Magnetic seizure therapy for treatment-resistant depression.
Magnetic seizure therapy (MST) is a potential alternative to electroconvulsive therapy (ECT). Reports to date on use of MST for patients with treatment-resistant depression (TRD) are limited. To evaluate the effects of MST in comparison with sham-MST, antidepressant, and other forms of electric or magnetic treatment for adults with TRD. In March 2020, we searched a wide range of international electronic sources for published, unpublished, and ongoing studies. We handsearched the reference lists of all included studies and relevant systematic reviews and conference proceedings of the Annual Meeting of the American College of Neuropsychopharmacology (ACNP), the Annual Scientific Convention and Meeting, and the Annual Meeting of the European College of Neuropsychopharmacology (ECNP) to identify additional studies. All randomised clinical trials (RCTs) focused on MST for adults with TRD. Two review authors extracted data independently. For binary outcomes, we calculated risk ratios (RRs) and 95% confidence intervals (CIs). For continuous data, we estimated mean differences (MDs) between groups and 95% CIs. We employed a random-effects model for analyses. We assessed risk of bias for included studies and created a 'Summary of findings' table using the GRADE approach. Our main outcomes of interest were symptom severity, cognitive function, suicide, quality of life, social functioning, dropout for any reason, serious adverse events, and adverse events that led to discontinuation of treatment. We included three studies (65 participants) comparing MST with ECT. Two studies reported depressive symptoms with the Hamilton Rating Scale for Depression (HAMD). However, in one study, the data were skewed and there was an imbalance in baseline characteristics. Analysis of these two studies showed no clear differences in depressive symptoms between treatment groups (MD 0.71, 95% CI -2.23 to 3.65; 2 studies, 40 participants; very low-certainty evidence). Two studies investigated multiple domains of cognitive function. However most of the outcomes were not measured by validated neuropsychological tests, and many of the data suffered from unbalanced baseline and skewed distribution. Analysis of immediate memory performance measured by the Wechsler Memory Scale showed no clear differences between treatment groups (MD 0.40, 95% CI -4.16 to 4.96; 1 study, 20 participants; very low-certainty evidence). Analysis of delayed memory performance measured by the Wechsler Memory Scale also showed no clear differences between treatment groups (MD 2.57, 95% CI -2.39 to 7.53; 1 study, 20 participants; very low-certainty evidence). Only one study reported quality of life, but the data were skewed and baseline data were unbalanced across groups. Analysis of quality of life showed no clear differences between treatment groups (MD 14.86, 95% CI -42.26 to 71.98; 1 study, 20 participants; very low-certainty evidence). Only one study reported dropout and adverse events that led to discontinuation of treatment. Analysis of reported data showed no clear differences between treatment groups for this outcome (RR 1.38, 95% CI 0.28 to 6.91; 1 study, 25 participants; very low-certainty evidence). Adverse events occurred in only two participants who received ECT (worsening of preexisting coronary heart disease and a cognitive adverse effect). None of the included studies reported outcomes on suicide and social functioning. No RCTs comparing MST with other treatments were identified. Evidence regarding effects of MST on patients with TRD is currently insufficient. Our analyses of available data did not reveal clearly different effects between MST and ECT. We are uncertain about these findings because of risk of bias and imprecision of estimates. Large, long, well-designed, and well-reported trials are needed to further examine the effects of MST.


Hyperglycemia after SAH: predictors, associated complications, and impact on outcome.
Hyperglycemia is common after subarachnoid hemorrhage (SAH). The extent to which prolonged hyperglycemia contributes to in-hospital complications and poor outcome after SAH is unknown. We studied an inception cohort of 281 SAH patients with an initial serum glucose level obtained within 3 days of SAH onset and who had at least 7 daily glucose measurements between SAH days 0 and 10. We defined mean glucose burden (GB) as the average peak daily glucose level >5.8 mmol/L (105 mg/dL). Hospital complications were recorded prospectively, and 3-month outcome was assessed with the modified Rankin scale. The median GB was 1.8 mmol/L (33 mg/dL). Predictors of high-GB included age > or =54 years, Hunt and Hess grade III-V, poor Acute Physiology and Chronic Health Evaluation (APACHE)-2 physiological subscores, and a history of diabetes mellitus (all P< or =0.001). In a multivariate analysis, GB was associated with increased intensive care unit length of stay (P=0.003) and the following complications: congestive heart failure, respiratory failure, pneumonia, and brain stem compression from herniation (all P<0.05). After adjusting for Hunt-Hess grade, aneurysm size, and age, GB was an independent predictor of death (odds ratio, 1.10 per mmol/L; 95% CI, 1.01 to 1.21; P=0.027) and death or severe disability (modified Rankin scale score of 4 to 6; odds ratio, 1.17 per mmol/L; 95% CI 1.07 to 1.28, P<0.001). Hyperglycemia after SAH is associated with serious hospital complications, increased intensive care unit length of stay, and an increased risk of death or severe disability.


Effect of gold wire bonding process on angular correlated color temperature uniformity of white light-emitting diode.
Gold wire bonding is an important packaging process of lighting emitting diode (LED). In this work, we studied the effect of gold wire bonding on the angular uniformity of correlated color temperature (CCT) in white LEDs whose phosphor layers were coated by freely dispersed coating process. Experimental study indicated that different gold wire bonding impacts the geometry of phosphor layer, and it results in different fluctuation trends of angular CCT at different spatial planes in one LED sample. It also results in various fluctuating amplitudes of angular CCT distributions at the same spatial plane for samples with different wire bonding angles. The gold wire bonding process has important impact on angular uniformity of CCT in LED package.


Estrogen receptor beta activation prevents glucocorticoid receptor-dependent effects of the central nucleus of the amygdala on behavior and neuroendocrine function.
Neuropsychiatric disorders such as anxiety and depression have formidable economic and societal impacts. A dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis leading to elevated endogenous glucocorticoid levels is often associated with such disorders. Chronically high glucocorticoid levels may act upon the central nucleus of the amygdala (CeA) to alter normally adaptive responses into those that are maladaptive and detrimental. In addition to glucocorticoids, other steroid hormones such as estradiol and androgens can also modify hormonal and behavioral responses to threatening stimuli. In particular, estrogen receptor beta (ERbeta) agonists have been shown to be anxiolytic. Consequently, these experiments addressed the hypothesis that the selective stimulation of glucocorticoid receptor (GR) in the CeA would increase anxiety-like behaviors and HPA axis reactivity to stress, and further, that an ERbeta agonist could modulate these effects. Young adult female Sprague-Dawley rats were ovariectomized and bilaterally implanted via stereotaxic surgery with a wax pellet containing the selective GR agonist RU28362 or a blank pellet, to a region just dorsal to the CeA. Four days later, animals were administered the ERbeta agonist S-DPN or vehicle (with four daily sc injections). Anxiety-type behaviors were measured using the elevated plus maze (EPM). Central RU28362 implants caused significantly higher anxiety-type behaviors in the EPM and greater plasma CORT levels than controls given a blank central implant. Moreover, S-DPN treated animals, regardless of type of central implant, displayed significantly lower anxiety-type behaviors and post-EPM plasma CORT levels than vehicle treated controls or vehicle treated animals implanted with RU28362. These results indicate that selective activation of GR within the CeA is anxiogenic, and peripheral administration of an ERbeta agonist can overcome this effect. These data suggest that estradiol signaling via ERbeta prevents glucocorticoid-dependent effects of the CeA on behavior and neuroendocrine function.


Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.
YMDD variants of hepatitis B virus (HBV) emerge in some patients with chronic hepatitis B who receive lamivudine. YMDD variants were examined in 794 patients in 4 controlled studies of 1 year's duration. The long-term effects of YMDD variants were examined in a subset of patients treated up to 4 years. YMDD variants were detected by polymerase chain reaction (PCR) and restriction fragment-length polymorphism assays. After 1 year, YMDD variants were detected in 81 (24%) of 335 patients. In these patients, the median serum HBV DNA concentration at 1 year was <20% of the baseline level, and serum alanine transaminase (ALT) levels and liver histologic findings had significantly improved. In patients with YMDD variants who were treated for up to 4 years, median HBV DNA and ALT levels showed improvements. Sex, baseline body mass index, and HBV DNA level were associated with emergence of YMDD variants. Patients with YMDD variants losing clinical response with a significant increase in the HBV DNA and ALT levels may require additional therapy.


Living on the Societal Edge: India's Transgender Realities.
The transgendered people have played an important role in ancient Indian culture over millennia. They were portrayed in famous Hindu religious scriptures such as Ramayana and Mahabharata. They were given imperative roles in the royal courtyards of Mughal emperors. Their downfall came only at the onset of British rule during the eighteenth century when they were blacklisted and treated as criminal elements in society. Only in 2014, India's Supreme Court has made a landmark ruling by declaring that the transgendered people must have access to equal opportunity in society. In spite of this legal recognition, transgenders at large have been forced to live on the fringes of the contemporary Indian society. This article explores their past glories, present struggles and future ambitions in the world's largest democracy.


On a class of non-linear transformation cure rate models.
In this paper, we propose a generalization of the mixture (binary) cure rate model, motivated by the existence of a zero-modified (inflation or deflation) distribution, on the initial number of causes, under a competing cause scenario. This non-linear transformation cure rate model is in the same form of models studied in the past; however, following our approach, we are able to give a realistic interpretation to a specific class of proper transformation functions, for the cure rate modeling. The estimation of the parameters is then carried out using the maximum likelihood method along with a profile approach. A simulation study examines the accuracy of the proposed estimation method and the model discrimination based on the likelihood ratio test. For illustrative purposes, analysis of two real life data-sets, one on recidivism and another on cutaneous melanoma, is also carried out.


Multilevel cultural evolution: From new theory to practical applications.
Evolutionary science has led to many practical applications of genetic evolution but few practical uses of cultural evolution. This is because the entire study of evolution was gene centric for most of the 20th century, relegating the study and application of human cultural change to other disciplines. The formal study of human cultural evolution began in the 1970s and has matured to the point of deriving practical applications. We provide an overview of these developments and examples for the topic areas of complex systems science and engineering, economics and business, mental health and well-being, and global change efforts.


