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University students are at risk of experiencing mental health and diet quality problems during their transition to university. This study aimed to examine the bidirectional associations between the diet quality and mental health of students during their transition to universities in the UK, and the impact of the transition on diet quality and mental health. The study adopted a cross-sectional design and took place during the first semester of year 2021-2022. Participants were first year undergraduate students at four UK universities, living at student halls. They were invited to participate by completing online surveys, including a diet quality instrument (Short Form Food Frequency Questionnaire), a mental health instrument (Depression Anxiety and Stress Scale) and a quality of transition instrument (College Adjustment Questionnaire). Results showed that a healthy diet was associated with good mental health (b = -3.46, 95% CI [-6.14, -.78]). Unfavourable mental health was associated with having an unhealthy diet (b = -.01, 95% CI [-.02, -.00]). Transition did not moderate the relationship between diet quality and mental health of students, or vice versa (ps> .05). Preliminary analyses showed a significant direct effect of good quality of transition to university on good mental health (b = -1.51, 95% CI [-1.88, -1.13]), but did not have an indirect effect via diet quality; there were no significant direct or indirect effects on diet quality, however larger studies are needed to replicate these preliminary analyses. Our current findings can inform university policies and health education research, and further research is needed to determine whether interventions to improve diet quality at the university level could reduce mental health issues, and whether interventions to support students under stress may lead to healthier dietary habits. Cross-sectional studies cannot determine the directionality of effects, hence longitudinal studies are required to enhance our understanding of the relationships between diet quality and mental health over time., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Solomou et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A key step towards understanding psychiatric disorders that disproportionately impact female mental health is delineating the emergence of sex-specific patterns of brain organization at the critical transition from childhood to adolescence. Prior work suggests that individual differences in the spatial organization of functional brain networks across the cortex are associated with psychopathology and differ systematically by sex., Aims: We aimed to evaluate the impact of sex on the spatial organization of person-specific functional brain networks., Method: We leveraged person-specific atlases of functional brain networks defined using nonnegative matrix factorization in a sample of n = 6437 youths from the Adolescent Brain Cognitive Development Study. Across independent discovery and replication samples, we used generalized additive models to uncover associations between sex and the spatial layout ("topography") of personalized functional networks (PFNs). Next, we trained support vector machines to classify participants' sex from multivariate patterns of PFN topography. Finally, we leveraged transcriptomic data from the Allen Human Brain Atlas to evaluate spatial correlations between sex differences in PFN topography and gene expression., Results: Sex differences in PFN topography were greatest in association networks including the fronto-parietal, ventral attention, and default mode networks. Machine learning models trained on participants' PFNs were able to classify participant sex with high accuracy. Brain regions with the greatest sex differences in PFN topography were enriched in expression of X-linked genes as well as genes expressed in astrocytes and excitatory neurons., Conclusions: Sex differences in PFN topography are robust, replicate across large-scale samples of youth, and are associated with expression patterns of X-linked genes. These results suggest a potential contributor to the female-biased risk in depressive and anxiety disorders that emerge at the transition from childhood to adolescence., Competing Interests: Declaration of Interest: R.T.S. and A.A-B. have received consulting income from Octave Bioscience and compensation for scientific reviewing from the American Medical Association. J.S. and A.A-B. are co-founders and equity holders in Centile Bioscience, and J.S. is on the board of directors for Centile Bioscience. All other authors declare no conflicts of interest.

Background: Online forums are widely used for mental health peer support. However, evidence of their safety and effectiveness is mixed. Further research focused on articulating the contexts in which positive and negative impacts emerge from forum use is required to inform innovations in implementation., Objective: This study aimed to develop a realist program theory to explain the impacts of online mental health peer support forums on users., Methods: We conducted a realist synthesis of literature published between 2019 and 2023 and 18 stakeholder interviews with forum staff., Results: Synthesis of 102 evidence sources and 18 interviews produced an overarching program theory comprising 22 context-mechanism-outcome configurations. Findings indicate that users' perceptions of psychological safety and the personal relevance of forum content are foundational to ongoing engagement. Safe and active forums that provide convenient access to information and advice can lead to improvements in mental health self-efficacy. Within the context of welcoming and nonjudgmental communities, users may benefit from the opportunity to explore personal difficulties with peers, experience reduced isolation and normalization of mental health experiences, and engage in mutual encouragement. The program theory highlights the vital role of moderators in creating facilitative online spaces, stimulating community engagement, and limiting access to distressing content. A key challenge for organizations that host mental health forums lies in balancing forum openness and anonymity with the need to enforce rules, such as restrictions on what users can discuss, to promote community safety., Conclusions: This is the first realist synthesis of online mental health peer support forums. The novel program theory highlights how successful implementation depends on establishing protocols for enhancing safety and strategies for maintaining user engagement to promote forum sustainability., Trial Registration: PROSPERO CRD42022352528; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=352528., (©Paul Marshall, Millissa Booth, Matthew Coole, Lauren Fothergill, Zoe Glossop, Jade Haines, Andrew Harding, Rose Johnston, Steven Jones, Christopher Lodge, Karen Machin, Rachel Meacock, Kristi Nielson, Jo-Anne Puddephatt, Tamara Rakic, Paul Rayson, Heather Robinson, Jo Rycroft-Malone, Nick Shryane, Zoe Swithenbank, Sara Wise, Fiona Lobban. Originally published in JMIR Mental Health (https://mental.jmir.org), 09.05.2024.)

Background: Mutations in the gene MTARC1 (mitochondrial amidoxime-reducing component 1) protect carriers from metabolic dysfunction-associated steatohepatitis (MASH) and cirrhosis. MTARC1 encodes the mARC1 enzyme, which is localized to the mitochondria and has no known MASH-relevant molecular function. Our studies aimed to expand on the published human genetic mARC1 data and to observe the molecular effects of mARC1 modulation in preclinical MASH models., Methods and Results: We identified a novel human structural variant deletion in MTARC1, which is associated with various biomarkers of liver health, including alanine aminotransferase levels. Phenome-wide Mendelian Randomization analyses additionally identified novel putatively causal associations between MTARC1 expression, and esophageal varices and cardiorespiratory traits. We observed that protective MTARC1 variants decreased protein accumulation in in vitro overexpression systems and used genetic tools to study mARC1 depletion in relevant human and mouse systems. Hepatocyte mARC1 knockdown in murine MASH models reduced body weight, liver steatosis, oxidative stress, cell death, and fibrogenesis markers. mARC1 siRNA treatment and overexpression modulated lipid accumulation and cell death consistently in primary human hepatocytes, hepatocyte cell lines, and primary human adipocytes. mARC1 depletion affected the accumulation of distinct lipid species and the expression of inflammatory and mitochondrial pathway genes/proteins in both in vitro and in vivo models., Conclusions: Depleting hepatocyte mARC1 improved metabolic dysfunction-associated steatotic liver disease-related outcomes. Given the functional role of mARC1 in human adipocyte lipid accumulation, systemic targeting of mARC1 should be considered when designing mARC1 therapies. Our data point to plasma lipid biomarkers predictive of mARC1 abundance, such as Ceramide 22:1. We propose future areas of study to describe the precise molecular function of mARC1, including lipid trafficking and subcellular location within or around the mitochondria and endoplasmic reticulum., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Purpose: Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients., Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC., Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates ( p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression., Conclusions: These results may help optimize personalized therapy when drugs specific to a patient's mutation profile have already been developed.

