°C) to a temperature higher than that of room temperature by different fluid warming devices (both dry and water heated) proved significantly beneficial to patients in terms of stable haemodynamic variables, and higher core temperature at the end of the surgery. Water garment warmer was significantly (P < 0.05) effective than forced-air warming in maintaining intraoperative normothermia in orthotopic liver transplantation patients. Extra warming with forced air compared to routine thermal care was effective in reducing the incidence of surgical wound infections and postoperative cardiac complications. Passive warming with reflective heating blankets or elastic bandages wrapped around the legs tightly were found to be ineffective in reducing the incidence or magnitude of hypothermia. There are significant benefits associated with forced-air warming. Evidence supports commencement of active warming preoperatively and monitoring it throughout the intraoperative period. Single strategies such as forced-air warming were more effective than passive warming; however, combined strategies, including preoperative commencement, use of warmed fluids plus forced-air warming as other active strategies were more effective in vulnerable groups (age or durations of surgeries).


Fast 4D flow MRI intracranial segmentation and quantification in tortuous arteries.
To describe, validate, and implement a centerline processing scheme (CPS) for semiautomated segmentation and quantification in carotid siphons of healthy subjects. 4D flow MRI enables blood flow measurement in all major cerebral arteries with one scan. Clinical translational hurdles are time demanding postprocessing and user-dependence induced variability during analysis. A CPS for 4D flow data was developed to automatically separate cerebral artery trees. Flow parameters were quantified at planes along the centerline oriented perpendicular to the vessel path. At 3T, validation against 2D phase-contrast (PC) magnetic resonance imaging (MRI) and 4D flow manual processing was performed on an intracranial flow phantom for constant flow, while pulsatile flow validation was performed in the internal carotid artery (ICA) of 10 healthy volunteers. The CPS and 4D manual processing times were measured and compared. Flow and area measurements were also demonstrated along the length of the ICA siphon. Phantom measurements for area and flow were highly correlated between the CPS and 2D measurements (area: R = 0.95, flow: R = 0.94), while in vivo waveforms were highly correlated (R = 0.93). Processing time was reduced by a factor of 4.6 compared with manual processing. Whole ICA measurements revealed a significantly decreased area in the most distal segment of the carotid siphon (P = 0.0017), with flow unchanged (P = 0.84). This study exhibits fast semiautomated analysis of intracranial 4D flow MRI. Internal consistency was shown through flow conservation along the tortuous ICA siphon, which is typically difficult to assess.


Comparison of chemical compositions and osteoprotective effects of different sections of velvet antler.
Velvet antlers (VA) have been claimed for centuries to have numerous medical benefits including strengthen bones. To investigate and compare the anti-osteoporotic activities from different sections of VA. Fresh VA prepared from farmed sika deers (Cervus nippon) was divided into upper (VAU), middle (VAM), and basal (VAB) sections. The chemical constituents and anti-osteoporotic effect of different sections from VA were evaluated using ovariectomized rats. Levels of water-soluble extracts, diluted alcoholic extract, amino acids, testosterone, insulin-like growth factor (IGF)-1 and testosterone plus estradiol significantly differed among the different sections. Levels of these constituents were significantly higher in the upper section than in the basal section. Moreover, levels of testosterone and IGF-1 of the VAM were also significantly higher than those of the VAB. Calcium level increased downward from the tip with statistical significance. The strength of vertebrae increased in all VA-treated groups compared to the control, but only treatment with VAU and VAM increased the strength of the femur and the microarchitecure of the trabecular bone. Alkaline phosphatase levels of VAU- and VAM-treated groups significantly decreased, but osteocalcin did not significantly change. Moreover, VAU and VAM dose-dependently increased proliferation and mineralization of MC3T3-E1 cells. Our study provides strong evidence for the regional differences in the effectiveness of velvet antler in treating osteoporosis. However, further studies are needed to elucidate the bioactive chemical constituents associated with the anti-osteoporotic effects of velvet antler.


