The Sensitivity of Single-Trial Mu-Suppression Detection for Motor Imagery Performance as Compared to Motor Execution and Motor Observation Performance.
Motor imagery (MI) has been widely used to operate brain-computer interface (BCI) systems for rehabilitation and some life assistive devices. However, the current performance of an MI-based BCI cannot fully meet the needs of its in-field applications. Most of the BCIs utilizing a generalized feature for all participants have been found to greatly hamper the efficacy of the BCI system. Hence, some attempts have made on the exploration of subject-dependent parameters, but it remains challenging to enhance BCI performance as expected. To this end, in this study, we used the independent component analysis (ICA), which has been proved capable of isolating the pure motor-related component from non-motor-related brain processes and artifacts and extracting the common motor-related component across MI, motor execution (ME), and motor observation (MO) conditions. Then, a sliding window approach was used to detect significant mu-suppression from the baseline using the electroencephalographic (EEG) alpha power time course and, thus, the success rate of the mu-suppression detection could be assessed on a single-trial basis. By comparing the success rates using different parameters, we further quantified the extent of the improvement in each motor condition to evaluate the effectiveness of both generalized and individualized parameters. The results showed that in ME condition, the success rate under individualized latency and that under generalized latency was 90.0% and 77.75%, respectively; in MI condition, the success rate was 74.14% for individual latency and 58.47% for generalized latency, and in MO condition, the success rate was 67.89% and 61.26% for individual and generalized latency, respectively. As can be seen, the success rate in each motor condition was significantly improved by utilizing an individualized latency compared to that using the generalized latency. Moreover, the comparison of the individualized window latencies for the mu-suppression detection across different runs of the same participant as well as across different participants showed that the window latency was significantly more consistent in the intra-subject than in the inter-subject settings. As a result, we proposed that individualizing the latency for detecting the mu-suppression feature for each participant might be a promising attempt to improve the MI-based BCI performance.


Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.
Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.


Protection against oxidative stress by vitamin D in cone cells.
Photoreceptor degeneration (PD) refers to a group of heterogeneous outer retinal dystrophies characterized by the death of photoreceptors. Both oxidative stress and inflammation are involved in the pathogenesis of PD. We investigate whether vitamin D has a potential for the treatment of PD by evaluating the anti-oxidative stress and anti-inflammatory properties of the active form of vitamin D3 , 1,α, 25-dihydroxyvitamin D3 , in a mouse cone cell line, 661W. Mouse cone cells were treated with H2 O2 or a mixture of H2 O2 and vitamin D; cell viability was determined. The production of reactive oxygen species (ROS) in treated and untreated cells was measured. The expression of key anti-oxidative stress and inflammatory genes in treated and untreated cells was determined. Treatment with vitamin D significantly increased cell viability and decreased ROS production in 661W cells under oxidative stress induced by H2 O2 . H2 O2 treatment in 661W cells can significantly down-regulate the expression of antioxidant genes and up-regulate the expression of neurotoxic cytokines. Vitamin D treatment significantly reversed these effects and restored the expression of antioxidant genes. Vitamin D treatment also can block H2 O2 induced oxidative damages. The data suggested that vitamin D may offer a therapeutic potential for patients with PD.


An Augmented Reality Endoscope System for Ureter Position Detection.
Iatrogenic injury of ureter in the clinical operation may cause the serious complication and kidney damage. To avoid such a medical accident, it is necessary to provide the ureter position information to the doctor. For the detection of ureter position, an ureter position detection and display system with the augmented ris proposed to detect the ureter that is covered by human tissue. There are two key issues which should be considered in this new system. One is how to detect the covered ureter that cannot be captured by the electronic endoscope and the other is how to display the ureter position that provides stable and high-quality images. Simultaneously, any delayed processing of the system should disturb the surgery. The aided hardware detection method and target detection algorithms are proposed in this system. To mark the ureter position, a surface-lighting plastic optical fiber (POF) with the encoded light-emitting diode (LED) light is used to indicate the ureter position. The monochrome channel filtering algorithm (MCFA) is proposed to locate the ureter region more precisely. The ureter position is extracted using the proposed automatic region growing algorithm (ARGA) that utilizes the statistical information of the monochrome channel for the selection of growing seed point. In addition, according to the pulse signal of encoded light, the recognition of bright and dark frames based on the aided hardware (BDAH) is proposed to expedite the processing speed. Experimental results demonstrate that the proposed endoscope system can identify 92.04% ureter region in average.


Real-world data about emotional stress, disability and need for social care in a German IBD patient cohort.
To date, there is insufficient insight into inflammatory bowel disease (IBD)-associated stress, recognized disability, and contact with the social care system. We aimed to assess these parameters in IBD patients and a non-IBD control group, who were invited to participate in an online survey developed specifically for this study (www.soscisurvey.de) with the help of IBD patients. 505 IBD patients and 166 volunteers (i.e., control group) participated in the survey. IBD patients reported significantly increased levels of stress within the last six months and five years (p<0.0001) and were more likely to have a recognized disability (p<0.0001). A low academic status was the strongest indicator of a disability (p = 0.006). Only 153 IBD patients (30.3%) reported contact with the social care system, and a disability was the strongest indicator for this (p<0.0001). Our study provides data on stress and disability in a large unselected German IBD cohort. We showed that patients with IBD suffer more often from emotional stress and more often have a recognized disability. As only about 1/3 of the patients had come into contact with the social care system and the corresponding support, this patient group is undersupplied in this area.


Constant mortality and fertility over age in Hydra.
Senescence, the increase in mortality and decline in fertility with age after maturity, was thought to be inevitable for all multicellular species capable of repeated breeding. Recent theoretical advances and compilations of data suggest that mortality and fertility trajectories can go up or down, or remain constant with age, but the data are scanty and problematic. Here, we present compelling evidence for constant age-specific death and reproduction rates in Hydra, a basal metazoan, in a set of experiments comprising more than 3.9 million days of observations of individual Hydra. Our data show that 2,256 Hydra from two closely related species in two laboratories in 12 cohorts, with cohort age ranging from 0 to more than 41 y, have extremely low, constant rates of mortality. Fertility rates for Hydra did not systematically decline with advancing age. This falsifies the universality of the theories of the evolution of aging that posit that all species deteriorate with age after maturity. The nonsenescent life history of Hydra implies levels of maintenance and repair that are sufficient to prevent the accumulation of damage for at least decades after maturity, far longer than the short life expectancy of Hydra in the wild. A high proportion of stem cells, constant and rapid cell turnover, few cell types, a simple body plan, and the fact that the germ line is not segregated from the soma are characteristics of Hydra that may make nonsenescence feasible. Nonsenescence may be optimal because lifetime reproduction may be enhanced more by extending adult life spans than by increasing daily fertility.


Moving towards routine evaluation of quality of inpatient pediatric care in Kenya.
Regular assessment of quality of care allows monitoring of progress towards system goals and identifies gaps that need to be addressed to promote better outcomes. We report efforts to initiate routine assessments in a low-income country in partnership with government. A cross-sectional survey undertaken in 22 'internship training' hospitals across Kenya that examined availability of essential resources and process of care based on review of 60 case-records per site focusing on the common childhood illnesses (pneumonia, malaria, diarrhea/dehydration, malnutrition and meningitis). Availability of essential resources was 75% (45/61 items) or more in 8/22 hospitals. A total of 1298 (range 54-61) case records were reviewed. HIV testing remained suboptimal at 12% (95% CI 7-19). A routinely introduced structured pediatric admission record form improved documentation of core admission symptoms and signs (median score for signs 22/22 and 8/22 when form used and not used respectively). Correctness of penicillin and gentamicin dosing was above 85% but correctness of prescribed intravenous fluid or oral feed volumes for severe dehydration and malnutrition were 54% and 25% respectively. Introduction of Zinc for diarrhea has been relatively successful (66% cases) but use of artesunate for malaria remained rare. Exploratory analysis suggests considerable variability of the quality of care across hospitals. Quality of pediatric care in Kenya has improved but can improve further. The approach to monitoring described in this survey seems feasible and provides an opportunity for routine assessments across a large number of hospitals as part of national efforts to sustain improvement. Understanding variability across hospitals may help target improvement efforts.


Alcohol use among young adolescents in low-income and middle-income countries: a population-based study.
Alcohol use remains a major public health problem worldwide because of its harmful effects on physical and mental health. Few studies have used a standardised methodology to assess alcohol use among adolescents in low-income and middle-income countries (LMICs). In the present study, we aimed to compare the prevalence of alcohol use, drunkenness episodes, and drin king-related problems among young adolescents in LMICs. For this population-based study, we used individual data from the Global School-based Student Health Surveys (GSHS) from between 2006 and 2013 in adolescents aged 12-15 years in LMICs. Data were collected using an anonymous self-reported questionnaire. This report is based on four questions assessing alcohol use, drunkenness episodes, alcohol-related drinking problems (ever had a hangover, felt sick, got into trouble with family or friends, missed school, or got into fights, as a result of drinking alcohol), and, in those who reported drinking, how alcohol was purchased. We calculated the overall and regional estimates using a meta-analysis with random-effects. GSHS data from 57 countries, corresponding to a total of 139 649 young adolescents, were included in this study. The prevalence of the variables varied largely according to country and region. The overall prevalence of having at least one drink during the past 30 days was 25·0% (95% CI 19·3-30·7), and was higher among boys (27·5%, 21·9-33·2) than girls (22·5%, 18·8-26·2), and at age 14-15 years (29·0%, 23·1-34·8) than at age 12-13 years (18·9%, 15·3-22·5). The overall prevalence of having been drunk at least once during the lifetime was 17·9% (13·6-22·1); and was higher among boys (21·3%, 16·8-25·7) than girls (14·5%, 12·1-16·9), and at age 14-15 years (21·5%, 17·0-26·0) than at age 12-13 years (12·2%, 9·5-15·0). The overall prevalence of drinking-related problems was 10·6% (8·9-12·2), and was higher among boys (12·5%, 10·4-14·5) than girls (8·9%, 7·5-10·2), and at age 14-15 years (12·3%, 10·4-14·2) than at age 12-13 years (7·8%, 6·6-9·1). Among those reporting drinking, 27·8% (24·8-30·7) accessed alcohol from their friends, 23·2% (19·5-26·9) got it from family, 19·5% (17·5-21·6) bought it in a store, 9·1% (8·0-10·2) gave someone money to buy some, 2·8% (2·3-3·3) stole it, and 14·4% (12·2-16·5) got it by some other way. Alcohol use, lifetime drunkenness, and alcohol-related problems were frequent among young adolescents in LMICs; however, with differences by country, region, sex, and age group. These findings emphasise the need for interventions to reduce alcohol use targeting young adolescents in LMICs with high prevalence of use and alcohol-related problems. Shandong University.