Introduction: Peer online mental health forums are commonly used and offer accessible support. Positive and negative impacts have been reported by forum members and moderators, but it is unclear why these impacts occur, for whom and in which forums. This multiple method realist study explores underlying mechanisms to understand how forums work for different people. The findings will inform codesign of best practice guidance and policy tools to enhance the uptake and effectiveness of peer online mental health forums., Methods and Analysis: In workstream 1, we will conduct a realist synthesis, based on existing literature and interviews with approximately 20 stakeholders, to generate initial programme theories about the impacts of forums on members and moderators and mechanisms driving these. Initial theories that are relevant for forum design and implementation will be prioritised for testing in workstream 2.Workstream 2 is a multiple case study design with mixed methods with several online mental health forums differing in contextual features. Quantitative surveys of forum members, qualitative interviews and Corpus-based Discourse Analysis and Natural Language Processing of forum posts will be used to test and refine programme theories. Final programme theories will be developed through novel triangulation of the data.Workstream 3 will run alongside workstreams 1 and 2. Key stakeholders from participating forums, including members and moderators, will be recruited to a Codesign group. They will inform the study design and materials, refine and prioritise theories, and codesign best policy and practice guidance., Ethics and Dissemination: Ethical approval was granted by Solihull Research Ethics Committee (IRAS 314029). Findings will be reported in accordance with RAMESES (Realist And MEta-narrative Evidence Syntheses: Evolving Standards) guidelines, published as open access and shared widely, along with codesigned tools., Trial Registration Number: ISRCTN 62469166; the protocol for the realist synthesis in workstream one is prospectively registered at PROSPERO CRD42022352528., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Family history is an important factor in determining hereditary cancer risk for many cancer types. The emergence of next-generation sequencing (NGS) has expedited the discovery of many hereditary cancer susceptibility genes and the development of rapid, affordable testing kits. Here, a 30-gene targeted NGS panel for hereditary cancer risk assessment was tested and validated in a Saudi Arabian population. A total of 310 subjects were screened, including 57 non-cancer patients, 110 index patients with cancer and 143 of the cancer patients' family members, 16 of which also had cancer. Of the 310 subjects, 119 (38.4%) were carriers of pathogenic or likely pathogenic variants (PVs) affecting one or more of the following genes: TP53, ATM, CHEK2, CDH1, CDKN2A, BRCA1, BRCA2, PALB2, BRIP1, RAD51D, APC, MLH1, MSH2, MSH6, PMS2, PTEN, NBN/NBS1 and MUTYH . Among 126 patients and relatives with a history of cancer, 49 (38.9%) were carriers of PVs or likely PVs. Two variants in particular were significantly associated with the occurrence of a specific cancer in this population (APC c.3920T>A - colorectal cancer/Lynch syndrome ( p = 0.026); TP53 c.868C>T; - multiple colon polyposis ( p = 0.048)). Diverse variants in BRCA2, the majority of which have not previously been reported as pathogenic, were found at higher frequency in those with a history of cancer than in the general patient population. There was a higher background prevalence of genetic variants linked to familial cancers in this cohort than expected based on prevalence in other populations.

Central nervous system (CNS) metastasis is the most common brain tumor type in adults. Compared to their primary tumors, these metastases undergo a variety of genetic changes to be able to survive and thrive in the complex tissue microenvironment of the brain. In clinical settings, the majority of traditional chemotherapies have shown limited efficacy against CNS metastases. However, the discovery of potential driver mutations, and the development of drugs specifically targeting affected signaling pathways, could change the treatment landscape of CNS metastasis. Genetic studies of brain tumors have so far focused mainly on common cancers in western populations. In this study, we performed Next Generation Sequencing (NGS) on 50 pairs of primary tumors, including but not limited to colorectal, breast, renal and thyroid tumors, along with their brain metastatic tumor tissue counterparts, from three different local tertiary centers in Saudi Arabia. We identified potentially clinically relevant mutations in brain metastases that were not detected in corresponding primary tumors, including mutations in the PI3K, CDK, and MAPK pathways. These data highlight the differences between primary cancers and brain metastases and the importance of acquiring and analyzing brain metastatic samples for further clinical management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Barakeh, Alsolme, Alqubaishi, Almutairi, Alhabeeb, Al Abdulmohsen, Almohsen, Alayed, AlAnazi, AlZahrani, Binowayn, AlOtaibi, Alkhureeb, Al Shakweer, Al-Hindi, Alassiri, Robinson and Abedalthagafi.)

Background: The likelihood of suicidal behaviour is elevated amongst people with psychosis or bipolar disorder. This study aimed to understand how carers experience supporting family members with psychosis or bipolar disorder who have also experienced suicidal behaviour., Methods: A qualitative thematic analysis of online peer forum posts was carried out on the Relatives Education and Coping Toolkit (REACT) website, an online intervention for carers of people with psychosis and bipolar disorder. Analysis was based on 178 posts by 29 forum users. Posts were selected based on their relevance to suicidal behaviour., Results: Three themes were generated. "Suicide as the ultimate threat" highlights fears emerging from carers' difficulties with understanding and managing suicidal behaviour. "Bouncing from one crisis to another" reflects carers' experiences of recurring crises and the challenges of relying on emergency healthcare support. "It definitely needs to be easier to get help" emphasises carers' desires to be acknowledged by healthcare professionals and included in support offered to service users., Conclusions: Digital platforms, including online forums, brief interventions such as safety planning, and interagency crisis models, hold the potential to meet carers' needs in this context. However, further research is required to investigate the effectiveness and implementation of these approaches.

Background: Relatives of people with psychosis or bipolar disorder experience high levels of distress but are typically not offered the support they need. Online peer forums may offer a solution, but knowledge about who uses them, how, and why is limited. This study reported on online forum use during the Relatives Education and Coping Toolkit (REACT) trial., Objective: We aimed to report who used the forum and why; how sociodemographic factors are associated with participation; the relationship among frequency, type of use, and outcomes; and how the forum was used., Methods: The relationships between key sociodemographic characteristics, levels of forum use, and distress were statistically analyzed. We used thematic and semantic analyses to understand the reasons for relatives joining the forum and the key topics initiated by them. We also used the University Centre for Computer Corpus Research on Language Semantic Analysis System to compare how relatives and REACT supporters (moderators) used the forum., Results: A total of 348 participants with full forum use data from REACT were included in this study. The forum was accessed by 59.4% (207/348) of the relatives across the entire age range, with no significant associations between sociodemographic factors and forum participation, or between level or type of use and relatives' distress levels. Relatives joined the forum primarily to find people in similar circumstances, express concerns, and talk about stressful events. Relatives were most concerned about recent events, negative emotions linked to caring, experiences of conflict or threat, and concerns about suicide. These posts underscored both the challenges the relatives were facing and the fact that they felt safe sharing them in this context., Conclusions: Although only a proportion of REACT participants engaged actively with its forum, they were widely distributed across age and other sociodemographic groupings. Relatives used the forum for information, support, and guidance and to offer detailed information about their experiences. The topics raised highlighted the burden carried by relatives and the potential value of easy-access, moderated, peer-supported forums in helping relatives to manage the challenges they faced., (©Steven Jones, Dimitrinka Atanasova, Susanna Dodd, Susan Flowers, Anna Rosala-Hallas, Heather Robinson, Elena Semino, Fiona Lobban. Originally published in JMIR Mental Health (https://mental.jmir.org), 20.10.2022.)