The interpretation of habitat preference metrics under use-availability designs.
Models of habitat preference are widely used to quantify animal-habitat relationships, to describe and predict differential space use by animals, and to identify habitat that is important to an animal (i.e. that is assumed to influence fitness). Quantifying habitat preference involves the statistical comparison of samples of habitat use and availability. Preference is therefore contingent upon both of these samples. The inferences that can be made from use versus availability designs are influenced by subjectivity in defining what is available to the animal, the problem of quantifying the accessibility of available resources and the framework in which preference is modelled. Here, we describe these issues, document the conditional nature of preference and establish the limits of inferences that can be drawn from these analyses. We argue that preference is not interpretable as reflecting the intrinsic behavioural motivations of the animal, that estimates of preference are not directly comparable among different samples of availability and that preference is not necessarily correlated with the value of habitat to the animal. We also suggest that preference is context-dependent and that functional responses in preference resulting from changing availability are expected. We conclude by describing advances in analytical methods that begin to resolve these issues.


Professional Development Perceptions and Practices Among U.S. Physicians: A Cross-Specialty National Survey.
Professional development (PD)-both for-credit continuing medical education (CME) and informal self-directed or point-of-care learning-is vital to all physicians. The authors sought to understand physicians' PD perceptions and practices and how these vary by specialty and practice type. The authors administered an Internet and paper survey, from September 2015 to April 2016, to randomly sampled U.S. physicians. Survey items addressed perceived PD needs and barriers and how physicians identify knowledge/skills gaps. Of 4,648 invitees, 988 (21.6%) responded. Respondents believed that they already know what they need to learn (mean 5.8 [1 = strongly disagree; 7 = strongly agree]), can answer clinical questions using available resources (5.9), and want credit for learning during patient care (5.1). They did not strongly desire help identifying learning gaps (4.0) or indicate difficulty accumulating CME credits (3.1). Most PD was done during personal time (5.5). Competencies regarding medical knowledge/skills, wellness, informatics, and practice/systems improvement were rated the highest priority, while research, teaching, and professionalism were rated the lowest. The most important sources used to identify knowledge/skills gaps were immediate patient care needs (4.1 [1 = not important; 5 = extremely important]), personal awareness (3.8), and practice updates (3.7). The most important barriers were time (3.5) and cost (2.9). Differences by specialty and practice type were generally small and not statistically significant. Physicians feel confident in identifying their own learning needs, perceive medical knowledge/skills as their highest-priority need, and desire more credit for learning during patient care.


Interpersonal relatedness and psychological functioning following traumatic brain injury: implications for marital and family therapists.
Recovery from a mild-to-moderate traumatic brain injury (TBI) is a challenging process for injured persons and their families. Guided by attachment theory, we investigated whether relationship conflict, social support, or sense of belonging were associated with psychological functioning. Community-dwelling persons with TBI (N = 75) and their relatives/significant others (N = 74) were surveyed on relationship variables, functional status, and TBI symptom severity. Results from this cross-sectional study revealed that only sense of belonging was a significant predictor of postinjury psychological functioning, although interpersonal conflict approached significance. No relevant preinjury or injury-related variables impacted these relationships, except marital status. Our findings suggest that interventions targeting strengthening the injured persons' sense of belonging and lowering interpersonal conflict may benefit those living with TBI.


A Single Hydrogen Molecule as an Intensity Chopper in an Electrically Driven Plasmonic Nanocavity.
Photon statistics is a powerful tool for characterizing the emission dynamics of nanoscopic systems and their photophysics. Recent advances that combine correlation spectroscopy with scanning tunneling microscopy induced luminescence (STML) have allowed the measurement of the emission dynamics from individual molecules and defects, demonstrating their nature as single-photon emitters. The application of correlation spectroscopy to the analysis of the dynamics of a well-characterized adsorbate system in an ultrahigh vacuum remained to be demonstrated. Here, we combine single-photon time correlations with STML to measure the dynamics of individual H2 molecules between a gold tip and an Au(111) surface. An adsorbed H2 molecule performs recurrent excursions below the tip apex. We use the fact that the presence of the H2 molecule in the junction modifies plasmon emission to study the adsorbate dynamics. Using the H2 molecule as a chopper for STM-induced optical emission intensity, we demonstrate bunching in the plasmonic photon train in a single measurement over 6 orders of magnitude in the time domain (from microseconds to seconds) that takes only a few seconds. Our findings illustrate the power of using photon statistics to measure the diffusion dynamics of adsorbates with STML.


