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Abstract: Living one's Christian faith and providing appropriate spiritual care in professional nursing practice can seem challenging. The IHS Global® Saline Process™ course equips Christian healthcare workers with knowledge and tools to provide appropriate spiritual support and consider how God is calling them to share his truth and love. After participating in a Saline Process™ course, ongoing engagement helps clinicians grow in practicing what they have learned. Nurses Christian Fellowship International (NCFI) partners with IHS Global® to bring the Saline Process™ to Christian nurses and other clinicians around the world, building the community of providers offering whole-person care., (Copyright © 2024 InterVarsity Christian Fellowship.)

Background: A multi-phase Canadian study was conducted as part of a large-scale community and academic research partnership focused on understanding and improving the employment experiences of people with intellectual disabilities., Method: This multi-method study utilized a sequential approach, using findings from qualitative interviews (n = 28) to inform an online survey (n = 149). Participants were invited to share their experiences with paid employment or with persons with intellectual disabilities., Results: Thematic analysis of data across interview and survey findings resulted in six themes: (1) assumptions and attitudes, (2) knowledge and awareness, (3) accessibility of processes, (4) use of accommodations, (5) workplace relationships, and (6) supports and resources., Conclusions: A holistic and systemic approach has the potential to improve inclusive employment experiences of people with intellectual disabilities. Action is needed mainly at the policy and employer level to reduce barriers and improve on facilitating measures reinforced by the themes shared in this study., (© 2024 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Objective of this study is to quantify benefit-risk tradeoffs pertaining to potential gene therapies among adults and parents/caregivers of children with sickle cell disease (SCD). A discrete-choice experiment survey was developed in which respondents selected their preferred treatment alternatives in a series of experimentally controlled pairs of hypothetical gene therapies and a "no gene therapy" option. Gene therapy alternatives were defined based on the chance of eliminating SCD symptoms, expected increases in life expectancy they could offer, treatment-related risk of death, and potential increases in lifetime cancer risk. Respondents made selections based on their current disease severity and in the context of expectations of worsened disease. Three clinical sites and 1 patient organization recruited 174 adult patients and 109 parents of children with SCD to complete the survey. Adult and parent respondents were generally willing to choose gene therapies, but the adults required higher expected levels of efficacy (ie, higher chance of eliminating symptoms) than parents to choose gene therapies that conferred mortality risks of ≥10%. When adults and parents of children with less severe symptoms were asked to consider scenarios of higher levels of disease severity, the increased risk tolerance, and the lowest acceptable level of efficacy for gene therapies with mortality risks dropped by >50%. Baseline SCD symptoms are a major driver of gene therapy acceptability. Adults and parents of patients with milder symptoms may prefer other treatment options; however, an expectation of symptoms deterioration triggers strong reassessment of the acceptable benefit-risk balance of this novel technology., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models. Kptn -/- mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants. Molecular and structural analysis of Kptn-/- mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1. By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Compelling evidence suggests that human cognitive function is strongly influenced by genetics. Here, we conduct a large-scale exome study to examine whether rare protein-coding variants impact cognitive function in the adult population (n = 485,930). We identify eight genes (ADGRB2, KDM5B, GIGYF1, ANKRD12, SLC8A1, RC3H2, CACNA1A and BCAS3) that are associated with adult cognitive function through rare coding variants with large effects. Rare genetic architecture for cognitive function partially overlaps with that of neurodevelopmental disorders. In the case of KDM5B we show how the genetic dosage of one of these genes may determine the variability of cognitive, behavioral and molecular traits in mice and humans. We further provide evidence that rare and common variants overlap in association signals and contribute additively to cognitive function. Our study introduces the relevance of rare coding variants for cognitive function and unveils high-impact monogenic contributions to how cognitive function is distributed in the normal adult population., (© 2023. The Author(s).)

Neoantigens derived from somatic mutations are specific to cancer cells and are ideal targets for cancer immunotherapy. KRAS is the most frequently mutated oncogene and drives the pathogenesis of several cancers. Here we show the identification and development of an affinity-enhanced T cell receptor (TCR) that recognizes a peptide derived from the most common KRAS mutant, KRAS G12D , presented in the context of HLA-A*11:01. The affinity of the engineered TCR is increased by over one million-fold yet fully able to distinguish KRAS G12D over KRAS WT . While crystal structures reveal few discernible differences in TCR interactions with KRAS WT versus KRAS G12D , thermodynamic analysis and molecular dynamics simulations reveal that TCR specificity is driven by differences in indirect electrostatic interactions. The affinity enhanced TCR, fused to a humanized anti-CD3 scFv, enables selective killing of cancer cells expressing KRAS G12D . Our work thus reveals a molecular mechanism that drives TCR selectivity and describes a soluble bispecific molecule with therapeutic potential against cancers harboring a common shared neoantigen., (© 2022. The Author(s).)

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions., (© 2021. The Author(s).)

The highly evolutionarily conserved transport protein particle (TRAPP) complexes (TRAPP II and III) perform fundamental roles in subcellular trafficking pathways. Here we identified biallelic variants in TRAPPC10, a component of the TRAPP II complex, in individuals with a severe microcephalic neurodevelopmental disorder. Molecular studies revealed a weakened interaction between mutant TRAPPC10 and its putative adaptor protein TRAPPC2L. Studies of patient lymphoblastoid cells revealed an absence of TRAPPC10 alongside a concomitant absence of TRAPPC9, another key TRAPP II complex component associated with a clinically overlapping neurodevelopmental disorder. The TRAPPC9/10 reduction phenotype was recapitulated in TRAPPC10-/- knockout cells, which also displayed a membrane trafficking defect. Notably, both the reduction in TRAPPC9 levels and the trafficking defect in these cells could be rescued by wild type but not mutant TRAPPC10 gene constructs. Moreover, studies of Trappc10-/- knockout mice revealed neuroanatomical brain defects and microcephaly, paralleling findings seen in the human condition as well as in a Trappc9-/- mouse model. Together these studies confirm autosomal recessive TRAPPC10 variants as a cause of human disease and define TRAPP-mediated pathomolecular outcomes of importance to TRAPPC9 and TRAPPC10 mediated neurodevelopmental disorders in humans and mice., Competing Interests: The authors have declared that no competing interests exist.