UGT1A10 is responsible for SN-38 glucuronidation and its expression in human lung cancers.
We previously reported that upregulation of glucuronidation activity catalyzed by uridine 5'diphosphoglucuronosyltransferase (UGT) is one of the mechanisms associated with irinotecan hydrochloride/7-ethyl-10-hydroaxycamptothecin (CPT-11/SN-38) resistance. In order to extend this result to the clinical setting, it is important to elucidate the role of SN-38 glucuronidation by UGT1A isoforms in CPT-11/SN-38 resistance in vivo. We examined SN-38 glucuronidation activity in COS-7 cells transfected with full-length cDNAs for human UGT isoforms (UGT1A1, UGT1A3, UGT1A6 and UGT1A10). The gene expression levels of UGT isoforms were examined in lung cancer cell lines and 14 lung cancer samples by semi, quantitative RT-PCR. Our HPLC assay results showed that both UGT1A1 and UGT1A10 are responsible for SN-38 glucuronidation. The levels of UGT1A1 and UGT1A10 expression in a CPT-11/SN-38-resistant cell line were increased compared to levels in the parent cell line. Furthermore, there was considerable intersubject variability in 14 lung cancer samples, but UGT1A1 and UGT1A10 expression levels were significantly correlated (r=0. 70, p=0.004). Our results suggest that not only UGT 1A1, but also UGT 1A10, plays an important role in detoxifying CPT-11/SN-38, leading to resistance to CPT-11/SN-38 in lung cancer.


Happy for Us not Them: Differences in neural activation in a vicarious reward task between family and strangers during adolescent development.
During adolescence social-interactions with other people become more relevant. One key aspect of these interactions is cooperative behavior. Cooperation relies on a set of cognitive and affective mechanisms. In this study, we focused on the mental ability to feel happy for another person's positive experience, called vicarious joy. We investigated the neural mechanisms of this ability using a false-choice vicarious reward fMRI task. Participants played a game where they could win monetary rewards for themselves, their mother, their father, and a stranger. A region-of-interest (ROI) analysis of the Nucleus Accumbens revealed robust activation in this region for personal reward as well as vicarious rewards for both parents. Vicarious reward for a stranger was not associated with activation within the Nucleus Accumbens. ROI activation was associated with self-reported vicarious joy for mother and father. A Prisoner's Dilemma game outside the scanner showed an increase in cooperative behavior until age 14 for parents and strangers, followed by a decline for the stranger but not for the parents. Together, these findings demonstrate that adolescence is an important time for developing ingroup-outgroup relations.


A limited association of generalized osteoarthritis with alleles at the type II collagen locus: COL2A1.
A significant genetic influence in osteoarthritis has been observed in the combination of Heberden's nodes and generalized osteoarthritis. We examined whether mutation in the gene encoding the major cartilage matrix protein type II collagen was responsible by comparing allele frequencies at the locus (COL2A1) in a group of 61 patients with nodal GOA with a control population and by analysing the COL2A1 genotypes of 21 affected sibling pairs. There were no significant allele differences but a slightly increased tendency over chance alone for affected siblings to have inherited the same COL2A1 alleles from their parents.


SURGICAL SAFETY CHECKLIST: FROM IDEA TO PRACTICAL APPLICATION.
Methods of surgical interventions performing, modifications, instruments used for operation became more developed every year. In spite of this fact, tendency of increase of the rate of iatrogenic errors took place and it was possible to prevent these mistakes by application of Surgical Safety Checklist. The «checklists» are easily available, not very expensive in practice and they are simple to use. An application of such questionnaires could improve the team work and understanding between members of the crew, which could influence directly on operation outcome. The article presents the history of creation of safety list, the analysis of efficacy of «checklist» application in clinical practice in different countries, information about controversial questions in «checklist», perspectives of its application.


IL-1β Production by Intermediate Monocytes Is Associated with Immunopathology in Cutaneous Leishmaniasis.
Cutaneous leishmaniasis due to Leishmania braziliensis infection is an inflammatory disease in which skin ulcer development is associated with mononuclear cell infiltrate and high levels of inflammatory cytokine production. Recently, NLRP3 inflammasome activation and IL-1β production have been associated with increased pathology in murine cutaneous leishmaniasis. We hypothesized that cutaneous leishmaniasis patients have increased expression of NLRP3, leading to high levels of IL-1β production. In this article we show high production of IL-1β in biopsy samples and Leishmania antigen-stimulated peripheral blood mononuclear cells from patients infected with L. braziliensis and reduced IL-1β levels after cure. IL-1β production positively correlated with the area of necrosis in lesions and duration of the lesions. The main source of IL-1β was intermediate monocytes (CD14++CD16+). Furthermore, our murine experiments show that IL-1β production in response to L. braziliensis was dependent on NLRP3, caspase-1, and caspase-recruiting domain (ASC). Additionally, we observed an increased expression of the NLRP3 gene in macrophages and the NLRP3 protein in intermediate monocytes from cutaneous leishmaniasis patients. These results identify an important role for human intermediate monocytes in the production of IL-1β, which contributes to the immunopathology observed in cutaneous leishmaniasis patients.


Synthesis and characterization of the crystal structure, the magnetic and the electrochemical properties of the new fluorophosphate LiNaFe[PO4]F.
The new compound LiNaFe[PO(4)]F was synthesized by a solid state reaction route, and its crystal structure was determined using neutron powder diffraction data. LiNaFe[PO(4)]F was characterized by (57)Fe Mössbauer spectroscopy, magnetic susceptibility, specific heat capacity, and electrochemical measurements. LiNaFe[PO(4)]F crystallizes with orthorhombic symmetry, space group Pnma, with a = 10.9568(6) Å, b = 6.3959(3) Å, c = 11.4400(7) Å, V = 801.7(1) Å(3) and Z = 8. The structure consists of edge-sharing FeO(4)F(2) octahedra forming FeFO(3) chains running along the b axis. These chains are interlinked by PO(4) tetrahedra forming a three-dimensional framework with the tunnels and the cavities filled by the well-ordered sodium and lithium atoms, respectively. The specific heat and magnetization measurements show that LiNaFe[PO(4)]F undergoes a three-dimensional antiferromagnetic ordering at T(N) = 20 K. The neutron powder diffraction measurements at 3 K show that each FeFO(3) chain along the b-direction is ferromagnetic (FM), while these FM chains are antiferromagnetically coupled along the a and c-directions with a non-collinear spin arrangement. The galvanometric cycling showed that without any optimization, one mole of alkali metal is extractable between 1.0 V and 5.0 V vs. Li(+)/Li with a discharge capacity between 135 and 145 mAh g(-1).


Associations between daily routines and social support among women with chronic fatigue syndrome.
Chronic fatigue syndrome (CFS) is characterised by extreme fatigue, as well as physical and cognitive symptoms. CFS is thrice as prevalent in women than in men. To compare women with and without CFS concerning social support and participation in daily routine occupations, and to assess the relationships between the two variables among women with CFS. This study included 110 women aged 24-69: 41 were diagnosed with CFS and 64 were not diagnosed with CFS. Participants completed the Occupational Questionnaire and the Medical Outcomes Study (MOS) Social Support Survey. Women with CFS reported lower participation in instrumental activities of daily living and work occupations than women without CFS. However, they spend more time resting and enjoying it. In addition, they reported less social support than women without CFS. Positive correlations were found between the number of close friends and time spent in play and leisure occupations and a negative correlation with sleep/rest. Women with CFS participate less in IADL and work occupations and more in rest/sleep than women without CFS and their social support is attenuated. Intervention plans should be developed for women with CFS, focussing on expanding their participation while considering their social support resources.


The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.
MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA-204-5p (miR-204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood. We performed RNA-sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR-204 five weeks after trans-aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR-204. The stretch induces miR-204 expression, and miR-204 inhibits the stretch-induced hypertrophic response of H9C2 cells. The mice lacking miR-204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno-associated virus serotype-9-mediated cardioselective miR-204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR-204 knockout mice following pressure overload suggested deregulation of apelin-receptor (APJ) signalling. We found that the stretch-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation and hypertrophy-related genes expression depend on the APJ, and both of these effects are subject to miR-204 levels. The dynamin inhibitor dynasore inhibited both stretch-induced APJ endocytosis and ERK1/2 activation. In contrast, the miR-204-induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR-204 increases the expression of ras-associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis. Our results show that miR-204 regulates trafficking of APJ and confers resistance to pressure overload-induced CH/CD, and boosting miR-204 can inhibit the development of CH/CD.


Effect of exercise, phenylbutazone, and furosemide on the plasma renin activity and angiotensin I in horses.
Circulating concentrations of angiotensin I and plasma renin activity (PRA) were determined in 45 Thoroughbreds before prerace medication (at rest), 1 to 1 1/2 hours before racing but after prerace medication (prerace), within 15 minutes after racing (immediately postrace), and between 1 to 2 hours after racing. Angiotensin I was measured by radioimmunoassay, and PRA was determined by the rate of generation of angiotensin I in plasma incubated at 37 C. Irrespective of prerace medication, there was a marked increase in angiotensin I (0.478 +/- 0.034 to 0.848 +/- 0.051 ng/ml) and PRA (0.191 +/- 0.018 to 0.522 +/- 0.061 ng/hour/ml) from the at-rest samples to the immediate-postrace samples, with the exception of anhidrotic horses in which increases in angiotensin I (0.7131 +/- 0.0794 to 0.8081 +/- 0.0608 ng/ml) and PRA (0.1635 +/- 0.0379 to 0.2176 +/- 0.0437 ng/hour/ml) were not as marked as they were in other horses. Administration of 1 mg of furosemide/kg 2 hours before racing caused an increase in PRA from 0.2438 +/- 0.0324 to 0.3706 +/- 0.1110 ng/hour/ml, whereas horses under the influence of 4 mg of phenylbutazone/kg had a decrease in PRA from 0.2090 +/- 0.0440 to 0.0669 +/- 0.0206 ng/hour/ml. Marked increases in angiotensin I and in PRA did not occur when horses were administered furosemide and phenylbutazone as prerace medication.