Assessment of equity in healthcare financing in Fiji and Timor-Leste: a study protocol.
Equitable health financing remains a key health policy objective worldwide. In low and middle-income countries (LMICs), there is evidence that many people are unable to access the health services they need due to financial and other barriers. There are growing calls for fairer health financing systems that will protect people from catastrophic and impoverishing health payments in times of illness. This study aims to assess equity in healthcare financing in Fiji and Timor-Leste in order to support government efforts to improve access to healthcare and move towards universal health coverage in the two countries. The study employs two standard measures of equity in health financing increasingly being applied in LMICs-benefit incidence analysis (BIA) and financing incidence analysis (FIA). In Fiji, we will use a combination of secondary and primary data including a Household Income and Expenditure Survey, National Health Accounts, and data from a cross-sectional household survey on healthcare utilisation. In Timor-Leste, the World Bank recently completed a health equity and financial protection analysis that incorporates BIA and FIA, and found that the distribution of benefits from healthcare financing is pro-rich. Building on this work, we will explore the factors that influence the pro-rich distribution. The study is approved by the Human Research Ethics Committee of University of New South Wales, Australia (Approval number: HC13269); the Fiji National Health Research Committee (Approval # 201371); and the Timor-Leste Ministry of Health (Ref MS/UNSW/VI/218). Study outcomes will be disseminated through stakeholder meetings, targeted multidisciplinary seminars, peer-reviewed journal publications, policy briefs and the use of other web-based technologies including social media. A user-friendly toolkit on how to analyse healthcare financing equity will be developed for use by policymakers and development partners in the region.


The Eating Attitudes Test: an index of the symptoms of anorexia nervosa.
Data on the development of a 40-item measure of the symptoms in anorexia nervosa are reported. The scale (EAT) is presented in a 6-point, forced choice, self-report format which is easily administered and scored. The EAT was validated using 2 groups of female anorexia nervosa patients (N = 32 and 33) and female control subjects (N = 34 and 59). Total EAT score was significantly correlated with criterion group membership (r = 0.87, P less than 0.001), suggesting a high level of concurrent validity. There was very little overlap in the frequency distributions of the 2 groups and only 7% of the normal controls scored as high as the lowest anorexic patient. Female obese and male subjects also scored significantly lower on the EAT than anorexics. Recovered anorexic patients scored in the normal range on the test, suggesting that the EAT is sensitive to clinical remission.


Cross-National Time Trends in Adolescent Mental Well-Being From 2002 to 2018 and the Explanatory Role of Schoolwork Pressure.
Previous research has shown inconsistent time trends in adolescent mental well-being, but potential underlying mechanisms for such trends are yet to be examined. This study investigates cross-national time trends in adolescent mental well-being (psychosomatic health complaints and life satisfaction) in mainly European countries and the extent to which time trends in schoolwork pressure explain these trends. Data from 915,054 adolescents from 36 countries (50.8% girls; meanage = 13.54; standard deviationage = 1.63) across five Health Behaviour in School-aged Children surveys (2002, 2006, 2010, 2014, and 2018) were included in the analyses. Hierarchical multilevel models estimated cross-national trends in adolescent mental well-being and schoolwork pressure. We also tested whether schoolwork pressure could explain these trends in mental well-being. A small linear increase over time in psychosomatic complaints and schoolwork pressure was found. No change in life satisfaction emerged. Furthermore, there was large cross-country variation in the prevalence of, and trends over time in, adolescent mental well-being and schoolwork pressure. Overall, declines in well-being and increases in schoolwork pressure were apparent in the higher income countries. Across countries, the small increase in schoolwork pressure over time partly explained the decline in psychosomatic health complaints. Our findings do not provide evidence for substantial declines in mental well-being among adolescents. Yet, the small declines in mental well-being and increases in schoolwork pressure appear to be quite consistent across high-income countries. This calls for the attention of public health professionals and policy-makers. Country differences in trends in both adolescent mental well-being outcomes and schoolwork pressure were considerable, which requires caution regarding the cross-national generalization of national trends.


