Topical and oral steroids for otitis media with effusion (OME) in children.
Otitis media with effusion (OME) is an accumulation of fluid in the middle ear cavity, common amongst young children. The fluid may cause hearing loss. Although most episodes of OME in children resolve spontaneously within a few months, when persistent it may lead to behavioural problems and a delay in expressive language skills. Management of OME includes watchful waiting, medical, surgical and other treatments, such as autoinflation. Oral or topical steroids are sometimes used to reduce inflammation in the middle ear. To assess the effects (benefits and harms) of topical and oral steroids for OME in children. We searched the Cochrane ENT Register, CENTRAL, Ovid MEDLINE, Ovid Embase, Web of Science, ClinicalTrials.gov, ICTRP and additional sources for published and unpublished studies on 20 January 2023. We included randomised controlled trials (RCTs) and quasi-randomised trials in children aged 6 months to 12 years with unilateral or bilateral OME. We included studies that compared topical or oral steroids with either placebo or watchful waiting (no treatment). We used standard Cochrane methods. Our primary outcomes, determined by a multi-stakeholder prioritisation exercise, were: 1) hearing, 2) OME-specific quality of life and 3) systemic corticosteroid side effects. Secondary outcomes were: 1) presence/persistence of OME, 2) other adverse effects (including local nasal effects), 3) receptive language skills, 4) speech development, 5) cognitive development, 6) psychosocial outcomes, 7) listening skills, 8) generic health-related quality of life, 9) parental stress, 10) vestibular function and 11) episodes of acute otitis media. We used GRADE to assess the certainty of evidence. Although we included all measures of hearing assessment, the proportion of children who returned to normal hearing was our preferred method to assess hearing, due to challenges in interpreting the results of mean hearing thresholds. We included 26 studies in this review (2770 children). Most studies of oral steroids used prednisolone for 7 to 14 days. Studies of topical (nasal) steroids used various preparations (beclomethasone, fluticasone and mometasone) for between two weeks and three months. All studies had at least some concerns regarding risk of bias. Here we report our primary outcomes and main secondary outcome, at the longest reported follow-up. Oral steroids compared to placebo Oral steroids probably result in little or no difference in the proportion of children with normal hearing after 12 months (69.7% of children with steroids, compared to 61.1% of children receiving placebo, risk ratio (RR) 1.14, 95% confidence interval (CI) 0.97 to 1.33; 1 study, 332 participants; moderate-certainty evidence). There is probably little or no difference in OME-related quality of life (mean difference (MD) in OM8-30 score 0.07, 95% CI -0.2 to 0.34; 1 study, 304 participants; moderate-certainty evidence). Oral steroids may reduce the number of children with persistent OME at 6 to 12 months, but the size of the effect was uncertain (absolute risk reduction ranging from 13.3% to 45%, number needed to treat (NNT) of between 3 and 8; low-certainty evidence). The evidence was very uncertain regarding the risk of systemic corticosteroid side effects, and we were unable to conduct any meta-analysis for this outcome. Oral steroids compared to no treatment Oral steroids may result in little or no difference in the persistence of OME after three to nine months (74.5% children receiving steroids versus 73% of those receiving placebo; RR 1.02, 95% CI 0.89 to 1.17; 2 studies, 258 participants; low-certainty evidence). The evidence on adverse effects was very uncertain. We did not identify any evidence on hearing or disease-related quality of life. Topical (intranasal) steroids compared to placebo We did not identify data on the proportion of children who returned to normal hearing. However, the mean change in hearing threshold after two months was -0.3 dB lower (95% CI -6.05 to 5.45; 1 study, 78 participants; very low-certainty evidence). The evidence suggests that nasal steroids make little or no difference to disease-specific quality of life after nine months (OM8-30 score, MD 0.05 higher, 95% CI -0.36 to 0.46; 1 study, 82 participants; low-certainty evidence). The evidence is very uncertain regarding the effect of nasal steroids on persistence of OME at up to one year. Two studies reported this: one showed a potential benefit for nasal steroids, the other showed a benefit with placebo (2 studies, 206 participants). The evidence was also very uncertain regarding the risk of corticosteroid-related side effects, as we were unable to provide a pooled effect estimate. Topical (intranasal) steroids compared to no treatment We did not identify data on the proportion of children who returned to normal hearing. However, the mean difference in final hearing threshold after four weeks was 1.95 dB lower (95% CI -3.85 to -0.05; 1 study, 168 participants; low-certainty evidence). Nasal steroids may reduce the persistence of OME after eight weeks, but the evidence was very uncertain (58.5% of children receiving steroids, compared to 81.3% of children without treatment, RR 0.72, 95% CI 0.57 to 0.91; 2 studies, 134 participants). We did not identify any evidence on disease-related quality of life or adverse effects. Overall, oral steroids may have little effect in the treatment of OME, with little improvement in the number of children with normal hearing and no effect on quality of life. There may be a reduction in the proportion of children with persistent disease after 12 months. However, this benefit may be small and must be weighed against the potential for adverse effects associated with oral steroid use. The evidence for nasal steroids was all low- or very low-certainty. It is therefore less clear if nasal steroids have any impact on hearing, quality of life or persistence of OME. Evidence on adverse effects was very limited. OME is likely to resolve spontaneously for most children. The potential benefit of treatment may therefore be small and should be balanced with the risk of adverse effects. Future studies should aim to determine which children are most likely to benefit from treatment, rather than offering interventions to all children.


D2 dopaminergic receptors: normal and abnormal transduction mechanisms.
Dopamine receptors of D2 type present on lactotroph cells are coupled to a large series of transduction mechanisms. Beside their negative coupling with adenylate cyclase, they are also coupled with potassium and calcium channels, leading to a decreased intracellular calcium concentration. In addition, D2 dopamine receptors also modulate phospholipase activities. Dopamine inhibits inositol phosphate production, through two distinct mechanisms. One of them could represent a direct negative coupling with phospholipase C. All these transduction mechanisms of the D2 dopamine receptors implicate G proteins sensitive to pertussis toxin. In contrast, these receptors are negatively coupled to phospholipase A2 through G proteins insensitive to this toxin. Both isoforms of the D2 dopamine receptor, generated by alternate splicing of a single gene, are present in lactotroph cells. After transfection in CH4C1 cells the two isoforms are coupled with adenylate cyclase while only the shortest isoform appears negatively coupled to phospholipase C. Functional D2 dopamine receptors are present in human prolactinomas. Resistance to bromocriptine therapy is associated with a decreased density of these receptors in the tumor. In addition, the ratio of the two receptor isoforms (measured by PCR) is different in responsive and resistant tumors. Furthermore, the activity of Gi/Go proteins coupled to adenylate cyclase appears also affected in resistant tumors. Resistance to bromocriptine therapy appears thus to involve multiple changes at the different levels of the multiple mechanisms of action of dopamine on lactotroph cells.


Chronic low back pain among French healthcare workers and prognostic factors of return to work (RTW): a non-randomized controlled trial.
Many factors influence the return to work of workers with chronic low back pain (CLBP). They have been said to vary according to socio-professional group. This study first aimed to compare prognostic factors influencing the return to work of CLBP healthcare workers (HCWs) and other workers (non-HCWs) after rehabilitation coupled with an occupational intervention. The second objective was to improve the evolution of indicators such as clinical examination, psychosocial impact and pain impact. Between 2007 and 2012, a cohort of 217 CLBP workers (54.8 %-women; mean age = 41.3 ± 9.5 years, 118 non-HCWs; 99 HCWs mainly from the public sector) was included in an ambulatory rehabilitation program (standard physiotherapy or intensive network physiotherapy) coupled with an occupational intervention. Workers completed a questionnaire and had a clinical examination at baseline and after 24 months' follow up. Physical, social and occupational data was collected at the same time. Statistical analyses were performed to evaluate prognostic factors for return to work and compare the two worker populations. There was no difference between groups for the rate of OP (occupational physician) intervention or type of physiotherapy. 77.3 % of workers returned to work after 2 years following inclusion. To be an HCW (OR 0.1; 95 % CI [0.03-0.34]), to have less than 112 sick- leave days (OR 1.00; 95 % CI [0.93-1.00]), a small fingertip-floor distance (OR 0.96; 95 % CI [0.93-0.99]), a low anxiety/depression score (OR 0.97; 95 % CI [0.95-1.00]), a low impact of CLBP on daily life (OR 0.96; 95 % CI [0.93-1.00]), and on quality of life (OR 0.98; 95 % CI [0.95-1.00]) at baseline were statistically associated with return to work after 2 years of follow up. Only the profession (workplace) was statistically associated with return to work after 2 years of follow up using multivariate analysis. To our knowledge, this is the first cohort study concerning predictive factors of RTW among CLBP workers after 2 years of follow up. Interventions in the work environment did not seem to predict job retention significantly. But only 50 % of the employees in both groups (HCW and non-HCW) had one intervention at their workplace after 2 years. This study underlined the fact that the type of physiotherapy with a well-trained physiotherapist used to take care of CLBP could not impact on the RTW forecast. To develop these initial results, it might be interesting to study the comparison between private and public sectors and to randomize the physiotherapeutic intervention.


Gibberellin deficiency and response mutations suppress the stem elongation phenotype of phytochrome-deficient mutants of Arabidopsis.
Plant growth and development are regulated by numerous internal and external factors. Among these, gibberellin (GA) (an endogenous plant growth regulator) and phytochrome (a photoreceptor) often influence the same processes. For example, in plants grown in the light Arabidopsis thaliana hypocotyl elongation is reduced by GA deficiency and increased by phytochrome deficiency. Here we describe experiments in which the phenotypes of Arabidopsis plants doubly homozygous for GA-related and phytochrome-related mutations were examined. The double mutants were studied at various stages in the plant life cycle, including the seed germination, young seedling, adult, and reproductive phases of development. The results of these experiments are complex, but indicate that a fully functional GA system is necessary for full expression of the elongated phenotypes conferred by phytochrome deficiency.


Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative.
This study investigates whether the incidence of new-onset diabetes mellitus (DM) is associated with statin use among postmenopausal women participating in the Women's Health Initiative (WHI). The WHI recruited 161,808 postmenopausal women aged 50 to 79 years at 40 clinical centers across the United States from 1993 to 1998 with ongoing follow-up. The current analysis includes data through 2005. Statin use was captured at enrollment and year 3. Incident DM status was determined annually from enrollment. Cox proportional hazards models were used to estimate the risk of DM by statin use, with adjustments for propensity score and other potential confounding factors. Subgroup analyses by race/ethnicity, obesity status, and age group were conducted to uncover effect modification. This investigation included 153,840 women without DM and no missing data at baseline. At baseline, 7.04% reported taking statin medication. There were 10,242 incident cases of self-reported DM over 1,004,466 person-years of follow-up. Statin use at baseline was associated with an increased risk of DM (hazard ratio [HR], 1.71; 95% CI, 1.61-1.83). This association remained after adjusting for other potential confounders (multivariate-adjusted HR, 1.48; 95% CI, 1.38-1.59) and was observed for all types of statin medications. Subset analyses evaluating the association of self-reported DM with longitudinal measures of statin use in 125,575 women confirmed these findings. Statin medication use in postmenopausal women is associated with an increased risk for DM. This may be a medication class effect. Further study by statin type and dose may reveal varying risk levels for new-onset DM in this population.


Pharmacologic Inhibition of FGFR Modulates the Metastatic Immune Microenvironment and Promotes Response to Immune Checkpoint Blockade.
The effectiveness of immunotherapy as a treatment for metastatic breast cancer is limited due to low numbers of infiltrating lymphocytes in metastatic lesions. Herein, we demonstrated that adjuvant therapy using FIIN4, a covalent inhibitor of fibroblast growth factor receptor (FGFR), dramatically delayed the growth of pulmonary metastases in syngeneic models of metastatic breast cancer. In addition, we demonstrated in a syngeneic model of systemic tumor dormancy that targeting of FGFR enhanced the immunogenicity of the pulmonary tumor microenvironment through increased infiltration of CD8+ lymphocytes and reduced presence of myeloid suppressor cells. Similar impacts on immune cell infiltration were observed upon genetic depletion of FGFR1 in tumor cells, which suggested a direct influence of FGFR signaling on lymphocyte trafficking. Suppression of CD8+ lymphocyte infiltration was consistent with FGFR-mediated inhibition of the T-cell chemoattractant CXCL16. Initial attempts to concomitantly administer FIIN4 with immune checkpoint blockade failed due to inhibition of immune-mediated tumor cell killing via blockade of T-cell receptor signaling by FIIN4. However, this was overcome by using a sequential dosing protocol that consisted of FIIN4 treatment followed by anti-PD-L1. These data illustrate the complexities of combining kinase inhibitors with immunotherapy and provide support for further assessment of FGFR targeting as an approach to enhance antitumor immunity and improve immunotherapy response rates in patients with metastatic breast cancer.


Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis.
The pathways that distinguish transport of folded and misfolded cargo through the exocytic (secretory) pathway of eukaryotic cells remain unknown. Using proteomics to assess global cystic fibrosis (CF) transmembrane conductance regulator (CFTR) protein interactions (the CFTR interactome), we show that Hsp90 cochaperones modulate Hsp90-dependent stability of CFTR protein folding in the endoplasmic reticulum (ER). Cell-surface rescue of the most common disease variant that is restricted to the ER, DeltaF508, can be initiated by partial siRNA silencing of the Hsp90 cochaperone ATPase regulator Aha1. We propose that failure of DeltaF508 to achieve an energetically favorable fold in response to the steady-state dynamics of the chaperone folding environment (the "chaperome") is responsible for the pathophysiology of CF. The activity of cargo-associated chaperome components may be a common mechanism regulating folding for ER exit, providing a general framework for correction of misfolding disease.


Methylation of histone H3 lysine-79 by Dot1p plays multiple roles in the response to UV damage in Saccharomyces cerevisiae.
Various proteins have been found to play roles in both the repair of UV damaged DNA and heterochromatin-mediated silencing in the yeast Saccharomyces cerevisiae. In particular, factors that are involved in the methylation of lysine-79 of histone H3 by Dot1p have been implicated in both processes, suggesting a bipartite function for this modification. We find that a dot1 null mutation and a histone H3 point mutation at lysine-79 cause increased sensitivity to UV radiation, suggesting that lysine-79 methylation is important for efficient repair of UV damage. Epistasis analysis between dot1 and various UV repair genes indicates that lysine-79 methylation plays overlapping roles within the nucleotide excision, post-replication and recombination repair pathways, as well as RAD9-mediated checkpoint function. In contrast, epistasis analysis with the H3 lysine-79 point mutation indicates that the lysine-to-glutamic acid substitution exerts specific effects within the nucleotide excision repair and post-replication repair pathways, suggesting that this allele only disrupts a subset of the functions of lysine-79 methylation. The overall results indicate the existence of distinct and separable roles of histone H3 lysine-79 methylation in the response to UV damage, potentially serving to coordinate the various repair processes.


Framework for understanding health inequalities over the life course: the embodiment dynamic and biological mechanisms of exogenous and endogenous origin.
Understanding how structural, social and psychosocial factors come to affect our health resulting in health inequalities is more relevant now than ever as trends in mortality gaps between rich and poor appear to have widened over the past decades. To move beyond description, we need to hypothesise about how structural and social factors may cause health outcomes. In this paper, we examine the construction of health over the life course through the lens of influential theoretical work. Based on concepts developed by scholars from different disciplines, we propose a novel framework for research on social-to-biological processes which may be important contributors to health inequalities. We define two broad sets of mechanisms that may help understand how socially structured exposures become embodied: mechanisms of exogenous and endogenous origin. We describe the embodiment dynamic framework, its uses and how it may be combined with an intersectional approach to examine how intermeshed oppressions affect social exposures which may be expressed biologically. We explain the usefulness of this framework as a tool for carrying out research and providing scientific evidence to challenge genetic essentialism, often used to dismiss social inequalities in health.


Reactions of GPs to a triage-controlled referral system for cancer genetics.
The demand for genetic services is increasing as public awareness about 'predictive' tests increases and commercial marketing initiatives develop. In the UK, genetic services vary widely between regions. To manage demand, an all-Wales cancer genetics service based on telephone triage and referral guidelines was designed and implemented. The aim of this study was to examine the reactions of GPs to a cancer genetics service controlled by referral guidelines and a triage system, and the perceived impact genetics will have on general practice. We conducted a structured qualitative study in primary care using sequential focus group discussions with 14 GPs, representing 12 practices divided into two groups (service providers and educationalists). The doctors were introduced to the 'new' genetics, briefed about the service and the referral guidelines and given an outline of the topics to be discussed. All discussions were recorded, transcribed and analysed. The GPs in this study had not considered how they and their teams would handle the practical implications of the 'new' genetics. They had no major objections to a triage system as a means of regulating access to a scarce specialist service, but were concerned about two issues. First, that an insistence on the completion of a postal questionnaire as a means of obtaining an initial assessment could disadvantage some individuals and, secondly, that it was not clear to either the GP or the patient that the risk assessment would be undertaken by a telephone interview. Although there was some concern about yet another set of referral guidelines, participants accepted that the potential demand for cancer genetics services had to be regulated. The acceptance by GPs of this triage system represented a reluctant acknowledgement that primary care, in its present organizational form, cannot provide high quality genetic counselling. However, the realization that this represented a relinquishment of the normal generalist role led to the emergence of ambivalence and a wish to consider how best to accommodate this new need in primary care.


Superoxide dismutase SodB is a protective antigen against Campylobacter jejuni colonisation in chickens.
Campylobacter is the leading cause of foodborne diarrhoeal illness in the developed world and consumption or handling of contaminated poultry meat is the principal source of infection. Strategies to control Campylobacter in broilers prior to slaughter are urgently required and are predicted to limit the incidence of human campylobacteriosis. Towards this aim, a purified recombinant subunit vaccine based on the superoxide dismutase (SodB) protein of C. jejuni M1 was developed and tested in White Leghorn birds. Birds were vaccinated on the day of hatch and 14 days later with SodB fused to glutathione S-transferase (GST) or purified GST alone. Birds were challenged with C. jejuni M1 at 28 days of age and caecal Campylobacter counts determined at weekly intervals. Across three independent trials, the vaccine induced a statistically significant 1 log10 reduction in caecal Campylobacter numbers in vaccinated birds compared to age-matched GST-vaccinated controls. Significant induction of antigen-specific serum IgY was detected in all vaccinated birds, however the magnitude and timing of SodB-specific IgY did not correlate with lower numbers of C. jejuni. Antibodies from SodB-vaccinated chickens detected the protein in the periplasm and not membrane fractions or on the bacterial surface, suggesting that the protection observed may not be strictly antibody-mediated. SodB may be useful as a constituent of vaccines for control of C. jejuni infection in broiler birds, however modest protection was observed late relative to the life of broiler birds and further studies are required to potentiate the magnitude and timing of protection.