Diabetic nephropathy is a leading cause of end-stage renal disease, characterized by endothelial dysfunction and a compromised glomerular permeability barrier. Dysregulation of the angiopoietin 1 (ANGPT1)/angiopoietin 2 (ANGPT2) signaling axis is implicated in disease progression. We recently described the discovery of an IgG 1 antibody, O010, with therapeutic potential to elevate circulating endogenous ANGPT1, a tyrosine kinase with Ig and epidermal growth factor (EGF) homology domains-2 (TIE2) agonist. Studies are described that detail the effect of various ANGPT1-elevating strategies to limit progression of renal dysfunction in diabetic-obese (db/db) mice. Results demonstrate that adeno-associated virus- or DNA minicircle-directed overexpression of ANGPT1 elicits a reduction in albuminuria (56%-73%) and an improvement in histopathology score (18% reduction in glomerulosclerosis). An improved acetylcholine response in isolated aortic rings was also observed indicative of a benefit on vascular function. In separate pharmacokinetic studies, an efficacious dose of the ANGPT1 DNA minicircle increased circulating levels of the protein by >80%, resulting in a concomitant suppression of ANGPT2. At a dose of O010-producing maximal elevation of circulating ANGPT1 achievable with the molecule (60% increase), no suppression of ANGPT2 was observed in db/db mice, suggesting insufficient pathway engagement; no reduction in albuminuria or improvement in histopathological outcomes were observed. To pinpoint the mechanism resulting in lack of efficacy, we demonstrate, using confocal microscopy, an interference with TIE2 translocation to adherens junctions, resulting in a loss of protection against vascular permeability normally conferred by ANGPT1. Results demonstrated the essential importance of ANGPT1 to maintain the glomerular permeability barrier, and, due to interference of O010 with this process, led to the discontinuation of the molecule for clinical development. SIGNIFICANCE STATEMENT: This body of original research demonstrates that elevation of systemic angiopoietin 1 (ANGPT1) is protective against diabetic nephropathy. However, using a novel biotherapeutic approach to elevate systemic ANGPT1 renoprotection was not observed; we demonstrate that protection was lost due to interference of the therapeutic with ANGPT1/ tyrosine kinase with Ig and EGF homology domains-2 translocation to adherens junctions. Thus, the clinical development of the antibody was terminated., (Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics.)

This study contrasted the efficacy of two strategies for emotion regulation, cognitive reappraisal (CR) and attentional control (AC), while using eye-tracking to examine gaze fixation patterns associated with each strategy. Participants (n = 98 undergraduates) viewed emotionally negative and neutral slides before and after one of three training conditions: CR training (verbal instructions to reframe interpretations of negative images), AC training (gaze-contingent feedback emphasizing fixation away from negative portions of images), or a no-training control condition. CR training led to the most beneficial consequences for self-reported emotion ratings; AC training improved emotion ratings more than the no-training control but not as much as CR. AC training led to significantly reduced time fixating gaze on negative content, whereas CR did not alter gaze fixations compared with the no-training control. Moreover, among the AC group, participants who looked away from negative content to a greater extent reported more beneficial change in emotional self-report, whereas that same pattern was not evident in the CR or no-training group. The findings add to evidence that CR training is more effective than distraction-related strategies and that CR does not necessitate gaze changes to be effective. Together, the findings contribute to furthering knowledge about distinct cognitive mechanisms involved in different strategies of emotion regulation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: Unintended pregnancy has been linked to poor health and social outcomes for both mother and child. Efforts to reduce unintended pregnancies have been challenged by many financial, social, religious, and cultural factors. This study aimed to investigate how contraception use and misuse in a cohort of females seeking termination of pregnancy contribute to unintended pregnancies., Methods: We conducted a cross-sectional study with women presenting to a women's health clinic for pregnancy termination from April to December 2017. Consenting participants completed a self-administered, confidential questionnaire that included questions on demographic, ethnic, and social characteristics, as well as behaviours and attitudes related to contraception. Data analysis used descriptive statistics., Results: Data were collected from 334 women; about half (45%) had used contraception at the time of conception, representing a variety of different methods. Contraceptive use was associated with higher education, stable relationship status, and ethnic majority status but not with previous pregnancies or immigration status. Among contraceptive users, imperfect and inconsistent use of contraception (50% and 31%, respectively), and method failure (48%), including condom breakage, were cited as reasons for the current pregnancy. Non-users reported perceived low risk of pregnancy (55%), concerns about contraception (47%), and problems accessing contraception (27%). While the majority of participants were aware of emergency contraception, only 52% reported ever using it. Most participants (89%) planned to use contraception in the future., Conclusion: Our study highlights contraceptive behaviours and patterns of individuals seeking abortion. Patient-centered contraceptive counselling in order to facilitate contraceptive choice and access can include information about the most effective contraceptives and the need for back-up contraception methods., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Background: Serum D-dimer is frequently used to rule out a diagnosis of venous thromboembolism (VTE), a recognised complication following total knee replacement (TKR). TKR is known to cause a rise in D-dimer levels, reducing its specificity. Previous studies have demonstrated that D-dimer remains elevated within 10 days of TKR and therefore should be avoided. The aim of this study was to determine whether serum D-dimer tests are clinically appropriate in identifying VTE when performed within 28 days of TKR., Methods: Case notes for patients who had a serum D-dimer test performed for clinically suspected VTE at ≥ 28 days following TKR were retrospectively reviewed for a 6-year period. Demographics, D-dimer result, time after surgery and further radiological investigations were recorded., Results: Fifty patients underwent D-dimer tests at ≥ 28 days following surgery (median 60 days, range 29-266); 48 of these patients had a positive result. Of these, five had confirmed VTE on radiological investigations. Serum D-dimer was raised in 96% of the patients. Only 10.42% of these patients had confirmed VTE. No patients with negative D-dimers had confirmed VTE., Conclusions: These findings suggest that serum D-dimer remains raised for at least 28 days and possibly considerably longer following TKR. Serum D-dimer should not be used in patients with clinically suspected VTE within this period because of its unacceptably low specificity of 4.44% and positive predictive value of 10.42%, which can lead to a delay in necessary further radiological investigations, waste of resources and unnecessary exposure to harm.

International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2017-016965., (©Heather Robinson, Duncan Appelbe, Susanna Dodd, Susan Flowers, Sonia Johnson, Steven H Jones, Céu Mateus, Barbara Mezes, Elizabeth Murray, Naomi Rainford, Anna Rosala-Hallas, Andrew Walker, Paula Williamson, Fiona Lobban. Originally published in JMIR Mental Health (http://mental.jmir.org), 17.07.2020.)

Background: Relatives caring for people with severe mental health problems find information and emotional support hard to access. Online support for self-management offers a potential solution., Objective: The objective was to determine the clinical effectiveness and cost-effectiveness of an online supported self-management tool for relatives: the Relatives' Education And Coping Toolkit (REACT)., Design and Setting: This was a primarily online (UK), single-blind, randomised controlled trial, comparing REACT plus a resource directory and treatment as usual with the resource directory and treatment as usual only, by measuring user distress and other well-being measures at baseline and at 12 and 24 weeks., Participants: A total of 800 relatives of people with severe mental health problems across the UK took part; relatives who were aged ≥ 16 years, were experiencing high levels of distress, had access to the internet and were actively seeking help were recruited., Intervention: REACT comprised 12 psychoeducation modules, peer support through a group forum, confidential messaging and a comprehensive resource directory of national support. Trained relatives moderated the forum and responded to messages., Main Outcome Measure: The main outcome was the level of participants' distress, as measured by the General Health Questionnaire-28 items., Results: Various online and offline strategies, including social media, directed potential participants to the website. Participants were randomised to one of two arms: REACT plus the resource directory ( n  = 399) or the resource directory only ( n  = 401). Retention at 24 weeks was 75% (REACT arm, n  = 292; resource directory-only arm, n  = 307). The mean scores for the General Health Questionnaire-28 items reduced substantially across both arms over 24 weeks, from 40.2 (standard deviation 14.3) to 30.5 (standard deviation 15.6), with no significant difference between arms (mean difference -1.39, 95% confidence interval -3.60 to 0.83; p  = 0.22). At 12 weeks, the General Health Questionnaire-28 items scores were lower in the REACT arm than in the resource directory-only arm (-2.08, 95% confidence interval -4.14 to -0.03; p  = 0.027), but this finding is likely to be of limited clinical significance. Accounting for missing data, which were associated with higher distress in the REACT arm (0.33, 95% confidence interval -0.27 to 0.93; p  = 0.279), in a longitudinal model, there was no significant difference between arms over 24 weeks (-0.56, 95% confidence interval -2.34 to 1.22; p  = 0.51). REACT cost £142.95 per participant to design and deliver (£62.27 for delivery only), compared with £0.84 for the resource directory only. A health economic analysis of NHS, health and Personal Social Services outcomes found that REACT has higher costs (£286.77), slightly better General Health Questionnaire-28 items scores (incremental General Health Questionnaire-28 items score adjusted for baseline, age and gender: -1.152, 95% confidence interval -3.370 to 1.065) and slightly lower quality-adjusted life-year gains than the resource directory only; none of these differences was statistically significant. The median time spent online was 50.8 minutes (interquartile range 12.4-172.1 minutes) for REACT, with no significant association with outcome. Participants reported finding REACT a safe, confidential environment (96%) and reported feeling supported by the forum (89%) and the REACT supporters (86%). No serious adverse events were reported., Limitations: The sample comprised predominantly white British females, 25% of participants were lost to follow-up and dropout in the REACT arm was not random., Conclusions: An online self-management support toolkit with a moderated group forum is acceptable to relatives and, compared with face-to-face programmes, offers inexpensive, safe delivery of National Institute for Health and Care Excellence-recommended support to engage relatives as peers in care delivery. However, currently, REACT plus the resource directory is no more effective at reducing relatives' distress than the resource directory only., Future Work: Further research in improving the effectiveness of online carer support interventions is required., Trial Registration: Current Controlled Trials ISRCTN72019945., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 32. See the NIHR Journals Library website for further project information., Competing Interests: Fiona Lobban reports grants from the National Institute for Health Research (NIHR) Health Technology Assessment (HTA) programme during the conduct of the study. Fiona Lobban and Lesley Chapman were involved in the design and development of the Relatives’ Education And Coping Toolkit (REACT); hence, this is not an independent evaluation. Bruce Hollingsworth reports that he was a NIHR Health Services and Delivery Research Commissioned Board member (2013–15). Paula Williamson reports grants from NIHR during the conduct of the study, and that the Clinical Trials Research Centre at the University of Liverpool was in receipt of NIHR Support Funding during the conduct of the study.

