The gut microbiota profile of adults with kidney disease and kidney stones: a systematic review of the literature.
There is mounting evidence that individuals with kidney disease and kidney stones have an abnormal gut microbiota composition. No studies to date have summarised the evidence to categorise how the gut microbiota profile of these individuals may differ from controls. Synthesis of this evidence is essential to inform future clinical trials. This systematic review aims to characterise differences of the gut microbial community in adults with kidney disease and kidney stones, as well as to describe the functional capacity of the gut microbiota and reporting of diet as a confounder in these studies. Included studies were those that investigated the gut microbial community in adults with kidney disease or kidney stones and compared this to the profile of controls. Six scientific databases (CINHAL, Medline, PubMed, Scopus, Web of Science and Cochrane Library), as well as selected grey literature sources, were searched. Quality assessment was undertaken independently by three authors. The system of evidence level criteria was employed to quantitatively evaluate the alteration of microbiota by strictly considering the number, methodological quality and consistency of the findings. Additional findings relating to altered functions of the gut microbiota, dietary intakes and dietary methodologies used were qualitatively summarised. Twenty-five articles met the eligibility criteria and included data from a total of 892 adults with kidney disease or kidney stones and 1400 controls. Compared to controls, adults with kidney disease had increased abundances of several microbes including Enterobacteriaceae, Streptococcaceae, Streptococcus and decreased abundances of Prevotellaceae, Prevotella, Prevotella 9 and Roseburia among other taxa. Adults with kidney stones also had an altered microbial composition with variations to Bacteroides, Lachnospiraceae NK4A136 group, Ruminiclostridium 5 group, Dorea, Enterobacter, Christensenellaceae and its genus Christensenellaceae R7 group. Differences in the functional potential of the microbial community between controls and adults with kidney disease or kidney stones were also identified. Only three of the 25 articles presented dietary data, and of these studies, only two used a valid dietary assessment method. The gut microbiota profile of adults with kidney disease and kidney stones differs from controls. Future study designs should include adequate reporting of important confounders such as dietary intake to assist with interpretation of findings.


Crystal structure of Escherichia coli malate synthase G complexed with magnesium and glyoxylate at 2.0 A resolution: mechanistic implications.
The crystal structure of selenomethionine-substituted malate synthase G, an 81 kDa monomeric enzyme from Escherichia coli has been determined by MAD phasing, model building, and crystallographic refinement to a resolution of 2.0 A. The crystallographic R factor is 0.177 for 49 242 reflections observed at the incident wavelength of 1.008 A, and the model stereochemistry is satisfactory. The basic fold of the enzyme is that of a beta8/alpha8 (TIM) barrel. The barrel is centrally located, with an N-terminal alpha-helical domain flanking one side. An inserted beta-sheet domain folds against the opposite side of the barrel, and an alpha-helical C-terminal domain forms a plug which caps the active site. Malate synthase catalyzes the condensation of glyoxylate and acetyl-coenzyme A and hydrolysis of the intermediate to yield malate and coenzyme A, requiring Mg(2+). The structure reveals an enzyme-substrate complex with glyoxylate and Mg(2+) which coordinates the aldehyde and carboxylate functions of the substrate. Two strictly conserved residues, Asp631 and Arg338, are proposed to provide concerted acid-base chemistry for the generation of the enol(ate) intermediate of acetyl-coenzyme A, while main-chain hydrogen bonds and bound Mg(2+) polarize glyoxylate in preparation for nucleophilic attack. The catalytic strategy of malate synthase appears to be essentially the same as that of citrate synthase, with the electrophile activated for nucleophilic attack by nearby positive charges and hydrogen bonds, while concerted acid-base catalysis accomplishes the abstraction of a proton from the methyl group of acetyl-coenzyme A. An active site aspartate is, however, the only common feature of these two enzymes, and the active sites of these enzymes are produced by quite different protein folds. Interesting similarities in the overall folds and modes of substrate recognition are discussed in comparisons of malate synthase with pyruvate kinase and pyruvate phosphate dikinase.


The determination of sense organs in Drosophila: effect of the neurogenic mutations in the embryo.
We have examined the early pattern of sensory mother cells in embryos mutant for six different neurogenic loci. Our results show that the neurogenic loci are required to restrict the number of competent cells that will become sensory mother cells, but are not involved in controlling the localization or the position-dependent specification of competent cells. We conclude that these loci are involved in setting up a system of mutual inhibition, which transforms graded differences within the proneural clusters into an all-or-none difference between one cell, which becomes the sense organ progenitor cell, and the other cells, which remain epidermal.


Toll-like receptor 8 agonist nanoparticles mimic immunomodulating effects of the live BCG vaccine and enhance neonatal innate and adaptive immune responses.
Newborns display distinct immune responses, leaving them vulnerable to infections and impairing immunization. Targeting newborn dendritic cells (DCs), which integrate vaccine signals into adaptive immune responses, might enable development of age-specific vaccine formulations to overcome suboptimal immunization. Small-molecule imidazoquinoline Toll-like receptor (TLR) 8 agonists robustly activate newborn DCs but can result in reactogenicity when delivered in soluble form. We used rational engineering and age- and species-specific modeling to construct and characterize polymer nanocarriers encapsulating a TLR8 agonist, allowing direct intracellular release after selective uptake by DCs. Chemically similar but morphologically distinct nanocarriers comprised of amphiphilic block copolymers were engineered for targeted uptake by murine DCs in vivo, and a range of TLR8 agonist-encapsulating polymersome formulations were then synthesized. Novel 96-well in vitro assays using neonatal human monocyte-derived DCs and humanized TLR8 mouse bone marrow-derived DCs enabled benchmarking of the TLR8 agonist-encapsulating polymersome formulations against conventional adjuvants and licensed vaccines, including live attenuated BCG vaccine. Immunogenicity of the TLR8 agonist adjuvanted antigen 85B (Ag85B)/peptide 25-loaded BCG-mimicking nanoparticle formulation was evaluated in vivo by using humanized TLR8 neonatal mice. Although alum-adjuvanted vaccines induced modest costimulatory molecule expression, limited TH-polarizing cytokine production, and significant cell death, BCG induced a robust adult-like maturation profile of neonatal DCs. Remarkably, TLR8 agonist polymersomes induced not only newborn DC maturation profiles similar to those induced by BCG but also stronger IL-12p70 production. On subcutaneous injection to neonatal mice, the TLR8 agonist-adjuvanted Ag85B peptide 25 formulation was comparable with BCG in inducing Ag85B-specific CD4+ T-cell numbers. TLR8 agonist-encapsulating polymersomes hold substantial potential for early-life immunization against intracellular pathogens. Overall, our study represents a novel approach for rational design of early-life vaccines.


A cobalt-containing eukaryotic nitrile hydratase.
Nitrile hydratase (NHase), an industrially important enzyme that catalyzes the hydration of nitriles to their corresponding amides, has only been characterized from prokaryotic microbes. The putative NHase from the eukaryotic unicellular choanoflagellate organism Monosiga brevicollis (MbNHase) was heterologously expressed in Escherichia coli. The resulting enzyme expressed as a single polypeptide with fused α- and β-subunits linked by a seventeen-histidine region. Size-exclusion chromatography indicated that MbNHase exists primarily as an (αβ)2 homodimer in solution, analogous to the α2β2 homotetramer architecture observed for prokaryotic NHases. The NHase enzyme contained its full complement of Co(III) and was fully functional without the co-expression of an activator protein or E. coli GroES/EL molecular chaperones. The homology model of MbNHase was developed identifying Cys400, Cys403, and Cys405 as active site ligands. The results presented here provide the first experimental data for a mature and active eukaryotic NHase with fused subunits. Since this new member of the NHase family is expressed from a single gene without the requirement of an activator protein, it represents an alternative biocatalyst for industrial syntheses of important amide compounds.


Regulation of glucose- and mitochondrial fuel-induced insulin secretion by a cytosolic protein histidine phosphatase in pancreatic beta-cells.
We report localization of a cytosolic protein histidine phosphatase (PHP; approximately 16 kDa) in INS 832/13 cells, normal rat islets, and human islets. siRNA-mediated knockdown of PHP markedly reduced glucose- or mitochondrial fuel-induced but not KCl-induced insulin secretion. siRNA-mediated knockdown of PHP also attenuated mastoparan-induced insulin secretion, suggesting its participation in G protein-sensitive signaling steps, leading to insulin secretion. Functional assays revealed that the beta-cell PHP catalyzes the dephosphorylation of ATP-citrate lyase (ACL). Silencing of PHP expression markedly reduced ACL activity, suggesting functional regulation of ACL by PHP in beta-cells. Coimmunoprecipitation studies revealed modest effects of glucose on the interaction between PHP and ACL. Confocal microscopic evidence indicated that glucose promotes association between ACL and nm23-H1, a known kinase histidine kinase, but not between PHP and ACL. Furthermore, metabolic viability of INS 832/13 cells was resistant to siRNA-PHP, suggesting no regulatory roles of PHP in cell viability. Finally, long-term exposure (24 h) of INS 832/13 cells or rat islets to high glucose (30 mM) increased the expression of PHP. Such increases in PHP expression were also seen in islets derived from the Zucker diabetic fatty rat compared with islets from the lean control animals. Together, these data implicate regulatory roles for PHP in a G protein-sensitive step involved in nutrient-induced insulin secretion. In light of the current debate on putative regulatory roles of ACL in insulin secretion, additional studies are needed to precisely identify the phosphoprotein substrate(s) for PHP in the cascade of events leading to nutrient-induced insulin secretion.


Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation.
Molecules of the TNF-R family have been shown to be essential in the regulation of lymphocyte growth and differentiation. The TNF-R family member CD27 binds to a type II transmembrane molecule belonging to the TNF gene family (CD27L) that is identical to the lymphocyte activation Ag CD70. Using transfected mouse fibroblasts expressing human CD70, we demonstrate here that interaction of CD27 with its ligand provides a potent second signal for cytokine production, induction of activation Ags, and proliferation of unprimed CD45RA+, and to a lesser extent, of primed CD45R0+ peripheral blood T cells. In contrast to costimulatory signals delivered via the CD28-ligand B7-1 (CD80), CD70 was found to induce relatively low IL-2, IL-4, and IL-10 but comparable TNF-alpha secretion. Proliferation of CD45RA+, but not of CD45R0+ T cells, was found to be largely resistant to blocking of IL-2/IL-2R interaction. Finally, the finding that CD70 and CD80 cooperate in the induction of T cell proliferation indicates that cooperation of both molecules may be essential for optimal T cell stimulation. The interaction between CD27 and its ligand CD70 might be of particular importance for the recruitment of T cells from the unprimed T cell pool. Moreover, as CD70 expression in vivo is confined to activated B and T lymphocytes, only a limited set of APC are able to generate this specific second signal for T cell expansion.


Teacher characteristics, social classroom relationships, and children's social, emotional, and behavioral classroom adjustment in special education.
The goal of this study was to explore relations between teacher characteristics (i.e., competence and wellbeing); social classroom relationships (i.e., teacher-child and peer interactions); and children's social, emotional, and behavioral classroom adjustment. These relations were explored at both the individual and classroom levels among 414 children with emotional and behavioral disorders placed in special education. Two models were specified. In the first model, children's classroom adjustment was regressed on social relationships and teacher characteristics. In the second model, reversed links were examined by regressing teacher characteristics on social relationships and children's adjustment. Results of model 1 showed that, at the individual level, better social and emotional adjustment of children was predicted by higher levels of teacher-child closeness and better behavioral adjustment was predicted by both positive teacher-child and peer interactions. At the classroom level, positive social relationships were predicted by higher levels of teacher competence, which in turn were associated with lower classroom levels of social problems. Higher levels of teacher wellbeing were directly associated with classroom adaptive and maladaptive child outcomes. Results of model 2 showed that, at the individual and classroom levels, only the emotional and behavioral problems of children predicted social classroom relationships. At the classroom level, teacher competence was best predicted by positive teacher-child relationships and teacher wellbeing was best predicted by classroom levels of prosocial behavior. We discuss the importance of positive teacher-child and peer interactions for children placed in special education and suggest ways of improving classroom processes by targeting teacher competence.


Validation of Risk Scoring Systems in Ursodeoxycholic Acid-Treated Patients With Primary Biliary Cholangitis.
Risk stratification based on biochemical variables is a useful tool for monitoring ursodeoxycholic acid (UDCA)-treated patients with primary biliary cholangitis (PBC). Several UDCA response criteria and scoring systems have been proposed for risk prediction in PBC, but these have not been validated in large external cohorts. We performed a study on data of 1746 UDCA-treated patients with PBC from 25 centers in Europe, United States, and Canada. The prognostic performance of the risk scoring systems (GLOBE and UK-PBC) and the UDCA response criteria (Barcelona, Paris I, Paris II, Rotterdam, and Toronto) were evaluated. We regarded cirrhosis-related complications (ascites, variceal bleeding, and/or hepatic encephalopathy) as clinical end points. A total of 171 patients reached a clinical end point during a median 7 years (range 1-16 years) of follow-up. The 5-, 10- and 15-year adverse outcome-free survivals were 95%, 85%, and 77%. The GLOBE and UK-PBC scores predicted cirrhosis-related complications better than the UDCA response criteria. The hazard ratio (HR) for a 1 standard deviation increase was HR 5.05 (95% confidence interval (CI): 4.43-5.74, P < 0.001) for the GLOBE score and HR 3.39 (95% CI: 3.10-3.72, P < 0.001) for the UK-PBC score. Overall, the GLOBE and UK-PBC risk scores showed similar and excellent prognostic performance (C-statistic, 0.93; 95% CI: 0.91%-95% vs 0.94; 95% CI: 0.91%-0.96%). In our international, multicenter PBC cohort, the GLOBE and UK-PBC risk scoring systems were good predictors of future cirrhosis-related complications.


Candidate gene analysis for loci affecting litter size and ovulation rate in swine.
A candidate gene approach was used to determine whether specific loci explain responses in ovulation rate (OR) and number of fully formed (FF), live (NBA), stillborn, and mummified pigs at birth observed in two lines selected for ovulation rate and litter size compared with a randomly selected control line. Line IOL was selected for an index of OR and embryonic survival for eight generations, followed by eight generations of two-stage selection for OR and litter size. Line C was selected at random for 16 generations. Line COL, derived from line C at Generation 8, underwent eight generations of two-stage selection. Lines IOL and C differed in mean EBV by 6.1 ova and 4.7 FF, whereas lines COL and C differed by 2.2 ova and 2.9 FF. Pigs of Generation 7 of two-stage selection lines were genotyped for the retinol binding protein 4 (RBP4, n = 190) and epidermal growth factor (EGF, n = 189) loci, whereas pigs of Generations 7 and 8 were genotyped for the estrogen receptor (ESR, n = 523), prolactin receptor (PRLR, n = 524), follicle-stimulating hormone beta (FSHbeta, n = 520), and prostaglandin-endoperoxide synthase 2 (PTGS2, n = 523) loci. Based on chi-square analysis for homogeneity of genotypic frequencies, distributions for PRLR, FSHbeta, and PTGS2 were different among lines (P < 0.005). Differences in gene frequencies between IOL vs C and COL vs C were 0.33 +/- 0.25 and 0.16 +/- 0.26 for PRLR, 0.35 +/- 0.20 and 0.15 +/- 0.24 for FSHbeta, and 0.16 +/- 0.16 and 0.08 +/- 0.18 for PTGS2. Although these differences are consistent with a model of selection acting on these loci, estimates of additive and dominance effects at these loci did not differ from zero (P > 0.05), and several of them had signs inconsistent with the changes in allele frequencies. We were not able to find significant associations between the polymorphic markers and phenotypes studied; however, we cannot rule out that other genetic variation within these candidate genes has an effect on the traits studied.


Effects of the ccd function of the F plasmid on bacterial growth.
The ccd segment of the mini F plasmid containing the ccdA and ccdB genes controls the coordination between plasmid proliferation and cell physiology and fate. When the DNA replication of a thermosensitive-replication plasmid carrying the ccd segment of mini F is blocked, plasmid DNA molecules are progressively diluted through cell division until the copy number reaches 1 per cell. From this time on, there is little increase in the number of viable cells, although cells continue to divide, resulting in a mixed population of viable cells (mostly plasmid containing), nonviable but residually dividing cells, and nonviable nondividing cells. Results are presented suggesting that plasmid-containing cells are viable and continue to divide, whereas plasmid-free segregants are nonviable and form filaments after a few residual divisions, with DNA synthesis reduced or arrested in the filaments. Although the ccd functions are known to induce the SOS response when plasmid replication is blocked, the production of nonviable plasmid-free segregants is independent of the SOS cell division inhibition mechanism determined by the sfiA and sfiC genes.


Determinants of mental health providers' expectations of patients' improvement.
Characteristics of individual mental health providers and of treatment settings were examined to determine their effects on providers' expectations about the improvement of patients with serious mental illness. The sample consisted of 1,567 treatment providers working in 107 inpatient and outpatient units or programs in 29 Veterans Affairs mental health facilities. They completed a questionnaire about their prognostic expectations and a broad range of attitudes toward job satisfaction, professional relations, and team functioning. Unit or program directors of all 107 units completed another questionnaire about the average functional ability of patients, unit workload, and unit size. Hierarchical linear modeling was used to assess the effects of both individual and unit-level attributes on providers' expectations of improvement in clinical symptomatology and social-functional skills of patients in their care. The providers had generally low expectations about the improvement of patients with serious mental illness. Expectations were higher among staff in units or programs that were smaller and that had an outpatient focus, a greater proportion of staff involved in the treatment team, and higher-functioning patients. Individual characteristics significantly associated with prognostic expectations were occupation, age, and membership on the treatment team. Prognostic expectations among providers of care to persons with serious mental illness vary with identifiable individual and unit or program characteristics. The latter may be amenable to manipulation and intervention to improve mental health providers' prognostic expectations.


The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium.
Natural cytotoxicity receptors (including NKp30, NKp44, and NKp46 in humans and NKp46 in mice) are type I transmembrane proteins that signal NK cell activation via ITAM-containing adapter proteins in response to stress- and pathogen-induced ligands. Although murine NKp46 expression (encoded by Ncr1) was thought to be predominantly restricted to NK cells, the identification of distinct intestinal NKp46(+) cell subsets that express the transcription factor Rorc and produce IL-22 suggests a broader function for NKp46 that could involve intestinal homeostasis and immune defense. Using mice carrying a GFP-modified Ncr1 allele, we found normal numbers of gut CD3(-)GFP(+) cells with a similar cell surface phenotype and subset distribution in the absence of Ncr1. Splenic and intestinal CD3(-)NKp46(+) cell subsets showed distinct patterns of cytokine secretion (IFN-gamma, IL-22) following activation via NK1.1, NKp46, IL-12 plus IL-18, or IL-23. However, IL-22 production was sharply restricted to intestinal CD3(-)GFP(+) cells with the CD127(+)NK1.1(-) phenotype and could be induced in an Ncr1-independent fashion. Because NKp46 ligands can trigger immune activation in the context of infectious pathogens, we assessed the response of wild-type and Ncr-1-deficient Rag2(-/-) mice to the enteric pathogen Citrobacter rodentium. No differences in the survival or clinical score were observed in C. rodentium-infected Rag2(-/-) mice lacking Ncr1, indicating that NKp46 plays a redundant role in the differentiation of intestinal IL-22(+) cells that mediate innate defense against this pathogen. Our results provide further evidence for functional heterogeneity in intestinal NKp46(+) cells that contrast with splenic NK cells.