Rationale, design and methods for the RIGHT Track Health Study: pathways from childhood self-regulation to cardiovascular risk in adolescence.
Cardiovascular risk factors during adolescence-including obesity, elevated lipids, altered glucose metabolism, hypertension, and elevated low-grade inflammation-is cause for serious concern and potentially impacts subsequent morbidity and mortality. Despite the importance of these cardiovascular risk factors, very little is known about their developmental origins in childhood. In addition, since adolescence is a time when individuals are navigating major life changes and gaining increasing autonomy from their parents or parental figures, it is a period when control over their own health behaviors (e.g. drug use, sleep, nutrition) also increases. The primary aim of this paper is to describe the rationale, design and methods for the RIGHT Track Health Study. This study examines self-regulation as a key factor in the development of cardiovascular risk, and further explores health behaviors as an explanatory mechanism of this association. We also examine potential moderators (e.g. psychosocial adversities such as harsh parenting) of this association. RIGHT Track is a longitudinal study that investigates social and emotional development. The RIGHT Track Health Study prospectively follows participants from age 2 through young adulthood in an effort to understand how self-regulatory behavior throughout childhood alters the trajectories of various cardiovascular risk factors during late adolescence via health behaviors. Individuals from RIGHT Track were re-contacted and invited to participate in adolescent data collection (~16.5, 17.5 and 18(+) years old). Individuals completed assessments of body composition, anthropometric indicators, fitness testing (via peak oxygen consumption), heart rate variability during orthostatic challenge, 7-day accelerometry for physical activity and sleep, 24-h dietary recalls, and blood analysis for biomarkers related to metabolic syndrome, inflammatory status and various hormones and cytokines. Individuals also completed extensive self-report measures on diet and eating regulation, physical activity and sedentary behaviors, sleep, substance use, medical history, medication use and a laboratory-day checklist, which chronicled previous day activities and menstrual information for female participants. Insights emerging from this analysis can help researchers and public health policy administrators target intervention efforts in early childhood, when preventing chronic disease is most cost-effective and behavior is more malleable.


Sexually dimorphic activation of dopaminergic areas depends on affiliation during courtship and pair formation.
For many species, dyadic interaction during courtship and pair bonding engage intense emotional states that control approach or avoidance behavior. Previous studies have shown that one component of a common social brain network (SBN), dopaminergic areas, are highly engaged during male songbird courtship of females. We tested whether the level of activity in dopaminergic systems of both females and males during courtship is related to their level of affiliation. In order to objectively quantify affiliative behaviors, we developed a system for tracking the position of both birds during free interaction sessions. During a third successive daily interaction session, there was a range of levels of affiliation among bird pairs, as quantified by several position and movement parameters. Because both positive and negative social interactions were present, we chose to characterize affiliation strength by pair valence. As a potential neural system involved in regulating pair valence, the level of activity of the dopaminergic group A11 (within the central gray) was selectively reduced in females of positive valence pairs. Further, activation of non-dopaminergic neurons in VTA was negatively related to valence, with this relationship strongest in ventral VTA of females. Together, these results suggest that inhibition of fear or avoidance networks may be associated with development of close affiliation, and highlight the importance of negative as well as positive emotional states in the process of courtship, and in development of long-lasting social bonds.


Adopting and implementing nutrition guidelines in recreational facilities: public and private sector roles. A multiple case study.
Recreational facilities are an important community resource for health promotion because they provide access to affordable physical activities. However, despite their health mandate, many have unhealthy food environments that may paradoxically increase the risk of childhood obesity. The Alberta Nutrition Guidelines for Children and Youth (ANGCY) are government-initiated, voluntary guidelines intended to facilitate children's access to healthy food and beverage choices in schools, childcare and recreational facilities, however few recreational facilities are using them. We used mixed methods within an exploratory multiple case study to examine factors that influenced adoption and implementation of the ANGCY and the nature of the food environment within three cases: an adopter, a semi-adopter and a non-adopter of the ANGCY. Diffusion of Innovations theory provided the theoretical platform for the study. Qualitative data were generated through interviews, observations, and document reviews, and were analysed using directed content analysis. Set theoretic logic was used to identify factors that differentiated adopters from the non-adopter. Quantitative sales data were also collected, and the quality of the food environment was scored using four complementary tools. The keys to adoption and implementation of nutrition guidelines in recreational facilities related to the managers' nutrition-related knowledge, beliefs and perceptions, as these shaped his decisions and actions. The manager, however, could not accomplish adoption and implementation alone. Intersectoral linkages with schools and formal, health promoting partnerships with industry were also important for adoption and implementation to occur. The food environment in facilities that had adopted the ANGCY did not appear to be superior to the food environment in facilities that had not adopted the ANGCY. ANGCY uptake may continue to falter under the current voluntary approach, as the environmental supports for voluntary action are poor. Where ANGCY uptake does occur, changes to the food environment may be relatively minor. Stronger government measures may be needed to require recreational facilities to improve their food environments and to limit availability of unhealthy foods.


Radioguided parathyroidectomy for tertiary hyperparathyroidism.
Tertiary hyperparathyroidism (3HPT) is defined as the persistent hyperproduction of parathyroid hormone and resulting hypercalcemia after renal transplantation. Here, we examine the utility of radioguided parathyroidectomy (RGP) in patients with 3HPT. We reviewed a prospective surgery database containing 80 3HPT patients who underwent RGP from January 2001-July 2014 at our institution. We evaluated patient demographics, operative management, radioguided neoprobe utilization, and operative outcomes. Data are reported as mean ± standard error of the mean. The mean age of the patients was 52 ± 1 y, and 46% were male. A total of 69 patients had hyperplasia and received subtotal parathyroidectomy, whereas 5 patients had double adenomas and 6 patients had single adenomas. The average calcium level among 3HPT patients was 10.8 ± 0.1 mg/dL preoperatively and 8.7 ± 0.1 mg/dL postoperatively. In vivo radioguided counts normalized to background counts averaged 145 ± 4%, whereas ex vivo counts normalized to background counts averaged 69 ± 5%. All but one ex vivo count was >20%. Ectopically located glands were successfully localized in 38 patients using the gamma probe. Ex vivo percentage did not correlate with parathyroid gland weight, preoperative parathyroid hormone, or preoperative calcium. Our radioguided approach achieved normocalcemia in 96% of 3HPT patients undergoing RGP; two patients developed recurrent disease. In this series, all enlarged parathyroid glands were localized and resected using the gamma probe. Thus, RGP reliably localizes adenomatous, hyperplastic, and ectopically located glands in patients with 3HPT, resulting in high cure rate after resection.


Mucinous versus nonmucinous gastric carcinoma: differentiation with helical CT.
To assess the capability of helical computed tomography (CT) to assist in the differentiation between mucinous and nonmucinous gastric carcinomas, with a focus on the thickened stomach wall itself. In 62 patients with pathologically proved mucinous (n = 21) or nonmucinous (n = 41) gastric carcinomas, contrast material-enhanced helical CT images were obtained. The gross appearance, contrast enhancement pattern, predominant thickened layer, and degree of enhancement were retrospectively evaluated. Statistical analyses were performed with Fisher exact, chi(2), and Student t tests. A P value of less than.05 was considered to indicate a statistically significant difference. The most common type of gross appearance in both carcinomas was fungating: It occurred in 71% of patients with mucinous carcinomas and in 59% of patients with nonmucinous carcinomas. The next most common gross appearance type was ulcerative (24% of patients) in nonmucinous carcinomas and diffusely infiltrative (29% of patients) in mucinous carcinomas (P =.009). The most common contrast enhancement pattern was homogeneous (61% of patients) in nonmucinous carcinomas and layered (62% of patients) in mucinous carcinomas (P =.001). These findings were significantly different. The predominantly affected thickened layer was the high-attenuating inner layer or the entire layer (88% of patients) in nonmucinous carcinomas and the low-attenuating middle or outer layer (57% of patients) in mucinous carcinomas. Only two mucinous tumors showed miliary punctate calcifications in infiltrative lesions. Helical CT may assist in distinguishing mucinous from nonmucinous gastric carcinoma, primarily on the basis of enhancement pattern, predominant layer of the thickened wall, gross appearance, and presence of calcifications.


A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults.
Adjunctive dexamethasone reduces mortality from tuberculous meningitis (TBM) but not disability, which is associated with brain infarction. We hypothesised that aspirin prevents TBM-related brain infarction through its anti-thrombotic, anti-inflammatory, and pro-resolution properties. We conducted a randomised controlled trial in HIV-uninfected adults with TBM of daily aspirin 81 mg or 1000 mg, or placebo, added to the first 60 days of anti-tuberculosis drugs and dexamethasone (NCT02237365). The primary safety endpoint was gastro-intestinal or cerebral bleeding by 60 days; the primary efficacy endpoint was new brain infarction confirmed by magnetic resonance imaging or death by 60 days. Secondary endpoints included 8-month survival and neuro-disability; the number of grade 3 and 4 and serious adverse events; and cerebrospinal fluid (CSF) inflammatory lipid mediator profiles. 41 participants were randomised to placebo, 39 to aspirin 81 mg/day, and 40 to aspirin 1000 mg/day between October 2014 and May 2016. TBM was proven microbiologically in 92/120 (76.7%) and baseline brain imaging revealed ≥1 infarct in 40/114 (35.1%) participants. The primary safety outcome occurred in 5/36 (13.9%) given placebo, and in 8/35 (22.9%) and 8/40 (20.0%) given 81 mg and 1000 mg aspirin, respectively (p=0.59). The primary efficacy outcome occurred in 11/38 (28.9%) given placebo, 8/36 (22.2%) given aspirin 81 mg, and 6/38 (15.8%) given 1000 mg aspirin (p=0.40). Planned subgroup analysis showed a significant interaction between aspirin treatment effect and diagnostic category (Pheterogeneity = 0.01) and suggested a potential reduction in new infarcts and deaths by day 60 in the aspirin treated participants with microbiologically confirmed TBM (11/32 (34.4%) events in placebo vs. 4/27 (14.8%) in aspirin 81 mg vs. 3/28 (10.7%) in aspirin 1000 mg; p=0.06). CSF analysis demonstrated aspirin dose-dependent inhibition of thromboxane A2 and upregulation of pro-resolving CSF protectins. The addition of aspirin to dexamethasone may improve outcomes from TBM and warrants investigation in a large phase 3 trial.