Despite significant advances in resolution, the potential for cryo-electron microscopy (EM) to be used in determining the structures of protein-drug complexes remains unrealized. Determination of accurate structures and coordination of bound ligands necessitates simultaneous fitting of the models into the density envelopes, exhaustive sampling of the ligand geometries, and, most importantly, concomitant rearrangements in the side chains to optimize the binding energy changes. In this article, we present a flexible-fitting pipeline where molecular dynamics flexible fitting (MDFF) is used to refine structures of protein-ligand complexes from 3 to 5 Å electron density data. Enhanced sampling is employed to explore the binding pocket rearrangements. To provide a model that can accurately describe the conformational dynamics of the chemically diverse set of small-molecule drugs inside MDFF, we use QM/MM and neural-network potential (NNP)/MM models of protein-ligand complexes, where the ligand is represented using the QM or NNP model, and the protein is represented using established molecular mechanical force fields (e.g., CHARMM). This pipeline offers structures commensurate to or better than recently submitted high-resolution cryo-EM or X-ray models, even when given medium to low-resolution data as input. The use of the NNPs makes the algorithm more robust to the choice of search models, offering a radius of convergence of 6.5 Å for ligand structure determination. The quality of the predicted structures was also judged by density functional theory calculations of ligand strain energy. This strain potential energy is found to systematically decrease with better fitting to density and improved ligand coordination, indicating correct binding interactions. A computationally inexpensive protocol for computing strain energy is reported as part of the model analysis protocol that monitors both the ligand fit as well as model quality.

Background: To reduce risk of antiretroviral resistance when stopping efavirenz (EFV)-based antiretroviral treatment (ART), staggered discontinuation of antiretrovirals (an NRTI tail) is recommended. However, no data directly support this recommendation., Objectives: We evaluated the prevalence of HIV drug resistance mutations in pregnant women living with HIV who stopped efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) postpartum., Method: In accordance with the prevailing Botswana HIV guidelines at the time, women with pre-treatment CD4 > 350 cells/mm 3 , initiated EFV/FTC/TDF in pregnancy and stopped ART at 6 weeks postpartum if formula feeding, or 6 weeks after weaning. A 7-day tail of FTC/TDF was recommended per Botswana guidelines. HIV-1 RNA and genotypic resistance testing (bulk sequencing) were performed on samples obtained 4-6 weeks after stopping EFV. Stanford HIV Drug Resistance Database was used to identify major mutations., Results: From April 2014 to May 2015, 74 women who had stopped EFV/FTC/TDF enrolled, with median nadir CD4 of 571 cells/mm 3 . The median time from cessation of EFV to sample draw for genotyping was 5 weeks (range: 3-13 weeks). Thirty-two (43%) women received a 1-week tail of FTC/TDF after stopping EFV. HIV-1 RNA was available from delivery in 70 (95%) women, 58 (83%) of whom had undetectable delivery HIV-1 RNA (< 40 copies/mL). HIV-1 RNA was available for 71 women at the time of genotyping, 45 (63%) of whom had HIV-1 RNA < 40 copies/mL. Thirty-five (47%) of 74 samples yielded a genotype result, and four (11%) had a major drug resistance mutation: two with K103N and two with V106M. All four resistance mutations occurred among women who did not receive an FTC/TDF tail (4/42, 10%), whereas no mutations occurred among 18 genotyped women who had received a 1-week FTC/TDF tail ( p = 0.053)., Conclusions: Viral rebound was slow following cessation of EFV/FTC/TDF in the postpartum period. Use of an FTC/TDF tail after stopping EFV was associated with the lower prevalence of subsequent NNRTI drug resistance mutation., Competing Interests: The authors declare that no competing interests exist., (© 2020. The Authors.)

Background: The evidence associating diet and risk of multiple sclerosis is inconclusive., Objective: We investigated associations between dietary patterns and risk of a first clinical diagnosis of central nervous system demyelination, a common precursor to multiple sclerosis., Methods: We used data from the 2003-2006 Ausimmune Study, a case-control study examining environmental risk factors for a first clinical diagnosis of central nervous system demyelination, with participants matched on age, sex and study region. Using data from a food frequency questionnaire, dietary patterns were identified using principal component analysis. Conditional logistic regression models ( n  = 698, 252 cases, 446 controls) were adjusted for history of infectious mononucleosis, serum 25-hydroxyvitamin D concentrations, smoking, race, education, body mass index and dietary misreporting., Results: We identified two major dietary patterns - healthy (high in poultry, fish, eggs, vegetables, legumes) and Western (high in meat, full-fat dairy; low in wholegrains, nuts, fresh fruit, low-fat dairy), explaining 9.3% and 7.5% of variability in diet, respectively. A one-standard deviation increase in the healthy pattern score was associated with a 25% reduced risk of a first clinical diagnosis of central nervous system demyelination (adjusted odds ratio 0.75; 95% confidence interval 0.60, 0.94; p  = 0.011). There was no statistically significant association between the Western dietary pattern and risk of a first clinical diagnosis of central nervous system demyelination., Conclusion: Following healthy eating guidelines may be beneficial for those at high risk of multiple sclerosis.