[Rocky Mountain spotted fever in Brazil].
Although the number of confirmed cases of spotted fever has been declining in Brazil since 2005, the mortality rate (20% to 30%) is still high in comparison to other countries. This high mortality rate is closely related to the difficulty in making the diagnosis and starting the correct treatment. Only two groups of antibiotics have proven clinical effectiveness against spotted fever: chloramphenicol and tetracyclines. Until recently, the use of tetracyclines was restricted to adults because of the associated bone and tooth changes in children. Recently, however, the American Academy of Pediatrics and various researchers have recommended the use of doxycycline in children. In more severe cases, chloramphenicol injections are often preferred in Brazil because of the lack of experience with injectable tetracycline. Since early diagnosis and the adequate drug treatment are key to a good prognosis, health care professionals must be better prepared to recognize and treat spotted fever.


Genome sequence of Phaeobacter daeponensis type strain (DSM 23529(T)), a facultatively anaerobic bacterium isolated from marine sediment, and emendation of Phaeobacter daeponensis.
TF-218(T) is the type strain of the species Phaeobacter daeponensis Yoon et al. 2007, a facultatively anaerobic Phaeobacter species isolated from tidal flats. Here we describe the draft genome sequence and annotation of this bacterium together with previously unreported aspects of its phenotype. We analyzed the genome for genes involved in secondary metabolite production and its anaerobic lifestyle, which have also been described for its closest relative Phaeobacter caeruleus. The 4,642,596 bp long genome of strain TF-218(T) contains 4,310 protein-coding genes and 78 RNA genes including four rRNA operons and consists of five replicons: one chromosome and four extrachromosomal elements with sizes of 276 kb, 174 kb, 117 kb and 90 kb. Genome analysis showed that TF-218(T) possesses all of the genes for indigoidine biosynthesis, and on specific media the strain showed a blue pigmentation. We also found genes for dissimilatory nitrate reduction, gene-transfer agents, NRPS/ PKS genes and signaling systems homologous to the LuxR/I system.


The status of dosage compensation in the multiple X chromosomes of the platypus.
Dosage compensation has been thought to be a ubiquitous property of sex chromosomes that are represented differently in males and females. The expression of most X-borne genes is equalized between XX females and XY males in therian mammals (marsupials and "placentals") by inactivating one X chromosome in female somatic cells. However, compensation seems not to be strictly required to equalize the expression of most Z-borne genes between ZZ male and ZW female birds. Whether dosage compensation operates in the third mammal lineage, the egg-laying monotremes, is of considerable interest, since the platypus has a complex sex chromosome system in which five X and five Y chromosomes share considerable genetic homology with the chicken ZW sex chromosome pair, but not with therian XY chromosomes. The assignment of genes to four platypus X chromosomes allowed us to examine X dosage compensation in this unique species. Quantitative PCR showed a range of compensation, but SNP analysis of several X-borne genes showed that both alleles are transcribed in a heterozygous female. Transcription of 14 BACs representing 19 X-borne genes was examined by RNA-FISH in female and male fibroblasts. An autosomal control gene was expressed from both alleles in nearly all nuclei, and four pseudoautosomal BACs were usually expressed from both alleles in male as well as female nuclei, showing that their Y loci are active. However, nine X-specific BACs were usually transcribed from only one allele. This suggests that while some genes on the platypus X are not dosage compensated, other genes do show some form of compensation via stochastic transcriptional inhibition, perhaps representing an ancestral system that evolved to be more tightly controlled in placental mammals such as human and mouse.


Hypertension in pregnancy after Escherichia coli O157:H7 gastroenteritis: a cohort study.
Escherichia coli O157:H7 is a common cause of bacterial gastroenteritis and may increase the risk of hypertension. We studied the risk of hypertension in pregnancy following a large E. coli O157:H7 outbreak that occurred in Walkerton, Canada, in the year 2000. We linked data collected from Walkerton residents to provincial healthcare databases. We studied the pregnancies of three groups of women: two groups from Walkerton (those with and without acute gastroenteritis during outbreak) and a third group from neighboring rural communities unaffected by the outbreak. The primary outcome was a composite of gestational hypertension or preeclampsia. Secondary outcomes were gestational hypertension and preeclampsia examined separately. The median time to pregnancy after cohort entry was five years. The composite outcome was not significantly higher among women with gastroenteritis during the outbreak compared with residents of neighboring communities (8 of 117 (6.8%) versus 96 of 2166 (4.4%) pregnancies, respectively; adjusted relative risk 1.5 (95% confidence interval (CI) 0.8 to 3.2)). When examined separately the risk of preeclampsia was significantly higher among women with gastroenteritis (4 of 117 (3.4%) versus 17 of 2166 (0.8%) pregnancies; adjusted relative risk 3.8 (95% CI 1.3 to 11.6)). However, the risk of preeclampsia was lower than expected in the referent group and overall there were a small number of events in all the groups. There was no significant association between E. coli O157:H7 gastroenteritis and our primary assessment of hypertension in pregnancy.


Photo-responsive [2]catenanes: synthesis and properties.
A series of novel dithienylethene-based macrocycles containing ammonium moieties has been synthesized. They have been employed as templates to construct [2]catenanes showing their photoisomerization properties by means of a dynamic covalent chemistry approach. Their structures have been reliably confirmed by NMR, ESI-MS or MALDI-QTOF-MS, and elemental analysis, and their energy-minimized structures of open- and closed-ring isomers were investigated by the theoretical calculation. Investigation of the photochromic properties of these dithienylethene-based [2]catenanes has revealed good reversibility and excellent fatigue resistance upon irradiation with UV or visible light. Notably, formation of the [2]catenanes enhanced the photochromic properties compared with those of the corresponding macrocyclic ammonium salt, implying that the non-covalently interacting components of the [2]catenanes could affect the photoswitchable properties.


Ocular toxicity of ethambutol.
To review the literature on ocular toxicity of ethambutol--its background, clinical presentation, toxicity characteristics, management, monitoring, and preventive measures. Literature search of Medline from 1962 to May 2005. All related literature in English using the search formula: (ethambutol OR myambutol) AND (eye* OR ophthal* OR ocular) AND (adverse OR toxic). All information was collected and analysed by authors. Ethambutol hydrochloride is a commonly used first-line anti-tuberculous agent. Although rare, ocular toxicity in the form of optic neuritis (most commonly retrobulbar neuritis) has been well documented since its first use in the 1960s. Classically described as dose- and duration-related and reversible on therapy discontinuation, reversibility of optic neuritis remains controversial. International guidelines on prevention and early detection of ethambutol-induced ocular toxicity have been published. Nonetheless, opinion of the clinical effectiveness of regular vision tests to enable early detection of toxicity is divided. The course of ethambutol-induced ocular toxicity is unpredictable. Measures to ensure a high level of awareness in medical staff and patients of this potential adverse effect appear to be the best current preventive method. Classified by the World Health Organization as a place with an intermediate tuberculosis burden and good health infrastructure, Hong Kong is in a good position to examine the unanswered questions about ethambutol-induced ocular toxicity.


High affinity binding of pyrethroids to the alpha subunit of brain sodium channels.
Na+ channels are the primary molecular targets of the pyrethroid insecticides. Na+ channels consisting of only a type IIA alpha subunit expressed in Chinese hamster ovary cells responded to pyrethroid treatment in a normal manner: a sustained Na+ current was induced progressively after each depolarizing pulse in a train of stimuli, and this Na+ current decayed slowly on repolarization. These modified Na+ channels could be reactivated at much more negative membrane potentials (V0.5 = -139 mV) than unmodified Na+ channels (V0.5 = -28 mV). These results indicate that pyrethroids can modify the functional properties of the Na+ channel alpha subunit expressed alone by blocking their inactivation, shifting their voltage dependence of activation, and slowing their deactivation. To demonstrate directly the specific interaction of pyrethroids with the alpha subunit of voltage-gated Na+ channels, a radioactive photosensitive derivative, [3H]RU58487, was used in binding and photolabeling studies. In the presence of a low concentration of the nonionic detergent Triton X-100, specific pyrethroid binding to Na+ channels in rat brain membrane preparations could be measured and reached 75% of total binding under optimal conditions. Binding approached equilibrium within 1 hr at 4 degrees, dissociated with a half-time of approximately 10 min, and had K(D) values of approximately 58-300 nM for three representative pyrethroids. Specific pyrethroid binding was enhanced by approximately 40% in the presence of 100 nM alpha-scorpion toxin, but no allosteric enhancement was observed in the presence of toxins acting at other Na+ channel receptor sites. Extensive membrane washing increased specific binding to 89%. Photolabeling with [3H]RU58487 under these optimal binding conditions revealed a radiolabeled band with an apparent molecular mass of 240 kDa corresponding to the Na+ channel alpha subunit. Anti-peptide antibodies recognizing sequences within the alpha subunit were able to specifically immunoprecipitate the covalently modified channel. Together, these results demonstrate that the pyrethroids can modify the properties of cells expressing only the alpha subunit of Na+ channels and can bind specifically to a receptor site on the alpha subunit.