Background: The Relatives Education And Coping Toolkit (REACT) is an online supported self-management toolkit for relatives of people with psychosis or bipolar designed to improve access to NICE recommended information and emotional support., Aims: Our aim was to determine clinical and cost-effectiveness of REACT including a Resource Directory (RD), versus RD-only., Methods: A primarily online, observer-blind randomised controlled trial comparing REACT (including RD) with RD only (registration ISRCTN72019945). Participants were UK relatives aged > = 16, with high distress (assessed using the GHQ-28), and actively help-seeking, individually randomised, and assessed online. Primary outcome was relatives' distress (GHQ-28) at 24 weeks. Secondary outcomes were wellbeing, support, costs and user feedback., Results: We recruited 800 relatives (REACT = 399; RD only = 401) with high distress at baseline (GHQ-28 REACT mean 40.3, SD 14.6; RD only mean 40.0, SD 14.0). Median time spent online on REACT was 50.8 min (IQR 12.4-172.1) versus 0.5 min (IQR 0-1.6) on RD only. Retention to primary follow-up (24 weeks) was 75% (REACT n = 292 (73.2%); RD-only n = 307 (76.6%)). Distress decreased in both groups by 24 weeks, with no significant difference between the two groups (- 1.39, 95% CI -3.60, 0.83, p = 0.22). Estimated cost of delivering REACT was £62.27 per person and users reported finding it safe, acceptable and convenient. There were no adverse events or reported side effects., Conclusions: REACT is an inexpensive, acceptable, and safe way to deliver NICE-recommended support for relatives. However, for highly distressed relatives it is no more effective in reducing distress (GHQ-28) than a comprehensive online resource directory., Trial Registration: ISRCTN72019945 prospectively registered 19/11/2015.

Background: Medicines and Healthcare products Regulatory Agency (MHRA) guidance for patients with metal-on-metal (MoM) hip replacements was provided in 2012 and updated in 2017 to assist in the early detection of soft-tissue reactions due to metal wear debris. A large number of MoM hip replacements were undertaken at our hospital trust. A program of recall for all patients with MoM hip replacements was undertaken and MHRA guidelines were implemented. In this study, we aimed to investigate the effectiveness of the revised MHRA guidelines in the detection of early adverse reactions to metal debris and to re-evaluate the indications for metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) and revision surgery., Methods: Identification and recall of all patients with MoM hip replacements from 2001 were conducted by using theatre logs, patient records, clinical coding information, and consultant logbooks. Two senior arthroplasty consultants reviewed X-rays and patient records. Postal questionnaires were forwarded to patients, together with requests for general practitioners to complete cobalt and chromium blood tests. The two consultant-led review of MOM replacements was undertaken with further radiological investigations (X-rays, MARS-MRI) performed according to the 2017 guidance with support of consultant radiologists., Results: Of 674 identified patients, 297 were available for review: 26 patients did not have MoM implants, 36 were untraceable, 59 refused follow-up, 87 moved out of area, 147 had died, and 22 already had revision. Of 297 patients, 126 were women and 171 were men; age range was 39 to 95 years (mean age, 69 years); 126 had resurfacing and 171 had MoM replacements. Twenty-six patients had elevated metal ions. Thirty-three patients underwent MARS-MRI: MARS-MRI results were positive in 17 and negative in 16. Of 17 patients with positive MARS-MRI, 10 patients were asymptomatic and seven were waiting revision., Conclusions: Positive MARS-MRI can often occur in the absence of elevated metal ion levels; elevated blood metal ion levels do not mean MARS-MRI will be positive. All patients with MoM replacements were at risk. It is imperative to assess patients regularly for symptoms that may raise clinical suspicion and maintain a low threshold to performing MARS-MRI., Competing Interests: CONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported., (Copyright © 2019 by The Korean Orthopaedic Association.)

Psychological models of bipolar disorder (BD), such as the self-regulation model (SRM; Leventhal, Nerenz, & Steele, 1984), highlight the crucial role of beliefs about mood in relapse vulnerability. To date, no studies have directly compared these beliefs between people with and without BD. Based on the SRM, the current research examined beliefs about mood in people with and without BD and explored the impact of current affect on these beliefs. Fifty euthymic people with a diagnosis of BD and 50 controls were recruited through an online screening study, clinical services, and support organizations. Experience sampling methodology (ESM) was used to assess beliefs (according to the Brief Illness Perceptions Questionnaire; Broadbent, Petrie, Main, & Weinman, 2006) across a typical week of everyday life. Data were analysed using multilevel modelling. Forty-two people with a diagnosis of BD and 50 controls were included in the analyses. Results indicated that the BD group reported less control over mood, a shorter duration of mood, and less understanding of mood and were more likely to report the cause of depressive symptoms as something internal, compared with controls. When controlling for current affect, the BD group also reported more positive consequences, made more internal attributions for hypomanic symptoms, and reported less concern about mood, compared with controls. Findings suggest important differences in beliefs about mood between people with and without BD that are not the result of current affect. These beliefs may be particularly important in understanding underlying vulnerability to future relapse into depression and/or mania., (© 2019 The Authors. Clinical Psychology & Psychotherapy published by John Wiley & Sons Ltd.)

Background: Alcohol use is a common problem in bipolar disorder (BD) and evidence indicates more promising outcomes for alcohol use than other substances. No trials have evaluated individual integrated motivational interviewing and cognitive behaviour therapy (MI-CBT) for problematic alcohol use in BD. We therefore assessed the feasibility and acceptability of a novel MI-CBT intervention for alcohol use in BD., Methods: A single blind RCT was conducted to compare MI-CBT plus treatment as usual (TAU) with TAU only. MI-CBT was delivered over 20 sessions with participants followed up at 3, 6, 9 and 12 months post-randomisation. Primary outcomes were the feasibility and acceptability of MI-CBT (recruitment to target, retention to follow-up and therapy, acceptability of therapy and absence of adverse events). We also conducted preliminary analyses of alcohol and mood outcomes (frequency and severity of alcohol use and time to mood relapse)., Results: 44 participants were recruited with 75% retention to 6 and 12 months follow-up. Therapy participants attended a mean of 17.6 (SD 4.5) sessions. Therapy alliance and treatment fidelity were acceptable. Qualitative interviews indicated the intervention was experienced as collaborative, and helpful, in addressing mood and alcohol issues, although risk of overconfidence following therapy was also identified. Clinical outcomes did not differ between arms at 12 months follow-up., Limitations: As a feasibility and acceptability trial any secondary results should be treated with caution., Conclusions: Integrated MI-CBT is feasible and acceptable, but lack of clinical impact, albeit in a feasibility study, suggests need for further development. Potential adaptations are discussed., (Copyright © 2019. Published by Elsevier B.V.)