Comprehensive Evaluation of Protein Coding Mononucleotide Microsatellites in Microsatellite-Unstable Colorectal Cancer.
Approximately 15% of colorectal cancers exhibit microsatellite instability (MSI), which leads to accumulation of large numbers of small insertions and deletions (indels). Genes that provide growth advantage to cells via loss-of-function mutations in microsatellites are called MSI target genes. Several criteria to define these genes have been suggested, one of them being simple mutation frequency. Microsatellite mutation rate, however, depends on the length and nucleotide context of the microsatellite. Therefore, assessing the general impact of mismatch repair deficiency on the likelihood of mutation events is paramount when following this approach. To identify MSI target genes, we developed a statistical model for the somatic background indel mutation rate of microsatellites to assess mutation significance. Exome sequencing data of 24 MSI colorectal cancers revealed indels at 54 million mononucleotide microsatellites of three or more nucleotides in length. The top 105 microsatellites from 71 genes were further analyzed in 93 additional MSI colorectal cancers. Mutation significance and estimated clonality of mutations determined the most likely MSI target genes to be the aminoadipate-semialdehyde dehydrogenase AASDH and the solute transporter SLC9A8 Our findings offer a systematic profiling of the somatic background mutation rate in protein-coding mononucleotide microsatellites, allowing a full cataloging of the true targets of MSI in colorectal cancer. Cancer Res; 77(15); 4078-88. ©2017 AACR.


Effect of Polarization and Chronic Inflammation on Macrophage Expression of Heparan Sulfate Proteoglycans and Biosynthesis Enzymes.
Heparan sulfate (HS) proteoglycans on immune cells have the ability to bind to and regulate the bioactivity more than 400 bioactive protein ligands, including many chemokines, cytokines, and growth factors. This makes them important regulators of the phenotype and behavior of immune cells. Here we review how HS biosynthesis in macrophages is regulated during polarization and in chronic inflammatory diseases such as rheumatoid arthritis, atherosclerosis, asthma, chronic obstructive pulmonary disease and obesity, by analyzing published micro-array data and mechanistic studies in this area. We describe that macrophage expression of many HS biosynthesis and core proteins is strongly regulated by macrophage polarization, and that these expression patterns are recapitulated in chronic inflammation. Such changes in HS biosynthetic enzyme expression are likely to have a significant impact on the phenotype of macrophages in chronic inflammatory diseases by altering their interactions with chemokines, cytokines, and growth factors.


The Effect of Visual, Spatial and Temporal Manipulations on Embodiment and Action.
The feeling of owning and controlling the body relies on the integration and interpretation of sensory input from multiple sources with respect to existing representations of the bodily self. Illusion paradigms involving multisensory manipulations have demonstrated that while the senses of ownership and agency are strongly related, these two components of bodily experience may be dissociable and differentially affected by alterations to sensory input. Importantly, however, much of the current literature has focused on the application of sensory manipulations to external objects or virtual representations of the self that are visually incongruent with the viewer's own body and which are not part of the existing body representation. The current experiment used MIRAGE-mediated reality to investigate how manipulating the visual, spatial and temporal properties of the participant's own hand (as opposed to a fake/virtual limb) affected embodiment and action. Participants viewed two representations of their right hand inside a MIRAGE multisensory illusions box with opposing visual (normal or grossly distorted), temporal (synchronous or asynchronous) and spatial (precise real location or false location) manipulations applied to each hand. Subjective experiences of ownership and agency towards each hand were measured alongside an objective measure of perceived hand location using a pointing task. The subjective sense of agency was always anchored to the synchronous hand, regardless of physical appearance and location. Subjective ownership also moved with the synchronous hand, except when both the location and appearance of the synchronous limb were incongruent with that of the real limb. Objective pointing measures displayed a similar pattern, however movement synchrony was not sufficient to drive a complete shift in perceived hand location, indicating a greater reliance on the spatial location of the real hand. The results suggest that while the congruence of self-generated movement is a sufficient driver for the sense of agency, the sense of ownership is additionally sensitive to cues about the visual appearance and spatial location of one's own body.


Infection and ultrastructure of conidia and pycnidia of Stenocarpella maydis in maize.
Stenocarpella maydis is the most prevalent ear rot pathogen of maize (Zea mays) in South Africa, the United States, and other countries. Infection and ultrastructure of propagules of S. maydis in maize were observed by light, scanning, and transmission electron microscopy. Two-celled conidia of S. maydis were found in the tissues of husk and kernels. Mycelia colonized inter- and intracellularly in the host tissues. Pycnidia were found abundantly inside the seed tissues of susceptible cultivars; within a single seed, pycnidia propagated preferentially in embryonic tissues. A pycnidium is composed of morphologically different resting spores mingled with some degraded organelles of the host cell. In this study, various enzymatic activities led to cell wall degradation, lacunae in endosperm tissues, and disrupted organelles in susceptible cultivars. In contrast, callose deposition surrounding fungal hyphae was clearly visible in resistant cultivars. Heavy infection was detected by maceration, even though there was no apparent symptom on the seed coat. The saprophytic nature and structurally different forms of propagules could contribute to a long-term survival of this pathogen in the field and during grain storage. Furthermore, S. maydis might pose a threat of diplodiatoxin intoxication to human and domestic animals when infected maize seeds are consumed.


Immunoassays of field isolates of Mycobacterium bovis and other mycobacteria by use of monoclonal antibodies.
Antigen extracts obtained by sonication of 22 strains of Mycobacterium bovis from cattle and badgers together with extracts of strains of M. tuberculosis, M. paratuberculosis, M. avium, M. africanum, M. kansasi, M. leprae and BCG were examined with a panel of 10 monoclonal antibodies to M. tuberculosis or M. leprae. Antigen extracts were coated in aqueous solution (wet coating) and the extracts were also dried on to the polyvinyl plates (dry coating). When dry coating was compared to wet coating, there was a major increase in the binding of monoclonal antibody ML03 to M. avium and M. paratuberculosis, monoclonal antibody ML02 to M. paratuberculosis, and monoclonal antibodies TB71 and TB72 to the majority of M. bovis isolates. The study confirmed that on wet-coated plates, monoclonal antibodies TB71 and TB72 bind poorly or not at all to M. bovis and that monoclonal antibodies TB68, TB78, TB77 and TB23 each bind to field strains of M. bovis while TB23 binds poorly to BCG in wet-coating conditions. Antibodies TB72 and TB71, originally thought to be specific for M. tuberculosis, each reacted with M. africanum. Antibody TB78 bound to M. paratuberculosis but did not react with M. avium, and M. avium and M. paratuberculosis were distinguished from M. bovis and M. tuberculosis by the binding of antibody ML03 to dry-coated plates. When wet-coated plates were used, ML03 bound strongly only to M. leprae. The panel of monoclonal antibodies did not demonstrate distinct serotype differences between the field isolates of M. bovis.


Current understanding of meningeal and cerebral vascular function underlying migraine headache.
The exact mechanisms underlying the onset of a migraine attack are not completely understood. It is, however, now well accepted that the onset of the excruciating throbbing headache of migraine is mediated by the activation and increased mechanosensitivity (i.e. sensitization) of trigeminal nociceptive afferents that innervate the cranial meninges and their related large blood vessels. To provide a critical summary of current understanding of the role that the cranial meninges, their associated vasculature, and immune cells play in meningeal nociception and the ensuing migraine headache. We discuss the anatomy of the cranial meninges, their associated vasculature, innervation and immune cell population. We then debate the meningeal neurogenic inflammation hypothesis of migraine and its putative contribution to migraine pain. Finally, we provide insights into potential sources of meningeal inflammation and nociception beyond neurogenic inflammation, and their potential contribution to migraine headache.


Support surfaces for pressure ulcer prevention.
Pressure ulcers (also known as bedsores, pressure sores, decubitus ulcers) are areas of localised damage to the skin and underlying tissue due to pressure, shear or friction. They are common in the elderly and immobile and costly in financial and human terms. Pressure-relieving beds, mattresses and seat cushions are widely used as aids to prevention in both institutional and non-institutional settings. This systematic review seeks to answer the following questions:(1) to what extent do pressure-relieving cushions, beds, mattress overlays and mattress replacements reduce the incidence of pressure ulcers compared with standard support surfaces?(2) how effective are different pressure-relieving surfaces in preventing pressure ulcers, compared to one another? For this second update the Cochrane Wounds Group Specialised Register was searched (28/2/08), The Cochrane Central Register of Controlled Trials (CENTRAL)(2008 Issue 1), Ovid MEDLINE (1950 to February Week 3 2008), Ovid EMBASE (1980 to 2008 Week 08) and Ovid CINAHL (1982 to February Week 3 2008). The reference sections of included studies were searched for further trials. Randomised controlled trials (RCTs), published or unpublished, which assessed the effectiveness of beds, mattresses, mattress overlays, and seating cushions for the prevention of pressure ulcers, in any patient group, in any setting. Study selection was undertaken by at least two authors independently with a third author resolving uncertainty. RCTs were eligible for inclusion if they reported an objective, clinical outcome measure such as incidence and severity of new of pressure ulcers developed. Studies which only reported proxy outcome measures such as interface pressure were excluded. Trial data were extracted by one researcher and checked by a second. The results from each study are presented as relative risk for dichotomous variables. Where deemed appropriate, similar studies were pooled in a meta analysis. For this second update 11 trials met the inclusion criteria bringing the total number of RCTs included in the review to 52.Foam alternatives to the standard hospital foam mattress can reduce the incidence of pressure ulcers in people at risk. The relative merits of alternating and constant low pressure devices are unclear. There is one high quality trial comparing the different alternating pressure devices for pressure ulcer prevention which suggests that alternating pressure mattresses may be more cost effective than alternating pressure overlays.Pressure-relieving overlays on the operating table have been shown to reduce postoperative pressure ulcer incidence, although two studies indicated that foam overlays resulted in adverse skin changes. Two trials indicated that Australian standard medical sheepskins prevented pressure ulcers. There is insufficient evidence to draw conclusions on the value of seat cushions, limb protectors and various constant low pressure devices as pressure ulcer prevention strategies.A study of Accident & Emergency trolley overlays did not identify a reduction in pressure ulcer incidence. There are tentative indications that foot waffle heel elevators, a particular low air loss hydrotherapy mattress and two types of operating theatre overlays are harmful. In people at high risk of pressure ulcer development higher specification foam mattresses rather than standard hospital foam mattresses should be used. The relative merits of higher-tech constant low pressure and alternating pressure for prevention are unclear but alternating pressure mattresses may be more cost effective than alternating pressure overlays. Medical grade sheepskins are associated with a decrease in pressure ulcer development. Organisations might consider the use of some forms of pressure relief for high risk patients in the operating theatre. Seat cushions and overlays designed for use in Accident & Emergency settings have not been adequately evaluated.