Linking genes to literature: text mining, information extraction, and retrieval applications for biology.
Efficient access to information contained in online scientific literature collections is essential for life science research, playing a crucial role from the initial stage of experiment planning to the final interpretation and communication of the results. The biological literature also constitutes the main information source for manual literature curation used by expert-curated databases. Following the increasing popularity of web-based applications for analyzing biological data, new text-mining and information extraction strategies are being implemented. These systems exploit existing regularities in natural language to extract biologically relevant information from electronic texts automatically. The aim of the BioCreative challenge is to promote the development of such tools and to provide insight into their performance. This review presents a general introduction to the main characteristics and applications of currently available text-mining systems for life sciences in terms of the following: the type of biological information demands being addressed; the level of information granularity of both user queries and results; and the features and methods commonly exploited by these applications. The current trend in biomedical text mining points toward an increasing diversification in terms of application types and techniques, together with integration of domain-specific resources such as ontologies. Additional descriptions of some of the systems discussed here are available on the internet http://zope.bioinfo.cnio.es/bionlp_tools/.


Optimum tracking with evolution strategies.
Evolutionary algorithms are frequently applied to dynamic optimization problems in which the objective varies with time. It is desirable to gain an improved understanding of the influence of different genetic operators and of the parameters of a strategy on its tracking performance. An approach that has proven useful in the past is to mathematically analyze the strategy's behavior in simple, idealized environments. The present paper investigates the performance of a multiparent evolution strategy that employs cumulative step length adaptation for an optimization task in which the target moves linearly with uniform speed. Scaling laws that quite accurately describe the behavior of the strategy and that greatly contribute to its understanding are derived. It is shown that in contrast to previously obtained results for a randomly moving target, cumulative step length adaptation fails to achieve optimal step lengths if the target moves in a linear fashion. Implications for the choice of population size parameters are discussed.


A role for neuropilins in the interaction between Schwann cells and meningeal cells.
In their natural habitat, the peripheral nerve, Schwann cells (SCs) form nicely aligned pathways (also known as the bands of Büngner) that guide regenerating axons to their targets. Schwann cells that are implanted in the lesioned spinal cord fail to align in pathways that could support axon growth but form cellular clusters that exhibit only limited intermingling with the astrocytes and meningeal cells (MCs) that are present in the neural scar. The formation of cell clusters can be studied in co-cultures of SCs and MCs. In these co-cultures SCs form cluster-like non-overlapping cell aggregates with well-defined boundaries. There are several indications that neuropilins (NRPs) play an important role in MC-induced SC aggregation. Both SCs and MCs express NRP1 and NRP2 and SCs express the NRP ligands Sema3B, C and E while MCs express Sema3A, C, E and F. We now demonstrate that in SC-MC co-cultures, siRNA mediated knockdown of NRP2 in SCs decreased the formation of SC clusters while these SCs maintained their capacity to align in bands of Büngner-like columnar arrays. Unexpectedly, knockdown of NRP1 expression resulted in a significant increase in SC aggregation. These results suggest that a reduction in NRP2 expression may enhance the capacity of implanted SCs to interact with MCs that invade a neural scar formed after a lesion of the spinal cord.


Word learning dogs (Canis familiaris) provide an animal model for studying exceptional performance.
Exceptional performance is present in various human activities but its origins are debated and challenging to study. We report evidence of exceptional performance and qualitative variation in learning object-names in dogs. 34 naïve family dogs and 6 knowledgeable individuals that knew multiple toy names, found in 2 years of search around the Globe, were exposed to 3 months of training to learn two novel toy-names and were tested in two-way choice tests. Only 1 naïve and all 6 knowledgeable dogs passed the tests. Additionally, only these dogs learned at least 10 new toy names over the 3 months, showing qualitative variation in this capacity. Although previous object-name knowledge could provide an explanation for the superior performance of the knowledgeable dogs, their rarity and the absence of previous training of this skill point to exceptional giftedness in these individuals, providing the basis to establish dogs as a model-species for studying talent.