Background: To measure trends in child growth and combat rising levels of obesity, Manchester University NHS Foundation Trust and the University of Manchester have developed Children's Health and Monitoring Programme (CHAMP). CHAMP collects an annual measurement for primary school children (aged 4 to 11) in Manchester, England, and offers feedback of Body Mass Index (BMI) results to parents via a secure website. No similar digital tool exists that both provides high resolution data on the trajectory of child growth and acts as a feedback and monitoring system. This study investigates how effectively this intervention engaged with parents and supported the reduction of childhood obesity., Methods: Anonymised CHAMP registration and BMI data (UK1990) were collected between September 2013 and March 2017 from a total of 63,337 children. BMI change over time was compared in matched cohorts of 24,551 children, whose parents had and had not registered with the CHAMP website. Qualitative focus groups and interviews were used to explore perspectives among 29 key informants (parents, school and healthcare professionals) from six schools in Manchester., Results: Overweight children whose parents had not registered with the CHAMP website gained a median of 0.14 BMI centile between measurements, whilst children of CHAMP-registered parents reduced their BMI by a median of 0.4 centile per year (P = 0.02). Normal weight children of registered parents decreased their BMI by 0.3 centile each year, whilst those not registered increased their BMI by 0.8 centile per year (P = 0.001). There was no significant association between registration and BMI centile change in children already classified as obese (P = 0.34). A qualitative, thematic analysis revealed that the annual measurement programme was widely supported by parents and staff. A range of psychological and behavioural impacts on families were reported as a result of the monitoring and feedback processes, in some cases prompting reflection and monitoring of health and lifestyle choices., Conclusion: These early findings indicate that CHAMP, as both a monitoring system and a digital intervention, could encourage positive lifestyle change and support healthier child growth trajectories.

Children's body mass index (BMI) growth trajectories are associated with adult health outcomes, and vary by geography and epoch. Understanding these trajectories could help to identify high risk children and thus support improved health outcomes. In this review, we compare and quantitatively analyse BMI level and trajectory data published since 2010. We characterise recent growth in children aged 4-11 years, an age range most frequently targeted for BMI intervention, yet less studied than young childhood or infancy. Through searches in OVID, we identified 54 relevant texts which describe either post-2000 summary BMI values by age and gender in cohorts with sample sizes of over 1000 children, or the results of latent class analyses of BMI trajectories within the 4-11 year age range. Population level median growth curves were projected and visualised as weighted means. These BMI curves, based on data from 729,692 children, can be visually clustered into 'high' and 'low' charting groups with extreme outlying values. Within populations, latent class analyses converge on 3-4 individual child trajectories, two of which predispose adult overweight. These growth pathways diverge early in childhood, yet are not effectively distinguished via isolated BMI measurements taken between 4 and 11 years, meaning some high risk children may currently be poorly identified.

Objective: The obesity paradox in which overweight/obesity is associated with mortality benefits is believed to be explained by confounding and reverse causality rather than by a genuine clinical benefit of excess body weight. We aimed to gain deeper insights into the paradox through analyzing mortality relationships with several adiposity measures; assessing subgroups with type 2 diabetes, with coronary heart disease (CHD), with cancer, and by smoking status; and adjusting for several confounders., Research Design and Methods: We studied the general UK Biobank population ( N = 502,631) along with three subgroups of people with type 2 diabetes ( n = 23,842), CHD ( n = 24,268), and cancer ( n = 45,790) at baseline. A range of adiposity exposures were considered, including BMI (continuous and categorical), waist circumference, body fat percentage, and waist-to-hip ratio, and the outcome was all-cause mortality. We used Cox regression models adjusted for age, smoking status, deprivation index, education, and disease history., Results: For BMI, the obesity paradox was observed among people with type 2 diabetes (adjusted hazard ratio for obese vs. normal BMI 0.78 [95% CI 0.65, 0.95]) but not among those with CHD (1.00 [0.86, 1.17]). The obesity paradox was pronounced in current smokers, absent in never smokers, and more pronounced in men than in women. For other adiposity measures, there was less evidence for an obesity paradox, yet smoking status consistently modified the adiposity-mortality relationship., Conclusions: The obesity paradox was observed in people with type 2 diabetes and is heavily modified by smoking status. The results of subgroup analyses and statistical adjustments are consistent with reverse causality and confounding., (© 2018 by the American Diabetes Association.)

Background: Co-morbid substance misuse, particularly alcohol, is common in bipolar disorder (BD) and associated with worse treatment outcomes. Research into psychological interventions for substance misuse in BD is at an early stage and no studies have specifically targeted problematic alcohol use. This paper describes the context and protocol for a feasibility and acceptability randomised controlled trial (RCT) evaluating a novel intervention combining motivational interviewing and cognitive behavioural therapy (MI-CBT) for participants with BD and problematic alcohol use, developed in collaboration with people with lived experience of both issues., Methods and Design: An RCT will assess the feasibility and acceptability of MI-CBT in addition to treatment as usual (TAU) compared with TAU alone. Participants will be recruited from across the North West of England through NHS services and self-referral. The primary outcomes will be the feasibility and acceptability of the intervention assessed by recruitment to target, adherence to intervention, retention rate at follow-up, absence of adverse events and qualitative analysis of participants' reported experiences of intervention. The effect size of the impact of the intervention on alcohol use and mood outcomes will also be estimated. In addition, we will explore a number of potential process variables in therapy., Discussion: This is the first RCT evaluating MI-CBT for BD and problematic alcohol use. Given the prevalence and impact of alcohol problems in BD this novel integrated intervention may have potential to offer important improvements in clinical and functional outcomes.

Road deicing has caused widespread environmental Na + and Cl - release for decades, yet the transport and retention of these contaminants in karst aquifers and soils are poorly understood. We examined the transport dynamics of Na + and Cl - from road salt in shallow groundwater during flooding and over seasonal timescales by intensively monitoring an urban and a rural karst spring over approximately 2 years. Furthermore, we used a 20-year dataset for the rural spring to determine how salt retention affected long-term geochemical trends in the shallow groundwater. Salt transport was governed by hydrologic pathways through karst aquifers: during winter and early spring floods, flow through preferential pathways rapidly transported salty meltwater or stormwater over hours to days, while the remaining salt-contaminated water moved diffusely through the rock matrix on timescales of months to years. Flood hydrograph separations revealed that event water constituted 61.2% of stormflow on average at the urban spring, leading to more extreme variability in salt concentrations during flooding and throughout the year. This variability indicates that baseflow contributions to urban streams overlying karst aquifers with preferential flowpaths are likely less effective at buffering salt concentrations. In contrast, salt concentrations were less variable in the baseflow-dominated rural spring (28.7% event water). Furthermore, salt was episodically released from soils to shallow groundwater throughout the year during first flush events. A Cl - mass balance indicates that Cl - applied during previous winters persists within the springs' recharge basins for more than a year, raising baseline concentrations as road salt is introduced faster than it can be flushed from the basin. Inter-annual salt retention by soils or slow groundwater movement likely caused significant Cl - and specific conductivity (SpC) increases at the rural spring from 1996 to 2016. Accumulation of salt in shallow groundwater can elevate baseflow concentrations in surface waters, where it threatens aquatic organisms., (Published by Elsevier B.V.)