Decoding reveals plasticity in V3A as a result of motion perceptual learning.
Visual perceptual learning (VPL) is defined as visual performance improvement after visual experiences. VPL is often highly specific for a visual feature presented during training. Such specificity is observed in behavioral tuning function changes with the highest improvement centered on the trained feature and was originally thought to be evidence for changes in the early visual system associated with VPL. However, results of neurophysiological studies have been highly controversial concerning whether the plasticity underlying VPL occurs within the visual cortex. The controversy may be partially due to the lack of observation of neural tuning function changes in multiple visual areas in association with VPL. Here using human subjects we systematically compared behavioral tuning function changes after global motion detection training with decoded tuning function changes for 8 visual areas using pattern classification analysis on functional magnetic resonance imaging (fMRI) signals. We found that the behavioral tuning function changes were extremely highly correlated to decoded tuning function changes only in V3A, which is known to be highly responsive to global motion with human subjects. We conclude that VPL of a global motion detection task involves plasticity in a specific visual cortical area.


Patient perceptions of innovative longitudinal integrated clerkships based in regional, rural and remote primary care: a qualitative study.
Medical students at the University of Wollongong experience continuity of patient care and clinical supervision during an innovative year-long integrated (community and hospital) clinical clerkship. In this model of clinical education, students are based in a general practice 'teaching microsystem' and participate in patient care as part of this community of practice (CoP). This study evaluates patients' perceptions of the clerkship initiative, and their perspectives on this approach to training 'much-needed' doctors in their community. Semi-structured, face-to-face, interviews with patients provided data on the clerkship model in three contexts: regional, rural and remote health care settings in Australia. Two researchers independently thematically analysed transcribed data and organised emergent categories into themes. The twelve categories that emerged from the analysis of transcribed data were clustered into four themes: learning as doing; learning as shared experience; learning as belonging to a community; and learning as 'becoming'. Patients viewed the clerkship learning environment as patient- and student-centred, emphasising that the patient-student-doctor relationship triad was important in facilitating active participation by patients as well as students. Patients believed that students became central, rather than peripheral, members of the CoP during an extended placement, value-adding and improving access to patient care. Regional, rural and remote patients valued the long-term engagement of senior medical students in their health care team(s). A supportive CoP such as the general practice 'teaching microsystem' allowed student and patient to experience increasing participation and identity transformation over time. The extended student-patient-doctor relationship was seen as influential in this progression. Patients revealed unique insights into the longitudinal clerkship model, and believed they have an important contribution to make to medical education and new strategies addressing mal-distribution in the medical workforce.


Cut-off scores for the Minimal Eating Observation and Nutrition Form - Version II (MEONF-II) among hospital inpatients.
The newly developed Minimal Eating Observation and Nutrition Form - Version II (MEONF-II) has shown promising sensitivity and specificity in relation to the Mini Nutritional Assessment (MNA). However, the suggested MEONF-II cut-off scores for deciding low/moderate and high risk for undernutrition (UN) (>2 and >4, respectively) have not been decided based on statistical criteria but on clinical reasoning. The objective of this study was to identify the optimal cut-off scores for the MEONF-II in relation to the well-established MNA based on statistical criteria. Cross-sectional study. The study included 187 patients (mean age, 77.5 years) assessed for nutritional status with the MNA (full version), and screened with the MEONF-II. The MEONF-II includes assessments of involuntary weight loss, Body Mass Index (BMI) (or calf circumference), eating difficulties, and presence of clinical signs ofUN. MEONF-II data were analysed by Receiver Operating Characteristics (ROC) curves and the area under the curve (AUC); optimal cut-offs were identified by the Youden index (J=sensitivity+specificity-1). According to the MEONF-II, 41% were at moderate or high UN risk and according to the MNA, 50% were at risk or already undernourished. The suggested cut-off scores were supported by the Youden indices. The lower cut-off for MEONF-II, used to identify any level of risk for UN (>2; J=0.52) gave an overall accuracy of 76% and the AUC was 80%. The higher cut-off for identifying those with high risk for UN (>4; J=0.33) had an accuracy of 63% and the AUC was 70%. The suggested MEONF-II cut-off scores were statistically supported. This improves the confidence of its clinical use.


Filling the gap: Using fishers' knowledge to map the extent and intensity of fishing activity.
Knowledge of the extent and intensity of fishing activities is critical to inform management in relation to fishing impacts on marine conservation features. Such information can also provide insight into the potential socio-economic impacts of closures (or other restrictions) of fishing grounds that could occur through the future designation of Marine Conservation Zones (MCZs). We assessed the accuracy and validity of fishing effort data (spatial extent and relative effort) obtained from Fishers' Local Knowledge (LK) data compared to that derived from Vessel Monitoring System (VMS) data for a high-value shellfish fishery, the king scallop (Pecten maximus L.) dredge fishery in the English Channel. The spatial distribution of fishing effort from LK significantly correlated with VMS data and the correlation increased with increasing grid cell resolution. Using a larger grid cell size for data aggregation increases the estimation of the total area of seabed impacted by the fishery. In the absence of historical VMS data for vessels ≤15 m LOA (Length Overall), LK data for the inshore fleet provided important insights into the relative effort of the inshore (<6 NM from land) king scallop fishing fleet in the English Channel. The LK data provided a good representation of the spatial extent of inshore fishing activity, whereas representation of the offshore fishery was more precautionary in terms of defining total impact. Significantly, the data highlighted frequently fished areas of particular importance to the inshore fleet. In the absence of independent sources of geospatial information, the use of LK can inform the development of marine planning in relation to both sustainable fishing and conservation objectives, and has application in both developed and developing countries where VMS technology is not utilised in fisheries management.


Urocortin-like immunoreactivity in the primary lymphoid organs of the duck (Anas platyrhynchos).
Urocortin (UCN) is a 40 aminoacid peptide which belongs to corticotropin-releasing factor (CRF) family. This family of peptides stimulates the secretion of proopiomelanocortin (POMC)-derived peptides, adrenocorticotropic hormone (ACTH), β-endorphin and melanocyte-stimulating hormone (MSH) in the pituitary gland. In the present study, using Western blotting and immunohistochemistry, the distribution of UCN in the primary lymphoid organs of the duck was investigated at different ages. In the cloacal burse and thymus, Western blot demonstrated the presence of a peptide having a molecular weight compatible with that of the mammalian UCN. In the cloacal burse, immunoreactivity was located in the medullary epithelial cells and in the follicular associated and corticomedullary epithelium. In the thymus, immunoreactivity was located in single epithelial cells. Double labelling immunofluorescence studies showed that UCN immunoreactivity completely colocalised with cytokeratin immunoreactivity in both the thymus and cloacal burse. Statistically significant differences in the percentage of UCN immunoreactivity were observed between different age periods in the cloacal burse. The results suggest that, in birds, urocortin has an important role in regulating the function of the immune system.


T'ai chi and qigong for health: patterns of use in the United States.
Little is known in the United States about those who practice t'ai chi and qigong, two mind-body techniques that originated in Asia. The objective of this study is to characterize use of t'ai chi and qigong for health with regard to sociodemographics, health status, medical conditions, perceptions of helpfulness, and disclosure of use to medical professionals. We analyzed associations of t'ai chi and qigong use for health using cross-sectional data from the 2002 National Health Interview Survey (NHIS) Alternative Medicine Supplement (n = 31,044). The 2002 NHIS estimated the number of t'ai chi and qigong users for health to be 2.5 and 0.5 million persons, respectively. We collapsed t'ai chi and qigong use into a single category (TCQ) for analysis, representing 2.8 million individuals. We found that neither age nor sex was associated with TCQ use. TCQ users were more likely than nonusers to be Asian than white (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.30-3.15), college educated (OR 2.44, 95% CI 1.97-3.03), and less likely to live in the Midwest (OR 0.64, 95% CI 0.42-0.96) or the southern United States (OR 0.51, 95% CI 0.36-0.72) than the West. TCQ use was associated independently with higher reports of musculoskeletal conditions (OR 1.43, 95% CI 1.11-1.83), severe sprains (OR 1.65, 95% CI 1.14-2.40), and asthma (OR 1.50, 95% CI 1.08-2.10). Half of TCQ users also used yoga for health in the last 12 months. Most TCQ users reported their practice to be important to maintain health, but only a quarter of users disclosed their practice to a medical professional. In the United States, TCQ is practiced for health by a diverse population, and users report benefits for maintaining health. Further research is needed to establish efficacy and safety for target populations, including those with musculoskeletal and pulmonary disease, as well as for preventive health.


Hydrogen peroxide/ceramide/Akt signaling axis play a critical role in the antileukemic potential of sanguinarine.
Dysregulation of apoptosis is a prime hallmark of leukemia. Therefore, drugs which restore the sensitivity of leukemic cells to apoptotic stimuli are promising candidates in the treatment of leukemia. Recently, we have demonstrated that sanguinarine (SNG), a benzophenanthridine alkaloid, isolated from Sanguinaria canadensis induces ROS-dependent ERK1/2 activation and autophagic cell death in human malignant glioma cells (Pallichankandy et al., 2015; [43]). In this study, we investigated the antileukemic potential of SNG in vitro, and further examined the molecular mechanisms of SNG-induced cell death. In human leukemic cells, SNG activated apoptotic cell death pathway characterized by activation of caspase cascade, DNA fragmentation and down-regulation of anti-apoptotic proteins. Importantly, we have identified a crucial role for hydrogen peroxide (H2O2)-dependent ceramide (Cer) generation in the facilitation of SNG-induced apoptosis. Additionally, we have found that SNG inhibits Akt, a key anti-apoptotic protein kinase by dephosphorylating it at Ser(473), leading to the dephosphorylation of its downstream targets, GSK3β and mTOR. Interestingly, inhibition of Cer generation, using acid sphingomyelinase inhibitor, significantly reduced the SNG-induced Akt dephosphorylation and apoptosis, whereas, activation of Cer generation using inhibitors of acid ceramidase and glucosylceramide synthase enhanced it. Furthermore, using a group of ceramide activated protein phosphatases (CAPPs) inhibitor (calyculin A, Okadaic acid, and phosphatidic acid), the involvement of protein phosphatase 1 form of CAPP in SNG-induced Akt dephosphorylation and apoptosis was demonstrated. Altogether, these results underscore a critical role for H2O2-Cer-Akt signaling axis in the antileukemic action of SNG.