Vine weevil, Otiorhynchus sulcatus F. (Coleoptera: Curculionidae), is an economically important pest species in many soft-fruit and ornamental crops. Economic losses arise from damage to the roots, caused by larvae, and to the leaves, caused by adults. As adults are nocturnal and larvae feed below ground, infestations can be missed initially, with controls applied too late. In the absence of a vine weevil sex or aggregation pheromone, the development of an effective semiochemical lure for better management of this pest is likely to focus on host-plant volatiles. Here, we investigate the electrophysiological and behavioral responses of adult vine weevils to volatile organic compounds (VOCs) originating from their preferred host plant Euonymus fortunei, and synthetic VOCs associated with this host when presented individually or as blends. Consistent electroantennographic responses were observed to a range of generalist VOCs. Behavioral responses of weevils to VOCs, when presented individually, were influenced by concentration. Vine weevil adults showed directional movement toward a mixture of seven plant volatiles, methyl salicylate, 1-octen-3-ol, (E)-2-hexenol, (Z)-3-hexenol, 1-hexanol, (E)-2-pentenol, and linalool, even though no, or negative, responses were recorded to each of these compounds presented individually. Similarly, vine weevils showed directional movement toward a 1:1 ratio mixture of (Z)-2-pentenol and methyl eugenol. Results presented here point to the importance of blends of generalist compounds and their concentrations in the optimization of a lure.

Objectives: The aim of this study was to provide an ultrasound-based super-resolution methodology that can be implemented using clinical 2-dimensional ultrasound equipment and standard contrast-enhanced ultrasound modes. In addition, the aim is to achieve this for true-to-life patient imaging conditions, including realistic examination times of a few minutes and adequate image penetration depths that can be used to scan entire organs without sacrificing current super-resolution ultrasound imaging performance., Methods: Standard contrast-enhanced ultrasound was used along with bolus or infusion injections of SonoVue (Bracco, Geneva, Switzerland) microbubble (MB) suspensions. An image analysis methodology, translated from light microscopy algorithms, was developed for use with ultrasound contrast imaging video data. New features that are tailored for ultrasound contrast image data were developed for MB detection and segmentation, so that the algorithm can deal with single and overlapping MBs. The method was tested initially on synthetic data, then with a simple microvessel phantom, and then with in vivo ultrasound contrast video loops from sheep ovaries. Tracks detailing the vascular structure and corresponding velocity map of the sheep ovary were reconstructed. Images acquired from light microscopy, optical projection tomography, and optical coherence tomography were compared with the vasculature network that was revealed in the ultrasound contrast data. The final method was applied to clinical prostate data as a proof of principle., Results: Features of the ovary identified in optical modalities mentioned previously were also identified in the ultrasound super-resolution density maps. Follicular areas, follicle wall, vessel diameter, and tissue dimensions were very similar. An approximately 8.5-fold resolution gain was demonstrated in vessel width, as vessels of width down to 60 μm were detected and verified (λ = 514 μm). Best agreement was found between ultrasound measurements and optical coherence tomography with 10% difference in the measured vessel widths, whereas ex vivo microscopy measurements were significantly lower by 43% on average. The results were mostly achieved using video loops of under 2-minute duration that included respiratory motion. A feasibility study on a human prostate showed good agreement between density and velocity ultrasound maps with the histological evaluation of the location of a tumor., Conclusions: The feasibility of a 2-dimensional contrast-enhanced ultrasound-based super-resolution method was demonstrated using in vitro, synthetic and in vivo animal data. The method reduces the examination times to a few minutes using state-of-the-art ultrasound equipment and can provide super-resolution maps for an entire prostate with similar resolution to that achieved in other studies.

Objectives: Conflicting results have been reported when the associations between metabolic health, obesity and depression were examined previously. The primary aim of this study was to determine whether metabolic health or obesity are independently associated with depressive symptoms, among a representative sample of older people living in England. Independent associations between covariates and depression were also examined., Design: Prospective study with a 2-year follow-up., Setting: The English Longitudinal Study of Ageing Wave 6 (2012-2013) and Wave 7 (2014-2015)., Participants: 6804 participants aged older than 50 years., Data Analysis: Multivariate models were used to determine whether metabolic health or obesity are independently associated with depressive symptoms at 2-year follow-up. Unadjusted and adjusted ORs with corresponding 95% CI were calculated; the adjusted ORs took account of baseline depression, gender, age, wealth, obesity and poor metabolic health., Results: Before adjusting for covariates, poor metabolic health was associated with depressive symptoms at 2-year follow-up (OR 1.24; 95% CI, 1.07 to 1.44, p<0.01). After adjusting for covariates, the association was no longer statistically significant (OR 1.17; 95% CI, 0.99 to 1.38, p=0.07). Similarly, obesity was associated with depressive symptoms at 2-year follow-up before adjusting for covariates (OR 1.54; 95% CI, 1.33 to 1.79, p<0.01). However, after adjusting for covariates the association between obesity and depressive symptoms at 2-year follow-up became statistically insignificant (OR 1.19; 95% CI, 1.00 to 1.41, p=0.06). The strongest predictors for future depression were baseline depression (OR 10.59; 95% CI, 8.90 to 12.53, p<0.01) and lower wealth (OR 3.23; 95% CI, 2.44 to 4.35, p<0.01)., Conclusion: Neither poor metabolic health nor obesity were associated with a risk of depressive symptoms at 2-year follow-up, after adjusting for covariates. As wealth inequalities continue to rise across England, the risk of depressive symptoms at 2-year follow-up is likely to be elevated in individuals living in the lower wealth quintiles., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To examine individual differences in pediatric cancer survivors' psychosocial adjustment and test the psychosocial predictors, assessed 2-3 years earlier, of those differences., Method: Pediatric cancer survivors (n = 209, aged 8-17 years at baseline) and their parents were followed for 4 years. They provided reports of survivors' psychosocial adjustment at 3 years post-baseline, and latent profile analysis (LPA) was used to identify subgroups of survivors who differed on those reports. Multinomial logistic regression was used to predict group membership from self- and parent-reported psychosocial factors at baseline (child adjustment, disposition, and parental functioning) and at 1 year post-baseline (child social relations)., Results: The LPA revealed a 3-class model as the best fit: a "Resilient" group (65%), characterized by good psychosocial adjustment; a "Self-Reported At-Risk" group (23%), characterized by subclinical elevations in self-reported internalizing and attention problems; and a "Parent-Reported At-Risk" group (12%), characterized by subclinical elevations in parent-reported internalizing, externalizing, and attention problems and in self-reported attention problems. Several psychosocial predictors, including child posttraumatic stress, affectivity, and connectedness to school, as well as parental distress and overprotection, differentiated the Resilient group from the other groups, in expected directions., Conclusions: The majority of pediatric cancer survivors exhibit enduring resilience. The protective factors identified for them-including positive affectivity and strong connectedness to school-may inform targeted prevention strategies for the minority of survivors who are at risk for maladjustment.