Architectural transitions in Vibrio cholerae biofilms at single-cell resolution.
Many bacterial species colonize surfaces and form dense 3D structures, known as biofilms, which are highly tolerant to antibiotics and constitute one of the major forms of bacterial biomass on Earth. Bacterial biofilms display remarkable changes during their development from initial attachment to maturity, yet the cellular architecture that gives rise to collective biofilm morphology during growth is largely unknown. Here, we use high-resolution optical microscopy to image all individual cells in Vibrio cholerae biofilms at different stages of development, including colonies that range in size from 2 to 4,500 cells. From these data, we extracted the precise 3D cellular arrangements, cell shapes, sizes, and global morphological features during biofilm growth on submerged glass substrates under flow. We discovered several critical transitions of the internal and external biofilm architectures that separate the major phases of V. cholerae biofilm growth. Optical imaging of biofilms with single-cell resolution provides a new window into biofilm formation that will prove invaluable to understanding the mechanics underlying biofilm development.


A hepatitis C virus cis-acting replication element forms a long-range RNA-RNA interaction with upstream RNA sequences in NS5B.
The genome of hepatitis C virus (HCV) contains cis-acting replication elements (CREs) comprised of RNA stem-loop structures located in both the 5' and 3' noncoding regions (5' and 3' NCRs) and in the NS5B coding sequence. Through the application of several algorithmically independent bioinformatic methods to detect phylogenetically conserved, thermodynamically favored RNA secondary structures, we demonstrate a long-range interaction between sequences in the previously described CRE (5BSL3.2, now SL9266) with a previously predicted unpaired sequence located 3' to SL9033, approximately 200 nucleotides upstream. Extensive reverse genetic analysis both supports this prediction and demonstrates a functional requirement in genome replication. By mutagenesis of the Con-1 replicon, we show that disruption of this alternative pairing inhibited replication, a phenotype that could be restored to wild-type levels through the introduction of compensating mutations in the upstream region. Substitution of the CRE with the analogous region of different genotypes of HCV produced replicons with phenotypes consistent with the hypothesis that both local and long-range interactions are critical for a fundamental aspect of genome replication. This report further extends the known interactions of the SL9266 CRE, which has also been shown to form a "kissing loop" interaction with the 3' NCR (P. Friebe, J. Boudet, J. P. Simorre, and R. Bartenschlager, J. Virol. 79:380-392, 2005), and suggests that cooperative long-range binding with both 5' and 3' sequences stabilizes the CRE at the core of a complex pseudoknot. Alternatively, if the long-range interactions were mutually exclusive, the SL9266 CRE may function as a molecular switch controlling a critical aspect of HCV genome replication.


Epidemic T2DM, early development and epigenetics: implications of the Chinese Famine.
The gene-environment interactions resulting from famine and the subsequent increased intergenerational risk of type 2 diabetes mellitus (T2DM) have contributed to the current epidemic of T2DM in China, which poses major social, health and economic challenges. The epidemic of T2DM could threaten national development in China through premature morbidity and mortality from T2DM and associated non-communicable diseases. The Chinese Famine (1959-1961), as a contributor to the nation's current national T2DM epidemic, provides an important and urgent public health warning. The effects of the famine give a strong message that research and actions that address the prevention of T2DM cannot be confined to lifestyle measures, as used in the landmark Da Qing study and the lifestyle prevention programmes and pharmaceutical interventions used in Western nations. To stem the T2DM epidemic, a new paradigm for prevention of T2DM must be developed. This paradigm should include a very strong emphasis on pregnancy planning and maternal and child health during and after the pregnancy. Without action, intergenerational cycles initiated by epigenetic modifications resulting from adverse environmental stimuli during the critical window of early development in utero might continue to fuel the T2DM epidemic in future generations.


Trends in energy intake in U.S. between 1977 and 1996: similar shifts seen across age groups.
To determine the trends in locations and food sources of Americans stratified by age group for both total energy and the meal and snack subcomponents. Nationally representative data was taken from the 1977 to 1978 Nationwide Food Consumption Survey and the 1989 to 1991 and 1994 to 1996 (and 1998 for children age 2 through 9) Continuing Surveys of Food Intake by Individuals. The sample consisted of 63,380 individuals, age 2 and up. For each survey year, the percentage of total energy intake from meals and snacks was calculated separately for 2- to 18-year-olds, 19- to 39-year-olds, 40- to 59-year-olds, and those 60 years and older. The percentage of energy intake by location (at-home consumption or preparation, vending, store eaten out, restaurant/fast-food, and school) and by specific food group was computed for all age groups separately. The trends in location and food sources were almost identical for all age groups. Key dietary behavior shifts included greater away-from-home consumption; large increases in total energy from salty snacks, soft drinks, and pizza; and large decreases in energy from low- and medium-fat milk and medium- and high-fat beef and pork. Total energy intake has increased over the past 20 years, with shifts away from meals to snacks and from at-home to away-from-home consumption. The similarity of changes across all age groups furthers the assertion that broad-based environmental changes are needed to improve the diets of Americans.


Persistence of antibody to hepatitis B surface antigen.
Sera from military personnel found to have antibodies to hepatitis B surface antigen (anti-HBS) in an epidemiological study of a hepatitis B outbreak were tested for persistence of that antibody 1 year later. Initially, 64% of the anti-HBS-positive sera reacted in passive hemagglutination tests with erythrocytes coated with hepatitis B surface antigen of both ayw and adw subtypes; the remaining sera reacted only with adw-coated erythrocytes (19%) or ayw-coated erythrocytes (17%). After 1 year, anti-HBS was detectable by passive hemagglutination tests in 87% of individuals with initial antibody to both subtypes but in only 41% and 16% (P less than 0.001) of those initially reacting only to adw- or ayw-coated erythrocytes, respectively. Seropositivity for anti-HBS correlated best with history of contact with jaundiced people (20.3%) and duty in Asia.


Methyl-compound use and slow growth characterize microbial life in 2-km-deep subseafloor coal and shale beds.
The past decade of scientific ocean drilling has revealed seemingly ubiquitous, slow-growing microbial life within a range of deep biosphere habitats. Integrated Ocean Drilling Program Expedition 337 expanded these studies by successfully coring Miocene-aged coal beds 2 km below the seafloor hypothesized to be "hot spots" for microbial life. To characterize the activity of coal-associated microorganisms from this site, a series of stable isotope probing (SIP) experiments were conducted using intact pieces of coal and overlying shale incubated at in situ temperatures (45 °C). The 30-month SIP incubations were amended with deuterated water as a passive tracer for growth and different combinations of 13C- or 15N-labeled methanol, methylamine, and ammonium added at low (micromolar) concentrations to investigate methylotrophy in the deep subseafloor biosphere. Although the cell densities were low (50-2,000 cells per cubic centimeter), bulk geochemical measurements and single-cell-targeted nanometer-scale secondary ion mass spectrometry demonstrated active metabolism of methylated substrates by the thermally adapted microbial assemblage, with differing substrate utilization profiles between coal and shale incubations. The conversion of labeled methylamine and methanol was predominantly through heterotrophic processes, with only minor stimulation of methanogenesis. These findings were consistent with in situ and incubation 16S rRNA gene surveys. Microbial growth estimates in the incubations ranged from several months to over 100 y, representing some of the slowest direct measurements of environmental microbial biosynthesis rates. Collectively, these data highlight a small, but viable, deep coal bed biosphere characterized by extremely slow-growing heterotrophs that can utilize a diverse range of carbon and nitrogen substrates.


Influence of Human Pressure on Forest Resources and Productivity at Stand and Tree Scales: The Case Study of Yunnan Pine in SW China.
This paper examines human impact on stands and individual trees of Pinus yunnanensis growing near the small mountain villages of Pianshui and Yangjuan in southwestern Sichuan Province, China. In an effort to assess whether use of these forests was sustainable, we examined the effects of human use in two ways. First, we directly measured the effect of cutting branches, for fuel and fodder, on tree growth. We hypothesized that branch cutting would negatively impact tree growth. We established 12 plots on four hills and compared 14 pairs of trees, one tree in each pair with an apparently full crown and the other with a considerable portion of the crown removed. Second, we assessed stand and tree properties over a 500 m elevation gradient above the villages where we hypothesized that as elevation increases, stand and tree properties should show fewer human impacts. Although extensive branch cutting reduced the live crown, tree height and diameter, compensatory processes likely enabled trees to recover and to add basal area increments (BAIs) similar to those added by trees with full crowns. Trees and stands close to villages showed less growth and lower basal areas, respectively, than stands and trees at intermediate or distant elevations from villages. Areas relatively close to the villages showed considerable effects of human-related disturbances such as branch cutting, grazing, tree and shrub removal, losses of litter, and human and animal trails. Such areas had increased soil erosion and often loss of the 'A' horizon. Stands close to villages had younger trees, lower stand basal areas, smaller basal area increments, and more stumps. Our results suggest an increasingly vulnerable interface between occupants of these two villages and their surrounding forests.