Critical illness-related corticosteroid insufficiency in cirrhotic patients with acute gastroesophageal variceal bleeding: risk factors and association with outcome*.
Critical illness-related corticosteroid insufficiency can adversely influence the prognosis of critically ill patients. However, its impact on the outcomes of patients with cirrhosis and acute gastroesophageal variceal bleeding remains unknown. We evaluated adrenal function using short corticotropin stimulation test in patients with cirrhosis and gastroesophageal variceal bleeding. The main outcomes analyzed were 5-day treatment failure and 6-week mortality. Prospective observational study. Ten-bed gastroenterology-specific medical ICU at a 3,613-bed university teaching hospital in Taiwan. Patients with liver cirrhosis and acute gastroesophageal variceal bleeding. None. We evaluated adrenal function using short corticotropin stimulation test in 157 episodes of gastroesophageal variceal bleeding in 143 patients with cirrhosis. Critical illness-related corticosteroid insufficiency occurred in 29.9% of patients. The patients with critical illness-related corticosteroid insufficiency had higher rates of treatment failure and 6-week mortality (63.8% vs 10.9%, 42.6% vs 6.4%, respectively; p < 0.001). The cumulative rates of survival at 6 weeks were 57.4% and 93.6% for the critical illness-related corticosteroid insufficiency group and normal adrenal function group, respectively (p < 0.001). The cortisol response to corticotropin was inversely correlated with Model for End-Stage Liver Disease and Child-Pugh scores and positively correlated with the levels of high-density lipoprotein and total cholesterol. Hypovolemic shock, high-density lipoprotein, platelet count, and bacterial infection at inclusion are independent factors predicting critical illness-related corticosteroid insufficiency, whereas critical illness-related corticosteroid insufficiency, Model for End-Stage Liver Disease score, hypovolemic shock, hepatocellular carcinoma, and active bleeding at endoscopy are independent factors to predict treatment failure. Multivariate analysis also identified Model for End-Stage Liver Disease score, hypovolemic shock, and bacterial infection at inclusion as independent factors associated with 6-week mortality. Critical illness-related corticosteroid insufficiency is common in cirrhotic patients with acute gastroesophageal variceal bleeding and is an independent factor to predict 5-day treatment failure.


Rational Design of Novel Glycomimetic Peptides for E-Selectin Targeting.
E-selectin is a cell-adhesion receptor with specific recognition capacity toward sialo-fucosylated Lewis carbohydrates present in leukocytes and tumor cells. E-selectin interactions mediate the progress of inflammatory processes and tumor metastasis, which aroused the interest in using this protein as a biomolecular target to design glycomimetic inhibitors for active targeting or therapeutic purposes. In this work, we report the rational discovery of two novel glycomimetic peptides targeting E-selectin based on mutations of the reference selectin-binding peptide IELLQAR. Sixteen single or double mutants at Ile1, Leu3, Leu4, and Arg7 residues were evaluated as potential candidates for E-selectin targeting using 50 ns molecular dynamics (MD) simulations. Nine peptides showing a stable association with the functional pocket were modified by adding a cysteine residue to the N-terminus to confer versatility for further chemical conjugation. Subsequent 50 ns MD simulations resulted in five cysteine-modified peptides with retained or improved E-selectin binding potential. Then, 300 ns accelerated MD (aMD) simulations were used to examine the binding properties of the best five cysteine-modified peptides. CIEELQAR and CIELFQAR exhibit the most selective association with the functional pocket of E-selectin, as revealed by potential of mean force profiles. Microscale thermophoresis experiments confirmed the E-selectin binding capacity of the selected peptides with KD values in the low micromolar range (CIEELQAR KD = 35.0 ± 1.4 μM; CIELFQAR KD = 16.4 ± 0.7 μM), which are 25-fold lower than the reported value for the native ligand sLex (KD = 878 μM). Our findings support the potential of CIEELQAR and CIELFQAR as novel E-selectin-targeting peptides with high recognition capacity and versatility for chemical conjugation, which are critical for enabling future applications in active targeting.


A role for BRCA1 in uterine leiomyosarcoma.
Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)-driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS.


Serological diagnosis of cystic echinococcosis in cattle.
An IgM murine monoclonal antibody (MAb) was obtained against the excretory-secretory antigen (ES-Ag) of in vitro reared protoscoleces of Echinococcus granulosus (Batsch, 1786). Western blotting revealed that the MAb recognised a 20.6 kDa protein of this ES-Ag. The MAb was used in sandwich enzyme-linked immunosorbent assay (s-ELISA) for selective sensitisation of the solid phase with the protoscolex-specific protein from its ES-Ag and somatic antigen (S-Ag) to examine serum samples of 108 cows from a cystic echinococcosis (CE) endemic area for specific antibodies and to compare the results with those from necropsies and an indirect ELISA (i-ELISA). The sensitivity of s-ELISA/ES-Ag, s-ELISA/S-Ag and i-ELISA/S-Ag was 48%, 52% and 62%, respectively. The low sensitivity of the ELISA was probably caused by the fact that 13 cows (62%) were infected with sterile cysts (acephalocysts and/or calcified foci) only. A relatively high specificity (80%) of s-ELISA/ES-Ag was observed in cows with fertile cysts. It also detected antibodies in the serum of two cows that had recovered from the disease according to the necropsy. The i-ELISA/S-Ag gave false results in testing sera from a healthy animal and from a cow with tubercular foci. Further analysis will be necessary to define more precisely the value of this study, because the duration of antibody elimination from the bloodstream of recovered cattle remains unknown. The solution of this problem will increase the specificity of the proposed test in monitoring herbivorous animals for CE.


Heterodimers of myogenic helix-loop-helix regulatory factors and E12 bind a complex element governing myogenic induction of the avian cardiac alpha-actin promoter.
Recent studies have shown that two genes regulating myogenesis (MyoD and myogenin) are coexpressed with cardiac alpha-actin during early stages of skeletal muscle development. Myogenin and MyoD are members of a family of regulatory proteins which share a helix-loop-helix (HLH) motif required for dimerization and DNA binding. Myogenin and MyoD form heterodimers with the ubiquitous HLH protein E12 which bind cis-acting DNA elements that have an E box (CANNTG) at their core. E boxes are present in the control regions of numerous muscle-specific genes, although their functional importance in regulating many of these genes has not yet been evaluated. In this report we examine the possibility that myogenin (or MyoD) directly transactivates the cardiac alpha-actin promoter. Heterodimers of myogenin and E12 (or MyoD and E12) specifically bound a restriction fragment extending from -200 to -103 relative to the start of cardiac alpha-actin transcription. Methylation interference footprints pinpointed the site of interaction to an E box immediately adjacent to a previously identified CArG box (CArG3). Site-directed mutations to the DNA-binding site revealed that either an intact E box or an intact CArG3 is required for induction of the cardiac alpha-actin promoter in myoblasts and for transactivation by myogenin in cotransfected fibroblasts. However, deletion and substitution experiments indicate that the complex E box/CArG3 element alone does not confer muscle-specific expression to a minimal promoter. These results suggest that direct and indirect pathways involving multiple cis-acting elements mediate the induction of the cardiac alpha-actin promoter by myogenin and MyoD.


Hereditary angioedema: an update on causes, manifestations and treatment.
Hereditary angioedema is a rare genetic disorder caused by deficiency of C1 esterase inhibitor (C1-INH) and characterized by recurrent episodes of severe swelling that affect the limbs, face, intestinal tract and airway. Since laryngeal oedema can be life-threatening as a result of asphyxiation, correct diagnosis and management of hereditary angioedema is vital. Hereditary angioedema attacks are mediated by bradykinin, the production of which is regulated by C1-INH. Hereditary angioedema therapy relies on treatment of acute attacks, and short- and long-term prophylaxis. Acute treatment options include C1-INH concentrate, icatibant and ecallantide. Self-administration of treatment is recommended and is associated with increased quality of life of patients with hereditary angioedema. Advances in diagnosis and management have improved the outcomes and quality of life of patients with hereditary angioedema.


Three-dimensional visualization of objects in scattering medium by use of computational integral imaging.
In this paper, we propose a method to three-dimensionally visualize objects in a scattering medium using integral imaging. Our approach is based on a particular use of the interference phenomenon between the ballistic photons getting through the scattering medium and the scattered photons being scattered by the medium. For three-dimensional (3D) sensing of the scattered objects, the synthetic aperture integral imaging system under coherent illumination records the scattered elemental images of the objects. Then, the computational geometrical ray propagation algorithm is applied to the scattered elemental images in order to eliminate the interference patterns between scattered and object beams. The original 3D information of the scattered objects is recovered by multiple imaging channels, each with a unique perspective of the object. We present both simulation and experimental results with virtual and real objects to demonstrate the proposed concepts.