Introduction: Despite clinical guidelines recommendations, many relatives of people with psychosis or bipolar disorder do not currently receive the support they need. Online information and support may offer a solution., Methods and Analysis: This single-blind, parallel, online randomised controlled trial will determine clinical and cost-effectiveness of the Relatives Education And Coping Toolkit (REACT) (including an online resource directory (RD)), compared with RD only, for relatives of people with psychosis or bipolar disorder. Both groups continue to receive treatment as usual. Independent, web-based variable, block, individual randomisation will be used across 666 relatives. Primary outcome is distress at 24 weeks (measured by General Health Questionnaire; GHQ-28) compared between groups using analysis of covariance, adjusting for baseline score. Secondary clinical outcomes are carer well-being and support. Cost-effectiveness analysis will determine cost of a significant unit change (three-point reduction) in the GHQ-28. Costs include offering and supporting the intervention in the REACT arm, relevant healthcare care costs including health professional contacts, medications prescribed and time off (or ability to) work for the relative. Cost utility analysis will be calculated as the marginal cost of changes in quality-adjusted life years, based on EuroQol. We will explore relatives' beliefs, perceived coping and amount of REACT toolkit use as possible outcome mediators. We have embedded two methodological substudies in the protocol to determine the relative effectiveness of a low-value (£10) versus higher value (£20) incentive, and an unconditional versus conditional incentive, on improving follow-up rates., Ethics and Dissemination: The trial has ethical approval from Lancaster National Research Ethics Service (NRES)Committee (15/NW/0732) and is overseen by an independent Data Monitoring and Ethics Committee and Trial Steering Committee. Protocol version 1.5 was approved on 9 January 2017. All updates to protocols are uploaded to the National Institute for Health Research (NIHR) Journals Library. A full statistical analysis plan is available at https://figshare.com/account/home#/projects/19975. Publications will be in peer-reviewed journals (open access wherever possible). Requests for access to the data at the end of the study will be reviewed and granted where appropriate by the Trial Management Group., Trial Registration Number: ISRCTN72019945, pre-results., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Microbial ecology provides insights into the ecological and evolutionary dynamics of microbial communities underpinning every ecosystem on Earth. Microbial communities can now be investigated in unprecedented detail, although there is still a wealth of open questions to be tackled. Here we identify 50 research questions of fundamental importance to the science or application of microbial ecology, with the intention of summarising the field and bringing focus to new research avenues. Questions are categorised into seven themes: host-microbiome interactions; health and infectious diseases; human health and food security; microbial ecology in a changing world; environmental processes; functional diversity; and evolutionary processes. Many questions recognise that microbes provide an extraordinary array of functional diversity that can be harnessed to solve real-world problems. Our limited knowledge of spatial and temporal variation in microbial diversity and function is also reflected, as is the need to integrate micro- and macro-ecological concepts, and knowledge derived from studies with humans and other diverse organisms. Although not exhaustive, the questions presented are intended to stimulate discussion and provide focus for researchers, funders and policy makers, informing the future research agenda in microbial ecology., (© FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Group psychoeducation is a low-cost National Institute for Health and Care Excellence-recommended treatment for bipolar disorder. However, the clinical effectiveness and acceptability of this intervention are unclear compared with unstructured peer support matched for delivery and aim of treatment, and for previous bipolar history. We aimed to assess the clinical effectiveness and acceptability of structured group psychoeducation versus optimised unstructured peer support for patients with remitted bipolar disorder., Methods: We did this pragmatic, multicentre, parallel-group, observer-blind, randomised controlled superiority trial at eight community sites in two regions in England. Participants aged 18 years or older with bipolar disorder and no episode in the preceding 4 weeks were recruited via self-referral or secondary care referral. Participants were individually randomly assigned (1:1), via a computer-generated stochastic allocation sequence, to attend 21 2-h weekly sessions of either structured group psychoeducation or optimised unstructured peer support. Randomisation was minimised by number of previous episodes (one to seven, eight to 19, or ≥20) and stratified by clinical site. Outcome assessors were masked to group allocation. The primary outcome was time from randomisation to next bipolar episode, with planned moderator analysis of number of previous bipolar episodes and qualitative interview of participant experience. We did analysis by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN62761948., Findings: Between Sept 28, 2009, and Jan 9, 2012, we randomly assigned 304 participants to receive psychoeducation (n=153) or peer support (n=151); all (100%) participants had complete primary outcome data. Attendance at psychoeducation groups was higher than at peer-support groups (median 14 sessions [IQR three to 18] vs nine sessions [two to 17]; p=0·026). At 96 weeks, 89 (58%) participants in the psychoeducation group had experienced a next bipolar episode compared with 98 (65%) participants in the peer-support group; time to next bipolar episode did not differ between groups (hazard ratio [HR] 0·83, 95% CI 0·62-1·11; p=0·217). Planned moderator analysis showed that psychoeducation was most beneficial in participants with few (one to seven) previous bipolar episodes (χ 2 ; HR 0·28, 95% CI 0·12-0·68; p=0·034). Four (1%) participants (one in the psychoeducation group and three in the peer-support group) died during follow-up; these deaths were deemed unrelated to the study interventions or procedures., Interpretation: Structured group psychoeducation was no more clinically effective than similarly intensive unstructured peer support, but was more acceptable and improved outcome in participants with fewer previous bipolar episodes. Optimum provision of structured psychological interventions, such as group psychoeducation, early in the course of bipolar disorder might have important benefits on the course of illness, and merits further research., Funding: National Institute for Health Research., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The wine yeast, Saccharomyces cerevisiae, is the best understood microbial eukaryote at the molecular and cellular level, yet its natural geographic distribution is unknown. Here we report the results of a field survey for S. cerevisiae,S. paradoxus and other budding yeast on oak trees in Europe. We show that yeast species differ in their geographic distributions, and investigated which ecological variables can predict the isolation rate of S. paradoxus, the most abundant species. We find a positive association between trunk girth and S. paradoxus abundance suggesting that older trees harbor more yeast. S. paradoxus isolation frequency is also associated with summer temperature, showing highest isolation rates at intermediate temperatures. Using our statistical model, we estimated a range of summer temperatures at which we expect high S. paradoxus isolation rates, and show that the geographic distribution predicted by this optimum temperature range is consistent with the worldwide distribution of sites where S. paradoxus has been isolated. Using laboratory estimates of optimal growth temperatures for S. cerevisiae relative to S. paradoxus, we also estimated an optimum range of summer temperatures for S. cerevisiae. The geographic distribution of these optimum temperatures is consistent with the locations where wild S. cerevisiae have been reported, and can explain why only human-associated S. cerevisiae strains are isolated at northernmost latitudes. Our results provide a starting point for targeted isolation of S. cerevisiae from natural habitats, which could lead to a better understanding of climate associations and natural history in this important model microbe.

A modular, selection-based method was developed for site-specific integration of transgenes into a genomic locus to create multigene stacks. High-frequency gene targeting was obtained using zinc finger nuclease (ZFN)-mediated double-strand break (DSB) formation at a pre-defined target genomic location using a unique intron directly downstream of a promoter driving a selectable marker gene to facilitate homology between target and donor sequences. In this system, only insertion into the target locus leads to a functional selectable marker, and regeneration from random insertions of the promoterless donor construct are reduced on selection media. A new stack of transgenes can potentially be loaded with each successive cycle of gene targeting by exchanging the selectable marker gene using the intron homology. This system was tested in maize using the pat selectable marker gene, whereby up to 30% of the plants regenerated on Bialaphos-containing medium were observed to have the donor construct integrated into the target locus. Unlike previous gene targeting methods that utilize defective or partial genes for selecting targeted events, the present method exchanges fully functional genes with every cycle of targeting, thereby allowing the recycling of selectable marker genes, hypothetically for multiple generations of gene targeting., (Copyright © 2015. Published by Elsevier B.V.)