Objective: Although cognitive dysfunction persists through affective and euthymic states in bipolar disorder (BD), its neurobiological correlates remain undetermined. We explore whole-cortex intracortical myelin (ICM) and cognition in BD-I and controls., Methods: T 1 -weighted images (3T) optimized for ICM measurement were analyzed using a surface-based approach. MRI signal was sampled at cortical mid-depth. Cognitive performance was measured via standardized computerized battery and paper-and-pencil Trails B., Results: ICM was associated with verbal memory (VM) in BD throughout a cortical network identified with pertinence to VM function, with strongest effects in left caudal middle temporal cortex and left dorsolateral prefrontal cortex (P corrected  < 0.05). Subanalyses revealed specific association with correct word recognition, without delay. Processing speed, executive function, and reaction time were also predicted by ICM in BD, but not controls, although this did not survive Bonferroni correction., Conclusion: This is the first study to show VM association with ICM in BD. ICM has been implicated in the integrity of neural connections and neural synchrony. VM dysfunction is one of the most replicated cognitive abnormalities in BD. Therefore, these results provide a novel mechanism for understanding cognitive dysfunction in BD, which can aid in the development of targeted therapeutics to improve cognitive outcomes in BD., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: The saddle gall midge, Haplodiplosis marginata (von Roser) (Diptera: Cecidomyiidae), is a pest of cereal crops in Europe. Outbreaks are difficult to predict and effective monitoring tools are required to ensure the effectiveness of pest management options. The female sex pheromone (R)-2-nonyl butyrate provides the basis of a highly effective lure for this insect. Here, we demonstrate how the success of this lure can be influenced by parameters such as trap location, lure age, and interference between traps fitted with these lures., Results: A pheromone lure containing (R)-2-nonyl butyrate attracted male midges for at least 9 weeks under field conditions. Pheromone-baited traps performed best when situated away from field margins and below the height of the crop. Interference between nearby traps was evident at distances <20 m., Conclusion: The results presented here offer new insights into the behavioural responses of male H. marginata to the female sex pheromone and provide practical recommendations for the use of H. marginata pheromone traps in the field. © 2017 Society of Chemical Industry., (© 2017 Society of Chemical Industry.)

Purpose: To inform efforts to reduce costly service utilization, the present study examined longitudinal trajectories of mental health-related outpatient and residential service use among at-risk youth with a history of early externalizing problems., Methods: A cohort of 809 children in the Fast Track Project, a multisite longitudinal study of children at risk for conduct disorder, were followed prospectively from kindergarten through 12th grade. They resided in high-risk areas with high rates of poverty, crime, and violence. Their outpatient and residential service use was assessed annually between sixth and 12th grades through parent report. Growth mixture modeling was applied to model individual differences in trajectories of service use during this period. Teacher, parent, and observer-reported childhood predictors of those trajectories were also examined., Results: Most youths had minimal service use during preadolescence into adolescence. However, approximately 31% had moderate probability of using outpatient counseling services, and approximately 8% had elevated probability of seeing a family doctor for mental health needs. For residential services, approximately 6% had moderate to high probability of service use that peaked during transition to high school, whereas close to 5% had service use that dramatically increased during high school. Childhood predictors of these trajectories included earlier externalizing, internalizing, and emotion regulation problems., Conclusions: This study is the first to use person-centered analytic methods to examine longitudinal trajectories in mental health-related service use among at-risk adolescents. Timely treatment for severe externalizing problems, comorbid internalizing problems, and emotion dysregulation during childhood may be crucial for preventing chronic service use., (Copyright © 2017 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.)

Purpose Notwithstanding the rising magnitude of system factors in patient safety improvement, "human factors" such as idiosyncratic deals (i-deals) which also contribute to the adjustment of system deficiencies should not be neglected. The purpose of this paper is to investigate the role of value-based HR practices in catalyzing i-deals, which then influence clinical error control. The research further examines the moderating role of corporate social responsibility (CSR) on the effect of value-based HR practices on i-deals. Design/methodology/approach The data were collected from middle-level clinicians from hospitals in the Vietnam context. Findings The research results confirmed the effect chain from value-based HR practices through i-deals to clinical error control with CSR as a moderator. Originality/value The HRM literature is expanded through enlisting i-deals and clinical error control as the outcomes of HR practices.

A model-based feedback system is presented enabling the simultaneous control of the stored energy through β n and the toroidal rotation profile of the plasma in National Spherical Torus eXperiment Upgrade device. Actuation is obtained using the momentum from six injected neutral beams and the neoclassical toroidal viscosity generated by applying three-dimensional magnetic fields. Based on a model of the momentum diffusion and torque balance, a feedback controller is designed and tested in closed-loop simulations using TRANSP, a time dependent transport analysis code, in predictive mode. Promising results for the ongoing experimental implementation of controllers are obtained.