Cellular receptors for matrix proteins in normal human kidney and human mesangial cells.
In the present study we evaluated the distribution of cell adhesion molecules, referred as very late antigens (VLA), in the normal human kidney and in mesangial cells in culture (MC). In addition, we assessed the functional properties of VLA proteins on MC. Normal human kidney and MC were stained by immunoperoxidase with mouse monoclonal antibodies to VLA proteins. We demonstrated that VLA-3, a protein that binds FN, laminin and collagen, is the predominant VLA protein in the human glomerulus and on MC. VLA-3 is located in the mesangium and on the glomerular visceral epithelial cell and endothelial cell surfaces in contact with the glomerular basement membrane. VLA-1 was demonstrated in the glomerular mesangium and VLA-5, an FN specific receptor, was present in the mesangium on glomerular endothelial cells and on MC. VLA-2 and VLA-4 were not present in the normal glomerulus nor on MC. In functional studies we evaluated the binding of MC to FN coated surfaces and the binding and phagocytosis of FN coated fluorescent beads by MC. We showed that MC bind to FN coated surfaces and that the binding is inhibited by anti-FN antibodies, EDTA and peptides containing the amino acid sequence Arg-Gly-Asp (RGD). In addition, anti-VLA-5 but not anti-VLA-3 antibodies inhibited significantly the binding of MC to FN, MC demonstrated binding and phagocytosis of FN coated beads and, purified FN inhibited both phenomena. By affinity chromatography and immunoprecipitation we demonstrated that MC FN binding proteins and MC VLA proteins are composed of two distinct protein chains that have Mr characteristics similar to those of normal human fibroblasts VLA proteins. In conclusion, the glomerular distribution of VLA-3 suggests that this protein is primarily involved on the adhesion of glomerular cells to basement membranes and matrix. MC FN receptors (VLA-5) mediate the binding of MC to FN and could mediate the phagocytosis of FN coated antigen or immune complexes by mesangial cells.


Determining Position Inside Non-industrial Buildings Using Ultrasound Transducers.
The position determination inside a building where no GPS signal is beingreceived can be ascertained using laser transmitters in industrial situations where there areno people or using triangulation of the signal strength, normally electro-magnetic signals,if the required accuracy is more than a metre. Our solution is aimed at situations wherepeople are present and where the required accuracy is less than 30 cm, such as in shoppingprecincts or supermarkets. To achieve this, a network of ultrasonic transmitters is fittedinto the ceiling which receives a synchronised time signal. Each transmitter has a uniqueidentifier code and emits its code with a delay with respect to the common time signalwhich is proportional to its code number with an ASK modulation over the ultrasonic bandcentred on 40 KHz. The receivers circulating beneath the transmitters receive the codes ofthose within their detection range, translate the time delays into distances and then obtaintheir position by triangulation since the receivers know the position of every transmitter.Since the receivers are not synchronised with the common time signal or the actual speedof the sound, whose value varies appreciably with temperature, relative humidity andatmospheric pressure, a consecutive approximation algorithm has been introduced. This isbased on the fact that the Z coordinator of the receiver is known and constant and thus it is possible, with only three different identifiers received, to deduce the phase of the common time signal and estimate the speed of the sound with a fourth identifier.


Quality improvement program to reduce the prevalence of pressure ulcers in an intensive care unit.
Critically ill patients are at increased risk for pressure ulcers, which increase patients' morbidity and mortality. Quality improvement projects decrease the frequency of pressure ulcers. To improve patients' outcomes by reducing the prevalence of pressure ulcers, identifying areas for improvement in prevention of pressure ulcers, and increasing the adoption of preventive strategies in an intensive care unit. Quasi-experimental methods were used for this quality improvement project in which 563 surveys of patients' skin were performed during 22 audits conducted during a 26-month period. One-on-one clinical instruction was provided to bedside nurses during the surveys, and pressure ulcer data were displayed in the clinical area. The frequency of pressure ulcers of all stages showed an overall downward trend, and the prevalence decreased from 50% to 8%. The appropriate allocation of pressure-relieving devices increased from 75% up to 95% to 100%. The likely origin of the ulcer (ie, whether it was hospital or community acquired) and the anatomical site of the pressure ulcers did not change during the study period. This program was successful in reducing the prevalence of pressure ulcers among vulnerable intensive care patients and indicates that quality improvement is a highly effective formula for improving patients' outcomes that is easily implemented by using clinical expertise and existing resources.


A novel method for characterization of peripheral nerve fiber size distributions by group delay measurements and simulated annealing optimization.
The ability to determine the characteristics of peripheral nerve fiber size distributions would provide additional information to clinicians for the diagnosis of specific pathologies of the peripheral nervous system. Investigation of these conditions, using electro-diagnostic techniques, is advantageous in the sense that such techniques tend to be minimally invasive yet provide valuable diagnostic information. One of the principal electro-diagnostic tools available to the clinician is the nerve conduction velocity test. While the peripheral nerve conduction velocity test can provide useful information to the clinician regarding the viability of the nerve under study, it is a single parameter test that yields no detailed information about the characteristics of the functioning nerve fibers within the nerve trunk. In this study we present a technique based on a decomposition of the maximal compound evoked potential and subsequent determination of the group delay of the contributing nerve fibers. The fiber group delay is then utilized as an initial estimation of the nerve fiber size distribution and the concomitant temporal propagation delays of the associated single fiber evoked potentials to a reference electrode. Subsequently the estimated single fiber evoked potentials are optimized against the template maximal compound evoked potential using a simulated annealing algorithm. Simulation studies, based on deterministic single fiber action potential functions, are used to demonstrate the robustness of the proposed technique in the presence of noise associated with variations in distance between the nerve fibers and the recording electrodes between the two recording sites.


Fundamental Host Range of Leptoypha hospita (Hemiptera: Tingidae), a Potential Biological Control Agent of Chinese Privet.
Chinese privet, Ligustrum sinense Lour., is an invasive shrub within riparian areas of the southeastern United States. Biological control is considered the most suitable management option for Chinese privet. The potential host range of the lace bug, Leptoypha hospita Drake et Poor, was evaluated on the basis of adult feeding and oviposition, combined oviposition-nymphal development no-choice tests, nymphal development no-choice tests, multiple generation comparison on Forestiera pubescens Nutt. and L. sinense no-choice tests, and multiple-choice tests with 45 plant species in 13 families. No-choice tests showed that the host range of L. hospita was restricted to the tribe Oleeae. In adult feeding and oviposition no-choice tests, the bug fed and oviposited significantly more on Chinese privet than all other test plant species except for three native Forestiera spp., two nonnative Syringa spp., and another exotic Ligustrum sp. Among those, only F. pubescens supported complete development in numbers comparable to Chinese privet. However, when reared for multiple generations lace bugs reared on F. pubescens were smaller and had lower fecundity than those reared on L. sinense, suggesting F. pubescens is not an optimal host. In multiple-choice tests, L. hospita displayed a strong preference for feeding and ovipositing on Chinese privet over other test plant species, with the exception of the closely related nonnative Syringa spp. and its congenic species Ligustrum vulgare. The results of this study suggest that the risk to nontarget plant species in North America is minimal, and L. hospita would be a promising candidate for Chinese privet biological control.


Automatic design of fiber-reinforced soft actuators for trajectory matching.
Soft actuators are the components responsible for producing motion in soft robots. Although soft actuators have allowed for a variety of innovative applications, there is a need for design tools that can help to efficiently and systematically design actuators for particular functions. Mathematical modeling of soft actuators is an area that is still in its infancy but has the potential to provide quantitative insights into the response of the actuators. These insights can be used to guide actuator design, thus accelerating the design process. Here, we study fluid-powered fiber-reinforced actuators, because these have previously been shown to be capable of producing a wide range of motions. We present a design strategy that takes a kinematic trajectory as its input and uses analytical modeling based on nonlinear elasticity and optimization to identify the optimal design parameters for an actuator that will follow this trajectory upon pressurization. We experimentally verify our modeling approach, and finally we demonstrate how the strategy works, by designing actuators that replicate the motion of the index finger and thumb.


Electronic pill-boxes in the evaluation of oral hypoglycemic agent compliance.
To compare compliance in type 2 diabetic patients treated with glimepiride once daily or glibenclamide twice to three times daily. Poorly controlled type 2 diabetic patients aged 35-65 years were randomized to glimepiride 1 mg once daily or to glibenclamide 1.25 mg twice daily. During initial titration, doses ranged from 1 to 6 mg once daily (glimepiride) and from 1.25 mg twice daily to 5 mg 3 times daily (glibenclamide) to achieve fasting blood glucose < 126 mg/dL. The final titration phase doses were continued during the maintenance phase. Both treatments were packed in electronic pill-boxes fitted with a microprocessor to record dates and times of each opening. Compliance was assessed in terms of mean daily compliance (MDC) and the ratio of days with adequate compliance (DAC). Glycemic control was assessed in terms of the adjusted mean final HbA1c, and the incidence of hypoglycemia. Patient satisfaction was evaluated using the Diabetes Treatment Satisfaction Questionnaire. Compliance over the whole study was generally good, but the MDC was significantly better with glimepiride (87+/-16%) than with glibenclamide (80+/-17%;P < 0.0001). The ratios of DAC for glimepiride and glibenclamide were 87+/-16% and 67+/-24% respectively (P < 0.0001). The adjusted final HbA1c, and the incidence of hypoglycemia were similar in the two groups. Treatment satisfaction on the DTSQc was greater with glimepiride than with glibenclamide (P = 0.0034). Patient compliance and treatment satisfaction with once-daily glimepiride were significantly better than with glibenclamide 2 to 3 times daily.


Epigenetic: A missing paradigm in cellular and molecular pathways of sulfur mustard lung: a prospective and comparative study.
Sulfur mustard (SM, bis- (2-chloroethyl) sulphide) is a chemical warfare agent that causes DNA alkylation, protein modification and membrane damage. SM can trigger several molecular pathways involved in inflammation and oxidative stress, which cause cell necrosis and apoptosis, and loss of cells integrity and function. Epigenetic regulation of gene expression is a growing research topic and is addressed by DNA methylation, histone modification, chromatin remodeling, and noncoding RNAs expression. It seems SM can induce the epigenetic modifications that are translated into change in gene expression. Classification of epigenetic modifications long after exposure to SM would clarify its mechanism and paves a better strategy for the treatment of SM-affected patients. In this study, we review the key aberrant epigenetic modifications that have important roles in chronic obstructive pulmonary disease (COPD) and compared with mustard lung.