Chiropractic management of myofascial trigger points and myofascial pain syndrome: a systematic review of the literature.
Myofascial pain syndrome (MPS) and myofascial trigger points (MTrPs) are important aspects of musculoskeletal medicine, including chiropractic. The purpose of this study was to review the most commonly used treatment procedures in chiropractic for MPS and MTrPs. The Scientific Commission of the Council on Chiropractic Guidelines and Practice Parameters (CCGPP) was charged with developing literature syntheses, organized by anatomical region, to evaluate and report on the evidence base for chiropractic care. This article is the outcome of this charge. As part of the CCGPP process, preliminary drafts of these articles were posted on the CCGPP Web site www.ccgpp.org (2006-8) to allow for an open process and the broadest possible mechanism for stakeholder input. PubMed, Excerpta Medica Database, Cumulative Index to Nursing and Allied Health Literature, and databases for systematic reviews and clinical guidelines were searched. Separate searches were conducted for (1) manual palpation and algometry, (2) chiropractic and other manual therapies, and (3) other conservative and complementary/alternative therapies. Studies were screened for relevance and rated using the Oxford Scale and Scottish Intercollegiate Guidelines Network rating system. A total of 112 articles were identified. Review of these articles resulted in the following recommendations regarding treatment: Moderately strong evidence supports manipulation and ischemic pressure for immediate pain relief at MTrPs, but only limited evidence exists for long-term pain relief at MTrPs. Evidence supports laser therapy (strong), transcutaneous electrical nerve stimulation, acupuncture, and magnet therapy (all moderate) for MTrPs and MPS, although the duration of relief varies among therapies. Limited evidence supports electrical muscle stimulation, high-voltage galvanic stimulation, interferential current, and frequency modulated neural stimulation in the treatment of MTrPs and MPS. Evidence is weak for ultrasound therapy. Manual-type therapies and some physiologic therapeutic modalities have acceptable evidentiary support in the treatment of MPS and TrPs.


Optimal surface segmentation in volumetric images--a graph-theoretic approach.
Efficient segmentation of globally optimal surfaces representing object boundaries in volumetric data sets is important and challenging in many medical image analysis applications. We have developed an optimal surface detection method capable of simultaneously detecting multiple interacting surfaces, in which the optimality is controlled by the cost functions designed for individual surfaces and by several geometric constraints defining the surface smoothness and interrelations. The method solves the surface segmentation problem by transforming it into computing a minimum s-t cut in a derived arc-weighted directed graph. The proposed algorithm has a low-order polynomial time complexity and is computationally efficient. It has been extensively validated on more than 300 computer-synthetic volumetric images, 72 CT-scanned data sets of different-sized plexiglas tubes, and tens of medical images spanning various imaging modalities. In all cases, the approach yielded highly accurate results. Our approach can be readily extended to higher-dimensional image segmentation.


An Augmented-Reality fNIRS-Based Brain-Computer Interface: A Proof-of-Concept Study.
Augmented reality (AR) enhances the user's environment by projecting virtual objects into the real world in real-time. Brain-computer interfaces (BCIs) are systems that enable users to control external devices with their brain signals. BCIs can exploit AR technology to interact with the physical and virtual world and to explore new ways of displaying feedback. This is important for users to perceive and regulate their brain activity or shape their communication intentions while operating in the physical world. In this study, twelve healthy participants were introduced to and asked to choose between two motor-imagery tasks: mental drawing and interacting with a virtual cube. Participants first performed a functional localizer run, which was used to select a single fNIRS channel for decoding their intentions in eight subsequent choice-encoding runs. In each run participants were asked to select one choice of a six-item list. A rotating AR cube was displayed on a computer screen as the main stimulus, where each face of the cube was presented for 6 s and represented one choice of the six-item list. For five consecutive trials, participants were instructed to perform the motor-imagery task when the face of the cube that represented their choice was facing them (therewith temporally encoding the selected choice). In the end of each run, participants were provided with the decoded choice based on a joint analysis of all five trials. If the decoded choice was incorrect, an active error-correction procedure was applied by the participant. The choice list provided in each run was based on the decoded choice of the previous run. The experimental design allowed participants to navigate twice through a virtual menu that consisted of four levels if all choices were correctly decoded. Here we demonstrate for the first time that by using AR feedback and flexible choice encoding in form of search trees, we can increase the degrees of freedom of a BCI system. We also show that participants can successfully navigate through a nested menu and achieve a mean accuracy of 74% using a single motor-imagery task and a single fNIRS channel.