A comparative analysis of the evolutionary patterning and mechanistic bases of lactate dehydrogenase thermal stability in porcelain crabs, genus Petrolisthes.
The kinetic properties of orthologous homologs (orthologs) of enzymes are typically correlated with environmental temperatures in species adapted to different thermal regimes, but correlations between adaptation temperature and enzyme thermal stability are less clear. Although the thermal stability of a protein is related chiefly to its primary structure (including post-translational modification), thermal stability can also be altered by extrinsic factors present in the intracellular milieu. Here, we present a comparative analysis of the thermal stability of lactate dehydrogenase (LDH) orthologs from 22 congeneric species of porcelain crab (genera Petrolisthes and Allopetrolisthes) from a broad range of thermal habitats. Interspecific diversity of LDH stability is high: temperatures required for a 50 % loss of activity in 10 min ranged from 65 to 75.5 degrees C, corresponding to half-lives of less than 1 min to more than 3 h at 70 degrees C. Although stability is positively correlated with maximal habitat temperature in some sister taxa, phylogenetic comparative analysis incorporating all 22 species does not indicate that the interspecific diversity of LDH stability represents an adaptive response to current thermal habitats. Examination of the mechanistic bases of LDH stabilization indicates that differences in stability are related both to properties of the LDH molecule itself (intrinsic stability) and to the effects of extrinsic protein(s). Intrinsic differences were shown by the unfolding of structure during heating, as measured by circular dichroism spectroscopy. Stabilizing effects of extrinsic proteins are implied by the results of cellular fractionation experiments that removed low-molecular-mass solutes and proteins from the muscle homogenates. We conclude that the overall structural stability and functional properties of proteins can evolve independently and that in vivo protein-protein interactions can provide another means to regulate protein stability selectively.


Analysis of MUM1/IRF4 protein expression using tissue microarrays and immunohistochemistry.
The gene encoding MUM1 was characterized as a possible translocation partner in chromosomal abnormalities involving a significant number of multiple myelomas. The overexpression of the MUM1 protein as a result of translocation t(6;14) (p25;q32) identified MUM1 as a putative regulatory molecule involved in B-cell differentiation and tumorigenesis. The expression of MUM1 protein in multiple myelomas supports this hypothesis. In the current study, using tissue microarray technology, we have tested the expression of the MUM1 protein in 1335 human malignancies and normal tissues. Our data show that the MUM1 protein is expressed in a wide spectrum of hematolymphoid neoplasms and in malignant melanomas but is absent in other human tumors. In addition, in tissue microarrays as well as in conventional paraffin sections, MUM1 staining was found to lack specificity in detecting plasmacytic differentiation as compared with two markers, CD138/Syndecan and VS38, commonly used in paraffin immunohistochemistry for detection of plasma cells.


Membrane properties of rat subicular neurons in vitro.
1. Conventional intracellular recordings were performed in rat hippocampal slices to investigate the electrophysiological properties of subicular neurons. These cells had a resting membrane potential (RMP) of -66 +/- 7.2 mV (mean +/- SD; n = 50), input resistance of 23.6 +/- 8.2 M omega (n = 51), time constant of 7.1 +/- 1.9 ms (n = 51), action potential amplitude of 85.8 +/- 13.8 mV (n = 50), and duration of 2.9 +/- 1.2 ms (n = 48). Analysis of the current-voltage relationship revealed membrane inward rectification in both depolarizing and hyperpolarizing direction. The latter type was readily abolished by Cs+ (3 mM; n = 6 cells). 2. Injection of depolarizing current pulses of threshold intensity induced in all subicular neurons (n = 51) recorded at RMP a burst of two to three fast action potentials (frequency = 212.7 +/- 90 Hz, n = 13 cells). This burst rode on a slow depolarizing envelope and was followed by an afterhyperpolarization and later by regular spiking mode once the pulse was prolonged. Similar bursts were also generated upon termination of a hyperpolarizing current pulse. 3. The slow depolarization underlying the burst resembled a low-threshold response, which in thalamic cells is caused by a Ca2+ conductance and is contributed by the Cs(+)-sensitive inward rectifier. However, bursts in subicular cells persisted in medium containing the Ca(2+)-channel blockers Co2+ (2 mM) and Cd2+ (1 mM) (n = 5 cells) but disappeared during application of TTX (1 microM; n = 3 cells). Hence they were mediated by Na+. Blockade of the hyperpolarizing inward rectification by Cs+ did not prevent the rebound response (n = 3 cells). 4. Our findings demonstrate that intrinsic bursts, presumably related to a "low-threshold" Na+ conductance are present in rat subicular neurons. Similar intrinsic characteristics have been suggested to underlie the rhythmic activity described in other neuronal networks, although in most cases the low-threshold electrogenesis was caused by Ca2+. We propose that the bursting mechanism might play a role in modulating incoming signals from the classical hippocampal circuit within the limbic system.


Are health systems interventions gender blind? examining health system reconstruction in conflict affected states.
Global health policy prioritizes improving the health of women and girls, as evident in the Sustainable Development Goals (SDGs), multiple women's health initiatives, and the billions of dollars spent by international donors and national governments to improve health service delivery in low-income countries. Countries recovering from fragility and conflict often engage in wide-ranging institutional reforms, including within the health system, to address inequities. Research and policy do not sufficiently explore how health system interventions contribute to the broader goal of gender equity. This paper utilizes a framework synthesis approach to examine if and how rebuilding health systems affected gender equity in the post-conflict contexts of Mozambique, Timor Leste, Sierra Leone, and Northern Uganda. To undertake this analysis, we utilized the WHO health systems building blocks to establish benchmarks of gender equity. We then identified and evaluated a broad range of available evidence on these building blocks within these four contexts. We reviewed the evidence to assess if and how health interventions during the post-conflict reconstruction period met these gender equity benchmarks. Our analysis shows that the four countries did not meet gender equitable benchmarks in their health systems. Across all four contexts, health interventions did not adequately reflect on how gender norms are replicated by the health system, and conversely, how the health system can transform these gender norms and promote gender equity. Gender inequity undermined the ability of health systems to effectively improve health outcomes for women and girls. From our findings, we suggest the key attributes of gender equitable health systems to guide further research and policy. The use of gender equitable benchmarks provides important insights into how health system interventions in the post-conflict period neglected the role of the health system in addressing or perpetuating gender inequities. Given the frequent contact made by individuals with health services, and the important role of the health system within societies, this gender blind nature of health system engagement missed an important opportunity to contribute to more equitable and peaceful societies.


High Dimensional Variable Selection with Error Control.
Background. The iterative sure independence screening (ISIS) is a popular method in selecting important variables while maintaining most of the informative variables relevant to the outcome in high throughput data. However, it not only is computationally intensive but also may cause high false discovery rate (FDR). We propose to use the FDR as a screening method to reduce the high dimension to a lower dimension as well as controlling the FDR with three popular variable selection methods: LASSO, SCAD, and MCP. Method. The three methods with the proposed screenings were applied to prostate cancer data with presence of metastasis as the outcome. Results. Simulations showed that the three variable selection methods with the proposed screenings controlled the predefined FDR and produced high area under the receiver operating characteristic curve (AUROC) scores. In applying these methods to the prostate cancer example, LASSO and MCP selected 12 and 8 genes and produced AUROC scores of 0.746 and 0.764, respectively. Conclusions. We demonstrated that the variable selection methods with the sequential use of FDR and ISIS not only controlled the predefined FDR in the final models but also had relatively high AUROC scores.


Functional capacity before and after cardioversion of atrial fibrillation: a controlled study.
To evaluate the effect of cardioversion on peak oxygen consumption (peak VO2) in patients with long-standing atrial fibrillation, to assess the importance of underlying heart disease with respect to the response to exercise, and to relate functional capacity to long-term arrhythmia outcome. Prospective controlled clinical trial. Tertiary referral centre. 63 consecutive patients with chronic atrial fibrillation accepted for treatment with electrical cardioversion. Before cardioversion all patients were treated with digoxin, verapamil, or a combination of both to attain a resting heart rate < or = 100 beats per minute. Electrical cardioversion. Peak VO2 measured before and 1 month after electrical cardioversion to compare patients who were in sinus rhythm and those in atrial fibrillation at these times. Maintenance of sinus rhythm for a mean follow up of 19 (7) months. Mean (1SD) peak VO2 in patients in sinus rhythm after 1 month (n = 37) increased from 21.4 (5.8) to 23.7 (6.4) ml/min/kg (+11%, P < 0.05), whereas in patients with a recurrence of atrial fibrillation 1 month after cardioversion (n = 26) peak VO2 was unchanged. In patients who were in sinus rhythm both those with and without underlying heart disease improved, and improvement was not related to functional capacity or left ventricular function before cardioversion. Baseline peak VO2 was not a predictive factor for long-term arrhythmia outcome. Restoration of sinus rhythm improved peak VO2 in patients with atrial fibrillation, irrespective of the presence of underlying heart disease. Peak VO2 was not a predictive factor for long-term arrhythmia outcome after cardioversion of atrial fibrillation. These findings suggest that cardioversion is the best method of improving functional capacity in patients with atrial fibrillation, whether or not they have underlying heart disease and whatever their functional state.


Applying the theory of planned behaviour to explain HIV testing in antenatal settings in Addis Ababa - a cohort study.
To facilitate access to the prevention of mother-to-child HIV transmission (PMTCT) services, HIV counselling and testing are offered routinely in antenatal care settings. Focusing a cohort of pregnant women attending public and private antenatal care facilities, this study applied an extended version of the Theory of Planned Behaviour (TPB) to explain intended- and actual HIV testing. A sequential exploratory mixed methods study was conducted in Addis Ababa in 2009. The study involved first time antenatal attendees from public- and private health care facilities. Three Focus Group Discussions were conducted to inform the TPB questionnaire. A total of 3033 women completed the baseline TPB interviews, including attitudes, subjective norms, perceived behavioural control and intention with respect to HIV testing, whereas 2928 completed actual HIV testing at follow up. Data were analysed using descriptive statistics, Chi-square tests, Fisher's Exact tests, Internal consistency reliability, Pearson's correlation, Linear regression, Logistic regression and using Epidemiological indices. P-values < 0.05 was considered significant and 95% Confidence Interval (CI) was used for the odds ratio. The TPB explained 9.2% and 16.4% of the variance in intention among public- and private health facility attendees. Intention and perceived barriers explained 2.4% and external variables explained 7% of the total variance in HIV testing. Positive and negative predictive values of intention were 96% and 6% respectively. Across both groups, subjective norm explained a substantial amount of variance in intention, followed by attitudes. Women intended to test for HIV if they perceived social support and anticipated positive consequences following test performance. Type of counselling did not modify the link between intended and actual HIV testing. The TPB explained substantial amount of variance in intention to test but was less sufficient in explaining actual HIV testing. This low explanatory power of TPB was mainly due to the large proportion of low intenders that ended up being tested contrary to their intention before entering the antenatal clinic. PMTCT programs should strengthen women's intention through social approval and information that testing will provide positive consequences for them. However, women's rights to opt-out should be emphasized in any attempt to improve the PMTCT programs.