Effects of Cognitive Behavioral Therapy on Neural Processing of Agoraphobia-Specific Stimuli in Panic Disorder and Agoraphobia.
Patients suffering from panic disorder and agoraphobia are significantly impaired in daily life due to anxiety about getting into a situation due to apprehension about experiencing a panic attack, especially if escape may be difficult. Dysfunctional beliefs and behavior can be changed with cognitive behavioral therapy; however, the neurobiological effects of such an intervention on the anticipation and observation of agoraphobia-specific stimuli are unknown. We compared changes in neural activation by measuring the blood oxygen level-dependent signal of 51 patients and 51 healthy controls between scans before and those after treatment (group by time interaction) during anticipation and observation of agoraphobia-specific compared to neutral pictures using 3-T fMRI. A significant group by time interaction was observed in the ventral striatum during anticipation and in the right amygdala during observation of agoraphobia-specific pictures; the patients displayed a decrease in ventral striatal activation during anticipation from pre- to posttreatment scans, which correlated with clinical improvement measured with the Mobility Inventory. During observation, the patients displayed decreased activation in the amygdala. These activational changes were not observed in the matched healthy controls. For the first time, neural effects of cognitive behavioral therapy were shown in patients suffering from panic disorder and agoraphobia using disorder-specific stimuli. The decrease in activation in the ventral striatum indicates that cognitive behavioral therapy modifies anticipatory anxiety and may ameliorate abnormally heightened salience attribution to expected threatening stimuli. The decreased amygdala activation in response to agoraphobia-specific stimuli indicates that cognitive behavioral therapy can alter the basal processing of agoraphobia-specific stimuli in a core region of the fear network.


Etching rate enhancement by shaped femtosecond pulse train electron dynamics control for microchannels fabrication in fused silica glass.
The dependence of the etching rate on the ultrafast pulse shaping is observed when microchannels are fabricated in fused silica glass using the method of femtosecond laser irradiation followed by chemical etching. In comparison with the conventional femtosecond pulses, the temporally shaped pulse trains can greatly enhance the etching rate under the same processing conditions. The enhancement is mainly attributed to the localized transient electron dynamics control by shaping the ultrafast pulse, resulting in higher photon absorption efficiency and uniform photomodification zone. Furthermore, processing parameters, including pulse delay and pulse energy distribution ratio, have also been investigated to optimize microchannels fabrication.


c-erbB-2 expression in different histological types of invasive breast carcinoma.
Sections of 149 breast carcinomas were examined for the over-expression of c-erbB-2 oncoprotein using the avidin-biotin immunoperoxidase technique and two different specific antibodies. These included the polyclonal antibody 21N and the monoclonal antibody 4D5. The tumours were divided into two main groups. The first included 75 cases of invasive ductal and classic invasive lobular carcinomas. The second group consisted of 74 cases with histological types known to have a good prognosis, including mucinous, alveolar variant of invasive lobular, medullary, tubular, cribriform and papillary carcinomas. Fifteen (20%) tumours of the first group were positive with the two antibodies. Fourteen of these were of the ductal type and one was a mixed invasive ductal and lobular carcinoma. Ten of the pure ductal cases had areas of comedo carcinoma. The intraductal elements in a further tumour were positively stained with 21N antibody only. None of the second group of tumours, which included histological types known to have good prognosis, stained with 4D5, although one mucinous carcinoma was positively stained with 21N. These findings suggest that in invasive breast carcinoma immunostaining for c-erbB-2 is mainly seen in a subgroup of ductal tumours, and that almost all other histological types, especially those associated with good prognosis, lack this expression.


Alternative seed-handling strategies in primates: seed-spitting by long-tailed macaques (Macaca fascicularis).
The seeds in fruits consumed by primates may be chewed and digested, swallowed and defecated intact, or separated from the flesh and spat out. We show by a combination of close field observations and experiments with caged animals, that long-tailed macaques (Macaca fascicularis) have a remarkably low threshold of 3-4 mm for swallowing seeds and also that wild macaques rarely break them. The seeds of 69% of the ripe fruit species eaten are spat out intact or cleaned outside the mouth and dropped. Seed-spitting significantly reduces the swallowed food bulk and may lessen the risk of releasing seed toxins during mastication. However, it requires that even small fruits are processed in the mouth one or a few at a time. We suggest that fruit storage in the cheek pouches of cercopithecine monkeys allows them to spit seeds individually without excessively slowing fruit intake while feeding on patchily distributed fruit. In contrast, Apes and New World monkeys apparently swallow and defecate most ripe seeds in their diet and colobine monkeys break and digest them, detoxifying seed defenses by bacterial fermentation.


Comparison of clinical and angiographic prognostic risk scores in patients with acute coronary syndromes: Analysis from the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial.
Several prognostic risk scores have been developed for patients with coronary artery disease, but their comparative use in patients with non-ST-segment elevation acute coronary syndromes (NSTEACS) undergoing percutaneous coronary intervention (PCI) has not been examined. We therefore investigated the accuracy of the Synergy Between PCI With Taxus and Cardiac Surgery (SYNTAX) score, Clinical Synergy Between PCI With Taxus and Cardiac Surgery score (CSS), New Risk Stratification (NERS) score (NERS), Age, Creatinine, Ejection Fraction (ACEF) score, Global Registry for Acute Coronary Events (GRACE) score, and Thrombolysis in Myocardial Infarction (TIMI) score for risk assessment of 1-year mortality, cardiac mortality, myocardial infarction, target vessel revascularization, and stent thrombosis in patients with NSTEACS undergoing PCI. The 6 scores were determined in 2,094 patients with NSTEACS treated with PCI enrolled in the angiographic substudy of the ACUITY trial. The prognostic accuracy of the 6 scores was assessed using the c statistic for discrimination and the Hosmer-Lemeshow test for calibration. The index of separation and net reclassification improvement (NRI) were also determined. Scores incorporating clinical and angiographic variables (CSS and NERS) showed the best tradeoff between discrimination and calibration for most end points, with the best discrimination for all end points and good calibration for most of them. The CSS had the best index of separation for most ischemic endpoints and displayed an NRI for cardiac death and myocardial infarction (MI) compared to the other scores, whereas NERS displayed an NRI for all-cause death and target vessel revascularization. The 3 scores-CSS, NERS, and SYNTAX-were the only scores to have both good discrimination and calibration for cardiac mortality. In patients with NSTEACS undergoing PCI, risk scores incorporating clinical and angiographic variables had the highest predictive accuracy for a broad spectrum of ischemic end points.


Characteristics of Ocular Findings of Patients With Coronavirus Disease 2019 (COVID-19) in Hubei Province, China.
While the outbreak of coronavirus disease 2019 (COVID-19) has resulted in more than 100 000 infected individuals in China and worldwide, there are few reports on the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with ocular abnormalities. Understanding ocular manifestations of patients with COVID-19 by ophthalmologists and others may facilitate the diagnosis and prevention of transmission of the disease. To investigate ocular manifestations and viral prevalence in the conjunctiva of patients with COVID-19. In this case series, patients with COVID-19 treated from February 9 to 15, 2020, at a hospital center in Hubei province, China, were retrospectively reviewed for ocular manifestations. During the period of treatment, the ocular signs and symptoms as well as results of blood tests and reverse transcriptase-polymerase chain reaction (RT-PCR) from nasopharyngeal and conjunctival swabs for SARS-CoV-2 were noted and analyzed. Ocular signs and symptoms as well as results of blood tests and RT-PCR for SARS-CoV-2. Of the 38 included patients with clinically confirmed COVID-19, 25 (65.8%) were male, and the mean (SD) age was 65.8 (16.6) years. Among them, 28 patients (73.7%) had positive findings for COVID-19 on RT-PCR from nasopharyngeal swabs, and of these, 2 patients (5.2%) yielded positive findings for SARS-CoV-2 in their conjunctival as well as nasopharyngeal specimens. A total of 12 of 38 patients (31.6%; 95% CI, 17.5-48.7) had ocular manifestations consistent with conjunctivitis, including conjunctival hyperemia, chemosis, epiphora, or increased secretions. By univariate analysis, patients with ocular symptoms were more likely to have higher white blood cell and neutrophil counts and higher levels of procalcitonin, C-reactive protein, and lactate dehydrogenase than patients without ocular symptoms. In addition, 11 of 12 patients with ocular abnormalities (91.7%; 95% CI, 61.5-99.8) had positive results for SARS-CoV-2 on RT-PCR from nasopharyngeal swabs. Of these, 2 (16.7%) had positive results for SARS-CoV-2 on RT-PCR from both conjunctival and nasopharyngeal swabs. In this study, one-third of patients with COVID-19 had ocular abnormalities, which frequently occurred in patients with more severe COVID-19. Although there is a low prevalence of SARS-CoV-2 in tears, it is possible to transmit via the eyes.


Epigenetics in Sepsis: Understanding Its Role in Endothelial Dysfunction, Immunosuppression, and Potential Therapeutics.
Sepsis has a complex pathophysiology in which both excessive and refractory inflammatory responses are hallmark features. Pro-inflammatory cytokine responses during the early stages are responsible for significant endothelial dysfunction, loss of endothelial integrity, and organ failure. In addition, it is now well-established that a substantial number of sepsis survivors experience ongoing immunological derangement and immunosuppression following a septic episode. The underpinning mechanisms of these phenomena are incompletely understood yet they contribute to a significant proportion of sepsis-associated mortality. Epigenetic mechanisms including DNA methylation, histone modifications, and non-coding RNAs, have an increasingly clear role in modulating inflammatory and other immunological processes. Recent evidence suggests epigenetic mechanisms are extensively perturbed as sepsis progresses, and particularly play a role in endothelial dysfunction and immunosuppression. Whilst therapeutic modulation of the epigenome is still in its infancy, there is substantial evidence from animal models that this approach could reap benefits. In this review, we summarize research elucidating the role of these mechanisms in several aspects of sepsis pathophysiology including tissue injury and immunosuppression. We also evaluate pre-clinical evidence for the use of "epi-therapies" in the treatment of poly-microbial sepsis.