Rubinstein-Taybi syndrome.
A case of Rubinstein-Taybi syndrome (RTS) is presented. The syndrome is characterized by broad thumbs and great toes, peculiar facial features and mental retardation. The oral findings of the patient are reported, and the dental management is discussed.


G. H. Mead in the history of sociological ideas.
My aim is to discuss the history of the reception of George Herbert Mead's ideas in sociology. After discussing the methodological debate between presentism and historicism, I address the interpretations of those responsible for Mead's inclusion in the sociological canon: Herbert Blumer, Jürgen Habermas, and Hans Joas. In the concluding section, I assess these reconstructions of Mead's thought and suggest an alternative more consistent with my initial methodological remarks. In particular, I advocate a reconstruction of Mead's ideas that apprehends simultaneously its evolution over time and its thematic breadth. Such a historically minded reconstruction can be not only a useful corrective to possible anachronisms incurred by contemporary social theorists, but also a fruitful resource for their theory-building endeavors. Only then can meaningful and enriching dialogue with Mead begin.


Purification and characterization of a protein that binds to the recombination signal sequence of the immunoglobulin J kappa segment.
A protein that binds to the recombination signal sequence (RS) of the immunoglobulin J kappa segment was purified almost to homogeneity from the nuclear extract of a murine pre-B cell line 38B9. A similar binding protein was found in lymphoid cell lines but not in non-lymphoid cell lines. The binding activity was associated with a polypeptide with a molecular weight of 60,000. DNase I footprinting analysis demonstrated that this binding protein interacted with the heptamer and several 3' bases close to the heptamer. The Kd value of the J kappa RS binding protein to the J kappa RS was 1 nM. One base substitution in the heptamer of the J kappa RS greatly reduced the affinity of the J kappa RS binding protein. The high specificity of the binding site of the J kappa RS binding protein suggests that this protein may be involved in V-J recombination.


Effects of emedastine and cetirizine, alone and with alcohol, on actual driving of males and females.
Emedastine is registered in its country of origin (Japan) as an antihistamine for the indication of seasonal allergic rhinitis. Further research on the drug's sedating properties was needed to secure its registration elsewhere. The present study was designed to compare the effects of emedastine 2 mg and 4 mg twice daily after single and repeated doses, on actual driving performance versus those of cetirizine 10 mg once daily and placebo; and to determine how repeated doses of each drug interact with alcohol to affect driving. Each treatment was administered for 5 days to 19 healthy volunteers (nine men and ten women, aged 21-45 years) according to a four-period double-blind cross-over design. Driving performance was measured in a standardized test between 3 and 4 h after administration of the morning dose on days 1, 4 and 5. Alcohol, sufficient for achieving a blood alcohol concentration of 0.05 g/dl was given before driving on day 5 of each period. Both emedastine doses similarly and significantly impaired driving in every test. The effects of cetirizine were less. They were significant over days 1, 4 and 5 combined, although not separately. Women were more impaired by both drugs. Alcohol increased driving impairment similarly in every condition. Subjects were only able to discriminate the sedating and impairing effects of the first dose of emedastine 4 mg from placebo. Emedastine, in oral doses of 2 mg and 4 mg twice daily, is sedating and impairs driving. The drug could therefore constitute a traffic hazard and its users should be warned accordingly.


CFTR Functions as a Tumor Suppressor and Is Regulated by DNA Methylation in Colorectal Cancer.
Cystic fibrosis transmembrane conductance regulator (CFTR) was shown to be downregulated or silenced in carcinomas and acts as a candidate tumor suppressor gene. However, the function of CFTR gene in colorectal cancer (CRC) is still unclear. This aim of this study was to investigate the CFTR promoter methylation status and its impact on the expression and functional role of CFTR in CRC development. CFTR expression in CRC tissues and CRC cell lines was detected via quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The promoter methylation status of CFTR was measured using methylation-specific PCR (MSP). colony formation, transwell, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays were used to evaluate the effect of CFTR overexpression in CRC cell lines. qRT-PCR and IHC results indicated that CFTR expression was downregulated in the CRC tissues compared to the adjacent normal tissues. The promoter methylation status of CFTR was further analyzed in 70 CRC specimens. MSP validation showed methylation of CFTR promoter in 62.2% (45/70) of CRC tissues. The methylation of CFTR promoter was significantly associated with age (P=0.013) and lymph node metastasis (P=0.026) in CRC tissues. Results of transwell, MTT, and colony formation assays showed that CFTR overexpression inhibited the migration, invasion, and proliferation of CRC cells. CFTR expression was downregulated in CRC and promoter methylation may be responsible for this downregulation. Overexpression of CFTR may suppress CRC tumor growth by inhibiting the proliferation, migration, and invasion of CRC cells. CFTR promoter methylation was significantly correlated with lymph node metastasis; thus, CFTR may be a potential marker for lymph node metastasis of CRC.


Atomic layer deposition of palladium nanoparticles on a functional electrospun poly-cyclodextrin nanoweb as a flexible and reusable heterogeneous nanocatalyst for the reduction of nitroaromatic compounds.
We here show a rational approach for the fabrication of a flexible, insoluble catalytic electrospun nanoweb of cross-linked cyclodextrin (CD) for the reduction of nitroaromatics. CD nanofibers were produced by electrospinning an aqueous HP-β-CD solution containing a multifunctional cross-linker (i.e., 1,2,3,4-butanetetracarboxylic acid, BTCA) and were subsequently cross-linked by heat treatment, which led to an insoluble electrospun poly-CD nanoweb. The poly-CD nanoweb was decorated with Pd nanoparticles (Pd-NPs) by atomic layer deposition (ALD) technique over 20 cycles to give rise to a catalytic electrospun nanoweb (i.e., Pd@poly-CD). The formation of the Pd-NPs on the poly-CD nanofiber surface was clearly evidenced by TEM and STEM imaging, which displayed the homogeneously distributed Pd-NPs with a mean size of 4.34 nm. ICP-MS analysis revealed that the Pd content on the Pd@poly-CD nanoweb was 0.039 mg per mg of nanoweb. The catalytic performance of the Pd@poly-CD nanoweb was tested for the reduction of a nitroaromatic compound (i.e., 4-nitrophenol (4-NP)), and high catalytic performance of the Pd@poly-CD nanoweb was observed with a corresponding TOF value of 0.0316 min-1. XPS was used to explore the oxidation state of Pd atoms before and after the catalytic reduction of 4-NP, and no significant change was observed after catalytic reactions. In brief, the Pd@poly-CD nanoweb having handy, flexible, structural stability and reusability can be effectively used in environmental applications as a heterogeneous nanocatalyst for the reduction of toxic nitroaromatics.


From "Step Away" to "Stand Down": Tailoring a Smartphone App for Self-Management of Hazardous Drinking for Veterans.
US military veterans who screen positive for hazardous drinking during primary care visits may benefit from a mobile app. Step Away is an evidence-based mobile intervention system for the self-management of hazardous drinking. However, Step Away was not designed for veterans, and differences between veterans and civilians could limit the reach and effectiveness of the app with this population. The primary objective of this study was to repurpose Step Away to address the needs and preferences of the veteran primary care population. The Method for Program Adaptation through Community Engagement (M-PACE) model was used to guide the adaptation process. This model can serve as a generalizable approach that other researchers and intervention developers can follow to systematically tailor mobile health tools for a new population. Veteran patients who screened positive for hazardous drinking during a primary care visit (n=12) and peer providers employed by the US Veterans Health Administration (n=11) were recruited to systematically review Step Away and provide feedback on its content and presentation via Web-based surveys and a semistructured interview. Participant feedback was reviewed through an iterative process by key stakeholders who adjudicated which suggested modifications to the app could enhance engagement and effectiveness with veterans while maintaining program integrity. Usability ratings of the individual modules of Step Away were uniformly positive across patients and peers, as was the perceived utility of the app overall. Personalized feedback on the health consequences and costs of drinking, options for customization, and the measurement-based care capabilities of the app were viewed as facilitators of engagement. Conversely, lengthy text, small font, and a lack of interactive features were viewed as potential barriers with the older primary care population. Modifications to create a veteran version of the app (Stand Down: Think Before You Drink) included altering the appearance of the app to incorporate more veteran-centric content, adding links and options for resources and activities for veterans, and reducing the amount of text and adding veteran-specific references and common concerns and triggers for drinking in this population. The M-PACE model provided a systematic approach to repurpose Step Away to fit the needs and preferences of veteran primary care patients who engage in hazardous drinking. Stand Down may serve as an innovative, low-cost means of expanding access to care for veterans who engage in hazardous drinking.


Human Cytomegalovirus Infection Dysregulates the Localization and Stability of NICD1 and Jag1 in Neural Progenitor Cells.
Human cytomegalovirus (HCMV) infection of the developing fetus frequently results in major neural developmental damage. In previous studies, HCMV was shown to downregulate neural progenitor/stem cell (NPC) markers and induce abnormal differentiation. As Notch signaling plays a vital role in the maintenance of stem cell status and is a switch that governs NPC differentiation, the effect of HCMV infection on the Notch signaling pathway in NPCs was investigated. HCMV downregulated mRNA levels of Notch1 and its ligand, Jag1, and reduced protein levels and altered the intracellular localization of Jag1 and the intracellular effector form of Notch1, NICD1. These effects required HCMV gene expression and appeared to be mediated through enhanced proteasomal degradation. Transient expression of the viral tegument proteins of pp71 and UL26 reduced NICD1 and Jag1 protein levels endogenously and exogenously. Given the critical role of Notch signaling in NPC growth and differentiation, these findings reveal important mechanisms by which HCMV disturbs neural cell development in vitro. Similar events in vivo may be associated with HCMV-mediated neuropathogenesis during congenital infection in the fetal brain. Congenital human cytomegalovirus (HCMV) infection is the leading cause of birth defects that primarily manifest as neurological disabilities. Neural progenitor cells (NPCs), key players in fetal brain development, are the most susceptible cell type for HCMV infection in the fetal brain. Studies have shown that NPCs are fully permissive for HCMV infection, which causes neural cell loss and premature differentiation, thereby perturbing NPC fate. Elucidation of virus-host interactions that govern NPC proliferation and differentiation is critical to understanding neuropathogenesis. The Notch signaling pathway is critical for maintaining stem cell status and functions as a switch for differentiation of NPCs. Our investigation into the impact of HCMV infection on this pathway revealed that HCMV dysregulates Notch signaling by altering expression of the Notch ligand Jag1, Notch1, and its active effector in NPCs. These results suggest a mechanism for the neuropathogenesis induced by HCMV infection that includes altered NPC differentiation and proliferation.