3D-Printable and Enzymatically Active Composite Materials Based on Hydrogel-Filled High Internal Phase Emulsions.
The immobilization of enzymes in biocatalytic flow reactors is a common strategy to increase enzyme reusability and improve biocatalytic performance. Extrusion-based 3D bioprinting has recently emerged as a versatile tool for the fabrication of perfusable hydrogel grids containing entrapped enzymes for the use in such reactors. This study demonstrates the suitability of water-in-oil high internal phase emulsions (HIPEs) as 3D-printable bioinks for the fabrication of composite materials with a porous polymeric scaffold (polyHIPE) filled with enzyme-laden hydrogel. The prepared HIPEs exhibited excellent printability and are shown to be suitable for the printing of complex three-dimensional structures without the need for sacrificial support material. An automated activity assay method for the systematic screening of different material compositions in small-scale batch experiments is presented. The monomer mass fraction in the aqueous phase and the thickness of printed objects were found to be the most important parameters determining the apparent activity of the immobilized enzyme. Mass transfer limitations and enzyme inactivation were identified as probable factors reducing the apparent activity. The presented HIPE-based bioinks enable the fabrication of flow-optimized and more efficient biocatalytic reactors while the automated activity assay method allows the rapid screening of materials to optimize the biocatalytic efficiency further without time-consuming flow-through experiments involving whole printed reactors.


Caffeic acid phenethyl ester induces apoptosis in colorectal cancer cells via inhibition of survivin.
Colorectal cancer is one of the most common types of cancer. Drug resistance and drug-induced damage of healthy tissues are major obstacles in cancer treatment. Therefore, to develop efficient anticancer therapy, it is necessary to find compounds that affect tumor cells, but do not exhibit toxicity to healthy cells. Caffeic acid phenethyl ester (CAPE) has been demonstrated to have anticancer properties in many types of cancer. In this study, the cytotoxic and apoptotic effects of CAPE on the RKO colorectal cancer cell line and CCD 841-CoN normal colorectal cell line was investigated. In addition, changes in the survivin expression were determined. According to the results, CAPE decreased cell viability in the RKO cell line in a dose-dependent manner. Likewise, CAPE induced apoptotic cell death in approximately 40% of the RKO cells. Furthermore, CAPE treatment increased the Serine 15 (Ser15) and Serine 46 (Ser46) phosphorylation of p53, while decreased the survivin expression. The results suggested that CAPE induced apoptosis by regulating p53 phosphorylation, leading to inhibition of the survivin expression. In accordance with the results, it is suggested that CAPE might be evaluated as an alternative drug in cancer therapy and further investigation is needed within this scope.


Cardiopulmonary resuscitation quality: [corrected] improving cardiac resuscitation outcomes both inside and outside the hospital: a consensus statement from the American Heart Association.
The "2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care" increased the focus on methods to ensure that high-quality cardiopulmonary resuscitation (CPR) is performed in all resuscitation attempts. There are 5 critical components of high-quality CPR: minimize interruptions in chest compressions, provide compressions of adequate rate and depth, avoid leaning between compressions, and avoid excessive ventilation. Although it is clear that high-quality CPR is the primary component in influencing survival from cardiac arrest, there is considerable variation in monitoring, implementation, and quality improvement. As such, CPR quality varies widely between systems and locations. Victims often do not receive high-quality CPR because of provider ambiguity in prioritization of resuscitative efforts during an arrest. This ambiguity also impedes the development of optimal systems of care to increase survival from cardiac arrest. This consensus statement addresses the following key areas of CPR quality for the trained rescuer: metrics of CPR performance; monitoring, feedback, and integration of the patient's response to CPR; team-level logistics to ensure performance of high-quality CPR; and continuous quality improvement on provider, team, and systems levels. Clear definitions of metrics and methods to consistently deliver and improve the quality of CPR will narrow the gap between resuscitation science and the victims, both in and out of the hospital, and lay the foundation for further improvements in the future.


Relapse dynamics during smoking cessation: recurrent abstinence violation effects and lapse-relapse progression.
Smoking cessation is a process that unfolds over time and is characterized by intermittent lapses. We used parametric recurrent event survival analyses to better understand the dynamic relationship between a set of Abstinence Violation Effect (AVE, Marlatt & Gordon, 1985) responses to lapsing and subsequent lapse-relapse progression. Participants were 203 smokers who achieved abstinence and responded to items assessing three core components of the AVE (internal attribution, abstinence self-efficacy and guilt) following a total of 1,001 lapse episodes in near real time. Neither self-blame, self-efficacy, nor guilt following participants' first lapse predicted relapse. Controlling for responses to their first lapse, responses to each additional lapse did prospectively predict lapse progression, such that drops in self-efficacy were associated with accelerated progression to a subsequent lapse (HR = 1.09, CI = 1.02-1.15), while increases in internal attributions of blame actually protected against lapsing (HR = 0.98, CI = 0.97-0.99). Treatment with nicotine patches slowed recurrent lapse progression (HR = 0.58, CI = 0.48-0.70), but this effect dissipated over multiple lapses, and was moderated by elevated ratings of postlapse guilt (HR = 1.08, CI = 1.01-1.18), which predicted accelerated progression within the active patch group, while protecting against lapse in the placebo group. Results highlight the dynamic nature of lapse responses during smoking cessation, indicating that self-efficacy predicts progression from one lapse to the next, while attributions of self-blame and guilt influenced progression in unexpected ways.


The comparative effects of supervisor helping motives on newcomer adjustment and socialization outcomes.
The preponderance of organizational socialization research has focused on the perceptions and interests of newcomers. Yet, insiders-particularly immediate supervisors-are central to newcomers' adjustment, primarily in providing newcomers help. To facilitate such behavior, however, it is necessary to understand supervisors' helping motivations. Beginning from a new theoretically grounded taxonomy, we examined how supervisor reports of their own self-oriented, other-oriented, and normative motives predicted newcomer-rated received help and subsequent adjustment/socialization outcomes. We also examined the moderating role of newcomer motive perceptions on whether help was reciprocated to supervisors. Our model was tested with multiwave data from newcomers and supervisors during the first 3 months of starting a job. Newcomers reported receiving greater help from supervisors who described themselves as being motivated by self-oriented tangible gains and other-orientation, whereas supervisors who described themselves as being motivated by self-oriented enhancement were seen as less helpful. Further, when newcomers perceived that supervisors were more motivated by other-orientation and less by self-oriented tangible gains, newcomers reciprocated more help to the supervisor later on. Our results advance theory about the role of interpersonal helping during socialization, revealing that not all provided help is interpreted similarly by newcomers, and that differing supervisor motivations should also be factored into account. (PsycInfo Database Record (c) 2020 APA, all rights reserved).


How is acetylcholinesterase phosphonylated by soman? An ab initio QM/MM molecular dynamics study.
Acetylcholinesterase (AChE) is a crucial enzyme in the cholinergic nerve system that hydrolyzes acetylcholine (ACh) and terminates synaptic signals by reducing the effective concentration of ACh in the synaptic clefts. Organophosphate compounds irreversibly inhibit AChEs, leading to irreparable damage to nerve cells. By employing Born-Oppenheimer ab initio QM/MM molecular dynamics simulations with umbrella sampling, a state-of-the-art approach to simulate enzyme reactions, we have characterized the covalent inhibition mechanism between AChE and the nerve toxin soman and determined its free energy profile for the first time. Our results indicate that phosphonylation of the catalytic serine by soman employs an addition-elimination mechanism, which is highly associative and stepwise: in the initial addition step, which is also rate-limiting, His440 acts as a general base to facilitate the nucleophilic attack of Ser200 on the soman's phosphorus atom to form a trigonal bipyrimidal pentacovalent intermediate; in the subsequent elimination step, Try121 of the catalytic gorge stabilizes the leaving fluorine atom prior to its dissociation from the active site. Together with our previous characterization of the aging mechanism of soman inhibited AChE, our simulations have revealed detailed molecular mechanistic insights into the damaging function of the nerve agent soman.


Mannan chain length controls lipoglycans signaling via and binding to TLR2.
TLR2 is a pattern-recognition receptor that is activated by a large variety of conserved microbial components, including lipoproteins, lipoteichoic acids, and peptidoglycan. Lipoglycans are TLR2 agonists found in some genera of the phylogenetic order Actinomycetales, including Mycobacterium. They are built from a mannosyl-phosphatidyl-myo-inositol anchor attached to a (alpha1-->6)-linked d-mannopyranosyl chain whose units can be substituted by d-mannopyranosyl and/or d-arabinofuranosyl units. At this time, little is known about the molecular bases underlying their ability to induce signaling via this receptor. We have recently shown that the anchor must be at least triacylated, including a diacylglyceryl moiety, whereas the contribution of the glycosidic moiety is not yet clearly defined. We show herein that lipoglycan activity is directly determined by mannan chain length. Indeed, activity increases with the number of units constituting the (alpha1-->6)-mannopyranosyl backbone but is also critically dependent on the substitution type of the 2-hydroxyl of these units. We thus provide evidence for the definition of a new pattern that includes the nonlipidic moiety of the molecules, most probably as a result of the (alpha1-->6)-mannopyranosyl backbone being a highly conserved structural feature among lipoglycans. Moreover, we demonstrate that lipoglycans can bind cell surface-expressed TLR2 and that their ability to induce signaling might be, at least in part, dictated by their avidity for the receptor. Finally, our data suggest that lipoglycans and lipoproteins have a common binding site. The present results are thus discussed in the light of the recently published crystal structure of a TLR1-TLR2-lipopeptide complex.