Immunoregulatory function of IL-27 and TGF-β1 in cardiac allograft transplantation.
Deciphering the mechanisms of tolerance represents a crucial aim of research in transplantation. We previously identified by DNA chip interleukin (IL)-27 p28 and transforming growth factor (TGF)-β1 as overexpressed in a model of rat cardiac allograft tolerance mediated by regulatory CD4CD25 T cells. The role of these two molecules on the control of the inflammatory response remains controversial. However, both are involved in the regulation of the T helper 17/Treg axis, suggesting their involvement in tolerance. We analyzed regulation of IL-27 and TGF-β1 expression in allograft response and their role in tolerance by using blocking anti-TGF-β antibody and by generating an adeno-associated virus encoding IL-27. Here, we confirmed the overexpression of IL-27 and TGF-β1 in tolerated cardiac allografts in two different rodent models. We observed that their expression correlates with inhibition of T helper 17 differentiation and with expansion of regulatory CD4CD25 T cells. We showed in a rat model that anti-TGF-β treatment abrogates infectious tolerance mediated by the transfer of regulatory CD4CD25 T cells. Moreover, overexpression of IL-27 by adeno-associated virus administration in combination with a short-term immunosuppression allows prolongation of cardiac allograft survival and one tolerant recipient. We found that IL-27 overexpression did not induce Foxp3CD4CD25 T-cell expansion but rather IL-10-expressing CD4 T cells in the tolerant recipient. Taken together, these data suggest that both TGF-β1 and IL-27 play a role in the mechanisms of tolerance. However, in contrast to TGF-β1, IL-27 seems not to be involved in regulatory CD4CD25 T-cell expansion but rather in their mode of action.


Low Concentration Microenvironments Enhance the Migration of Neonatal Cells of Glial Lineage.
Glial tumors have demonstrated abilities to sustain growth via recruitment of glial progenitor cells (GPCs), which is believed to be driven by chemotactic cues. Previous studies have illustrated that mouse GPCs of different genetic backgrounds are able to replicate the dispersion pattern seen in the human disease. How GPCs with genetic backgrounds transformed by tumor paracrine signaling respond to extracellular cues via migration is largely unexplored, and remains a limiting factor in utilizing GPCs as therapeutic targets. In this study, we utilized a microfluidic device to examine the chemotaxis of three genetically-altered mouse GPC populations towards tumor conditioned media, as well as towards three growth factors known to initiate the chemotaxis of cells excised from glial tumors: Hepatocyte Growth Factor (HGF), Platelet-Derived Growth Factor-BB (PDGF-BB), and Transforming Growth Factor-α (TGF-α). Our results illustrate that GPC types studied exhibited chemoattraction and chemorepulsion by different concentrations of the same ligand, as well as enhanced migration in the presence of ultra-low ligand concentrations within environments of high concentration gradient. These findings contribute towards our understanding of the causative and supportive roles that GPCs play in tumor growth and reoccurrence, and also point to GPCs as potential therapeutic targets for glioma treatment.


Periplakin-dependent re-organisation of keratin cytoskeleton and loss of collective migration in keratin-8-downregulated epithelial sheets.
Collective migration of epithelial sheets requires maintenance of cell-cell junctions and co-ordination of the movement of the migrating front. We have investigated the role of keratin intermediate filaments and periplakin, a cytoskeletal linker protein, in the migration of simple epithelial cells. Scratch wounding induces bundling of keratins into a cable of tightly packed filaments adjacent to the free wound edge. Keratin re-organisation is preceded by a re-distribution of periplakin away from the free wound edge. Periplakin participates with dynamic changes in the keratin cytoskeleton via its C-terminal linker domain that co-localises with okadaic-acid-treated keratin granules. Stable expression of the periplakin C-terminal domain increases keratin bundling and Ser431 keratin phosphorylation at wound edge resulting in a delay in wound closure. Ablation of periplakin by siRNA inhibits keratin cable formation and impairs wound closure. Knockdown of keratin 8 with siRNA results in (1) a loss of desmoplakin localisation at cell borders, (2) a failure of MCF-7 epithelial sheets to migrate as a collective unit and (3) accelerated wound closure in vimentin-positive HeLa and Panc-1 cell lines. Thus, keratin 8 is required for the maintenance of epithelial integrity during migration and periplakin participates in the re-organisation of keratins in migrating cells.


Locking of iridium magnetic moments to the correlated rotation of oxygen octahedra in Sr₂IrO₄ revealed by x-ray resonant scattering.
Sr2IrO4 is a prototype of the class of Mott insulators in the strong spin-orbit interaction (SOI) limit described by a Jeff = 1/2 ground state. In Sr2IrO4, the strong SOI is predicted to manifest itself in the locking of the canting of the magnetic moments to the correlated rotation by 11.8(1)° of the oxygen octahedra that characterizes its distorted layered perovskite structure. Using x-ray resonant scattering at the Ir L3 edge we have measured accurately the intensities of Bragg peaks arising from different components of the magnetic structure. From a careful comparison of integrated intensities of peaks due to basal-plane antiferromagnetism, with those due to b-axis ferromagnetism, we deduce a canting of the magnetic moments of 12.2(8)°. We thus confirm that in Sr2IrO4 the magnetic moments rigidly follow the rotation of the oxygen octahedra, indicating that, even in the presence of significant non-cubic structural distortions, it is a close realization of the Jeff = 1/2 state.


Long-term protection after immunization with protein-polysaccharide conjugate vaccines in infancy.
The polysaccharide-encapsulated bacteria, Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae are important causes of invasive bacterial infection in childhood, accounting for most of the cases of bacterial pneumonia and meningitis worldwide. Protein-polysaccharide conjugate vaccines have been developed over the last 20 years and have proven very effective in controlling these infections. Although studies have consistently shown that herd immunity is critical for population protection, long-term individual protection against polysaccharide-encapsulated bacteria appears to depend on persisting antibody and, perhaps to a lesser extent, immunological memory. However, some studies have reported that the concentration of serum antibody and vaccine effectiveness are not sustained after infant immunization, despite persistence of immunological memory. In this article, we detail the mechanisms of protection against invasion by encapsulated bacteria, describe the age-dependent B-cell and antibody responses to protein-polysaccharide conjugate vaccines and propose strategies to guarantee protection during periods of increased disease burden.


Coccidioidomycosis in African Americans.
Coccidioidomycosis is caused by Coccidioides species, a fungus endemic to the desert regions of the southwestern United States, and is of particular concern for African Americans. We performed a PubMed search of the English-language medical literature on coccidioidomycosis in African Americans and summarized the pertinent literature. Search terms were coccidioidomycosis, Coccidioides, race, ethnicity, African, black, and Negro. The proceedings of the national and international coccidioidomycosis symposia were searched. All relevant articles and their cited references were reviewed; those with epidemiological, immunologic, clinical, and therapeutic data pertaining to coccidioidomycosis in African Americans were included in the review. Numerous studies documented an increased predilection for severe coccidioidal infections, coccidioidomycosis-related hospitalizations, and extrapulmonary dissemination in persons of African descent; however, most of the published studies are variably problematic. The immunologic mechanism for this predilection is unclear. The clinical features and treatment recommendations are summarized. Medical practitioners need to be alert to the possibility of coccidioidomycosis in persons with recent travel to or residence in an area where the disease is endemic.


The knowledge and use of screening tests for colorectal and prostate cancer: data from the 1987 National Health Interview Survey.
Data based on the 1987 National Health Interview Survey are presented depicting factors associated with the knowledge and use of three tests for the early detection of colorectal and prostate cancer: digital rectal examination, fecal occult blood tests, and flexible sigmoidoscopy. The percentage of the at risk adult population who have ever heard of or had these tests is reported. The association of demographic, personal resource, and health system factors with knowledge of these tests is explored using multivariate logistic regression. Health system factors are most consistently associated with use of the tests and with knowledge. Family income, family size, education, knowledge of cancer early warning signs, and measures of encounters with the health care system are associated both with knowledge of and, independent of knowledge, with use of the tests. Residency in the non-South, being white or female, and having an optimistic attitude about cancer prevention are all factors associated with greater knowledge of the tests, but not greater use among those aware of the tests. Membership in a health maintenance organization is more strongly associated with knowledge and use of fecal occult blood tests than the other tests. No association was found between current smoking status and knowledge of or use of any of the tests.


The contribution of aerobic fitness and back strength to lift capacity.
This study used a concurrent validation design with 45 healthy female participants. To measure the relative contributions of aerobic capacity and back strength to lift capacity. This was the first concurrent study of the relations among spine strength, aerobic capacity, and lift capacity. Previous research had demonstrated moderate to strong relations between spine strength and lift capacity and between aerobic capacity and lift capacity. Multiple regression techniques were used on reliable and valid measures of each construct to study the individual and joint contributions of spine strength and aerobic capacity to lift capacity. Both spine strength and aerobic capacity make significant independent contributions to lift capacity, accounting for 11% and 27% of the variance, respectively. Taken together, the predictive power of these variables on lift capacity accounts for 43% of the variance. Lift capacity is dependent on both back strength and aerobic capacity. It may be inappropriate to use lift capacity as an indicator for the severity of spine impairment in a disability determination system without taking into account the individual's aerobic capacity. Treatment intended to improve the lift capacity of persons with spine impairment should anticipate that improvement in both back strength and aerobic capacity will improve lift capacity.