Effect of molasses-based liquid supplements on digestibility of creeping bluestem and performance of mature cows on winter range.
Poor quality of tropical range forage leads to excessive weight loss and poor reproductive performance of beef cows. This research measured 1) the digestibility by steers fed creeping bluestem (Schizachyrium scoparium var. stoloniferum) diets supplemented with cane molasses (0 or 20% of diet DM) and(or) added CP (no added CP, urea, or soybean meal) and 2) the performance of mature cows grazing creeping bluestem range and supplemented with 1.6 kg/(cow.d) (DM basis) of either molasses-urea or molasses-cottonseed meal-urea, each containing 30% CP (DM basis). Bluestem averaged 4.7% CP and 37.0% in vitro OM digestion. In the digestion trial, diets supplemented with molasses had greater (P < .01) apparent OM digestibility but lower (P < .01) apparent NDF, ADF, and hemicellulose digestibilities than diets not supplemented with molasses. Apparent OM digestibility of diets supplemented with soybean meal was greater (P < .05) than that of diets supplemented with urea but not different (P > .05) from the control. While grazing range, mature cows supplemented with molasses-urea lost less (P < .05) body condition (-1.7 vs -1.3) than cows supplemented with molasses-cottonseed meal-urea. Treatment did not affect cow weight loss on range (P = .85) or pregnancy rate (P = .51). Cows supplemented with molasses-urea tended to wean a heavier calf (P = .09). When fed at 1.6 kg/(cow.d) to mature cows grazing range, a molasses-based supplement containing urea was of equal value to one containing a natural protein.


Surgical management of renal cell carcinoma associated with complex inferior vena caval thrombi.
The operative morbidity and mortality of radical nephrectomy are considerably higher when the vena cava is involved by the tumor. The prognostic significance of vena caval extension in this setting remains controversial. We reviewed our experience of vena caval thrombectomy specifically addressing prognostic factors. We retrospectively studied 96 patients treated at our institution between 1985 and 2001. The study population included 28 women and 68 men; (37 left- and 59 right-sided tumors). Twenty-seven patients had metastatic disease at presentation. Prognostic features (age, sex, race, side of tumor, embolization, tumor grade, tumor confinement by renal capsule, cephalic extent of thrombus, nodal status, and presence of distant metastasis) were evaluated using a Cox proportional hazards model (univariate and multivariate). These prognostic features were analyzed in the group as a whole and in the subgroup of patients who did not have metastatic disease at presentation and did not die perioperatively. There were 5 perioperative deaths. Extracapsular tumor extension and regional node involvement were present in 64% and 17% of the patients, respectively. Level of tumor thrombus were as follows: level I (41%), II (29%), III (7%), IV (15%). Fuhrman's grade was 2 in 17%, 3 in 45%, and 4 in 30% of the patients. For all 96 patients, median overall survival (OS) was 35 months. Five-year OS was 35%. The presence of distant metastasis at presentation did not significantly alter median OS (20 months with metastasis vs. 38 months without, P = 0.3), although this finding may have been confounded by selection. The presence of nodal metastasis was associated with decreased OS by multivariate analysis (P < 0.01). After exclusion of patients dying perioperatively and patients with metastasis at presentation, median OS and progression-free survival were 40 and 18 months, respectively (5-year OS was 40%). In the multivariate model, none of the factors examined were associated with OS, but age <58 years, and the presence of extracapsular tumor extension were associated with an increased risk of recurrence. In patients with renal tumors and extension of tumor thrombus into the vena cava, the level of propagation of the thrombus does not predict for OS. Selected patients with metastatic renal cancer may benefit from aggressive surgical resection of the primary tumor and associated tumor thrombus.


Catalysis of soluble hemoglobin oxidation by free iron on sickle red cell membranes.
Abnormal deposition of hemichrome on the inner aspect of the sickle red cell membrane promotes premature cell demise. The steps proximate to hemichrome formation in these cells are poorly understood. To test the hypothesis that the pathologic deposits of free ferric iron located on the inner aspect of sickle cell membranes would be redox active and promote oxidation of soluble oxyhemoglobin, we incubated native versus iron-stripped sickle or normal ghost membranes with oxyhemoglobin S. We found that sickle membranes exerted an exaggerated effect on methemoglobin formation in solution, an effect completely accounted for by their abnormal content of free iron. This ability of sickle membranes to promote hemoglobin oxidation was not diminished by catalase or by presence of a high-affinity, iron-inactivating chelator that is unable to remove membrane iron. Examination of those membranes likewise revealed that their free iron content promoted deposition of additional heme-protein. These results establish that the potential redox couple formed by membrane-associated ferric iron and cytoplasmic oxyhemoglobin is promotive of hemoglobin oxidation and deposition of hemichrome on the membrane. This predicts that removal of pathologic membrane iron might help prevent the detrimental formation of methemoglobin and hemichrome in vivo, insofar as this is accelerated by transition metal.


Drosophila Blimp-1 is a transient transcriptional repressor that controls timing of the ecdysone-induced developmental pathway.
Regulatory mechanisms controlling the timing of developmental events are crucial for proper development to occur. ftz-f1 is expressed in a temporally regulated manner following pulses of ecdysteroid and this precise expression is necessary for the development of Drosophila melanogaster. To understand how insect hormone ecdysteroids regulate the timing of FTZ-F1 expression, we purified a DNA binding regulator of ftz-f1. Mass spectroscopy analysis revealed this protein to be a fly homolog of mammalian B lymphocyte-induced maturation protein 1 (Blimp-1). Drosophila Blimp-1 (dBlimp-1) is induced directly by 20-hydroxyecdysone, and its product exists during high-ecdysteroid periods and turns over rapidly. Forced expression of dBlimp-1 and RNA interference analysis indicate that dBlimp-1 acts as a repressor and controls the timing of FTZ-F1 expression. Furthermore, its prolonged expression results in delay of pupation timing. These results suggest that the transient transcriptional repressor dBlimp-1 is important for determining developmental timing in the ecdysone-induced pathway.


Cutting edge: Expression of functional CD137 receptor by dendritic cells.
Interaction between dendritic cells (DCs) and T cells is a prerequisite for the initiation of a T cell response. The molecular nature of this interaction remains to be fully characterized. We report in this work that freshly isolated mouse splenic DCs and bone marrow-derived DCs express CD137 on the cell surface and in soluble form. Triggering CD137 increased the secretion of IL-6 and IL-12 from DCs. More importantly, infusion of an agonistic mAb to CD137 into naive mice enhanced the ability of DCs to stimulate T cell proliferation in response to both alloantigens and a nominal Ag in vitro. This enhancement of DC function is not mediated through activation of T cells, because the effect was also observed in RAG-1 knockout mice that lack T cells. Our findings implicate CD137 as an important receptor involved in the modulation of DC function.


The extracellular region of the receptor for advanced glycation end products is composed of two independent structural units.
The receptor for advanced glycation end products (RAGE) is an important cell surface receptor being pursued as a therapeutic target because it has been implicated in complications arising from diabetes and chronic inflammatory conditions. RAGE is a single membrane spanning receptor containing a very small approximately 40 residue cytosolic domain and a large extracellular region composed of 3 Ig-like domains. In this study, high level bacterial expression systems and purification protocols were generated for the extracellular region of RAGE (sRAGE) and the five permutations of single and tandem domain constructs to enable biophysical and structural characterization of its tertiary and quaternary structure. The structure and stability of each of these six protein constructs was assayed by biochemical methods including limited proteolysis, dynamic light scattering, CD, and NMR. A homology model of sRAGE was constructed to aid in the interpretation of the experimental data. Our results show that the V and C1 domains are not independent domains, but rather form an integrated structural unit. In contrast, C2 is attached to VC1 by a flexible linker and is fully independent. The interaction with a known RAGE ligand, Ca2+-S100B, was mapped to VC1, with the major contribution from the V domain but clearly defined secondary effects from the C1 domain. The implications of these results are discussed with respect to models for RAGE signaling.


Fish macroparasites as indicators of heavy metal pollution in river sites in Austria.
This paper describes two approaches to evaluate the use of fish macroparasites as bioindicators of heavy metal pollution at selected river stretches in Austria. Firstly changes in the diversity and richness of endoparasites of the cyprinid barbel, Barbrus barbuls (L.), were tested in relation to heavy metal contents in the aquatic system. Secondly, the bioaccumulation potential of cadmium, lead and zinc was assessed in the acanthocephalan, Pomphorhynchus laevis (Miller, 1776), and compared with that in the muscle, liver and intestine of its barbel host. The present results indicated that in order to validate the role of parasite community patterns related to heavy metal pollution, more investigations on food web dynamics, interelationships between parasites and the presence/absence of intermediate hosts will be essential. Heavy metal concentrations differed significantly between the organs of barbel and P. laevis (P=0.001) with levels up to 2860 fold in the parasite. The high level of heavy metal accumulation in P. laevis compared with that in its barbel host, suggests that despite variability in the parasite infrapopulation, host mobility and feeding behaviour, P. laevis is a most sensitive indicator of heavy metals in aquatic ecosystems.