Canonical DNA minor groove insertion of bisbenzamidine-Ru(ii) complexes with chiral selectivity.
We report the first Ru(ii) coordination compounds that interact with DNA through a canonical minor groove insertion mode and with selectivity for A/T rich sites. This was made possible by integrating a bis-benzamidine minor groove DNA-binding agent with a ruthenium(ii) complex. Importantly, one of the enantiomers (Δ-[Ru(bpy)2 b4bpy]2+, Δ-4Ru) shows a considerably higher DNA affinity than the parent organic ligand and the other enantiomer, particularly for the AATT sequence, while the other enantiomer preferentially targets long AAATTT sites with overall lower affinity. Finally, we demonstrate that the photophysical properties of these new binders can be exploited for DNA cleavage using visible light.


Host in the machine: A neurobiological perspective on psychological stress and cardiovascular disease.
Psychological stress still attracts scientific, clinical, and public interest because of its suspected connection to health, particularly cardiovascular health. Psychological stress is thought to arise from appraisal processes that imbue events and contexts with personal significance and threat-related meaning. These appraisal processes are also thought to be instantiated in brain systems that generate and control peripheral physiological stress reactions through visceral motor (brain-to-body) and visceral sensory (body-to-brain) mechanisms. In the short term, physiological stress reactions may enable coping and adaptive action. Among some individuals, however, the patterning of these reactions may predict or contribute to pathology in multiple organ systems, including the cardiovascular system. At present, however, we lack a precise understanding of the brain systems and visceral control processes that link psychological appraisals to patterns of stress physiology and physical health. This understanding is important: A mechanistic account of how the brain connects stressful experiences to bodily changes and health could help refine biomarkers of risk and targets for cardiovascular disease prevention and intervention. We review research contributing to this understanding, focusing on the neurobiology of cardiovascular stress reactivity and cardiovascular health. We suggest that a dysregulation of visceral motor and visceral sensory processes during stressful experiences may confer risk for poor cardiovascular health among vulnerable individuals. We further describe a need for new interpretive frameworks and markers of this brain-body dysregulation in cardiovascular behavioral medicine. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Modeling the effect of task and graphical representation on response latency in a graph reading task.
We report an investigation into the processes involved in a common graph-reading task using two types of Cartesian graph. We describe an experiment and eye movement study, the results of which show that optimal scan paths assumed in the task analysis approximate the detailed sequences of saccades made by individuals. The research demonstrates the computational inequivalence of two sets of informationally equivalent graphs and illustrates how the computational advantages of a representation outweigh factors such as user unfamiliarity. We describe two models, using the ACT rational perceptual motor (ACT-R/PM) cognitive architecture, that replicate the pattern of observed response latencies and the complex scan paths revealed by the eye movement study. Finally, we outline three guidelines for designers of visual displays: Designers should (a) consider how different quantities are encoded within any chosen representational format, (b) consider the full range of alternative varieties of a given task, and (c) balance the cost of familiarization with the computational advantages of less familiar representations. Actual or potential applications of this research include informing the design and selection of appropriate visual displays and illustrating the practice and utility of task analysis, eye tracking, and cognitive modeling for understanding interactive tasks with external representations.


Atmospheric deposition, CO2, and change in the land carbon sink.
Concentrations of atmospheric carbon dioxide (CO2) have continued to increase whereas atmospheric deposition of sulphur and nitrogen has declined in Europe and the USA during recent decades. Using time series of flux observations from 23 forests distributed throughout Europe and the USA, and generalised mixed models, we found that forest-level net ecosystem production and gross primary production have increased by 1% annually from 1995 to 2011. Statistical models indicated that increasing atmospheric CO2 was the most important factor driving the increasing strength of carbon sinks in these forests. We also found that the reduction of sulphur deposition in Europe and the USA lead to higher recovery in ecosystem respiration than in gross primary production, thus limiting the increase of carbon sequestration. By contrast, trends in climate and nitrogen deposition did not significantly contribute to changing carbon fluxes during the studied period. Our findings support the hypothesis of a general CO2-fertilization effect on vegetation growth and suggest that, so far unknown, sulphur deposition plays a significant role in the carbon balance of forests in industrialized regions. Our results show the need to include the effects of changing atmospheric composition, beyond CO2, to assess future dynamics of carbon-climate feedbacks not currently considered in earth system/climate modelling.


Understanding the in vivo uptake kinetics of a phosphatidylethanolamine-binding agent (99m)Tc-Duramycin.
(99m)Tc-Duramycin is a peptide-based molecular probe that binds specifically to phosphatidylethanolamine (PE). The goal was to characterize the kinetics of molecular interactions between (99m)Tc-Duramycin and the target tissue. High level of accessible PE is induced in cardiac tissues by myocardial ischemia (30 min) and reperfusion (120 min) in Sprague-Dawley rats. Target binding and biodistribution of (99m)Tc-duramycin were captured using SPECT/CT. To quantify the binding kinetics, the presence of radioactivity in ischemic versus normal cardiac tissues was measured by gamma counting at 3, 10, 20, 60 and 180 min after injection. A partially inactivated form of (99m)Tc-Duramycin was analyzed in the same fashion. A compartment model was developed to quantify the uptake kinetics of (99m)Tc-Duramycin in normal and ischemic myocardial tissue. (99m)Tc-duramycin binds avidly to the damaged tissue with a high target-to-background radio. Compartment modeling shows that accessibility of binding sites in myocardial tissue to (99m)Tc-Duramycin is not a limiting factor and the rate constant of target binding in the target tissue is at 2.2 ml/nmol/min/g. The number of available binding sites for (99m)Tc-Duramycin in ischemic myocardium was estimated at 0.14 nmol/g. Covalent modification of D15 resulted in a 9-fold reduction in binding affinity. (99m)Tc-Duramycin accumulates avidly in target tissues in a PE-dependent fashion. Model results reflect an efficient uptake mechanism, consistent with the low molecular weight of the radiopharmaceutical and the relatively high density of available binding sites. These data help better define the imaging utilities of (99m)Tc-Duramycin as a novel PE-binding agent.


Absence of antiretroviral therapy and other risk factors for morbidity and mortality in Malaysian compulsory drug detention and rehabilitation centers.
Throughout Asia, people who use drugs are confined in facilities referred to as compulsory drug detention and rehabilitation centers. The limited transparency and accessibility of these centers has posed a significant challenge to evaluating detainees and detention conditions directly. Despite HIV being highly prevalent in this type of confined setting, direct evaluation of detainees with HIV and their access to medical care has yet to be reported in the literature. We evaluated the health status of 100 adult male detainees with HIV and their access to medical care in the two largest Malaysian compulsory drug detention and rehabilitation centers holding HIV-infected individuals. Approximately 80% of all detainees with HIV were surveyed in each detention center. Most participants reported multiple untreated medical conditions. None reported being able to access antiretroviral therapy during detention and only 9% reported receiving any HIV-related clinical assessment or care. Nearly a quarter screened positive for symptoms indicative of active tuberculosis, yet none reported having been evaluated for tuberculosis. Although 95% of participants met criteria for opioid dependence prior to detention, none reported being able to access opioid substitution therapy during detention, with 86% reporting current cravings for opioids and 87% anticipating relapsing to drug use after release. Fourteen percent of participants reported suicidal ideation over the previous two weeks. We identified a lack of access to antiretroviral therapy in two of the six compulsory drug detention and rehabilitation centers in Malaysia designated to hold HIV-infected individuals and found significant, unmet health needs among detainees with HIV. Individuals confined under such conditions are placed at considerably high risk for morbidity and mortality. Our findings underscore the urgent need for evidence-based drug policies that respect the rights of people who use drugs and seek to improve, rather than undermine, their health.


Footwear for the neuropathic patient: offloading and stability.
Diabetic neuropathy is related to plantar ulceration through a variety of factors of which increased plantar pressures and loss of protective sensation are the most important. Loss of sensation in the lower limbs is also related to postural instability and an increased risk of falling. Ankle and foot proprioception play an important role in postural control and this sensory function is also affected by neuropathy. It is conceivable that footwear, orthotics, casts and braces used for treatment or prevention of plantar ulceration through offloading of the injured or at-risk foot area can exacerbate the postural instability and risk of falling. This has, however, received very limited attention in the literature. There are studies that have demonstrated that footwear adjustments can influence balance and stability in healthy, elderly subjects. The adjustments made to footwear for the diabetic foot are generally more dramatic and, therefore, are expected to have a greater influence on postural stability. Furthermore, casts and braces tend to deviate even more from normal footwear. This may seriously interfere with normal gait and posture and, therefore, stability. So far the evidence suggests that patients wearing such devices demonstrate markedly reduced activity levels. This reduced activity could add to the effect of offloading. This could also be interpreted to indicate problems with stability. This presentation will review the different types of offloading interventions frequently used for ulcer treatment and prevention and will consider the mechanical effect of these interventions on stability.


An investigation of the factors effecting high-risk individuals' decision-making about prophylactic total gastrectomy and surveillance for hereditary diffuse gastric cancer (HDGC).
Hereditary diffuse gastric cancer has an early onset and poor prognosis, therefore, individuals who carry a pathogenic (CDH1) mutation in the E-cadherin gene (CDH1) are offered endoscopic surveillance and advised to undergo prophylactic total gastrectomy (PTG) in their early to mid-twenties. Patients not ready or fit to undergo gastrectomy, or in whom the genetic testing result is unknown or ambiguous, are offered surveillance. Little is known about the factors that influence decisions to undergo or decline PTG, making it difficult to provide optimal support for those facing these decisions. Qualitative interviews were carried out with 35 high-risk individuals from the Familial Gastric Cancer Study in the UK. Twenty-seven had previously undergone PTG and eight had been identified as carrying a pathogenic CDH1 mutation but had declined surgery at the time of interview. The interviews explored the experience of decision-making and factors influencing risk-management decisions. The data suggest that decisions to proceed with PTG are influenced by a number of potentially competing factors: objective risk confirmation by genetic testing and/or receiving a positive biopsy; perceived familial cancer burden and associated risk perceptions; perceptions of post-surgical life; an increasing inability to tolerate endoscopic procedures; a concern that surveillance could miss a cancer developing and individual's life stage. These findings have implications for advising this patient group.


Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer's Disease Patients: A Pilot Study.
Pathological hallmarks of Alzheimer's disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins-HSPA1A, NPEPPS, and PTGFRN-involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD.


Terminally differentiated CD8⁺ T cells negatively affect bone regeneration in humans.
There is growing evidence that adaptive immunity contributes to endogenous regeneration processes: For example, endogenous bone fracture repair is modulated by T cells even in the absence of infection. Because delayed or incomplete fracture healing is associated with poor long-term outcomes and high socioeconomic costs, we investigated the relationship between an individual's immune reactivity and healing outcome. Our study revealed that delayed fracture healing significantly correlated with enhanced levels of terminally differentiated CD8(+) effector memory T (TEMRA) cells (CD3(+)CD8(+)CD11a(++)CD28(-)CD57(+) T cells) in peripheral blood. This difference was long lasting, reflecting rather the individual's immune profile in response to lifelong antigen exposure than a post-fracture reaction. Moreover, CD8(+) TEMRA cells were enriched in fracture hematoma; these cells were the major producers of interferon-γ/tumor necrosis factor-α, which inhibit osteogenic differentiation and survival of human mesenchymal stromal cells. Accordingly, depletion of CD8(+) T cells in a mouse osteotomy model resulted in enhanced endogenous fracture regeneration, whereas a transfer of CD8(+) T cells impaired the healing process. Our data demonstrate the high impact of the individual adaptive immune profile on endogenous bone regeneration. Quantification of CD8(+) TEMRA cells represents a potential marker for the prognosis of the healing outcome and opens new opportunities for early and targeted intervention strategies.


Outcomes of psychiatric residency training during the past decade.
An assumption has existed that training in a psychoanalytically or psychodynamically oriented residency program would narrow the range of the trainees' interests and limit career pathways with a predominance of private practice. In order to test this assumption, a survey was undertaken of graduates of a psychoanalytically oriented program over a ten-year period with a view to determining the nature of their present professional activities. Results of the survey were compared to available national statistics for patterns of psychiatric professional practice and prove the assumptions to be invalid. We discuss some implications of this study and possible alternate explanations for the professional practice patterns that have emerged.


Methylation-related chromatin structure is associated with exclusion of transcription factors from and suppressed expression of the O-6-methylguanine DNA methyltransferase gene in human glioma cell lines.
There is considerable interest in identifying factors responsible for expression of the O-6-methylguanine DNA methyltransferase (MGMT) gene, as MGMT is a major determinant in the response of glioma cells to the chemotherapeutic agent 1,3 bis(2-chloroethyl)-1-nitrosourea. Recently we have shown that MGMT expression is correlated in a direct, graded fashion with methylation in the body of the MGMT gene and in an inverse, graded fashion with promoter methylation in human glioma cell lines. To determine if promoter methylation is an important component of MGMT expression, this study addressed the complex interactions between methylation, chromatin structure, and in vivo transcription factor occupancy in the MGMT promoter of glioma cell lines with different levels of MGMT expression. Our results show that the basal promoter in MGMT-expressing glioma cell lines, which is 100% unmethylated, was very accessible to restriction enzymes at all sites tested, suggesting that this region may be nucleosome free. The basal promoter in glioma cells with minimal MGMT expression, however, which is 75% unmethylated, was much less accessible, and the basal promoter in nonexpressing cells, which is 50% unmethylated, was entirely inaccessible to restriction enzymes. Despite the presence of the relevant transcription factors in all cell lines examined, in vivo footprinting showed DNA-protein interactions at six Sp1 binding sites and one novel binding site in MGMT-expressing cell lines but no such interactions in nonexpressors. We conclude that in contrast to findings of previous in vitro studies, Sp1 is an important component of MGMT transcription. These correlations also strongly suggest that methylation and chromatin structure, by determining whether Sp1 and other transcription factors can access the MGMT promoter, set the transcriptional state of the MGMT gene.


Isolation of deoxynivalenol-transforming bacteria from the chicken intestines using the approach of PCR-DGGE guided microbial selection.
Contamination of grains with trichothecene mycotoxins, especially deoxynivalenol (DON), has been an ongoing problem for Canada and many other countries. Mycotoxin contamination creates food safety risks, reduces grain market values, threatens livestock industries, and limits agricultural produce exports. DON is a secondary metabolite produced by some Fusarium species of fungi. To date, there is a lack of effective and economical methods to significantly reduce the levels of trichothecene mycotoxins in food and feed, including the efforts to breed Fusarium pathogen-resistant crops and chemical/physical treatments to remove the mycotoxins. Biological approaches, such as the use of microorganisms to convert the toxins to non- or less toxic compounds, have become a preferred choice recently due to their high specificity, efficacy, and environmental soundness. However, such approaches are often limited by the availability of microbial agents with the ability to detoxify the mycotoxins. In the present study, an approach with PCR-DGGE guided microbial selection was developed and used to isolate DON -transforming bacteria from chicken intestines, which resulted in the successful isolation of several bacterial isolates that demonstrated the function to transform DON to its de-epoxy form, deepoxy-4-deoxynivalenol (DOM-1), a product much less toxic than DON. The use of conventional microbiological selection strategies guided by PCR-DGGE (denaturing gradient gel electrophoresis) bacterial profiles for isolating DON-transforming bacteria has significantly increased the efficiency of the bacterial selection. Ten isolates were identified and isolated from chicken intestines. They were all able to transform DON to DOM-1. Most isolates were potent in transforming DON and the activity was stable during subculturing. Sequence data of partial 16S rRNA genes indicate that the ten isolates belong to four different bacterial groups, Clostridiales, Anaerofilum, Collinsella, and Bacillus. The approach with PCR-DGGE guided microbial selection was effective in isolating DON-transforming bacteria and the obtained bacterial isolates were able to transform DON.


The global epidemic of atherosclerotic cardiovascular disease.
Of the 50 million deaths that occur in the world, 40 million occur in developing countries. Already a substantial proportion of these deaths are due to cardiovascular diseases. It is projected that by the year 2025 well over 80-90% of all the cardiovascular diseases in the world will be occurring in low income and middle income countries. This increase in cardiovascular disease is due to a number of causes which include the following: (1) conquest of deaths in childhood and infancy from nutritional deficiencies and infection; (2) urbanization with increasing levels of obesity; (3) increasing longevity of the population so that a higher proportion of individuals reach the age when they are subject to chronic diseases, and (4) increasing use of tobacco worldwide. In most countries in the world other than those in the West, the burden of disease is still due to a combination of infections and nutritional disorders as well as those due to chronic diseases. This double burden of disease poses a challenge that is not only medical and epidemiological, but also social and political. Tackling this projected global epidemic of cardiovascular disease therefore needs policies that combine sound knowledge of prevention, good clinical care, but also deals with the allocation of resources for both individual level and community level preventive strategies. The former involves dealing with high-risk individuals through appropriate medical and therapeutic interventions. The latter involves societal level changes including laws that curb the use of tobacco, and strategies that promote physical activities, and appropriate nutrition.


AI4VIS: Survey on Artificial Intelligence Approaches for Data Visualization.
Visualizations themselves have become a data format. Akin to other data formats such as text and images, visualizations are increasingly created, stored, shared, and (re-)used with artificial intelligence (AI) techniques. In this survey, we probe the underlying vision of formalizing visualizations as an emerging data format and review the recent advance in applying AI techniques to visualization data (AI4VIS). We define visualization data as the digital representations of visualizations in computers and focus on data visualization (e.g., charts and infographics). We build our survey upon a corpus spanning ten different fields in computer science with an eye toward identifying important common interests. Our resulting taxonomy is organized around WHAT is visualization data and its representation, WHY and HOW to apply AI to visualization data. We highlight a set of common tasks that researchers apply to the visualization data and present a detailed discussion of AI approaches developed to accomplish those tasks. Drawing upon our literature review, we discuss several important research questions surrounding the management and exploitation of visualization data, as well as the role of AI in support of those processes. We make the list of surveyed papers and related material available online at.


Educational intervention to decrease stigmatizing attitudes of undergraduate nurses towards people with mental illness.
Health professionals can hold stigmatizing views about people with mental illness. In addition to being discriminatory, these beliefs cause anxiety that can affect learning in the clinical environment. A review of an undergraduate nursing curriculum introduced the Modern Apprenticeship curriculum model and provided an opportunity for an educational intervention designed to address stigmatizing beliefs about people with mental health and addiction problems. The aim of the present study was to measure the extent to which an educational intervention - guided clinical experience in an acute mental health unit during the first year of the curriculum - decreased stigmatizing beliefs of undergraduate nurses towards those with mental health and addiction issues. In a before-and-after design, Corrigan's Attribution Questionnaire was used to collect data pre- and post-guided clinical experience in an acute mental health unit. The intervention resulted in a significant positive change in stigmatizing attitudes for four of the nine factors tested. There was a non-significant positive change in three factors, while two factors showed a non-significant negative change. Using guided clinical experience as an educational intervention in the first year of an undergraduate nursing curriculum can contribute to positive change in undergraduate nurses' stigmatizing beliefs. The findings have implications for teaching of mental health content in undergraduate nursing programmes.