Control of blood flow distribution and tissue homeostasis depend on the tight regulation of and coordination between the microvascular network and circulating blood cells. Channels formed by connexins or pannexins that connect the intra- and extracellular compartments allow the release of paracrine signals, such as ATP and prostaglandins, and thus play a central role in achieving fine regulation and coordination of vascular function. This review focuses on vascular connexin hemichannels and pannexin channels. We review their expression pattern within the arterial and venous system with a special emphasis on how post-translational modifications by phosphorylation and S-nitrosylation of these channels modulate their function and contribute to vascular homeostasis. Furthermore, we highlight the contribution of these channels in smooth muscle cells and endothelial cells in the regulation of vasomotor tone as well as how these channels in endothelial cells regulate inflammatory responses such as during ischemic and hypoxic conditions. In addition, this review will touch on recent evidence implicating a role for these proteins in regulating red blood cell and platelet function.

Objectives: The aim of the study was to evaluate for the presence of drug resistance to HIV medications in treatment-naive individuals in Botswana., Methods: Two different populations were evaluated for evidence of HIV drug resistance at three different geographical locations in Botswana. In the first study population, consisting of pregnant females diagnosed with HIV during pregnancy, participants were enrolled at the time of their HIV diagnosis. The second population included pre-ART enrollees at Infectious Diseases Care Clinics (IDCCs) who had a CD4 T cell count >350 cells/μL., Results: A total of 422 genotypes were determined: 234 for samples from antenatal clinic (ANC) participants and 188 for samples from IDCC participants. Between 2012 and 2014, 6 of 172 (3.5%) genotypes from ANC participants exhibited transmitted drug resistance (TDR), with 3 (1.7%) showing resistance to first-line ART. In a subset of samples from Gaborone, Botswana's capital and largest city, the TDR rate was 3 in 105 (2.9%), but only 1 in 105 (1.0%) showed first-line ART resistance. Between December 2014 and April 2015, the rate of resistance to any ART in Gaborone was 6 in 62 (9.7%), with 5 (8.1%) exhibiting first-line ART resistance., Conclusions: These data demonstrate that TDR rates for HIV differ geographically and temporally in Botswana, with significant increases in TDR observed at ANCs in Gaborone between 2012 and 2015. These findings stress the importance of continued testing for TDR, particularly as access to HIV treatment increases and guidelines recommend treatment at the time of HIV diagnosis., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Objective: Valve sparing root replacement (VSRR) is an attractive option for the management of aortic root aneurysms with a normal native aortic valve. Therefore, we reviewed our experience with a modification of the David V VSRR and compared it with stented pericardial bioprosthetic valve conduit (BVC) root replacement in an age-matched cohort of older patients., Methods: A total of 48 VSRRs were performed at our institution, excluding those on bicuspid aortic valves. We compared these cases with 15 aortic root replacements performed using a BVC during the same period. Subgroup analysis was performed comparing 16 VSRR cases and 15 age-matched BVC cases., Results: The greatest disparity between the VSRR and BVC groups was age (53 vs 69 years, respectively; P < .0005). The matched patients were similar in terms of baseline demographics and differed only in concomitant coronary artery bypass grafting (2 VSRR vs 7 BVC patients; P = .036). None of the VSRR and 3 of the BVC procedures were performed for associated dissection (P = .101). Postoperative aortic insufficiency grade was significantly different between the 2 groups (P = .004). The cardiopulmonary bypass, crossclamp, and circulatory arrest times were not different between the VSRR and BVC groups (174 vs 187 minutes, P = .205; 128 vs 133 minutes, P = .376; and 10 vs 13 minutes, respectively; P = .175). No differences were found between the 2 groups with respect to postoperative complications. One postoperative death occurred in the BVC group and none in the VSRR group. The postoperative length of stay and aortic valve gradients were less in the VSRR group (6 vs 8 days, P = .038; 6 vs 11.4 mm Hg, P = .001). The intensive care unit length of stay was significantly less in the VSRR group (54 vs 110 hours, P = .001)., Conclusions: VSRR is an effective alternative to the BVC for aortic root aneurysm., (Copyright © 2014 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Effective therapies are limited for patients with parenteral nutrition-dependent short bowel syndrome. We previously showed that intestinal expression of the transcriptional coregulator tetradecanoyl phorbol acetate-induced sequence 7 (tis7) is markedly increased during the adaptive response following massive small bowel resection and tis7 plays a role in normal gut lipid metabolism. Here, we further explore the functional implications of tis7 deletion in intestinal lipid metabolism and the adaptive response following small bowel resection. Intestinal tis7 transgenic (tis7(tg)), tis7(-/-), and wild-type (WT) littermates were subjected to 50% small bowel resection. Mice were fed a control or a high-saturated-fat (42% energy) diet for 21 days. Survival, body weight recovery, lipid absorption, mucosal lipid analysis, and the morphometric adaptive response were analyzed. Quantitative real-time PCR was performed to identify tis7 downstream gene targets. Postresection survival was markedly reduced in high-fat, but not control, diet-fed tis7(-/-) mice. Decreased survival was associated with anastomotic inflammation and intestinal obstruction postresection. High-fat, but not control, diet-fed tis7(-/-) mice had increased intestinal IL-6 expression. Intestinal lipid trafficking was altered in tis7(-/-) compared with WT mice postresection. In contrast, high-fat diet-fed tis7(tg) mice had improved survival postresection compared with WT littermates. High-fat diet feeding in the setting of tis7 deletion resulted in postresection anastomotic inflammation and small bowel obstruction. Tolerance of a calorie-rich, high-fat diet postresection may require tis7 and its target genes. The presence of luminal fat in the setting of tis7 deletion promotes an intestinal inflammatory response postresection.