Novel GNB1 mutations disrupt assembly and function of G protein heterotrimers and cause global developmental delay in humans.
Global developmental delay (GDD), often accompanied by intellectual disability, seizures and other features is a severe, clinically and genetically highly heterogeneous childhood-onset disorder. In cases where genetic causes have been identified, de novo mutations in neuronally expressed genes are a common scenario. These mutations can be best identified by exome sequencing of parent-offspring trios. De novo mutations in the guanine nucleotide-binding protein, beta 1 (GNB1) gene, encoding the Gβ1 subunit of heterotrimeric G proteins, have recently been identified as a novel genetic cause of GDD. Using exome sequencing, we identified 14 different novel variants (2 splice site, 2 frameshift and 10 missense changes) in GNB1 in 16 pediatric patients. One mutation (R96L) was recurrently found in three ethnically diverse families with an autosomal dominant mode of inheritance. Ten variants occurred de novo in the patients. Missense changes were functionally tested for their pathogenicity by assaying the impact on complex formation with Gγ and resultant mutant Gβγ with Gα. Signaling properties of G protein complexes carrying mutant Gβ1 subunits were further analyzed by their ability to couple to dopamine D1R receptors by real-time bioluminescence resonance energy transfer (BRET) assays. These studies revealed altered functionality of the missense mutations R52G, G64V, A92T, P94S, P96L, A106T and D118G but not for L30F, H91R and K337Q. In conclusion, we demonstrate a pathogenic role of de novo and autosomal dominant mutations in GNB1 as a cause of GDD and provide insights how perturbation in heterotrimeric G protein function contributes to the disease.


Proinflammatory Cytokines Are Soluble Mediators Linked with Ventricular Arrhythmias and Contractile Dysfunction in a Rat Model of Metabolic Syndrome.
Metabolic syndrome (MS) increases cardiovascular risk and is associated with cardiac dysfunction and arrhythmias, although the precise mechanisms are still under study. Chronic inflammation in MS has emerged as a possible cause of adverse cardiac events. Male Wistar rats fed with 30% sucrose in drinking water and standard chow for 25-27 weeks were compared to a control group. The MS group showed increased weight, visceral fat, blood pressure, and serum triglycerides. The most important increases in serum cytokines included IL-1β (7-fold), TNF-α (84%), IL-6 (41%), and leptin (2-fold), the latter also showing increased gene expression in heart tissue (35-fold). Heart function ex vivo in MS group showed a decreased mechanical performance response to isoproterenol challenge (ISO). Importantly, MS hearts under ISO showed nearly twofold the incidence of ventricular fibrillation. Healthy rat cardiomyocytes exposed to MS group serum displayed impaired contractile function and Ca2+ handling during ISO treatment, showing slightly decreased cell shortening and Ca2+ transient amplitude (23%), slower cytosolic calcium removal (17%), and more frequent spontaneous Ca2+ release events (7.5-fold). As spontaneous Ca2+ releases provide a substrate for ventricular arrhythmias, our study highlights the possible role of serum proinflammatory mediators in the development of arrhythmic events during MS.


Consumers discard a lot more food than widely believed: Estimates of global food waste using an energy gap approach and affluence elasticity of food waste.
This work provides an internationally comparable consumer food waste dataset based on food availability, energy gap and consumer affluence. Such data can be used for constructing meaningful and internationally comparable metrics on food waste, such as those for Sustainable Development Goal 12. The data suggests that consumer food waste follows a linear-log relationship with consumer affluence and starts to emerge when consumers reach a threshold of approximately $6.70/day/capita level of expenditure. These findings also imply that most empirical models overestimate consumption by not accounting for the possibility of food waste in their analysis. The results also show that the most widely cited global estimate of food waste is underestimated by a factor greater than 2 (214 Kcal/day/capita versus 527 Kcal/day/capita). Comparison with estimates of US consumer food waste based on national survey data shows this approach can reasonably reproduce the results without needing extensive data from national surveys.


Topologically ordered amorphous silica obtained from the collapsed siliceous zeolite, silicalite-1-F: a step toward "perfect" glasses.
A dense amorphous form of silica was prepared at high pressure from the highly compressible, siliceous zeolite, silicalite-1-F. Reverse Monte Carlo modeling of total X-ray scattering data shows that the structure of this novel amorphous form of SiO(2) recovered under ambient conditions is distinct from vitreous SiO(2) and retains the basic framework topology (i.e., chemical bonds) of the starting crystalline zeolite. This material is, however, amorphous over the different length scales probed by Raman and X-ray scattering due to strong geometrical distortions. This is thus an example of new topologically ordered, amorphous material with a different intermediate-range structure, a lower entropy with respect to a standard glass, and distinct physical and mechanical properties, eventually approaching those of an "ordered" or "perfect" glass. The same process in more complex aluminosilicate zeolites will, in addition, lead to an amorphous material which conserves the framework topology and chemical order of the crystal. The large volume collapse in this material may also be of considerable interest for new applications in shock wave absorption.


Single-Cell Stretching in Viscoelastic Fluids with Electronically Triggered Imaging for Cellular Mechanical Phenotyping.
Cellular mechanical phenotypes in connection to physiological and pathological states of cells have become a promising intrinsic biomarker for label-free cell analysis in various biological research and medical diagnostics. In this work, we present a microfluidic system capable of high-throughput cellular mechanical phenotyping based on a rapid single-cell hydrodynamic stretching in a continuous viscoelastic fluid flow. Randomly introduced single cells are first aligned into a single streamline in viscoelastic fluids before being guided to a flow splitting junction for consistent hydrodynamic stretching. The arrival of individual cells prior to the flow splitting junction can be detected by an electrical sensing unit, which produces a triggering signal to activate a high-speed camera for on-demand imaging of the cell motion and deformation through the flow splitting junction. Cellular mechanical phenotypes, including cell size and cell deformability, are extracted from the analysis of these captured single-cell images. We have evaluated the sensitivity of the developed microfluidic mechanical phenotyping system by measuring the synthesized hydrogel microbeads with known Young's modulus. With this microfluidic cellular mechanical phenotyping system, we have revealed the statistical difference in the deformability of microfilament disrupted, normal, and fixed NIH 3T3 fibroblast cells. Furthermore, with the implementation of a machine-learning-based classification of MCF-10A and MDA-MB-231 mixtures, our label-free cellular phenotyping system has achieved a comparable cell analysis accuracy (0.9:1, 5.03:1) with respect to the fluorescence-based flow cytometry results (0.97:1, 5.33:1). The presented microfluidic mechanical phenotyping technique will open new avenues for high-throughput and label-free single-cell analysis in diverse biomedical applications.


Effect of ryodipine on electromechanical parameters of heart and vessels, cAMP phosphodiesterase activity and swelling-contraction cycle of mitochondria.
2,6-Dimethyl-3,5-dimethoxycarbonyl-4-(o-difluoromethoxyphenyl)-1,4 -dihydropyridine (ryodipine, PP-1466), an effective Ca2+ channel blocker, diminishes contraction force and decreases duration of action potential in the frog heart ventricle strips. Dissociation constants K0.5 are 2 x 10(-7), 5 x 10(-7), and 10(-6) mol/l for PP-1466, nifedipine and nicardipine, respectively (at 0.25-0.3 Hz stimulation). One molecule of PP-1466 or nifedipine apparently interacts with two receptors on the channel (n = 0.5), nicardipine with one receptor (n = 1). The binding energy of PP-1466 and nifedipine increases at closed and diminishes at open channels which is in contrast to nicardipine, whose effect is irreversible. Thus, the site of nicardipine action differs from that of PP-1466 and nifedipine. PP-1466 (10(-8) mol/l--10(-6) mol/l) suppresses contraction force and diminishes frequency of spontaneous contractions of the rabbit atria, and also displays antagonism to the effect of Ca2+ upon rabbit auricle contractions. In the isolated rabbit aorta and portal vein PP-1466 is more antagonistic to contractions caused by Ca2+ than by epinephrine. Both competitive and non-competitive types of antagonism can be distinguished.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparative accuracy of typhoid diagnostic tools: A Bayesian latent-class network analysis.
Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population. We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity. We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 99% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting. In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded.


Cross-Sectional Variations in Structure and Function of Coral Reef Microbiome With Local Anthropogenic Impacts on the Kenyan Coast of the Indian Ocean.
Coral reefs face an increased number of environmental threats from anthropomorphic climate change and pollution from agriculture, industries and sewage. Because environmental changes lead to their compositional and functional shifts, coral reef microbial communities can serve as indicators of ecosystem impacts through development of rapid and inexpensive molecular monitoring tools. Little is known about coral reef microbial communities of the Western Indian Ocean (WIO). We compared taxonomic and functional diversity of microbial communities inhabiting near-coral seawater and sediments from Kenyan reefs exposed to varying impacts of human activities. Over 19,000 species (bacterial, viral and archaeal combined) and 4,500 clusters of orthologous groups of proteins (COGs) were annotated. The coral reefs showed variations in the relative abundances of ecologically significant taxa, especially copiotrophic bacteria and coliphages, corresponding to the magnitude of the neighboring human impacts in the respective sites. Furthermore, the near-coral seawater and sediment metagenomes had an overrepresentation of COGs for functions related to adaptation to diverse environments. Malindi and Mombasa marine parks, the coral reef sites closest to densely populated settlements were significantly enriched with genes for functions suggestive of mitigation of environment perturbations including the capacity to reduce intracellular levels of environmental contaminants and repair of DNA damage. Our study is the first metagenomic assessment of WIO coral reef microbial diversity which provides a much-needed baseline for the region, and points to a potential area for future research toward establishing indicators of environmental perturbations.