Bird communities of the arctic shrub tundra of Yamal: habitat specialists and generalists.
The ratio of habitat generalists to specialists in birds has been suggested as a good indicator of ecosystem changes due to e.g. climate change and other anthropogenic perturbations. Most studies focusing on this functional component of biodiversity originate, however, from temperate regions. The Eurasian Arctic tundra is currently experiencing an unprecedented combination of climate change, change in grazing pressure by domestic reindeer and growing human activity. Here we monitored bird communities in a tundra landscape harbouring shrub and open habitats in order to analyse bird habitat relationships and quantify habitat specialization. We used ordination methods to analyse habitat associations and estimated the proportions of specialists in each of the main habitats. Correspondence Analysis identified three main bird communities, inhabiting upland, lowland and dense willow shrubs. We documented a stable structure of communities despite large multiannual variations of bird density (from 90 to 175 pairs/km(2)). Willow shrub thickets were a hotspot for bird density, but not for species richness. The thickets hosted many specialized species whose main distribution area was south of the tundra. If current arctic changes result in a shrubification of the landscape as many studies suggested, we would expect an increase in the overall bird abundance together with an increase of local specialists, since they are associated with willow thickets. The majority of these species have a southern origin and their increase in abundance would represent a strengthening of the boreal component in the southern tundra, perhaps at the expense of species typical of the subarctic zone, which appear to be generalists within this zone.


Distinct types of non-cholinergic pedunculopontine neurons are differentially modulated during global brain states.
The pedunculopontine nucleus (PPN) is critically involved in brain-state transitions that promote neocortical activation. In addition, the PPN is involved in the control of several behavioral processes including locomotion, motivation and reward, but the neuronal substrates that underlie such an array of functions remain elusive. Here we analyzed the physiological properties of non-cholinergic PPN neurons in vivo across distinct brain states, and correlated these with their morphological properties after juxtacellular labeling. We show that non-cholinergic neurons in the PPN whose firing is not strongly correlated to neocortical activity are highly heterogeneous and are composed of at least three different subtypes: (1) "quiescent" neurons, which are nearly silent during slow-wave activity (SWA) but respond robustly to neocortical activation; (2) "tonic firing" neurons, which have a stationary firing rate that is independent of neocortical activity across different brain states; and (3) "irregular firing" neurons, which exhibit a variable level of correlation with neocortical activity. The majority of non-cholinergic neurons have an ascending axonal trajectory, with the exception of some irregular firing neurons that have descending axons. Furthermore, we observed asymmetric synaptic contacts within the PPN arising from the axon collaterals of labeled neurons, suggesting that excitatory, non-cholinergic neurons can shape the activity of neighboring cells. Our results provide the first evidence of distinct firing properties associated with non-cholinergic neuronal subtypes in the PPN, suggesting a functional heterogeneity, and support the notion of a local network assembled by projection neurons, the properties of which are likely to determine the output of the PPN in diverse behavioral contexts.


Ancient pigs reveal a near-complete genomic turnover following their introduction to Europe.
Archaeological evidence indicates that pig domestication had begun by ∼10,500 y before the present (BP) in the Near East, and mitochondrial DNA (mtDNA) suggests that pigs arrived in Europe alongside farmers ∼8,500 y BP. A few thousand years after the introduction of Near Eastern pigs into Europe, however, their characteristic mtDNA signature disappeared and was replaced by haplotypes associated with European wild boars. This turnover could be accounted for by substantial gene flow from local European wild boars, although it is also possible that European wild boars were domesticated independently without any genetic contribution from the Near East. To test these hypotheses, we obtained mtDNA sequences from 2,099 modern and ancient pig samples and 63 nuclear ancient genomes from Near Eastern and European pigs. Our analyses revealed that European domestic pigs dating from 7,100 to 6,000 y BP possessed both Near Eastern and European nuclear ancestry, while later pigs possessed no more than 4% Near Eastern ancestry, indicating that gene flow from European wild boars resulted in a near-complete disappearance of Near East ancestry. In addition, we demonstrate that a variant at a locus encoding black coat color likely originated in the Near East and persisted in European pigs. Altogether, our results indicate that while pigs were not independently domesticated in Europe, the vast majority of human-mediated selection over the past 5,000 y focused on the genomic fraction derived from the European wild boars, and not on the fraction that was selected by early Neolithic farmers over the first 2,500 y of the domestication process.


Surfactants: physicochemical interactions with biological macromolecules.
Macromolecules are essential cellular components in biological systems responsible for performing a large number of functions that are necessary for growth and perseverance of living organisms. Proteins, lipids and carbohydrates are three major classes of biological macromolecules. To predict the structure, function, and behaviour of any cluster of macromolecules, it is necessary to understand the interaction between them and other components through basic principles of chemistry and physics. An important number of macromolecules are present in mixtures with surfactants, where a combination of hydrophobic and electrostatic interactions is responsible for the specific properties of any solution. It has been demonstrated that surfactants can help the formation of helices in some proteins thereby promoting protein structure formation. On the other hand, there is extensive research towards the use of surfactants to solubilize drugs and pharmaceuticals; therefore, it is evident that the interaction between surfactants with macromolecules is important for many applications which includes environmental processes and the pharmaceutical industry. In this review, we describe the properties of different types of surfactants that are relevant for their physicochemical interactions with biological macromolecules, from macromolecules-surfactant complexes to hydrophobic and electrostatic interactions.


Project Lazarus: community-based overdose prevention in rural North Carolina.
In response to some of the highest drug overdose death rates in the country, Project Lazarus developed a community-based overdose prevention program in Western North Carolina. The Wilkes County unintentional poisoning mortality rate was quadruple that of the state's in 2009 and due almost exclusively to prescription opioid pain relievers, including fentanyl, hydrocodone, methadone, and oxycodone. The program is ongoing. The overdose prevention program involves five components: community activation and coalition building; monitoring and surveillance data; prevention of overdoses; use of rescue medication for reversing overdoses by community members; and evaluating project components. Principal efforts include education of primary care providers in managing chronic pain and safe opioid prescribing, largely through the creation of a tool kit and face-to-face meetings. Preliminary unadjusted data for Wilkes County revealed that the overdose death rate dropped from 46.6 per 100,000 in 2009 to 29.0 per 100,000 in 2010. There was a decrease in the number of victims who received prescriptions for the substance implicated in their fatal overdose from a Wilkes County physician; in 2008, 82% of overdose decedents received a prescription for an opioid analgesic from a Wilkes prescriber compared with 10% in 2010. While the results from this community-based program are preliminary, the number and nature of prescription opioid overdose deaths in Wilkes County changed during the intervention. Further evaluation is required to understand the localized effect of the intervention and its potential for replication in other areas.


Improving visual perception through neurofeedback.
Perception depends on the interplay of ongoing spontaneous activity and stimulus-evoked activity in sensory cortices. This raises the possibility that training ongoing spontaneous activity alone might be sufficient for enhancing perceptual sensitivity. To test this, we trained human participants to control ongoing spontaneous activity in circumscribed regions of retinotopic visual cortex using real-time functional MRI-based neurofeedback. After training, we tested participants using a new and previously untrained visual detection task that was presented at the visual field location corresponding to the trained region of visual cortex. Perceptual sensitivity was significantly enhanced only when participants who had previously learned control over ongoing activity were now exercising control and only for that region of visual cortex. Our new approach allows us to non-invasively and non-pharmacologically manipulate regionally specific brain activity and thus provide "brain training" to deliver particular perceptual enhancements.


A web-based rapid prototyping and clinical conversational system that complements electronic patient record system.
Even the most extensive hospital information system cannot support all the complex and ever-changing demands associated with a clinical database, such as providing department or personal data forms, and rating scales. Well-designed clinical dialogue programs may facilitate direct interaction of patients with their medical records. Incorporation of extensive and loosely structured clinical data into an existing medical record system is an essential step towards a comprehensive clinical information system, and can best be achieved when the practitioner and the patient directly enter the contents. We have developed a rapid prototyping and clinical conversational system that complements the electronic medical record system, with its generic data structure and standard communication interfaces based on Web technology. We believe our approach can enhance collaboration between consumer-oriented and provider-oriented information systems.


Immunologic criteria are poor predictors of virologic outcome: implications for HIV treatment monitoring in resource-limited settings.
Viral load (VL) quantification is considered essential for determining antiretroviral treatment (ART) success in resource-rich countries. However, it is not widely available in resource-limited settings where the burden of human immunodeficiency virus infection is greatest. In the absence of VL monitoring, switches to second-line ART are based on World Health Organization (WHO) clinical or immunologic failure criteria. We assessed the performance of CD4 cell criteria to predict virologic outcomes in a large ART program in Nigeria. Laboratory monitoring consists of CD4 cell count and VL at baseline, then every 6 months. Failure was defined as 2 consecutive VLs >1000 copies/mL after at least 6 months of ART. Virologic outcomes were compared with the 3 WHO-defined immunologic failure criteria. A total of 9690 patients were included in the analysis (median follow-up, 33.2 months). A total of 1225 patients experienced failure by both immunologic and virologic criteria, 872 by virologic criteria only, and 1897 by immunologic criteria only. The sensitivity of CD4 cell criteria to detect viral failure was 58%, specificity was 75%, and the positive-predictive value was 39%. For patients with both virologic and immunologic failure, VL criteria identified failure significantly earlier than CD4 cell criteria (median, 10.4 vs 15.6 months; P < .0001). Because of the low sensitivity of immunologic criteria, a substantial number of failures are missed, potentially resulting in accumulation of resistance mutations. In addition, specificity and predictive values are low, which may result in large numbers of unnecessary ART switches. Monitoring solely by immunologic criteria may result in increased costs because of excess switches to more expensive ART and development of drug-resistant virus.


Indoor air quality, ventilation and health symptoms in schools: an analysis of existing information.
We reviewed the literature on Indoor Air Quality (IAQ), ventilation, and building-related health problems in schools and identified commonly reported building-related health symptoms involving schools until 1999. We collected existing data on ventilation rates, carbon dioxide (CO2) concentrations and symptom-relevant indoor air contaminants, and evaluated information on causal relationships between pollutant exposures and health symptoms. Reported ventilation and CO2 data strongly indicate that ventilation is inadequate in many classrooms, possibly leading to health symptoms. Adequate ventilation should be a major focus of design or remediation efforts. Total volatile organic compounds, formaldehyde (HCHO) and microbiological contaminants are reported. Low HCHO concentrations were unlikely to cause acute irritant symptoms (<0.05 ppm), but possibly increased risks for allergen sensitivities, chronic irritation, and cancer. Reported microbiological contaminants included allergens in deposited dust, fungi, and bacteria. Levels of specific allergens were sufficient to cause symptoms in allergic occupants. Measurements of airborne bacteria and airborne and surface fungal spores were reported in schoolrooms. Asthma and 'sick building syndrome' symptoms are commonly reported. The few studies investigating causal relationships between health symptoms and exposures to specific pollutants suggest that such symptoms in schools are related to exposures to volatile organic compounds (VOCs), molds and microbial VOCs, and allergens.