Background: The indocyanine green dilution method is one of the methods available to estimate plasma volume, although some researchers have questioned the accuracy of this method., Methods: We developed a new, physiologically based mathematical model of indocyanine green kinetics that more accurately represents indocyanine green kinetics during the first few minutes postinjection than what is assumed when using the traditional mono-exponential back-extrapolation method. The mathematical model is used to develop an optimal back-extrapolation method for estimating plasma volume based on simulated indocyanine green kinetics obtained from the physiological model., Results: Results from a clinical study using the indocyanine green dilution method in 36 subjects with type 2 diabetes indicate that the estimated plasma volumes are considerably lower when using the traditional back-extrapolation method than when using the proposed back-extrapolation method (mean (standard deviation) plasma volume = 26.8 (5.4) mL/kg for the traditional method vs 35.1 (7.0) mL/kg for the proposed method). The results obtained using the proposed method are more consistent with previously reported plasma volume values., Conclusions: Based on the more physiological representation of indocyanine green kinetics and greater consistency with previously reported plasma volume values, the new back-extrapolation method is proposed for use when estimating plasma volume using the indocyanine green dilution method.

Background: Birth-related perineal trauma has a major impact on women's health. Appropriate management of perineal injuries requires clinical knowledge and skill. At present, there is no agreement as to what constitutes an effective clinical training programme, despite the presence of sufficient evidence to support standardised perineal repair techniques. To address this deficiency, we developed and validated an interactive distance learning multi-professional training package called MaternityPEARLS., Method: MaternityPEARLS was developed as a comprehensive e-learning package in 2010. The main aim of the MaternityPEARLS project was to develop, refine and validate this multi-professional e-learning tool. The effect of MaternityPEARLS in improving clinical skills and knowledge was compared with two other training models; traditional training (lectures + model-based hands on training) and offline computer lab-based training. Midwives and obstetricians were recruited for each training modality from three maternity units. An analysis of covariance was done to assess the effects of clinical profession and years of experience on scoring within each group. Feedback on MaternityPEARLS was also collected from participants. The project started in January 2010 and was completed in December 2010., Results: Thirty-eight participants were included in the study. Pretraining and post-training scores in each group showed considerable improvement in skill scores (p<0.001 in all groups). Mean changes were similar across all three groups for knowledge (3.24 (SD 5.38), 3.00 (SD 3.74), 3.30 (SD 3.73)) and skill (25.34 (SD 8.96), 22.82 (SD 9.24), 20.7 (SD 9.76)) in the traditional, offline computer lab-based and e-learning groups, respectively. There was no evidence of any effect of clinical experience and baseline knowledge on outcomes., Conclusions: MaternityPEARLS is the first validated perineal trauma management e-learning package. It provides a level of improvement in skill and knowledge comparable to traditional methods of training. However, as an e-learning system, it has the advantage of ensuring the delivery of a standardised, continuously updated curriculum that has global accessibility.

Leucine rich repeat transmembrane protein 3 (LRRTM3) is member of a synaptic protein family. LRRTM3 is a nested gene within α-T catenin (CTNNA3) and resides at the linkage peak for late-onset Alzheimer's disease (LOAD) risk and plasma amyloid β (Aβ) levels. In-vitro knock-down of LRRTM3 was previously shown to decrease secreted Aβ, although the mechanism of this is unclear. In SH-SY5Y cells overexpressing APP and transiently transfected with LRRTM3 alone or with BACE1, we showed that LRRTM3 co-localizes with both APP and BACE1 in early endosomes, where BACE1 processing of APP occurs. Additionally, LRRTM3 co-localizes with APP in primary neuronal cultures from Tg2576 mice transduced with LRRTM3-expressing adeno-associated virus. Moreover, LRRTM3 co-immunoprecipitates with both endogenous APP and overexpressed BACE1, in HEK293T cells transfected with LRRTM3. SH-SY5Y cells with knock-down of LRRTM3 had lower BACE1 and higher CTNNA3 mRNA levels, but no change in APP. Brain mRNA levels of LRRTM3 showed significant correlations with BACE1, CTNNA3 and APP in ∼400 humans, but not in LRRTM3 knock-out mice. Finally, we assessed 69 single nucleotide polymorphisms (SNPs) within and flanking LRRTM3 in 1,567 LOADs and 2,082 controls and identified 8 SNPs within a linkage disequilibrium block encompassing 5'UTR-Intron 1 of LRRTM3 that formed multilocus genotypes (MLG) with suggestive global association with LOAD risk (p = 0.06), and significant individual MLGs. These 8 SNPs were genotyped in an independent series (1,258 LOADs and 718 controls) and had significant global and individual MLG associations in the combined dataset (p = 0.02-0.05). Collectively, these results suggest that protein interactions between LRRTM3, APP and BACE1, as well as complex associations between mRNA levels of LRRTM3, CTNNA3, APP and BACE1 in humans might influence APP metabolism and ultimately risk of AD.

We describe an observational study of clinical, virologic and drug resistance profiles in HIV-positive antiretroviral adherent subjects with stable low level viremia (LLV) 50-1,000 copies/mL for more than 12 months. Subjects were followed from time of first detectable viral load (VL). In total, 102 episodes of LLV were detected among 80 individuals. The median (mean, range) HIV copy number at genotyping was 250 (486, <50-3900) copies/mL after 14 (17.9, 0-58) months of LLV. Few patients maintained LLV for the entire 9 year period of observation, with half (52%) experiencing viremic progression following a stable period of LLV either spontaneously or after treatment interruption or failed regimen intensification. In the setting of prolonged periods of sustained LLV, mean duration 22 (range 8 - 106) months, drug resistance (DR) was almost universal. Resistance to ≥1 on-treatment drugs was defined in 97% of specimens and DR to all drugs in the treatment regimen in over half of all patients. Evolution of DR mutations during the period of LLV was observed in 20/28 (71%) subjects with specimens available for follow-up testing. This evolution was associated with viremic progression to levels >1000 copies/mL (p=0.03). Our data suggest that DR present in patients with LLV is likely to impact long term clinical outcomes, highlighting the importance of optimizing techniques to detect the presence of drug resistant HIV in the setting of LLV and the need for larger prospective studies to assess the emergence of DR in the setting of sustained LLV and the impact of this DR on treatment outcomes.