Tissue inhibitor of metalloproteinases 3-dependent microvascular endothelial cell barrier function is disrupted under septic conditions.
Sepsis is associated with dysfunction of microvascular endothelial cells (MVEC) leading to tissue edema and multiple organ dysfunction. Metalloproteinases can regulate MVEC function through processing of cell surface proteins, and tissue inhibitor of metalloproteinases 3 (TIMP3) regulates metalloproteinase activity in the lung following injury. We hypothesize that TIMP3 promotes normal pulmonary MVEC barrier function through inhibition of metalloproteinase activity. Naive Timp3(-/-) mice had significantly higher basal pulmonary microvascular Evans blue (EB) dye-labeled albumin leak vs. wild-type (WT) mice. Additionally, cecal-ligation/perforation (CLP)-induced sepsis significantly increased pulmonary microvascular EB-labeled albumin leak in WT but not Timp3(-/-) mice. Similarly, PBS-treated isolated MVEC monolayers from Timp3(-/-) mice displayed permeability barrier dysfunction vs. WT MVEC, evidenced by lower transendothelial electrical resistance and greater trans-MVEC flux of fluorescein-dextran and EB-albumin. Cytomix (equimolar interferon γ, tumor necrosis factor α, and interleukin 1β) treatment of WT MVEC induced significant barrier dysfunction (by all three methods), and was associated with a time-dependent decrease in TIMP3 mRNA and protein levels. Additionally, basal Timp3(-/-) MVEC barrier dysfunction was associated with disrupted MVEC surface VE-cadherin localization, and both barrier dysfunction and VE-cadherin localization were rescued by treatment with GM6001, a synthetic metalloproteinase inhibitor. TIMP3 promotes normal MVEC barrier function, at least partially, through inhibition of metalloproteinase-dependent disruption of adherens junctions, and septic downregulation of TIMP3 may contribute to septic MVEC barrier dysfunction.


Civilian Unemployment and Mental Health: The Moderating Impact of Alcohol Misuse in Returning National Guard.
Postdeployment civilian unemployment has become a common problem and source of additional stress for National Guard (NG) personnel. This study evaluated 126 California NG members, exploring the relationship between immediate postdeployment employment status and self-reported mental health symptoms, including evidence of alcohol misuse. Participants were recruited from a NG unit within the first 3 months after returning home in August 2011. Over one-third of participants reported being unemployed beyond the part-time NG commitment. Mental health symptoms were greater in those participants without civilian employment. Additionally, those participants with comorbid alcohol misuse with either depression or post-traumatic stress disorder were significantly more likely to lack civilian employment. Interaction testing revealed a significant interaction between employment status and alcohol misuse for both depression and post-traumatic stress disorder. Alcohol use was concluded to moderate the relationship between civilian unemployment and mental health symptoms. Results suggest that the part-time employment provided through NG service may serve as a protective factor in the development of negative psychological outcomes, except for cases where alcohol misuse is present.


Lost in Translation: Why Are Rates of Hypertension Control Getting Worse Over Time?
Treatment of hypertension to decrease rates of cardiovascular disease is the most well studied and most broadly applicable treatment in cardiovascular prevention. Blood pressure can be measured anywhere, not just in a physician's office; medications are readily available, inexpensive, and have highly favorable benefit/harm ratios with relatively minimal side effects; and stepped medication regimens can be prescribed in algorithmic fashion by a variety of practitioners. Yet overall hypertension control rates in the United States have never exceeded 60%, and the last 5-10 years have seen decreased, rather than increased, rates of control. Here, I describe the scale of this massive failure to deliver on the promise of preventive hypertension care; outline the populations most affected and the contemporaneous events that have impacted hypertension control; discuss the disparate paths of hypertension science and health care delivery; and highlight novel interventions, approaches, and future opportunities to bend the curve back toward improvements in hypertension control.


Defining the specialization of pediatric occupational therapy.
Occupational therapists who work primarily with children were surveyed regarding their skill levels in competencies that define pediatric practice. The subjects were 90 advanced practitioners who received specialty certification in pediatric occupational therapy in 1992 and 52 inexperienced practitioners with 5 or fewer years' experience. Respondents rated themselves from needs assistance to highly skilled on 94 competencies. A principle components analysis of the 142 surveys identified six primary constructs that described related areas of skill in the respondents: child evaluation, communication and consultation, working with families, understanding service provision systems, use of assistive technology, and neonatology and feeding. Child evaluation, with emphasis on developmental framework, analysis of sensory integration, and neuromotor function, was the strongest construct; respondents rated it the highest. Communication and consultation with team and family members also received high ratings. The advanced practitioner respondents rated themselves higher than the inexperienced practitioner respondents in 73 of the 80 competencies in the factors identified. The differences were greatest in the competencies of analysis of sensory processing and integration, analysis of neuromotor components, and consultation with other professionals. Findings suggest that advanced practitioners develop expertise in sensory integration and neuromotor analysis, and that evaluation and consultation are important skill areas in advanced occupational therapy practice.


Factors related to the continuation of employment during pregnancy among Japanese women.
To determine the relationship between the working situation (full-time housewife, stopped working during pregnancy, or currently employed) and the lifestyle factors, reasons for stopping work during pregnancy, and effects of working conditions in order to identify the factors that are related to the continuation of employment among pregnant Japanese women. In a cross-sectional study, a questionnaire was administered to pregnant women who visited an obstetrics clinic in a Tokyo suburb for an outpatient medical check-up during July and August 2004. The data of 530 healthy pregnant women were analyzed. The pregnant women who stopped working during their pregnancy had lower mental health scores than the full-time housewives and employed pregnant women. In each trimester, the employed pregnant women reported a shorter daytime sleep duration than the pregnant women who stopped working during their pregnancy and the full-time housewives. The reasons for stopping work during pregnancy were categorized as somatic symptoms due to pregnancy, working conditions, and a sense of values or social reasons. The employed women in the third trimester more often reported the availability of, and access to, a rest area in their company, compared to those in the first and second trimesters. The lifestyle factors of the pregnant women were different, based on their work situation. In particular, the employed pregnant women had a shorter daytime sleep duration. The pregnant women who stopped working during their pregnancy could have benefited from mental health support. In addition, the reasons for stopping work during pregnancy were different in the three trimesters. A flexible system is needed for working women that adapts to the physical changes that occur during pregnancy.


The effect of leukocyte elastase on tissue factor pathway inhibitor.
Tissue factor pathway inhibitor (TFPI) is a multivalent Kunitz-type inhibitor that directly inhibits factor Xa and, in a factor Xa-dependent fashion, also inhibits the factor VIIa/tissue factor (TF) catalytic complex. The Kunitz-2 domain in TFPI is needed for the binding and inhibition of factor Xa, while the Kunitz-1 domain appears to be responsible for binding factor VIIa in a quaternary factor Xa-TFPI-factor VIIa/TF inhibitory complex. Human leukocyte elastase (HLE) proteolytically cleaves TFPI between threonine-87 and threonine-88 within the polypeptide that links the Kunitz-1 and Kunitz-2 domains in the TFPI molecule. HLE treatment not only affects the ability of TFPI to inhibit factor VIIa/TF, but also dramatically reduces its inhibition of factor Xa. Both purified HLE and stimulated neutrophils regenerate TF activity from a preformed factor Xa-TFPI-factor VIIa/TF inhibitory complex. Kinetic analysis suggests that HLE cleavage does not effect the affinity of the initial encounter interaction between factor Xa and TFPI, whereas it markedly reduces the affinity of the final factor Xa:TFPI complex with Ki (final) values for untreated and HLE-treated TFPI of 58 pmol/L and 4.4 nmol/L, respectively. Thus, an epitope in the amino-terminal region of TFPI or a conformation of the TFPI molecule that requires the presence of this region is needed in concert with the Kunitz-2 domain to produce optimal inhibition of factor Xa by TFPI.


The larval specific lymphatic filarial ALT-2: induction of protection using protein or DNA vaccination.
Genes from the infective stage of lymphatic filarial parasites expressed at the time of host invasion have been identified as potential vaccine candidates. By screening an L3 cDNA library with sera from uninfected longstanding residents of an area endemic for onchocerciasis, so-called "endemic normals" (EN), we have cloned and characterized one such gene termed the abundant larval transcript two (ALT-2). The stage specificity of ALT-2 gene transcription and protein synthesis was confirmed by PCR using genespecific primers, and by western blot analysis of protein extracts from various stages of the parasite life cycle using specific antisera. Significant differences in antibody response to the recombinant ALT-2 were observed in endemic populations with differing clinical manifestations of lymphatic filariasis with an antibody response present in sera from 18 of 25 (72%) EN subjects compared to 9 of 25 (36%) with subclinical microfilaracmia (MF) and 14 of 25 (52%) of those with chronic lymphatic obstruction (CP) (P=0.01 for comparison of EN to CP or to MF). This differential responsiveness suggests that the protective immunity postulated to account for their uninfected status might be associated with a response to this protein. When the utility of ALT-2 as a vaccine candidate was tested in a murine model using either recombinant protein or a DNA vaccine construct, statistically significant protection was observed when compared to a control filarial gene product expressed across all stages of the parasite lifecycle (SXP-1; P=0.02 for protein and P=0.01 for the DNA vaccine) or compared to adjuvant alone. This level of protection indicates that this vaccine is a promising candidate for further development.


Regional variation in hip fracture incidence among Japanese hemodialysis patients.
Hip fracture incidence in Japanese hemodialysis patients is five-fold higher than in the general population, although the mechanisms underlying this difference are not fully understood. Substantial regional variation exists in hip fracture incidence in the general Japanese population, despite a uniform health care and insurance system and lack of ethnic and racial variation. In this study, we determined whether the regional variation seen in the general population also applies to hemodialysis patients in Japan. Standardized incidence ratios were calculated for each regional district, and regional variations of hip fracture incidence among hemodialysis patients were evaluated using data obtained from the Japanese Society for Dialysis Therapy registry (data collected from December 2007 to December 2008). Standardized hip fracture incidence ratios across the districts ranged from 0.71 to 1.29 for male and 0.49 to 1.36 for female hemodialysis patients. Incidence ratios tended to be higher in western Japan and lower in eastern Japan, suggesting that regional variation also exists among hemodialysis patients. Our findings suggest that common risk factors for hip fracture may be shared among the general population and hemodialysis patients. Further research aimed at identifying factors, including those associated with regional variation, may help decrease hip fracture incidence in both the general population and hemodialysis patients in Japan.