Effects of ultrasound on the reaction step of boric acid production process from colemanite.
Colemanite is one of the most important boron minerals used for production of boric acid. Boric acid (H(3)BO(3)) is produced by the reaction of colemanite (2CaO.3B(2)O(3).5H(2)O) with sulfuric acid in a heterogeneous solid-liquid reaction leading to crystallization of gypsum as a byproduct. The influence of ultrasound on the dissolution of colemanite in H(2)SO(4) solution and on the precipitation of the gypsum during the reaction was investigated. Experiments have been carried out in a batch stirred vessel at 85 degrees C in the absence and presence of ultrasound. The stirring rates were chosen as 600 rpm (for 500-600 microm) and 800 rpm (for 1000-1180 microm) to provide a homogeneous suspension during the reaction. The boric acid and calcium ion concentrations in the solution were determined as a function of time. The results showed that ultrasound enhances the dissolution of colemanite and precipitation rate of the gypsum in the solution after 1h. It has been shown that the use of ultrasound decreases the size of gypsum crystals.


Accurate light microscopic diagnosis of South-East Asian ovalocytosis.
South-East Asian ovalocytosis (SAO) is a common inherited red blood cell polymorphism in South-East Asian and Melanesian populations, coinciding with areas of malaria endemicity. Validation of light microscopy as a diagnostic alternative to molecular genotyping may allow for its cost-effective use either prospectively or retrospectively by analysis of archived blood smears. We assessed light microscopic diagnosis of SAO compared to standard PCR genotyping. Three trained microscopists each assessed the same 971 Giemsa-stained thin blood films for which SAO genotypic confirmation was available by PCR. Generalized mixed modeling was used to estimate the sensitivity, specificity, positive predictive value, and negative predictive value of light microscopy vs "gold standard" PCR. Among red cell morphologic parameters evaluated, knizocytes, rather than ovalocytic morphology, proved the strongest predictor of SAO status (odds ratio [OR] = 19.2; 95% confidence interval [95% CI] = 14.6-25.3; P ≤ 0.0001). The diagnostic performance of a knizocyte-centric microscopic approach was microscopist dependent: two microscopists applied this approach with a sensitivity of 0.89 and a specificity of 0.93. Inter-rater reliability among the microscopists (κ = 0.20) as well as between gold standard and microscopist (κ = 0.36) underperformed due to misclassification of stomatocytes as knizocytes by one microscopist, but improved substantially when excluding the error-prone reader (κ = 0.65 and 0.74, respectively). Light microscopic diagnosis of SAO by knizocyte visual cue performed comparable to time-consuming and costlier molecular methods, but requires specific training that includes successful differentiation of knizocytes from stomatocytes.


Dark homogeneous streak dermoscopic pattern correlating with specific KIT mutations in melanoma.
Mutations driving melanoma growth have diagnostic, prognostic, and therapeutic implications. Traditional classification systems do not correlate optimally with underlying melanoma growth-promoting mutations. Our objective was to determine whether unique dermoscopic growth patterns directly correlate with driving mutations. We evaluated common driving mutations in 4 different dermoscopic patterns (rhomboidal, negative pigmented network, polygonal, and dark homogeneous streaks) of primary cutaneous melanomas; 3 melanomas per pattern were tested. Three of the 4 patterns lacked common mutations in BRAF, NRAS, KIT, GNAQ, and HRAS. One pattern, the dark homogeneous streaks pattern, had unique KIT mutations in the second catalytic domain of KIT in exon 17 for all 3 samples tested. Two tumors with the dark homogeneous streaks pattern turned out to be different primary melanomas from the same patient and had different sequence mutations but had an impact on the same KIT domain. While future study is required, these results have multiple implications. (1) The underlying melanoma-driving mutations may give rise to specific dermoscopic growth patterns, (2) BRAF/NRAS mutations in early melanomas may not be as common as previously thought, and (3) patients may be predisposed to developing specific driving mutations giving rise to melanomas or nevi of similar growth patterns.


WHOLE-BODY VIBRATION EXERCISE IMPROVES FUNCTIONAL PARAMETERS IN PATIENTS WITH OSTEOGENESIS IMPERFECTA: A SYSTEMATIC REVIEW WITH A SUITABLE APPROACH.
Patients with osteogenesis imperfecta (OI) have abnormal bone modelling and resorption. The bone tissue adaptation and responsivity to dynamic and mechanical loading may be of therapeutic use under controlled circumstances. Improvements due to the wholebody vibration (WBV) exercises have been reported in strength, motion, gait, balance, posture and bone density in several osteopenic individuals, as in post-menopausal women or children with disabling conditions, as patients with OI. The aim of this investigation was to systematically analyse the current available literature to determine the effect of WBV exercises on functional parameters of OI patients. Three reviewers independently accessed bibliographical databases. Searches were performed in the PubMed, Scopus, Science Direct and PEDro databases using keywords related to possible interventions (including WBV) used in the management of patients with osteogenesis imperfecta. Three eligible studies were identified by searches in the analysed databases. It was concluded that WBV exercises could be an important option in the management of OI patients improving the mobility and functional parameters. However, further studies are necessary for establishing suitable protocols for these patients.