Healthcare maintenance in elderly patients with inflammatory bowel disease.
The increasing number of older patients (age ≥60 years) with inflammatory bowel disease (IBD) highlights the importance of healthcare maintenance in this vulnerable population. Older IBD patients are more susceptible and have higher rates of many disease- and treatment-related adverse effects. Compared to younger IBD patients, older patients are at increased risk for infection, malignancy, bone disease, eye disease, malnutrition and thrombotic complications. Preventive strategies in the elderly differ from those in younger adults and are imperative. Changes to the immune system with aging can decrease the efficacy of vaccinations. Cancer screening guidelines in older IBD patients have to account for unique considerations, such as life expectancy, functional performance status, multimorbidity, financial status, and patient desires. Additionally, providers need to be vigilant in screening for osteoporosis, ocular disease, depression, and adverse events arising from polypharmacy.


Retreat and extinction of the Late Pleistocene cave bear (Ursus spelaeus sensu lato).
The cave bear (Ursus spelaeus sensu lato) is a typical representative of Pleistocene megafauna which became extinct at the end of the Last Glacial. Detailed knowledge of cave bear extinction could explain this spectacular ecological transformation. The paper provides a report on the youngest remains of the cave bear dated to 20,930 ± 140 14C years before present (BP). Ancient DNA analyses proved its affiliation to the Ursus ingressus haplotype. Using this record and 205 other dates, we determined, following eight approaches, the extinction time of this mammal at 26,100-24,300 cal. years BP. The time is only slightly earlier, i.e. 27,000-26,100 cal. years BP, when young dates without associated collagen data are excluded. The demise of cave bear falls within the coldest phase of the last glacial period, Greenland Stadial 3. This finding and the significant decrease in the cave bear records with cooling indicate that the drastic climatic changes were responsible for its extinction. Climate deterioration lowered vegetation productivity, on which the cave bear strongly depended as a strict herbivore. The distribution of the last cave bear records in Europe suggests that this animal was vanishing by fragmentation into subpopulations occupying small habitats. One of them was the Kraków-Częstochowa Upland in Poland, where we discovered the latest record of the cave bear and also two other, younger than 25,000 14C years BP. The relatively long survival of this bear in karst regions may result from suitable microclimate and continuous access to water provided by deep aquifers, indicating a refugial role of such regions in the Pleistocene for many species.


Constructing authentic decisions: proxy decision making for research involving adults who lack capacity to consent.
Research involving adults who lack capacity to consent relies on proxy (or surrogate) decision making. Proxy decisions about participation are ethically complex, with a disparity between normative accounts and empirical evidence. Concerns about the accuracy of proxies' decisions arise, in part, from the lack of an ethical framework which takes account of the complex and morally pluralistic world in which proxy decisions are situated. This qualitative study explored the experiences of family members who have acted as a research proxy in order to develop an understanding of the ethical concepts involved, and the interactions between those concepts. Proxies described a complex process of respecting the wishes and preferences of the person they represented, whist integrating preferences with what they viewed as being in the interests of the person. They aimed to make a decision that was 'best' for the person and protected them from harm; they also aimed to make the 'right' decision, viewed as being authentic to the person's values and life. Decisions were underpinned by the relationship between the person and their proxy, in which both trust and trustworthiness were key. Proxies' decisions, based both on respect for the person and the need to protect their interests, arose out of their dual role as both proxy and carer. The findings raise questions about accounts which rely on existing normative assumptions with a focus on accuracy and discrepancy, and which fail to take account of the requirement for proxies to make authentic decisions that arise out of their caring obligations.


Persistent export of 231Pa from the deep central Arctic Ocean over the past 35,000 years.
The Arctic Ocean has an important role in Earth's climate, both through surface processes such as sea-ice formation and transport, and through the production and export of waters at depth that contribute to the global thermohaline circulation. Deciphering the deep Arctic Ocean's palaeo-oceanographic history is a crucial part of understanding its role in climatic change. Here we show that sedimentary ratios of the radionuclides thorium-230 ((230)Th) and protactinium-231 ((231)Pa), which are produced in sea water and removed by particle scavenging on timescales of decades to centuries, respectively, record consistent evidence for the export of (231)Pa from the deep Arctic and may indicate continuous deep-water exchange between the Arctic and Atlantic oceans throughout the past 35,000 years. Seven well-dated box-core records provide a comprehensive overview of (231)Pa and (230)Th burial in Arctic sediments during glacial, deglacial and interglacial conditions. Sedimentary (231)Pa/(230)Th ratios decrease nearly linearly with increasing water depth above the core sites, indicating efficient particle scavenging in the upper water column and greater influence of removal by lateral transport at depth. Although the measured (230)Th burial is in balance with its production in Arctic sea water, integrated depth profiles for all time intervals reveal a deficit in (231)Pa burial that can be balanced only by lateral export in the water column. Because no enhanced sink for (231)Pa has yet been found in the Arctic, our records suggest that deep-water exchange through the Fram strait may export (231)Pa. Such export may have continued for the past 35,000 years, suggesting a century-scale replacement time for deep waters in the Arctic Ocean since the most recent glaciation and a persistent contribution of Arctic waters to the global ocean circulation.


Household Tenure and Its Associations with Multiple Long-Term Conditions amongst Working-Age Adults in East London: A Cross-Sectional Analysis Using Linked Primary Care and Local Government Records.
Multiple long-term conditions (MLTCs) are influenced in extent and nature by social determinants of health. Few studies have explored associations between household tenure and different definitions of MLTCs. This study aimed to examine associations between household tenure and MLTCs amongst working-age adults (16 to 64 years old, inclusive). This cross-sectional study used the 2019−2020 wave of an innovative dataset that links administrative data across health and local government for residents of a deprived borough in East London. Three definitions of MLTCs were operationalised based on a list of 38 conditions. Multilevel logistic regression models were built for each outcome and adjusted for a range of health and sociodemographic factors. Compared to working-age owner-occupiers, odds of basic MLTCs were 36% higher for social housing tenants and 19% lower for private renters (OR 1.36; 95% CI 1.30−1.42; p < 0.001 and OR 0.81, 95% CI 0.77−0.84, p < 0.001, respectively). Results were consistent across different definitions of MLTCs, although associations were stronger for social housing tenants with physical-mental MLTCs. This study finds strong evidence that household tenure is associated with MLTCs, emphasising the importance of understanding household-level determinants of health. Resources to prevent and tackle MLTCs among working-age adults could be differentially targeted by tenure type.


An Introduction to DLforum - An online discussion forum for data linkage researchers and practitioners https://dmm.anu.edu.au/DLforum/.
Data linkage, the process of identifying records that refer to the same entities across databases, is a crucial component of Population Data Science. Data linkage has a history going back over fifty years with many different methods and techniques being developed in various disciplines including computer science, statistics, and health informatics. Data linkage researchers and practitioners are commonly only familiar with methods and techniques that have been developed or are used in their own discipline, and they often only follow research that is being published at venues in their own discipline. There is currently no single online resource that allows data linkage researchers and practitioners across different disciplines to exchange ideas, post questions, or advertise new publications, software, open positions, or upcoming conferences and workshops. This leads to a communication gap in the multi-disciplinary field of data linkage. We aim to address this gap with the DLforum, a public online discussion forum for data linkage. DLforum contains several discussion areas, including publication announcements, resources (software and datasets), information about upcoming conferences and workshops, job opportunities, and general questions related to data linkage. The forum includes a moderation process where all registered users can post content and reply to posts by other users. We anticipate that the number of users registered and the amount of content posted in the forum will show that such an online forum is of value to data linkage researchers and practitioners from different disciplines to effectively communicate and exchange their knowledge, and thus form an online community of practice. In this paper we describe the methods of developing the DLforum, its structure and content, and our plan on how to evaluate the forum. The DLforum is freely available at: https://dmm.anu.edu.au/DLforum/.


Diurnal fluctuations in seawater pH influence the response of a calcifying macroalga to ocean acidification.
Coastal ecosystems that are characterized by kelp forests encounter daily pH fluctuations, driven by photosynthesis and respiration, which are larger than pH changes owing to ocean acidification (OA) projected for surface ocean waters by 2100. We investigated whether mimicry of biologically mediated diurnal shifts in pH-based for the first time on pH time-series measurements within a kelp forest-would offset or amplify the negative effects of OA on calcifiers. In a 40-day laboratory experiment, the calcifying coralline macroalga, Arthrocardia corymbosa, was exposed to two mean pH treatments (8.05 or 7.65). For each mean, two experimental pH manipulations were applied. In one treatment, pH was held constant. In the second treatment, pH was manipulated around the mean (as a step-function), 0.4 pH units higher during daylight and 0.4 units lower during darkness to approximate diurnal fluctuations in a kelp forest. In all cases, growth rates were lower at a reduced mean pH, and fluctuations in pH acted additively to further reduce growth. Photosynthesis, recruitment and elemental composition did not change with pH, but δ(13)C increased at lower mean pH. Including environmental heterogeneity in experimental design will assist with a more accurate assessment of the responses of calcifiers to OA.


Reinforcement Learning Trees.
In this paper, we introduce a new type of tree-based method, reinforcement learning trees (RLT), which exhibits significantly improved performance over traditional methods such as random forests (Breiman, 2001) under high-dimensional settings. The innovations are three-fold. First, the new method implements reinforcement learning at each selection of a splitting variable during the tree construction processes. By splitting on the variable that brings the greatest future improvement in later splits, rather than choosing the one with largest marginal effect from the immediate split, the constructed tree utilizes the available samples in a more efficient way. Moreover, such an approach enables linear combination cuts at little extra computational cost. Second, we propose a variable muting procedure that progressively eliminates noise variables during the construction of each individual tree. The muting procedure also takes advantage of reinforcement learning and prevents noise variables from being considered in the search for splitting rules, so that towards terminal nodes, where the sample size is small, the splitting rules are still constructed from only strong variables. Last, we investigate asymptotic properties of the proposed method under basic assumptions and discuss rationale in general settings.