Rat bone mesenchymal stem cells exert antiproliferative effects on nicotine‑exposed T cells via iNOS production.
Adoptive transfer of bone marrow‑derived mesenchymal stem cells (BMSCs) significantly alleviates smoking‑induced chronic obstructive pulmonary disease (COPD) in rats. Considering the critical roles of T cells during COPD development, the present study aimed to further identify the molecular mechanisms underlying the antiproliferative effect of BMSCs on splenic T cells isolated from rats following chronic exposure to nicotine. Splenic T cells were co‑cultured with rat BMSCs at various ratios and subsequently, T‑cell proliferation was measured using the Cell Counting Kit‑8 assay. The effects of the inducible nitric oxide synthase (iNOS) inhibitor N‑nitro‑L‑arginine methylester (L‑NAME) and short hairpin (sh)RNA‑lentivirus‑mediated knockdown of iNOS in BMSCs on T‑cell proliferation were evaluated. The expression levels of iNOS and STAT5 phosphorylation in BMSCs and T cells, respectively, were assessed by reverse transcription‑quantitative PCR and western blotting. A higher ratio of BMSCs to T cells resulted in increased inhibition of T‑cell proliferation; therefore, the ratio of 1:20 was selected for further in vitro experiments. At a dose of 5 µM, L‑NAME displayed the strongest ability to reverse the antiproliferative effects of BMSCs in the co‑culture system. Both L‑NAME treatment and shRNA‑mediated knockdown of iNOS expression significantly decreased the suppressive effects of BMSCs, downregulated iNOS expression at the mRNA and protein levels in BMSCs, and enhanced STAT5 phosphorylation in T cells. BMSCs inhibited the proliferation of nicotine‑exposed T cells, which was associated with iNOS expression in BMSCs and decreased STAT5 phosphorylation in T cells. The present study indicated the potential mechanisms underlying the beneficial effects of BMSC infusion in patients with chronic smoking‑induced COPD and emphysema.


Attack rate and success of the parasitoid Diaeretiella rapae on specialist and generalist feeding aphids.
Lipaphis erysimi (Kaltenbach) is a specialist crucifer feeding aphid and Myzus persicae (Sulzer) is a generalist feeding aphid. The foraging behavior of Diaeretiella rapae (McIntosh), a parasitoid with the ability to parasitize both of these species, was assessed using a series of attack rate and success bioassays, with turnip, Brassica rapa var rapifera, as the host plant. The attack rate of D. rapae was significantly greater on L. erysimi than on M. persicae when aphids were feeding on turnip leaf discs in Petri dishes, irrespective of the aphid species upon which the parasitoids were originally reared. Attack rate bioassays with leaf discs absent, using both satiated and starved aphids, revealed that background chemistry and internal aphid chemistry may have small effects on attack rate. Excision of D. rapae pupae from mummy cases and subsequent use of the fully developed adults in attack rate bioassays showed that cues received by D. rapae at the time of adult emergence provide cues that prime D. rapae to attack L. erysimi at a greater rate than M. persicae. However, the relative success of D. rapae on these two aphid species, in terms of the percentage of attacks resulting in a successful adult parasitoid, was not significantly different.


The physiological role of mitochondrial calcium revealed by mice lacking the mitochondrial calcium uniporter.
Mitochondrial calcium has been postulated to regulate a wide range of processes from bioenergetics to cell death. Here, we characterize a mouse model that lacks expression of the recently discovered mitochondrial calcium uniporter (MCU). Mitochondria derived from MCU(-/-) mice have no apparent capacity to rapidly uptake calcium. Whereas basal metabolism seems unaffected, the skeletal muscle of MCU(-/-) mice exhibited alterations in the phosphorylation and activity of pyruvate dehydrogenase. In addition, MCU(-/-) mice exhibited marked impairment in their ability to perform strenuous work. We further show that mitochondria from MCU(-/-) mice lacked evidence for calcium-induced permeability transition pore (PTP) opening. The lack of PTP opening does not seem to protect MCU(-/-) cells and tissues from cell death, although MCU(-/-) hearts fail to respond to the PTP inhibitor cyclosporin A. Taken together, these results clarify how acute alterations in mitochondrial matrix calcium can regulate mammalian physiology.


Ultraviolet signals in birds are special.
Recent behavioural experiments have shown that birds use ultraviolet (UV)-reflective and fluorescent plumage as cues in mate choice. It remains controversial, however, whether such UV signals play a special role in sexual communication, or whether they are part of general plumage coloration. We use a comparative approach to test for a general association between sexual signalling and either UV-reflective or fluorescent plumage. Among the species surveyed, 72% have UV colours and there is a significant positive association between UV reflectance and courtship displays. Among parrots (Psittaciformes), 68% of surveyed species have fluorescent plumage, and again there is a strong positive association between courtship displays and fluorescence. These associations are not artefacts of the plumage used in courtship displays, being generally more 'colourful' because there is no association between display and colours lacking UV reflectance or fluorescence. Equally, these associations are not phylogenetic artefacts because all results remain unchanged when families or genera, rather than species, are used as independent data points. We also find that, in parrots, fluorescent plumage is usually found adjacent to UV-reflective plumage. Using a simple visual model to examine one parrot, the budgerigar Melopsittacus undulatus, we show that the juxtaposition of UV-reflective and fluorescent plumage leads to a 25-fold increase in chromatic contrast to the budgerigar's visual system. Taken together, these results suggest that signals based on UV contrast are of special importance in the context of active sexual displays. We review briefly six hypotheses on why this may be the case: suitability for short-range signalling; high contrast with backgrounds; invisibility to predators; exploitation of pre-existing sensory biases; advertisement of feather structure; and amplification of behavioural signals.


Structural and functional insights into phosphomannose isomerase: the role of zinc and catalytic residues.
Phosphomannose isomerase (PMI) is a housekeeping enzyme that is found in organisms ranging from bacteria to fungi to mammals and is important for cell-wall synthesis, viability and signalling. PMI is a zinc-dependent enzyme that catalyses the reversible isomerization between mannose 6-phosphate (M6P) and fructose 6-phosphate (F6P), presumably via the formation of a cis-enediol intermediate. The reaction is hypothesized to involve ring opening of M6P, the transfer of a proton from the C2 atom to the C1 atom and between the O1 and O2 atoms of the substrate, followed by ring closure resulting in the product F6P. Several attempts have been made to decipher the role of zinc ions and various residues in the catalytic function of PMI. However, there is no consensus on the catalytic base and the mechanism of the reaction catalyzed by the enzyme. In the present study, based on the structure of PMI from Salmonella typhimurium, site-directed mutagenesis targeting residues close to the bound metal ion and activity studies on the mutants, zinc ions were shown to be crucial for substrate binding. These studies also suggest Lys86 as the most probable catalytic base abstracting the proton in the isomerization reaction. Plausible roles for the highly conserved residues Lys132 and Arg274 could also be discerned based on comparison of the crystal structures of wild-type and mutant PMIs. PMIs from prokaryotes possess a low sequence identity to the human enzyme, ranging between 30% and 40%. Since PMI is important for the virulence of many pathogenic organisms, the identification of catalytically important residues will facilitate its use as a potential antimicrobial drug target.


Similarities and differences in health-related behavior clustering among older adults in Eastern and Western countries: A latent class analysis of global aging cohorts.
To quantify variations in health-related behaviors (HRB) clustering of older adults in Western and Eastern countries. Using six aging cohorts from the USA, England, Europe, Japan, Korea and China, latent class analysis was applied to access the clustering of smoking, alcohol consumption, physical activity and social activity. A total of 104 552 participants (55% women) aged ≥50 years in 2010 were included. Despite a different number of clusters identified, three consistent cluster profiles emerged: "Multiple-HRB" (ex-/never smoking, moderate drinking, frequent physical and social activity); "Inactives" (socially and physically inactive without other risk behaviors); and "(ex-)Smokers with Risk Behaviors". Sex and cohort variations were shown. For men in Western cohorts, "Multiple-HRB" was the predominant cluster, whereas their Asian counterparts were more likely to be members of the "Smokers with risk behavior" and "Inactives" clusters. Most women, particularly those in Asian cohorts, were never smokers and non-drinkers, and most of them belonged to the socially "Inactives" cluster. We provide a person-centered understanding of HRB clustering of older adults over selected countries by sex, informing tailored health promotion for the target population. Geriatr Gerontol Int 2019; 19: 930-937.


Sulfonylureas and their use in clinical practice.
Many anti-diabetic drugs with different mechanisms of action are now available for treatment of type 2 diabetes mellitus. Sulfonylureas have been extensively used for treatment of type 2 diabetes for nearly 50 years and, even in our times, are widely used for treatment of this devastating chronic illness. Here, we review some of the available data on sulfonylureas, evaluating their mechanism of action and their effects on glycemic control. We can conclude that sulfonylureas are still the most used anti-diabetic agents: maybe this is due to their lower cost, to the possibility of mono-dosing and to the presence of an association with metformin in the same tablet. However, sulfonylureas, especially the older ones, are linked to a greater prevalence of hypoglycemia, and cardiovascular risk; newer prolonged-release preparations of sulfonylureas are undoubtedly safer, mainly due to reducing hypoglycemia, and for this reason should be preferred.