Micropatterned sensing hydrogels integrated with reconfigurable microfluidics for detecting protease release from cells.
Matrix metalloproteinases (MMPs) play a central role in the breakdown of the extracellular matrix and are typically upregulated in cancer cells. The goal of the present study is to develop microwells suitable for capture of cells and detection of cell-secreted proteases. Hydrogel microwells comprised of poly(ethylene glycol) (PEG) were photopatterned on glass and modified with ligands to promote cell adhesion. To sense protease release, peptides cleavable by MMP9 were designed to contain a donor/acceptor FRET pair (FITC and DABCYL). These sensing molecules were incorporated into the walls of the hydrogel wells to enable a detection scheme where cells captured within the wells secreted protease molecules which diffused into the gel, cleaved the peptide, and caused a fluorescence signal to come on. By challenging sensing hydrogel microstructures to known concentrations of recombinant MMP9, the limit of detection was determined to be 0.625 nM with a linear range extending to 40 nM. To enhance sensitivity and to limit cross-talk between adjacent sensing sites, microwell arrays containing small groups (∼20 cells/well) of lymphoma cells were integrated into reconfigurable PDMS microfluidic devices. Using this combination of sensing hydrogel microwells and reconfigurable microfluidics, detection of MMP9 release from as few as 11 cells was demonstrated. Smart hydrogel microstructures capable of sequestering small groups of cells and sensing cell function have multiple applications ranging from diagnostics to cell/tissue engineering. Further development of this technology will include single-cell analysis and function-based cell sorting capabilities.


Prevalence of vitamin D deficiency in rheumatoid arthritis and association with disease activity and cardiovascular risk factors: data from the COMEDRA study.
The relationship between vitamin D and rheumatoid arthritis (RA) activity remains controversial. RA is a cardiovascular risk factor. A low level of vitamin D may increase blood pressure (BP) and decrease HDL-cholesterol. We aimed to determine the prevalence of vitamin D deficiency in RA patients compared to controls, and also to investigate the relationship between vitamin D and RA activity, and between vitamin D and cardiovascular risk factors. Patients in the COMEDRA study with established inactive RA (1987 ACR criteria) were matched with subjects from the NUTRINET-SANTE cohort (age, gender, latitude, sampling season). Vitamin D deficiency was defined as <10 ng/mL, and insufficiency as 10 to 29.9 ng/mL. Eight hundred and ninety-four RA patients were analysed, of which 861 were matched with controls. The prevalence of vitamin D insufficiency and deficiency was lower in RA patients than in controls: 480 (55.8%) vs. 508 (59%) and 31 (3.6%) vs. 45 (5.23%), respectively; p=0.04. There was an inverse correlation between vitamin D levels and RA activity assessed by DAS28-CRP (p=0.01), SDAI (p<0.001) and CDAI (p=0.001), but not DAS28-ESR after adjustment for age, gender, inclusion season, body mass index (BMI), vitamin D supplementation, disease duration, RF or anti-CCP status and RA treatments. Vitamin D levels were inversely correlated with BMI (p<0.001), but not with BP, total cholesterol, LDL-cholesterol, HDL-cholesterol or blood glucose. This study demonstrates that vitamin D is inversely correlated with RA activity and BMI, but not with other cardiovascular risk factors.


Public opinion and the politics of obesity in America.
Health policy experts have recently sounded the warning about the severe health and economic consequences of America's growing rates of obesity. Despite this fact, obesity has only begun to enter America's political consciousness and we have little information about what average Americans think of obesity or whether they support obesity-related policies. Using unique survey data collected by the authors, this essay examines public attitudes toward obesity and obesity policy. We find that, contrary to the views of health experts, most Americans are not seriously concerned with obesity, express relatively low support for obesity-targeted policies, and still view obesity as resulting from individual failure rather than environmental or genetic sources. Given the absence of elite discourse on this problem, we also find that typical determinants of policy preferences, such as ideology or partisanship, are not good predictors of attitudes on obesity policy. Rather, with a low-valence issue such as obesity, the public utilizes other attitudinal frameworks such as their opinions on smoking policy and the environmental culpability for obesity. The implications of these findings for obesity policy and research on health-related public opinion are discussed.


Coparenting relationship trajectories: Marital violence linked to change and variability after separation.
Associations between marital intimate partner violence (IPV) and postseparation coparenting relationship trajectories were examined among 135 mothers who participated in 5 interviews at 3-month intervals in the year following their divorce filing. Growth curve analysis was conducted to assess change and variability in coparenting dimensions (i.e., conflict, support, communication about child rearing, and harassment) in the overall sample and by type of IPV. In the overall sample, coparenting conflict, communication about child rearing, and harassment decreased across the year following separation. However, coparenting relationships differed considerably based on marital IPV experiences. At Time 1, mothers in relationships with coercive controlling violence (CCV) reported higher levels of harassment and conflict, and lower levels of support and communication about coparenting, than mothers with situational couple violence (SCV) or no violence (NV). Furthermore, coparenting relationship trajectories differed significantly by IPV group, with mothers who experienced CCV showing more variability in conflict and harassment, and more marked changes in conflict, support, and harassment. Despite many similarities, mothers with SCV showed higher initial levels of harassment compared to mothers with NV. Findings can support family court and social service professionals' efforts to individualize interventions with divorcing parents based on IPV experiences. In cases of CCV, for example, attention to heightened control dynamics in the immediate separation period remain critical but the persistent volatility across the first year suggests the potential for chronic stress. With SCV, practitioners may be able to capitalize on parents' reasonable levels of communication and steady coparenting support. (PsycINFO Database Record


Transperineal template-guided biopsy for diagnosis of prostate cancer in patients with at least two prior negative biopsies.
To evaluate the prostate cancer (PCa) detection rate, PCa location, PCa significance and complications of a standardized 24-core template-guided transperineal biopsy (TPB) approach in patients with at least two negative transrectal biopsies. We prospectively recruited 50 men who had at least two negative transrectal ultrasound-guided extended biopsies in the past 24 months, a prostate-specific antigen (PSA) < 20 ng/mL, a prostate volume < 100 mL, and life expectancy of at least 90 % at 10 years. All patients underwent a standardized 24-core template-guided TPB biopsy. The PCa detection rate, PCa location, PCa significance, and complications were recorded. Median age was 57.5 years and the median PSA level was 7.3 ng/ml. PCa was detected in 24 patients (48 %). The anterior zone was involved in 16 (32 %) PCa. Six PCa (25 %) were insignificant. Biopsy related complications occurred in 2 patients (4 %). A 24-core TPB is a safe procedure with a high PCa detection rate. Few of the detected PCa are clinically insignificant. Men with at least two negative transrectal biopsies may be counseled to undergo TPB.


Bird Migration and Avian Influenza: A Comparison of Hydrogen Stable Isotopes and Satellite Tracking Methods.
Satellite-based tracking of migratory waterfowl is an important tool for understanding the potential role of wild birds in the long-distance transmission of highly pathogenic avian influenza. However, employing this technique on a continental scale is prohibitively expensive. This study explores the utility of stable isotope ratios in feathers in examining both the distances traveled by migratory birds and variation in migration behavior. We compared the satellite-derived movement data of 22 ducks from 8 species captured at wintering areas in Bangladesh, Turkey, and Hong Kong with deuterium ratios (δD) of these and other individuals captured at the same locations. We derived likely molting locations from the satellite tracking data and generated expected isotope ratios based on an interpolated map of δD in rainwater. Although δD was correlated with the distance between wintering and molting locations, surprisingly, measured δD values were not correlated with either expected values or latitudes of molting sites. However, population-level parameters derived from the satellite-tracking data, such as mean distance between wintering and molting locations and variation in migration distance, were reflected by means and variation of the stable isotope values. Our findings call into question the relevance of the rainfall isotope map for Asia for linking feather isotopes to molting locations, and underscore the need for extensive ground truthing in the form of feather-based isoscapes. Nevertheless, stable isotopes from feathers could inform disease models by characterizing the degree to which regional breeding populations interact at common wintering locations. Feather isotopes also could aid in surveying wintering locations to determine where high-resolution tracking techniques (e.g. satellite tracking) could most effectively be employed. Moreover, intrinsic markers such as stable isotopes offer the only means of inferring movement information from birds that have died as a result of infection. In the absence of feather based-isoscapes, we recommend a combination of isotope analysis and satellite-tracking as the best means of generating aggregate movement data for informing disease models.