Characteristics and patterns of care of endometrial cancer before and during COVID-19 pandemic.
Coronavirus disease 2019 (COVID-19) outbreak has correlated with the disruption of screening activities and diagnostic assessments. Endometrial cancer (EC) is one of the most common gynecological malignancies and it is often detected at an early stage, because it frequently produces symptoms. Here, we aim to investigate the impact of COVID-19 outbreak on patterns of presentation and treatment of EC patients. This is a retrospective study involving 54 centers in Italy. We evaluated patterns of presentation and treatment of EC patients before (period 1: March 1, 2019 to February 29, 2020) and during (period 2: April 1, 2020 to March 31, 2021) the COVID-19 outbreak. Medical records of 5,164 EC patients have been retrieved: 2,718 and 2,446 women treated in period 1 and period 2, respectively. Surgery was the mainstay of treatment in both periods (p=0.356). Nodal assessment was omitted in 689 (27.3%) and 484 (21.2%) patients treated in period 1 and 2, respectively (p<0.001). While, the prevalence of patients undergoing sentinel node mapping (with or without backup lymphadenectomy) has increased during the COVID-19 pandemic (46.7% in period 1 vs. 52.8% in period 2; p<0.001). Overall, 1,280 (50.4%) and 1,021 (44.7%) patients had no adjuvant therapy in period 1 and 2, respectively (p<0.001). Adjuvant therapy use has increased during COVID-19 pandemic (p<0.001). Our data suggest that the COVID-19 pandemic had a significant impact on the characteristics and patterns of care of EC patients. These findings highlight the need to implement healthcare services during the pandemic.


The C. elegans Hox gene egl-5 is required for correct development of the hermaphrodite hindgut and for the response to rectal infection by Microbacterium nematophilum.
Members of the Hox gene family encode transcription factors that specify positional identity along the anterior-posterior axis of nearly all metazoans. One among the Caenorhabditis elegans Hox genes is egl-5. A deletion allele of egl-5 was isolated in a screen for animals which fail to develop swollen tails when exposed to the bacterial pathogen Microbacterium nematophilum. We show that compromised rectal development, which occurs as a result of loss of egl-5 function, results in a failure of rectal epithelial cells to express the ERK MAP kinase mpk-1, which was previously shown to mediate tail-swelling in response to bacterial infection. Tissue-specific rescue experiments demonstrated that egl-5 and mpk-1 act autonomously in rectal cells in the morphological response. The weak egl-5 allele (n1439), which does not compromise rectal development, fails to affect tail-swelling. We find that this allele carries an inserted repeat element approximately 13.8 kb upstream of the egl-5 open reading frame, which specifically disrupts the cell-specific expression of this gene in HSN egg-laying neurons. Together these findings extend the complexity of regulation and function of Hox genes in C. elegans and demonstrate the importance of their tissue-specific expression for correct development and response to infection.


Expression and induction of nuclear factor-kappa B-related proteins in thymocytes.
Thymocytes mature in response to the cues from the thymic micro-environment, which regulate stage-specific gene expression during development. We find that several proteins that bind the kappa B sequence in vitro are constitutively activated in freshly isolated thymocytes. These include the rel-related p50 homodimers, p50/p65 heterodimers, low levels of c-rel, and two other factors that may be thymus specific. Disruption of the thymic micro-environment resulted in loss of DNA-binding, suggesting that lymphocyte-stromal cell interactions induce and maintain these proteins in a DNA-binding form. Phorbol ester and ionomycin treatment induced p50, p65, and p68 c-rel kappa B DNA-binding activity. Expression of p68 c-rel protein, but not p50 or p65, was suppressed by the immunosuppressive drug FK506. Because FK506 specifically inhibits the appearance of mature single-positive thymocytes, gene expression regulated by p68 c-rel may play a role in selection and maturational signals involved in the double-positive to single-positive transition.