Complex diversity in a mainly tropical group of ant parasitoids: Revision of the Orasema stramineipes species group (Hymenoptera: Chalcidoidea: Eucharitidae).
Twenty-nine species are recognized in the Orasema stramineipes species group, including 22 new species in what is now the most diverse species group of the New World ant-parasitoid genus Orasema Cameron. Orasema aenea Gahan syn. n. is synonymized with O. freychei (Gemignani), the holotype of which has been rediscovered. Orasema smithi Howard syn. n. is synonymized with Orasema minutissima Howard. Orasema violacea Gemignani syn. n. and its replacement name Orasema gemignanii De Santis syn. n. are synonymized with O. worcesteri (Girault). Twenty-two species are described as new: O. arimbome Dominguez, Heraty Burks n. sp., O. carchi Heraty, Burks Dominguez n. sp., and the following 20 species by Burks, Heraty Dominguez: O. chunpi n. sp., O. cozamalotl n. sp., O. evansi n. sp., O. hyarimai n. sp., O. kaspi n. sp., O. kulli n. sp., O. llanthu n. sp., O. llika n. sp., O. mati n. sp., O. nyamo n. sp., O. pirca n. sp., O. pisi n. sp., O. qillu n. sp., O. qincha n. sp., O. rikra n. sp., O. taku n. sp., O. tapi n. sp., O. torrensi n. sp., O. woolleyi n. sp., and O. yaax n. sp. The stramineipes-group has much greater diversity in tropical America than outside the tropics, and is much more diverse than its sister-group, the susanae-group, which is mainly present in temperate regions of Argentina. A hypothesis of phylogenetic relationships is proposed based on an analysis of 28S-D2 rDNA and cytochrome oxidase I (COI) for 14 stramineipes-group species. Species concepts were established using both morphological and molecular data. Most species in the stramineipes-group have a tropical distribution, with only a few species in temperate regions. Ant hosts for the group include Pheidole Westwood, Wasmannia Forel, and possibly Solenopsis Westwood (Formicidae: Myrmicinae). Orasema minutissima is a common parasitoid of Wasmannia auropunctata Roger in the Caribbean and has the potential to be a biological control agent in other areas of the world. Two distinct size morphs are recognized for O. minutissima, which are correlated with attacking either Wasmannia (small morph) or different castes of Pheidole (medium to large size morphs). Some species of Orasema have been regarded as pests due to scarring or secondary infections of leaves or fruit of banana, yerba mate or blueberry, but outbreaks are rare and the threat is usually temporary.


Molecular Characterization of Nasal Methicillin-Resistant Staphylococcus aureus Isolates Showing Increasing Prevalence of Mupirocin Resistance and Associated Multidrug Resistance following Attempted Decolonization.
Sequential methicillin-resistant Staphylococcus aureus (MRSA) isolates from patients following attempted mupirocin nasal decolonization showed an increase in mupirocin resistance (MR) from 6.6% to 20%. MR isolates from patients who failed decolonization yielded indistinguishable spa types and carried multiple antimicrobial and antiseptic resistance genes, which may guide infection control and prevention.


Adopting systems models for multiple incident analysis: utility and usability.
This study aims to present two system models widely used in Human Factors and Ergonomics (HF/E) and evaluate whether the models are adoptable to England's national patient safety team in improving the exploration and understanding of multiple incident reports of an active patient safety issue and the development of the remedial actions for a potential National Patient Safety Alert. The existing process of examining multiple incidents is based on inductive thematic analysis and forming the remedial actions is based on barrier analysis of intelligence on potential solutions. However, no formal systems models evaluated in this study have been used. AcciMap and Systems Engineering Initiative for Patient Safety (SEIPS) were selected, applied and evaluated to the analysis of two different sets of patient safety incidents: (i) incidents concerning ingestion of superabsorbent polymer granules and (ii) incidents concerning the interruption in use of High Nasal Flow Oxygen. The first set was analysed by the first author and the utility and usability were reflected. The second set was analysed collectively by a purposeful sample of patient safety team members, who create the National Patient Safety Alerts from incident-level data and information. All of them attended a 30-min video-based training and a 1.5 h case-based online workshop. Post-workshop individual interviews were conducted to evaluate their perceived utility and usability of each model. The patient safety team showed overwhelming support for the utility of the system models as a 'framework' that provides a systematic, structured way of looking at an issue and examining the causes, whilst also sharing concerns regarding their usability. AcciMap was viewed useful particularly in providing a visual comprehensive overview of the issue but considered chaotic by some participants due to many arrows between factors. SEIPS was perceived easier to understand due to the familiarity of the structure (Donbedian's model), but the non-hierarchical format of SEIPS was considered less useful. The participants of the study agreed with the high level of utility of both models for their unique strengths, but shared some concern for the usability of them in terms of complexity and further training/coaching time would be required to adopt these models in their daily practices. It is recommended that the gap between HF/E practitioners and patient safety practitioners can be narrowed by strengthening education, and coaching and mentoring relationships between the two groups, led by the increasing number of healthcare practitioners who embrace their membership to HF/E practice.


Hypoalbuminemia-related platelet hypersensitivity in two dogs with nephrotic syndrome.
Platelet aggregation studies in 2 dogs with nephrotic syndrome disclosed increased platelet sensitivity to a low dose of adenosine diphosphate. Subsequent studies with isolated platelets and plasma indicated that a plasma factor was responsible primarily for inducing platelet hypersensitivity. The increased platelet aggregation response was corrected by increasing the albumin concentration of the plasma. The study suggested an important role for albumin in modulating platelet aggregation and may partially explain the tendency toward thrombosis noted in hypoalbuminemic dogs with nephrotic syndrome.


Degeneration of structural brain networks is associated with cognitive decline after ischaemic stroke.
Over one-third of stroke patients has long-term cognitive impairment. The likelihood of cognitive dysfunction is poorly predicted by the location or size of the infarct. The macro-scale damage caused by ischaemic stroke is relatively localized, but the effects of stroke occur across the brain. Structural covariance networks represent voxelwise correlations in cortical morphometry. Atrophy and topographical changes within such distributed brain structural networks may contribute to cognitive decline after ischaemic stroke, but this has not been thoroughly investigated. We examined longitudinal changes in structural covariance networks in stroke patients and their relationship to domain-specific cognitive decline. Seventy-three patients (mean age, 67.41 years; SD = 12.13) were scanned with high-resolution magnetic resonance imaging at sub-acute (3 months) and chronic (1 year) timepoints after ischaemic stroke. Patients underwent a number of neuropsychological tests, assessing five cognitive domains including attention, executive function, language, memory and visuospatial function at each timepoint. Individual-level structural covariance network scores were derived from the sub-acute grey-matter probabilistic maps or changes in grey-matter probability maps from sub-acute to chronic using data-driven partial least squares method seeding at major nodes in six canonical high-order cognitive brain networks (i.e. dorsal attention, executive control, salience, default mode, language-related and memory networks). We then investigated co-varying patterns between structural covariance network scores within canonical distributed brain networks and domain-specific cognitive performance after ischaemic stroke, both cross-sectionally and longitudinally, using multivariate behavioural partial least squares correlation approach. We tested our models in an independent validation data set with matched imaging and behavioural testing and using split-half validation. We found that distributed degeneration in higher-order cognitive networks was associated with attention, executive function, language, memory and visuospatial function impairment in sub-acute stroke. From the sub-acute to the chronic timepoint, longitudinal structural co-varying patterns mirrored the baseline structural covariance networks, suggesting synchronized grey-matter volume decline occurred within established networks over time. The greatest changes, in terms of extent of distributed spatial co-varying patterns, were in the default mode and dorsal attention networks, whereas the rest were more focal. Importantly, faster degradation in these major cognitive structural covariance networks was associated with greater decline in attention, memory and language domains frequently impaired after stroke. Our findings suggest that sub-acute ischaemic stroke is associated with widespread degeneration of higher-order structural brain networks and degradation of these structural brain networks may contribute to longitudinal domain-specific cognitive dysfunction.


From project aid to sustainable HIV services: a case study from Zambia.
Sustainable service delivery is a major challenge in the HIV response that is often not adequately addressed in project implementation. Sustainable strategies must be built into project design and implementation to enable HIV efforts to continue long after donor-supported projects are completed. This paper presents the experiences in operational sustainability of Family Health International's Zambia Prevention, Care and Treatment Partnership in Zambia, which is supported by the US President's Emergency Plan for AIDS Relief through United States Agency for International Development (October 2004 to September 2009). The partnership worked with Zambia's Ministry of Health to scale up HIV clinical services in five of the country's nine provinces, reaching 35 districts and 219 facilities. It provided technical and financial support from within the ministry's systems and structures. By completion of the project, 10 of the 35 districts had graduated beyond receiving ongoing technical support. By working within the ministry's policies, structures and systems, the partnership was able to increase the ministry's capacity to add a comprehensive HIV service delivery component to its health services. Ministry structures were improved through renovations of health facilities, training of healthcare workers, procurement of essential equipment, and establishment of a quality assurance plan to ensure continued quality of care. The quality assurance tools were implemented by both the ministry and project staff as the foundation for technical graduation. Facilities that met all the quality criteria for more than six months were graduated from project technical support, as were districts where most supported facilities met the criteria. The district health offices then provided ongoing supervision of services. This predetermined "graduation" exit strategy, with buy in of the provincial and district health offices, set the stage for continued delivery of high-quality HIV services. Achieving operational sustainability in a resource-limited setting is feasible. Developing and institutionalizing a quality assurance/quality improvement system is the basis on which facilities and districts can move beyond project support and, therefore, sustain services. Quality assurance/quality improvement tools should be based on national standards, and project implementation should use and improve existing health system structures.


La Crosse viremias in white-tailed deer and chipmunks exposed by injection or mosquito bite.
To further understand the role of wild mammals in the maintenance of La Crosse virus (LACV) in nature, we investigated the effects of inoculation method and virus source on the duration and amplitude of LACV viremia in vertebrate hosts. Earlier work suggested that deer are not sufficiently susceptible to LACV to play an important role in its maintenance. We re-evaluated the susceptibility of deer since subsequent studies showed that they constitute 65% of Aedes triseriatus blood meals, and thus would be exposed frequently to the virus. In our study, deer developed higher and longer viremia following exposure to LACV by infected Ae. triseriatus than those previously reported by inoculation with needle and syringe. However, susceptible Ae. triseriatus that fed on these viremic animals did not become infected. Because a large number of uninfected mosquitoes can feed upon a viremic deer in nature, we believe that deer should not be disregarded completely as a possible amplifier in the LACV transmission cycle. We also infected chipmunks to determine if there were significant differences in viremia response from mosquito delivery of virus to the chipmunk host, compared with artificial exposure by injection. Chipmunks exposed to infected mosquitoes had higher and longer viremias than the ones produced by intramuscular injection of an LACV suspension. These findings show the importance of using LACV infected mosquitoes for transmission experiments in mammals.