Risk of Hospitalization for Serious Adverse Gastrointestinal Events Associated With Sodium Polystyrene Sulfonate Use in Patients of Advanced Age.
Sodium polystyrene sulfonate is commonly prescribed for the treatment of hyperkalemia. Case reports of intestinal injury after administration of sodium polystyrene sulfonate with sorbitol resulted in a US Food and Drug Administration warning and discontinuation of combined 70% sorbitol-sodium polystyrene sulfonate formulations. There are ongoing concerns about the gastrointestinal (GI) safety of sodium polystyrene sulfonate use. To assess the risk of hospitalization for adverse GI events associated with sodium polystyrene sulfonate use in patients of advanced age. Population-based, retrospective matched cohort study of eligible adults of advanced age (≥66 years) dispensed sodium polystyrene sulfonate from April 1, 2003, to September 30, 2015, in Ontario, Canada, with maximum follow-up to March 31, 2016. Initial data analysis was conducted from August 1, 2018, to October 3, 2018; revision analysis was conducted from February 25, 2019, to April 2, 2019. Cox proportional hazards regression models were used to examine the association of sodium polystyrene sulfonate use with a composite of GI adverse events compared with nonuse that was matched via a high-dimensional propensity score. Additional analyses were limited to a subpopulation with baseline laboratory values of estimated glomerular filtration rate and serum potassium level. Dispensed sodium polystyrene sulfonate in an outpatient setting. The primary outcome was a composite of adverse GI events (hospitalization or emergency department visit with intestinal ischemia/thrombosis, GI ulceration/perforation, or resection/ostomy) within 30 days of initial sodium polystyrene sulfonate prescription. From a total of 1 853 866 eligible adults, 27 704 individuals were dispensed sodium polystyrene sulfonate (mean [SD] age, 78.5 [7.7] years; 54.7% male), and 20 020 sodium polystyrene sulfonate users were matched to 20 020 nonusers. Sodium polystyrene sulfonate use compared with nonuse was associated with a higher risk of an adverse GI event over the following 30 days (37 events [0.2%]; incidence rate, 22.97 per 1000 person-years vs 18 events [0.1%]; incidence rate, 11.01 per 1000 person-years) (hazard ratio, 1.94; 95% CI, 1.10-3.41). Results were consistent in additional analyses, including the subpopulation with baseline laboratory values (hazard ratio, 2.91; 95% CI, 1.38-6.12), and intestinal ischemia/thrombosis was the most common type of GI injury. The use of sodium polystyrene sulfonate is associated with a higher risk of hospitalization for serious adverse GI events. These findings require confirmation and suggest caution with the ongoing use of sodium polystyrene sulfonate.


Bacterial quorum sensing: its role in virulence and possibilities for its control.
Quorum sensing is a process of cell-cell communication that allows bacteria to share information about cell density and adjust gene expression accordingly. This process enables bacteria to express energetically expensive processes as a collective only when the impact of those processes on the environment or on a host will be maximized. Among the many traits controlled by quorum sensing is the expression of virulence factors by pathogenic bacteria. Here we review the quorum-sensing circuits of Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, and Vibrio cholerae. We outline these canonical quorum-sensing mechanisms and how each uniquely controls virulence factor production. Additionally, we examine recent efforts to inhibit quorum sensing in these pathogens with the goal of designing novel antimicrobial therapeutics.


Ablation of nonmuscle myosin II-B and II-C reveals a role for nonmuscle myosin II in cardiac myocyte karyokinesis.
Ablation of nonmuscle myosin (NM) II-A or NM II-B results in mouse embryonic lethality. Here, we report the results of ablating NM II-C as well as NM II-C/II-B together in mice. NM II-C ablated mice survive to adulthood and show no obvious defects compared with wild-type littermates. However, ablation of NM II-C in mice expressing only 12% of wild-type amounts of NM II-B results in a marked increase in cardiac myocyte hypertrophy compared with the NM II-B hypomorphic mice alone. In addition, these hearts develop interstitial fibrosis associated with diffuse N-cadherin and β-catenin localization at the intercalated discs, where both NM II-B and II-C are normally concentrated. When both NM II-C and II-B are ablated the B-C-/B-C- cardiac myocytes show major defects in karyokinesis. More than 90% of B-C-/B-C- myocytes demonstrate defects in chromatid segregation and mitotic spindle formation accompanied by increased stability of microtubules and abnormal formation of multiple centrosomes. This requirement for NM II in karyokinesis is further demonstrated in the HL-1 cell line derived from mouse atrial myocytes, by using small interfering RNA knockdown of NM II or treatment with the myosin inhibitor blebbistatin. Our study shows that NM II is involved in regulating cardiac myocyte karyokinesis by affecting microtubule dynamics.


Screening of Patients with Snoring and Obstructive Sleep Apnoea using Heart Rate Variability Indices.
Snoring and obstructive sleep apnea (OSA) are common disorders. Snoring associated with excessive daytime sleepiness is the most prevalent symptoms of OSA. Heart rate variability (HRV) is altered in patients with OSA and the degree of alteration may be linked to the severity of OSA. Alterations in HRV in 24 hour tachograms have recently been used in screening OSA patients. Autonomic components causing HRV can be reliably studied using spectral analysis techniques involving fast Fourier transformation (FFT). Twenty-three subjects, 13 with severe OSA and 10 controls matched for age and body mass index, were selected from patients who had undergone polysomnography (PSG) for snoring at Sultan Qaboos University Hospital, Oman. A 24- hour electrocardiogram (ECG) Holter recording was done at home, starting at 10am. Spectral analysis of ECG from sleep Holter and PSG recordings was analysed using fast Fourier transformation (FFT). The ECG RR intervals of snorers with OSA were significantly shorter than in snorers without OSA (p<0.01). The low frequency (LF) spectral densities of HRV from polysomnography and Holter were significantly higher in OSA patients than in snorers, (p< 0.0001). The power spectral density of the high frequency bands was similar in the two groups. The overnight ECG Holter accurately identified all 13 snorers with severe OSA. The spectral power of the LF band obtained using FFT of sleep HRV from Holter tachograms may be a useful and cost effective test in identifying snorers with severe OSA.


The resorcylic acid lactone hypothemycin selectively inhibits the mitogen-activated protein kinase kinase-extracellular signal-regulated kinase pathway in cells.
The resorcylic acid lactone hypothemycin has been shown to inactivate protein kinases by binding to a cysteine conserved in 46 protein kinases, including mitogen-activated protein kinase kinase (MEK), extracellular signal-regulated kinase (ERK) and platelet-derived growth factor receptor (PDGFR). We assessed the selectivity of hypothemycin in cellular contexts. Hypothemycin normalized the morphology and inhibited anchorage-independent growth of Ki-ras transformed normal rat kidney (NRK) cells with selectivity and potency comparable to or greater than that of the MEK inhibitor U0126. In Ki-ras-transformed and phorbol 12-myristate 13-acetate (PMA)-treated NRK cells, hypothemycin blocked ERK activation but showed a minimal effect on autophosphorylation of protein kinase D1 (PKD1), another kinase containing the conserved cysteine. Hypothemycin potently inhibited PDGFR autophosphorylation and activation of the MEK-ERK pathway in platelet-derived growth factor (PDGF)-treated NRK cells. However, the phosphoinositide-3-kinase (PI3K) pathway was only modestly attenuated. Hypothemycin also inhibited growth factor- and anchorage-independent growth of human cancer cell lines with a constitutively active MEK-ERK pathway. Although hypothemycin has the potential to inactivate various protein kinases, the results indicate that in intracellular environments, hypothemycin can inhibit the MEK-ERK axis with sufficient selectivity to normalize transformed phenotypes of cells dependent on this pathway.


Stimulation Pattern Efficiency in Percutaneous Auricular Vagus Nerve Stimulation: Experimental Versus Numerical Data.
Percutaneous electrical stimulation of the auricular vagus nerve (pVNS) is an electroceutical technology. The selection of stimulation patterns is empirical, which may lead to under-stimulation or over-stimulation. The objective is to assess the efficiency of different stimulation patterns with respect to individual perception and to compare it with numerical data based on in-silico ear models. Monophasic (MS), biphasic (BS) and triphasic stimulation (TS) patterns were tested in volunteers. Different clinically-relevant perception levels were assessed. In-silico models of the human ear were created with embedded fibers and vessels to assess different excitation levels. TS indicates experimental superiority over BS which is superior to MS while reaching different perception levels. TS requires about 57% and 35% of BS and MS magnitude, respectively, to reach the comfortable perception. Experimental thresholds decrease from non-bursted to bursted stimulation. Numerical results indicate a slight superiority of BS and TS over MS while reaching different excitation levels, whereas the burst length has no influence. TS yields the highest number of asynchronous action impulses per stimulation symbol for the used tripolar electrode set-up. The comparison of experimental and numerical data favors the novel TS pattern. The analysis separates excitatory pVNS effects in the auricular periphery, as accounted by in-silico data, from the combination of peripheral and central pVNS effects in the brain, as accounted by experimental data. The proposed approach moves from an empirical selection of stimulation patterns towards efficient and optimized pVNS settings.


Practical Recommendations for Prehospital Selection of Pediatric Pelvic Circumferential Compression Devices.
Although the instances of Special Operations Forces (SOF) medical providers treating pediatric pelvic fractures are rare, such fractures are notable injuries in terror attacks and are at high risk for morbidity and mortality for the patient as well as stress for the provider. Presently, guidelines for pediatric-sized pelvic stabilization device application are limited to measured pelvic circumference. This study aims to inform more practical sizing guidelines. Subjects aged 1 year to 14 years were enrolled. Subject height, weight, pelvic circumference, and fit on the Broselow Pediatric Emergency Tape® (Armstrong Medical Industries), fit with the Pediatric PelvicBinder® (PelvicBinder), and fit with the small SAM Pelvic Sling® (SAM® Medical) were collected. The primary outcome was the proportion of subjects fitting each device. Sixty-five subjects were recruited; median age was 5 years (interquartile range, 1-8 years); 40 (62%) subjects were male. Ninety-one percent of subjects fit within the scale of the Broselow Tape (height <143-cm). One hundred percent of subjects with a height <143-cm had an appropriate fit with the Pediatric PelvicBinder (95% confidence level [CI], 91.8-100%), while 91.7% of subjects with a height >143-cm fit the SAM Pelvic Sling (95%CI, 61.5-99.8%). Providers should attempt to fit the Pediatric PelvicBinder for children >1 year old with suspected unstable pelvic fracture who fall on the Broselow Tape (<143-cm). The small SAM Pelvic Sling should be used for those taller than 143-cm.