Background: Consumer assessment of health care is an important metric for evaluating quality of care. These assessments can help purchasers, health plans, and providers deliver care that fits patients' needs., Objective: To examine differences in reports and ratings of care delivered to adults and children and whether they vary by site., Research Design: This observational study compares adult and child experiences with care at a large west coast medical center and affiliated clinics and a large mid-western health plan using Consumer Assessment of Healthcare Providers and Systems Clinician & Group 1.0 Survey data., Results: Office staff helpfulness and courtesy was perceived more positively for adult than pediatric care in the west coast site. In contrast, more positive perceptions of pediatric care were observed in both sites for coordination of care, shared decision making, overall rating of the doctor, and willingness to recommend the doctor to family and friends. In addition, pediatric care was perceived more positively in the mid-west site for access to care, provider communication, and office staff helpfulness and courtesy. The differences between pediatric care and adult care were larger in the mid-western site than the west coast site., Conclusions: There are significant differences in the perception of care for children and adults with care provided to children tending to be perceived more positively. Further research is needed to identify the reasons for these differences and provide more definitive information at sites throughout the United States.

Unlabelled: The probability that an individual is able to live independently decreases sharply below the threshold score of 57 units on the physical functional performance (PFP-10) test., Purpose: To examine the relation between brachial artery flow-mediated dilation (BAFMD) on individual and total scores on the PFP-10. We hypothesized that lower scores on the PFP-10 test would be associated with lower BAFMD., Methods: Sixty-four men (age, 84 +/- 11 yr) from the Louisiana Healthy Aging Study were studied. Participants were classified by their performance on the PFP-10 test (Class I, score <26; Class II, score between 26 and 57; and Class III, score > 57). BAFMD was assessed after 5 min of forearm occlusion, using high-resolution ultrasonography., Results: The average total score on the PFP-10 test and BAFMD were 42.9 +/- 22 U and 2.76 +/- 2.13%, respectively. The BAFMD was associated with total PFP-10 score (r = 0.45, P = 0.0001) and age (r = -0.36, P = 0.003). BAFMD was significantly different (P = 0.001) between the PFP-10 classes (Class I, 1.44% [95% CI, 0.49-2.39]; Class II, 2.67% [95% CI, 1.95-3.38]; and Class III, 4.01% [95% CI, 3.16-4.85])., Conclusions: This study reports significant relationships between BAFMD and individual and combined measures of physical function in elderly men. More specifically, when individuals were categorized based on their PFP-10 total score, those in the highest functional class, exhibited the highest BAFMD, compared to those in the middle class, who had greater vasoreactivity than those in the lowest functional class.

Parvovirus B19 is a common infection in adults and children. There are reports of secondary parvovirus infection in immunocompromised persons, but no reports of symptomatic secondary infection in healthy persons. We describe a healthy 39-year-old woman who presented with fever, rash, and arthralgia. Her symptoms were thought most compatible with parvovirus B19 infection, but she reported prior positive parvovirus antibody 2 years earlier during prenatal care. Tests were therefore also sent for HIV, streptococcal infection, hepatitis C, and Lyme disease. Testing revealed both elevated IgG and IgM antibodies for parvovirus B19; previously, the patient was positive only for IgG. On a subsequent visit she related that a community outbreak of parvovirus developed in her town and church group. We believe this case demonstrates that a symptomatic secondary infection with parvovirus can occur in healthy persons, and that prior positive antibody test does not preclude the development of acute infection.

This article considers the development of two walking programmes by a health visiting team to encourage parents and children to undertake regular exercise. Government reports have stressed the importance of regular physical activity to promote physical and mental health. A survey of physical activity within a semi-rural caseload highlighted that the majority of families did not take regular exercise to maintain health. A programme of walks for post-natal mothers and a programme of activity walks for parents and young children were developed. Evaluation indicated that the walking programmes provided an acceptable and supported opportunity for parents and children to participate in physical activity. Participants increased their levels of regular physical activity and reported psychological benefits. This initiative demonstrates that health visitors have a key role in influencing, enabling and supporting people to participate in health activities.

A prototype hybrid system consisting of active and passive components for controlling far-field locomotive exhaust noise has been designed, assembled, and tested on a locomotive. The system consisted of a resistive passive silencer for controlling high-frequency broadband noise and a feedforward multiple-input, multiple-output active control system for suppressing low-frequency tonal noise. The active system used ten roof-mounted bandpass speaker enclosures with 2-12-in. speakers per enclosure as actuators, eight roof-mounted electret microphones as residual sensors, and an optical tachometer that sensed locomotive engine speed as a reference sensor. The system was installed on a passenger locomotive and tested in an operating rail yard. Details of the system are described and the near-field and far-field noise reductions are compared against the design goal.

Government reports have stressed the importance of community-based interventions in addressing health inequalities. This article discusses the pivotal role played by a health visitor and school nurse team in identifying the health needs of a local community and working in partnership with local people, key community groups, health and youth workers to address these specific needs. A health needs assessment highlighted the need for a parenting programme to support parents in managing young children's behaviour, a forum for teenagers to socialize and access pertinent health information and health days to raise public awareness of key community health issues. To date the parenting programme and the youth club have been implemented. Evaluation has considered how accessible, appropriate, efficient and effective they have been and the knowledge and skills gained by participants. This community development demonstrates how health promotion works through effective community action.