Dynamic DNA enzyme-based walkers complete their stepwise movements along the prescribed track through a series of reactions, including hybridization, enzymatic cleavage, and strand displacement; however, their overall translocation kinetics is not well understood. Here, we perform mechanistic studies to elucidate several key parameters that govern the kinetics and processivity of DNA enzyme-based walkers. These parameters include DNA enzyme core type and structure, upper and lower recognition arm lengths, and divalent metal cation species and concentration. A theoretical model is developed within the framework of single-molecule kinetics to describe overall translocation kinetics as well as each reaction step. A better understanding of kinetics and design parameters enables us to demonstrate a walker movement near 5 μm at an average speed of ∼1 nm s(-1). We also show that the translocation kinetics of DNA walkers can be effectively controlled by external light stimuli using photoisomerizable azobenzene moieties. A 2-fold increase in the cleavage reaction is observed when the hairpin stems of enzyme catalytic cores are open under UV irradiation. This study provides general design guidelines to construct highly processive, autonomous DNA walker systems and to regulate their translocation kinetics, which would facilitate the development of functional DNA walkers.

Executive functions (EF) encompass a variety of higher-order capacities such as judgment, planning, decision-making, response monitoring, insight, and self-regulation. Measuring such abilities quantitatively and establishing their neural correlates has proven to be challenging. Here, using a lesion-deficit approach, we report the neural correlates of a variety of EF tests that were developed under the auspices of the NINDS-supported EXAMINER project (Kramer, 2011; www.examiner.ucsf.edu). We administered a diverse set of EF tasks that tap three general domains--cognitive, social/emotional, and insight--to 37 patients with focal lesions to the frontal lobes, and 25 patients with lesions outside the frontal lobes. Using voxel-based lesion-symptom mapping (VLSM), we found that damage to the ventromedial prefrontal cortex (vmPFC) was predominately associated with deficits in social/emotional aspects of EF, while damage to dorsolateral prefrontal cortex (dlPFC) and anterior cingulate was predominately associated with deficits in cognitive aspects of EF. Evidence for an important role of some non-frontal regions (e.g., the temporal poles) in some aspects of EF was also found. The results provide further evidence for the neural basis of EF, and extend previous findings of the dissociation between the roles of the ventromedial and dorsolateral prefrontal sectors in organizing, implementing, and monitoring goal-directed behavior.

Objective: Anxiety predicts cardiovascular events, although the mechanism remains unclear. We hypothesized that anxiety symptoms will correlate with impaired resistance and conduit vessel function in participants aged 55 to 90 years., Methods: Anxiety symptoms were measured with the Symptom Checklist-90--Revised in 89 participants with clinically diagnosed atherosclerotic cardiovascular disease and 54 healthy control participants. Vascular function in conduit arteries was measured using flow-mediated dilatation, and vascular function in forearm resistance vessels (FRVs) was measured using intra-arterial drug administration and plethysmography., Results: Anxiety symptoms were not associated with flow-mediated dilatation in either group. Participants with atherosclerosis exhibited significant inverse associations of anxiety symptoms with FRV dilatation (acetylcholine: β = -.302, p = .004). Adjustment for medication, risk factors, and depression symptoms did not alter the association between anxiety and FRV dysfunction, except for body mass index (BMI; anxiety: β = -.175, p = .060; BMI: β = -.494, p < .001). Although BMI was more strongly associated with FRV function than anxiety, combined BMI and anxiety accounted for greater variance in FRV function than either separately. Control participants showed no association of anxiety with FRV function., Conclusions: Anxiety is uniquely and substantially related to poorer resistance vessel function (both endothelial and vascular smooth muscle functions) in individuals with atherosclerosis. These relationships are independent of medication, depression, and cardiovascular risk factors, with the exception of BMI. These findings support the concept that anxiety potentially increases vascular events through worsening of vascular function in atherosclerotic disease.

Migrant farmworkers risk occupational injury and are at risk for developing chronic health conditions. Exercise may enhance health and help to reduce the risk of occupational injury and/or reduce the risk of developing a chronic health condition. Little is known, however, about the exercise habits of Latino migrant farmworkers. Male Latino migrant farmworkers completed an exercise and health habits questionnaire at health screening clinics. One hundred fifty-three (58.2%) subjects reported exercising during the week. There was no difference in age between those who reported exercising and those who did not (p = .78). Only 42 (16%) of all workers reported exercising for 3 or more hours a week. Seventeen percent of the subjects reported smoking and almost 10% reported chewing tobacco. A majority of subjects do not meet the Centers for Disease Control and Prevention (CDC) exercise guidelines. Tobacco use is highest among individuals who do not exercise. These findings suggest the need for health education interventions for this population. Additional studies are warranted to understand exercise and health habits of this population.

Background: There is increased recognition of the importance of breastfeeding at a national level as evidenced by the increased number of Canadian mothers initiating breastfeeding. However, adolescent mothers (<19 years), compared to all other mothers, have lower rates of breastfeeding initiation and duration. The purpose of this study was to examine the facilitating influences and barriers to initiating, and continuing breastfeeding, as perceived by adolescent mothers in Durham Region, Ontario, Canada., Methods: The principles of interpretive description guided this qualitative study. A purposeful, homogenous sample of 16 adolescent mothers (15-19 years) were recruited to complete individual, semi-structured, face-to-face interviews. Conventional content analysis was used to code data, identify concepts and synthesize them into overall themes., Results: Adolescent mothers in this study expressed that the decision to breastfeed was made prenatally and while partner and family member opinions about breastfeeding initiation were influential, the decision was made independently. Mothers were primarily motivated to initiate breastfeeding due to the health benefits for the infant. Lower breastfeeding duration rates were found among mothers who decided to only "try" breastfeeding when compared to the mothers who committed to breastfeeding. Influences on continued breastfeeding included: 1) the impact of breastfeeding on social and intimate relationships; 2) the availability of social support; 3) the physical demands of breastfeeding; 4) mothers' knowledge of breastfeeding practices and benefits; and 5) mothers' perceived sense of comfort in breastfeeding., Conclusions: The results of this study provide health care providers new conceptual insight and understanding of the factors that influence adolescents' decisions to "try" breastfeeding and to continue providing breastmilk to their infants. Professional implications drawn from this study include active engagement of adolescents in the pre and postnatal periods, including early assessment of potential barriers surrounding breastfeeding decisions. This early professional interaction highlights the professional as a form of support, and allows for sharing of evidence-informed breastfeeding information and practical breastfeeding skills. Inclusion of adolescents' positive social support networks should be emphasized in professional breastfeeding support. Motivational interviewing is a promising prenatal strategy to influence behavior change and reduce ambivalence in decision-making about breastfeeding, creating opportunities for health care providers to tailor interventions.

A 30-year-old woman with stage V chronic kidney disease presented at 7 weeks gestation. She had no uremic symptoms; however, blood urea nitrogen (BUN) was 33.6 mg/dL. Because of the well-established negative relationship between BUN and fetal outcomes, dialysis was initiated with a nocturnal home hemodialysis (NHD)-like prescription performed in-center for logistical reasons. She received 36 hours per week of dialysis. Following the initiation of renal replacement therapy, the predialysis BUN was within the normal physiologic range. The patient had an uncomplicated pregnancy with delivery of a healthy 3000 g infant at 39 weeks gestation. This case adds to the growing literature that supports more intensive dialysis in the pregnant women than was previously recommended. This dose of dialysis should be offered to women in an in-center setting if nocturnal home hemodialysis is not available or feasible., (2011 The Authors; Hemodialysis International. 2011 International Society for Hemodialysis.)