Subclinical coronary atherosclerosis, HIV infection and antiretroviral therapy: Multicenter AIDS Cohort Study.
To evaluate the association of HIV infection and cumulative exposure to highly active antiretroviral therapy (HAART) with the presence and extent of coronary artery calcification (CAC). A cross-sectional study of 947 male participants (332 HIV-seronegative, 84 HAART-naive and 531 HAART-experienced HIV-infected) from the Multicenter AIDS Cohort Study. The main outcome was CAC score calculated as the geometric mean of the Agatston scores of two computed tomography replicates. Presence of CAC was defined as calcification score above 10, and extent of CAC by the score for those with CAC present. Multivariable regression was used to evaluate the association between HIV infection and HAART and presence and extent of calcification. Increasing age was most strongly associated with both prevalence and extent of CAC for all study groups. After adjustment for age, race, family history, smoking, high-density lipoprotein-C, low-density lipoprotein-C and hypertension, HIV infection (odds ratio, 1.35; 95% confidence interval, 0.70, 2.61) and long-term HAART use (odds ratio, 1.33; 95% confidence interval, 0.87, 2.05) increased the odds for presence of CAC. In contrast, after adjustment for these covariates, the extent of CAC was lower among HAART users. Among those not taking lipid-lowering therapy, HAART usage of at least 8 years was associated with significantly reduced CAC scores (relative CAC score, 0.43; 95% confidence interval, 0.24, 0.79). HAART use may have different effects on the presence and extent of coronary calcification. Although prevalence of calcification was marginally increased among long-term HAART users, the extent of calcification was significantly reduced among HAART users compared with HIV-seronegative controls.


Identification and immunocytochemical characterization of Piccolino, a novel Piccolo splice variant selectively expressed at sensory ribbon synapses of the eye and ear.
Piccolo is one of the largest cytomatrix proteins present at active zones of chemical synapses, where it is suggested to play a role in recruiting and integrating molecules relevant for both synaptic vesicle exo- and endocytosis. Here we examined the retina of a Piccolo-mutant mouse with a targeted deletion of exon 14 in the Pclo gene. Piccolo deficiency resulted in its profound loss at conventional chemical amacrine cell synapses but retinal ribbon synapses were structurally and functionally unaffected. This led to the identification of a shorter, ribbon-specific Piccolo variant, Piccolino, present in retinal photoreceptor cells, bipolar cells, as well as in inner hair cells of the inner ear. By RT-PCR analysis and the generation of a Piccolino-specific antibody we show that non-splicing of intron 5/6 leads to premature translation termination and generation of the C-terminally truncated protein specifically expressed at active zones of ribbon synapse containing cell types. With in situ proximity ligation assays we provide evidence that this truncation leads to the absence of interaction sites for Bassoon, Munc13, and presumably also ELKS/CAST, RIM2, and the L-type Ca(2) (+) channel which exist in the full-length Piccolo at active zones of conventional chemical synapses. The putative lack of interactions with proteins of the active zone suggests a function of Piccolino at ribbon synapses of sensory neurons different from Piccolo's function at conventional chemical synapses.


Efficacy of genetically modified Bt toxins alone and in combinations against pink bollworm resistant to Cry1Ac and Cry2Ab.
Evolution of resistance in pests threatens the long-term efficacy of insecticidal proteins from Bacillus thuringiensis (Bt) used in sprays and transgenic crops. Previous work showed that genetically modified Bt toxins Cry1AbMod and Cry1AcMod effectively countered resistance to native Bt toxins Cry1Ab and Cry1Ac in some pests, including pink bollworm (Pectinophora gossypiella). Here we report that Cry1AbMod and Cry1AcMod were also effective against a laboratory-selected strain of pink bollworm resistant to Cry2Ab as well as to Cry1Ab and Cry1Ac. Resistance ratios based on the concentration of toxin killing 50% of larvae for the resistant strain relative to a susceptible strain were 210 for Cry2Ab, 270 for Cry1Ab, and 310 for Cry1Ac, but only 1.6 for Cry1AbMod and 2.1 for Cry1AcMod. To evaluate the interactions among toxins, we tested combinations of Cry1AbMod, Cry1Ac, and Cry2Ab. For both the resistant and susceptible strains, the net results across all concentrations tested showed slight but significant synergism between Cry1AbMod and Cry2Ab, whereas the other combinations of toxins did not show consistent synergism or antagonism. The results suggest that the modified toxins might be useful for controlling populations of pink bollworm resistant to Cry1Ac, Cry2Ab, or both.


Self-contained tubular drill guard for anterior cervical fusion.
A self-contained tubular drill guard was adapted for use in performing anterior cervical discectomies and interbody fusions. The use of this instrument eliminates steps, provides absolute safety against drilling too deeply, allows for adjustment in individual cases, provides for easy inspection of the trephine hole, permits electing the cephalocaudal angle of the drill, and gives a measurement of the ultimate depth of the trephine hole. In 171 consecutive operations only one neurological complication occurred, and total morbidity related to cervical surgery was 6% (7% morbidity was associated with surgery at the donor site). The data suggest that the technical modification herein advocated reduces the surgical complication rate.


Bacterial community responses during a possible CO2 leaking from sub-seabed storage in marine polluted sediments.
Carbon capture and storage (CCS) is a viable option to reduce high concentrations of CO2 and mitigate their negative effects. This option has associated risks such as possible CO2 leakage from the storage sites. So far, negative effects deriving from a CO2 release have been reported for benthic macrofauna in both polluted and nonpolluted sediments. However, bacterial communities has no considered. In this work, risk assessment was carried out in order to evaluate the possible effects in a contaminated area considering bacterial responses (total number of cells, respiring activity, changes in the bacterial community composition and diversity). Four microcosms were placed into an integrated CO2 injection system with a non-pressurized chamber to simulate four different pH treatments (pH control 7.8, 7, 6.5 and 6). Results showed an impact on bacterial communities because of the CO2 treatment. Changes in respiring activity, community composition groups and diversity were found. This study highlights the use of respiring bacteria activity not only as bioindicator for environmental risk assessment and monitoring purposes but also as a bioindicador during a CO2 leakage event or CO2 enrichment process among all the responses studied.


Perceived sensitivity of mammographic screening: women's views on test accuracy and financial compensation for missed cancers.
To estimate women's expectations of the accuracy of screening mammography and to explore attitudes towards compensation for missed cancers. Cross sectional survey (by telephone). Australia; population-based survey conducted in April 1996. Random sample of women aged 30-69 years. A total of 2935 women completed the Breast Health Survey (adjusted response rate 65%). A random sample of 115 completed this sub-survey on perceived sensitivity of mammographic screening and compensation for missed cancers. About one third of women (32.2%, 95% CI 23.7, 40.7) had an unrealistically high expectation of the sensitivity of screening mammography, reporting it to be 95% or higher. Approximately 40% of the women (43.5%, 95% CI 34.4, 52.6) thought that screening mammography should pick up all cancers (should have a sensitivity of 100%). Just under half the women (45.2%, 95% CI 36.1, 54.3) said financial compensation should be awarded for a cancer missed by screening mammography even if the cancer was missed as a consequence of the small failure rate of the test. Younger women living in metropolitan areas and women who had realistic expectations of the accuracy of the tests were more likely to favour financial compensation. Unrealistically high expectations of the sensitivity of screening mammography were common in this group of women. Many women favoured financial compensation for missed cancers even if the cancer was missed solely because of the failure rate of the test. Public education is required to inform women of the limited sensitivity of breast cancer tests but this may not reduce claims for financial compensation when cancers are missed.


Current management and recommendations on hepatitis B therapy in HIV-coinfected patients.
The match between the real-life therapeutic management of chronic hepatitis B (CHB) in HIV-infected patients and the recommendations that existed at the time has never been assessed on a case-by-case basis. A total of 73 HBV-HIV coinfected patients, 34 of whom were first followed in 2003-2005 and 39 in 2006-2008 (before and after the 2005 European Consensus Conference on the treatment of chronic viral hepatitis in HIV coinfected patients), were included. All the data were retrospectively collected from their first visit to October 2008 through a standardised questionnaire. Baseline HBV DNA quantification and/or liver histology were missing in 44.1 and 28.2% of cases before and after 2005, respectively (p = 0.16). The observed management significantly differed from the recommendations for the whole population (p = 0.009), for the 2003-2005 group (p = 0.02), and tended to differ for the 2006-2008 group (p = 0.07). Therapeutic management of CHB was in accordance with the recommendations in 27 (57.4%) cases, with a higher rate of untreated patients in the 2003-2005 group, and a high rate of patients on dual therapy in both groups despite the fact that HBV therapy was not recommended. Even though global management of HBV-HIV coinfected patients is improving, baseline evaluation of CHB though necessary is still often insufficient. The strong rationale for early dual anti-HIV and anti-HBV therapy, and the reality of everyday clinical practice, bring support to the recent simplification of the recommendations widening the use of tenofovir and emtricitabine in HBV-HIV coinfected patients, irrespective of immunological, virological, or histological considerations.


Anti-HIV activity of extracts from Calendula officinalis flowers.
Extracts of dried flowers from Calendula officinalis were examined for their ability to inhibit the human immunodeficiency virus type 1 (HIV-1) replication. Both organic and aqueous extracts were relatively nontoxic to human lymphocytic Molt-4 cells, but only the organic one exhibited potent anti-HIV activity in an in vitro MTT/tetrazolium-based assay. In addition, in the presence of the organic extract (500 micrograms/mL), the uninfected Molt-4 cells were completely protected for up to 24 h from fusion and subsequent death, caused by cocultivation with persistently infected U-937/HIV-1 cells. It was also found that the organic extract from Calendula officinalis flowers caused a significant dose- and time-dependent reduction of HIV-1 reverse transcription (RT) activity. An 85% RT inhibition was achieved after a 30 min treatment of partially purified enzyme in a cell-free system. These results suggested that organic extract of flowers from Calendula officinalis possesses anti-HIV properties of therapeutic interest.