Cytochrome P450 102 (CYP102 or Cytochrome P450(BM)(-)(3)) is induced in Bacillus megaterium by barbiturates, perioxisome proliferators, estrogen, and nonsteroidal antiinflammatory drugs. We have previously demonstrated that a CYP102 construct (BMC 143) coupled with a luciferase reporter gene can be used to identify the inducers of CYP102. We now describe the effect of added phytochemicals on the induction of CYP102 by phenobarbital (PB) in B. megaterium. The isoflavones genistein, biochanin A, coumestrol, and equol, the green tea flavanoid epicatechin, and the fungal toxin zearalenone inhibit the induction of CYP102 by PB in a dose-dependent manner. However, the isoflavone daidzein, the phytoalexin glyceollin, and catechin, an epimer of epicatechin, failed to exhibit a similar inhibitory effect on PB-mediated CYP102 induction.

CYP102 (Cytochrome P450BM-3) is induced in Bacillus megaterium by barbiturates, peroxisome proliferators, and nonsteroidal anti-inflammatory drugs. We now describe the induction of CYP102 in B. megaterium by 17 beta-estradiol and by 4-sec-butylphenol. These estrogens interact with the repressor protein Bm3R1, causing it to dissociate with the operator of the CYP102 gene and allowing transcription to occur. We have developed a stable transfection of a construct into B. megaterium of a truncated CYP102 gene coupled with the luciferase gene in a promoterless plasmid and have used this construct to test the induction of CYP102 by these estrogens. Estradiol demonstrated a dose-dependent induction of CYP102 which saturated at a 2-fold increase at 150 microM 4 hr post-addition. 4-sec-Butylphenol produced a dose-dependent and time-dependent induction up to 300 microM and 6 hr post-induction.

An evaluation was conducted of the approaches, costs, and quality-of-life outcomes associated with communication aid assessment programs for the speech-impaired provided by specialist Communication Aids Centres (CACs) in the United Kingdom. The average costs of CAC assessment programs was 410 pounds per client, which is not excessive. There was evidence of moderate quality-of-life benefits from clients' use of the recommended aids.

A survey of the functioning of the six communication aid centres (CACs) in England and Wales was undertaken. All CACs are specialist units drawing clients from a wide area of the country which means that referrals are more likely to come from outside, rather than from within the districts in which the CACs are located. All CACs have developed individual assessment procedures, with some CACs undertaking continuous assessment of clients, and others recommending an aid after a single session. Funding of aids was often a problem because CACs were only able to recommend aid provision and did not supply them; their stocks of aids were used in assessment sessions or for interim loan to clients until a definitive aid had been acquired. CAC staff engaged in a variety of other functions including the organisation of courses, acting as an advice and information service, and undertaking research.

This paper reports the findings of an evaluation (funded by the Department of Health) of six Communication Aid Centres established in 1983. The evaluation was undertaken to assess the effectiveness of these Centres in meeting their set objectives, and to examine service costs and client satisfaction. The findings show that the work of each Centre was effective in meeting its stated objectives, but that the work of individual Centres reflected its own specialised interests. Two problems with current funding arrangements were highlighted. First, the need to replace the original funding by locally based finance, and second, the funding of communication aids for clients. The findings also show that the specialist service provided by these Centres can be managed at costs per person assessed at, or below, non-specialist services in health districts. Client satisfaction with the services provided by the Centres was high.

The present study compares the effectiveness of 0.25% ropivacaine and 0.25% bupivacaine in 44 patients receiving a subclavian perivascular brachial plexus block for upper extremity surgery. The patients were assigned to two equal groups in this randomized, double-blind study; one group received ropivacaine 0.25% (112.5 mg) and the other, bupivacaine 0.25% (112.5 mg), both without epinephrine. Onset times for analgesia and anesthesia in each of the C-5 through T-1 brachial plexus dermatomes did not differ significantly between the two groups. The mean onset time for analgesia ranged from 11.2 to 20.2 min, and the mean onset time for anesthesia ranged from 23.3 to 48.2 min. The onset of motor block differed only with respect to paresis in the hand, with bupivacaine demonstrating a shorter onset time than ropivacaine. The duration of sensory and motor block also was not significantly different between the two groups. The mean duration of analgesia ranged from 9.2 to 13.0 h, and the mean duration of anesthesia ranged from 5.0 to 10.2 h. Both groups required supplementation with peripheral nerve blocks or general anesthesia in a large number of cases, with 9 of the 22 patients in the bupivacaine group and 8 of the 22 patients in the ropivacaine group requiring supplementation to allow surgery to begin. In view of the frequent need for supplementation noted with both 0.25% ropivacaine and 0.25% bupivacaine, we do not recommend using the 0.25% concentrations of these local anesthetics to provide brachial plexus block.

Little attention has been given to the preparation of the patient's family prior to surgery, even though nurses' clinical experience suggests that family members are often more anxious than the patient. This study explored the knowledge and anxiety of spouses and significant others of patients preparing for cardiac surgery. The subjects were selected by convenience from a preoperative class offered at the hospital where surgery was to occur. Before and after the class, the subjects completed a cardiac-surgery knowledge test and an anxiety test. The significant others were significantly more anxious than the patients prior to the class. The anxiety level of significant others was significantly reduced after the class. There were no statistically significant differences between patients and significant others on the cardiac-surgery knowledge test. These results suggest that significant others may benefit from preoperative instruction.

With the increasing cost of health care and the growing constraints made by third party payers, in-hospital time for preoperative teaching is quickly being reduced. Seventy-two patients attended preoperative instruction either as an inpatient the day before surgery or as an outpatient 4-8 days before surgery. Anxiety and knowledge levels were measured before and after class and the evening before surgery. No differences were found between the groups on a measure of anxiety levels. Both groups demonstrated a moderate anxiety level with no significant change over the testing period. Using the knowledge pretest as a covariate, repeated measures analysis of variance suggested the knowledge gained with the class was significantly greater for the outpatient group than the inpatient group (P = 0.018). There was also a significant positive relationship between the knowledge score and knowing someone who had cardiac surgery (t = 2.34, d.f. = 66, P = 0.022). The results suggest that it makes little difference whether patients receive information up to a week before surgery or just the day before; therefore, the more economical preadmission teaching may be the path of choice.