Objective: To evaluate the need for increased doses of postpartum rhesus immune globulin in a woman at risk for rhesus alloimmunization., Methods: Using data from the Nova Scotia Atlee Perinatal Database (NSAPD) and the Rh Program of Nova Scotia Database, Rh negative women delivering infants with a birth weight greater than 500 grams and gestational age greater than 20 weeks at the IWK Health Centre from 1998 to 2007 were identified. Within this population, Rh(D) negative women who received both antepartum and postpartum anti-D prophylaxis were identified. Logistic regression was used to estimate peripartum predictive factors for elevated postpartum Kleihauer and the need for administration of additional rhesus immune globulin., Results: The NSAPD and Rh Program Database identified 4323 Rh negative women who received both antepartum and postpartum prophylaxis from 1998 and 2007. Following logistic regression, a postpartum Kleihauer value of > 0.2% was found to be predicted by multiparity (OR 1.47; 95% CI 1.03 to 2.08), multiple gestation (OR 3.03; 95% CI 1.61 to 5.70), antepartum risks for fetomaternal hemorrhage (OR 63.6; 95% CI 30.2 to 134), and Caesarean section (OR 2.03; 95% CI 1.42 to 2.91). A postpartum Kleihauer value of > 0.5% was found to be predicted by antepartum risks for fetomaternal hemorrhage (OR 29.1; 95% CI 12.9 to 65.5), and Caesarean section (OR 2.01; 95% CI 1.18 to 3.42)., Conclusion: While there are recognized events that increase the risk for Rh(D) alloimmunization, multiparity, multiple gestation, and Caesarean section should be additional factors for consideration, especially with rising rates of CS. Adequate postpartum prophylaxis may be optimized by conducting routine screening for fetomaternal hemorrhage, especially when lower doses of Rh(D) immune globulin are administered.

Translesion synthesis DNA polymerases contribute to DNA damage tolerance by mediating replication of damaged templates. Due to the low fidelity of these enzymes, lesion bypass is often mutagenic. We have previously shown that, in Saccharomyces cerevisiae, the contribution of the error-prone DNA polymerase zeta (Polzeta) to replication and mutagenesis is greatly enhanced if the normal replisome is defective due to mutations in replication genes. Here we present evidence that this defective-replisome-induced mutagenesis (DRIM) results from the participation of Polzeta in the copying of undamaged DNA rather than from mutagenic lesion bypass. First, DRIM is not elevated in strains that have a high level of endogenous DNA lesions due to defects in nucleotide excision repair or base excision repair pathways. Second, DRIM remains unchanged when the level of endogenous oxidative DNA damage is decreased by using anaerobic growth conditions. Third, analysis of the spectrum of mutations occurring during DRIM reveals the characteristic error signature seen during replication of undamaged DNA by Polzeta in vitro. These results extend earlier findings in Escherichia coli indicating that Y-family DNA polymerases can contribute to the copying of undamaged DNA. We also show that exposure of wild-type yeast cells to the replication inhibitor hydroxyurea causes a Polzeta-dependent increase in mutagenesis. This suggests that DRIM represents a response to replication impediment per se rather than to specific defects in the replisome components.

Vigilant surveillance of virus prevalence in mosquitoes is essential for risk assessment and outbreak prediction. Accurate virus detection methods are essential for arbovirus surveillance. We have developed a model to estimate the probability of accurately detecting a virus-positive mosquito from pooled field collections using standard molecular techniques. We discuss several factors influencing the probability of virus detection, including the number of virions in the sample, the total sample volume, and the portion of the sample volume that is being tested. Our model determines the probability of obtaining at least 1 virion in the sample that is tested. The model also determines the optimal sample volume that is required in any test to ensure a desired probability of virus detection is achieved, and can be used to support the accuracy of current tests or to optimize existing techniques.

We have determined, for the first time, the enthalpic contributions to the energy change associated with ligand reorganization (LR) upon the binding of the same ligand to multiple sites within human serum albumine (HSA). Quantum mechanics based density functional theory (DFT) has been used for the LR calculations, which provides much better accuracy than previously used molecular mechanics methods (MM). Our findings show that for some ligands these enthalpic contributions can be attributed to specific structural and conformational changes.

Objective: To improve access to clinical information for nurses and doctors providing after hours community palliative care in a regional Australian setting., Design: This was an action research project designed to improve collation and distribution of succinct, pertinent and timely information about unstable palliative care patients to nurses and general practitioners (GPs) involved in after hours care. Each week day, each patient's purpose-designed single-page information sheet was updated on the community palliative care service computers. This sheet was designed to give key abstracted information on each patient's history, current condition, treatment and plans for future care. Patients considered to be unstable had their sheets faxed to the GPs on call., Setting and Subjects: This procedure was followed for all adult patients admitted to Ballarat Hospice Care Inc, Victoria, Australia between June and August 2004. The nurses and Executive Officer at Ballarat Hospice Care Inc and thirteen GPs from the Ballarat and District Division of General Practitioners were involved in the study., Main Outcome Measures: Surveys and feedback from palliative care nurses and GPs., Results: A one-page information sheet provided essential clinical information to nurses and doctors. The nurses' confidence markedly increased with ready access to the information sheets on a hand held Palm Pilot. The nurses also reported improved outcomes for patients using this approach and there was favourable feedback from GPs., Conclusions: This project led to the development of a simple, effective and low cost means of improving communication between professionals caring for palliative care patients after hours.

Aims: This paper presents an evaluation of a communication enhancement intervention on staff and patients in a complex continuing care facility., Background: The importance of effective communication as a fundamental element of nursing has been emphasized and is regarded as integral to the provision of quality patient care. For people residing in complex continuing care (similar to long-term care facilities), opportunities for socialization occur primarily during interactions or communication with staff, and these interactions have been found to be limited. One way to improve nursing staff communication is through a communication enhancement intervention., Methods: Twenty-one nursing staff members (Registered Nurses, Registered Practical Nurses and healthcare aides) working in a complex continuing care environment and 16 patients participated in this study, conducted in the summer of 2003. A repeated measures design was used to evaluate the effects of the communication enhancement intervention on outcomes. Data were collected from patients and nurses at baseline, 5 weeks into the intervention and at 10 weeks after the intervention. Nurse outcome variables included nurses' job satisfaction and their relationships with patients; patient outcome variables included two measures of patient satisfaction with care., Results: Nursing staff felt closer to their patients (F(2,40) = 3.0, P = 0.045) following the intervention and reported higher levels of job satisfaction (F(2,40) = 4.1, P = 0.02). No changes were found in the level of patient satisfaction with care., Conclusions: Our results suggest that nursing staff can feel better about their job and about their patients as they enhance their communication skills. Understanding the barriers to finding time to talk with patients for a few minutes a day, outside of direct hands-on caregiving, requires further exploration.

Objective: To examine differences in labor induction and cesarean delivery rates by socioeconomic status in Nova Scotia, Canada., Methods: We studied all women in Nova Scotia who delivered between 1988 and 1995 after a singleton pregnancy. Information was obtained from the Nova Scotia Atlee Perinatal Database and the federal income tax (T1) Family Files maintained by the Small Area and Administrative Data Division of Statistics Canada (n = 76,440). Labor induction and cesarean delivery rates were contrasted by family income and other indices, with adjustment for risk factors carried out using logistic models., Results: Maternal characteristics and other factors varied by socioeconomic status; in the lowest income group 4.4% of women were aged 35 years or older, and 49.4% were nonsmokers, whereas in the highest income group 17.7% were aged 35 years or older, and 88.7% were nonsmokers. Crude induction rates were similar across income groups (17.7% compared with 18.1% in the lowest compared with highest income groups), but there were significant differences in crude cesarean (17.7% compared with 21.2%) and crude primary cesarean rates (12.5% compared with 17.0%). Controlling for differences in risk factors altered these relationships. Adjusted rate ratios, 95% confidence intervals (CIs) and P values contrasting the lowest compared with highest income groups were labor induction 1.09 (95% CI 1.00-1.19), P = .05; overall cesarean delivery 1.12 (95% CI 1.03-1.23), P = .01; primary cesarean delivery 1.09 (95% CI 0.98-1.21), P = .12., Conclusion: Affluent women in Canada are not more likely to have labor induction or cesarean delivery compared with less affluent women., Level of Evidence: II-2.