A requirement for Lim domain binding protein 1 in erythropoiesis.
During erythrocyte development, the nuclear cofactor Lim domain binding protein 1 (Ldb1) functions as a core subunit of multiprotein DNA binding complexes that include the transcription factors Scl and Gata-1 and the Lim-only adapter Lmo2. Scl, Gata-1, and Lmo2 are each required for erythropoiesis, suggesting that Ldb1-nucleated transcription complexes regulate key steps during erythropoiesis. We documented a requirement for Ldb1 in erythropoiesis in mice. Analysis of ldb1(-/-) embryos revealed a critical requirement for Ldb1 during primitive erythropoiesis, and conditional inactivation of ldb1 at later stages of gestation and in adult mice demonstrated that Ldb1 is continuously required for both definitive erythropoiesis and megakaryopoiesis. Down-regulation of Ldb1 in erythroblasts inhibited the expression of multiple erythroid-specific and prosurvival genes. These results represent the first unequivocal demonstration of a role for Ldb1 in erythropoiesis in vivo and establish a critical function for Ldb1-nucleated complexes in regulating the erythroid/megakaryocyte transcriptional program.


The partitioned LASSO-patternsearch algorithm with application to gene expression data.
In systems biology, the task of reverse engineering gene pathways from data has been limited not just by the curse of dimensionality (the interaction space is huge) but also by systematic error in the data. The gene expression barcode reduces spurious association driven by batch effects and probe effects. The binary nature of the resulting expression calls lends itself perfectly to modern regularization approaches that thrive in high-dimensional settings. The Partitioned LASSO-Patternsearch algorithm is proposed to identify patterns of multiple dichotomous risk factors for outcomes of interest in genomic studies. A partitioning scheme is used to identify promising patterns by solving many LASSO-Patternsearch subproblems in parallel. All variables that survive this stage proceed to an aggregation stage where the most significant patterns are identified by solving a reduced LASSO-Patternsearch problem in just these variables. This approach was applied to genetic data sets with expression levels dichotomized by gene expression bar code. Most of the genes and second-order interactions thus selected and are known to be related to the outcomes. We demonstrate with simulations and data analyses that the proposed method not only selects variables and patterns more accurately, but also provides smaller models with better prediction accuracy, in comparison to several alternative methodologies.


Development of a directly observed therapy adherence intervention for adolescents with human immunodeficiency virus-1: application of focus group methodology to inform design, feasibility, and acceptability.
To obtain input from adolescents with human immunodeficiency virus-1 (HIV-1) infection to inform the design of a community-based modified directly observed therapy (MDOT) antiretroviral adherence intervention. Pediatric AIDS Clinical Trials Group (PACTG) protocol 1036A conducted three focus groups with 17 adolescents aged 17-22 years (10 female, 65% African-American) from three geographically distinct US PACTG sites. Focus group sessions were scripted, audio-taped, and transcribed verbatim. A coding dictionary was developed and validated; Ethnograph version 5.08 was used to summarize coded data across and within the three sites. Prevalent themes were identified via frequencies and are reported as percentages. Adolescents provided the following specific input: the MDOT provider should be familiar with the participant and empathic; the MDOT location should be mutually agreed on, flexible, and private; and participant and provider communication should be bidirectional, preferably by phone. Ideally the MDOT program should be continued until adolescents independently demonstrate adherence and should include a weaning phase as a test of skill acquisition. The most commonly endorsed barrier to the proposed program was that MDOT would be an invasion of privacy. Initially, after introduction to the purpose of the focus group, all but one adolescent expressed the belief that MDOT could benefit persons other than themselves; however, at the conclusion of the focus group discussion, a significant shift in openness to the intervention occurred, in that 11 participants indicated they would consider participation in an MDOT program if such a program were offered. Focus group feedback clarified the feasibility, logistics, and patient concerns about the design and implementation of a proposed MDOT intervention for adolescents with HIV-1 infection who struggle with medication adherence.


Gradients in the brain: the control of the development of form and function in the cerebral cortex.
In the developing brain, gradients are commonly used to divide neurogenic regions into distinct functional domains. In this article, we discuss the functions of morphogen and gene expression gradients in the assembly of the nervous system in the context of the development of the cerebral cortex. The cerebral cortex is a mammal-specific region of the forebrain that functions at the top of the neural hierarchy to process and interpret sensory information, plan and organize tasks, and to control motor functions. The mature cerebral cortex is a modular structure, consisting of anatomically and functionally distinct areas. Those areas of neurons are generated from a uniform neuroepithelial sheet by two forms of gradients: graded extracellular signals and a set of transcription factor gradients operating across the field of neocortical stem cells. Fgf signaling from the rostral pole of the cerebral cortex sets up gradients of expression of transcription factors by both activating and repressing gene expression. However, in contrast to the spinal cord and the early Drosophila embryo, these gradients are not subsequently resolved into molecularly distinct domains of gene expression. Instead, graded information in stem cells is translated into discrete, region-specific gene expression in the postmitotic neuronal progeny of the stem cells.


Precise length definition of active GaAs-based optoelectronic devices for low-loss silicon photonics integration.
The length variation associated with standard cleaving of III-V optoelectronic chips is a major source of loss in the integration with the micron-scale silicon-on-insulator waveguides. To this end, a new, to the best of our knowledge, approach for precise definition of the III-V chip length is reported. The method employs lithography and wet etching of cleave marks outside the active III-V waveguides. The marks follow a specific crystallographic orientation and are used to initiate and guide the cleaving process. Besides minimizing the air gap between the butt-coupled III-V and Si waveguides and hence minimizing the coupling losses, the use of precisely defined length significantly improves the integration yield owing to the increased length uniformity. We apply this technique to defining the lengths of GaAs-based semiconductor optical amplifiers and demonstrate length control with an accuracy better than 250 nm per facet. This variation is more than 1 order of magnitude smaller than with the traditional cleaving methods, resulting in improvement of coupling by several dBs.


Regulation of phospho-2-keto-3-deoxy-heptonate aldolase (DAHP synthase) and anthranilate synthase of Pseudomonas aureofaciens.
Phospho-2-keto-3-deoxy-heptonate aldolase (DAHP synthase) of Pseudomonas aureofaciens ATCC 15926 was inhibited by L-tyrosine. The inhibition was competitive with erythrose 4-phosphate as the varied substrate but non-competitive with respect to phosphoenolpyruvate. Anthranilate synthase was inhibited by L-tryptophan. The inhibition was competitive with respect to chorismate but non-competitive with L-glutamine or NH4+ as the varied substrate. DAHP synthase and anthranilate synthase were not repressed when aromatic amino acids were included in the growth medium. In bacteria grown in the presence of L-phenylalanine, the anthranilate synthase activity was enhanced about threefold compared with the control. Similar results were obtained with the mutant strain P. aureofaciens ACN, which produces increased amounts of pyrrolnitrin.


Components of SurA required for outer membrane biogenesis in uropathogenic Escherichia coli.
SurA is a periplasmic peptidyl-prolyl isomerase (PPIase) and chaperone of Escherichia coli and other Gram-negative bacteria. In contrast to other PPIases, SurA appears to have a distinct role in chaperoning newly synthesized porins destined for insertion into the outer membrane. Previous studies have indicated that the chaperone activity of SurA rests in its "core module" (the N- plus C-terminal domains), based on in vivo envelope phenotypes and in vitro binding and protection of non-native substrates. In this study, we determined the components of SurA required for chaperone activity using in vivo phenotypes relevant to disease causation by uropathogenic E. coli (UPEC), namely membrane resistance to permeation by antimicrobials and maturation of the type 1 pilus usher FimD. FimD is a SurA-dependent, integral outer membrane protein through which heteropolymeric type 1 pili, which confer bladder epithelial binding and invasion capacity upon uropathogenic E. coli, are assembled and extruded. Consistent with prior results, the in vivo chaperone activity of SurA in UPEC rested primarily in the core module. However, the PPIase domains I and II were not expendable for wild-type resistance to novobiocin in broth culture. Steady-state levels of FimD were substantially restored in the UPEC surA mutant complemented with the SurA N- plus C-terminal domains. The addition of PPIase domain I augmented FimD maturation into the outer membrane, consistent with a model in which domain I enhances stability of and/or substrate binding by the core module. Our results confirm the core module of E. coli SurA as a potential target for novel anti-infective development.


Real world outcomes using 20 mm balloon expandable SAPIEN 3/ultra valves compared to larger valves (23, 26, and 29 mm)-a propensity matched analysis.
Small balloon expandable valves have higher echocardiographic transvalvular gradients and rates of prosthesis-patient mismatch (PPM) compared to larger valves. However, the impact of these echocardiographic findings on clinical outcomes is unknown. We sought to determine the clinical outcomes of 20 mm SAPIEN 3 (S3 BEV) compared to larger S3 BEV in relation to echocardiographic hemodynamics. Using the STS/ACC transcatheter valve registry, we performed a propensity-matched comparison of patients undergoing treatment of native aortic valve stenosis using transfemoral, balloon-expandable implantation of 20 mm and ≥ 23 mm S3 BEVs. Baseline and procedure characteristics, echocardiographic variables and survival were analyzed. Multivariable logistic regression was used to identify predictors of 1-year mortality. After propensity matching of the 20 mm and ≥ 23 mm SAPIEN 3 valves, 3,931 pairs with comparable baseline characteristics were identified. Small valves were associated with significantly higher echocardiographic gradients at discharge (15.7 ± 7.1 mmHg vs. 11.7 ± 5.5 mmHg, p < 0.0001) and severe PPM rates (21.5% vs. 9.7%, p < 0.0001). There was no significant difference in 1-year all-cause mortality (20 mm: 13.0% vs. ≥23 mm: 12.7%, p = 0.72) or other major adverse event rates and outcomes between the two cohorts. Based on a multivariable analysis, elevated discharge mean gradient (>20 mmHg), severe PPM and the use of 20 mm versus ≥23 mm were not independent predictors of 1-year mortality. SAPIEN 3 20 mm valves were associated with higher echocardiographic gradients, and severe PPM rates compared to larger valves but these factors were not associated with significant differences in 1-year all-cause mortality or rehospitalization.