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Item Metadata only Assessing the risk of bias of quantitative analytical studies: introducing the vision for critical appraisal within JBI systematic reviews(Lippincott, Williams & Wilkins, 2023) Munn, Z.; Stone, J.; Aromataris, E.; Klugar, M.; Sears, K.; Leonardi-Bee, J.; Barker, T.H.A key step in the systematic review process is the assessment of the methodological quality (or risk of bias) of the included studies. At JBI, we have developed several tools to assist with this evaluation. As evidence synthesis methods continue to evolve, it has been necessary to revise and reflect on JBI's current approach to critical appraisal and to plan a strategy for the future. In this first paper of a series focusing on risk of bias assessment, we introduce our vision for risk of bias assessment for JBI. In future papers in this series, the methodological approach taken for this revision process will be discussed, along with the revised tools and guidance for using these tools.Item Metadata only A Transgenic Line That Reports CSF1R Protein Expression Provides a Definitive Marker for the Mouse Mononuclear Phagocyte System(The American Association of Immunologists, 2020) Grabert, K.; Sehgal, A.; Irvine, K.M.; Wollscheid-Lengeling, E.; Ozdemir, D.D.; Stables, J.; Luke, G.A.; Ryan, M.D.; Adamson, A.; Humphreys, N.E.; Sandrock, C.J.; Rojo, R.; Verkasalo, V.A.; Mueller, W.; Hohenstein, P.; Pettit, A.R.; Pridans, C.; Hume, D.A.The proliferation, differentiation, and survival of cells of the mononuclear phagocyte system (MPS; progenitors, monocytes, macrophages, and classical dendritic cells) are controlled by signals from the M-CSF receptor (CSF1R). Cells of the MPS lineage have been identified using numerous surface markers and transgenic reporters, but none is both universal and lineage restricted. In this article, we report the development and characterization of a CSF1R reporter mouse. A FusionRed (FRed) cassette was inserted in-frame with the C terminus of CSF1R, separated by a T2A-cleavable linker. The insertion had no effect of CSF1R expression or function. CSF1R-FRed was expressed in monocytes and macrophages and absent from granulocytes and lymphocytes. In bone marrow, CSF1R-FRed was absent in lineage-negative hematopoietic stem cells, arguing against a direct role for CSF1R in myeloid lineage commitment. It was highly expressed in marrow monocytes and common myeloid progenitors but significantly lower in granulocyte-macrophage progenitors. In sections of bone marrow, CSF1R-FRed was also detected in osteoclasts, CD169+ resident macrophages, and, consistent with previous mRNA analysis, in megakaryocytes. In lymphoid tissues, CSF1R-FRed highlighted diverse MPS populations, including classical dendritic cells. Whole mount imaging of nonlymphoid tissues in mice with combined CSF1R-FRed/Csf1r-EGFP confirmed the restriction of CSF1R expression to MPS cells. The two markers highlight the remarkable abundance and regular distribution of tissue MPS cells, including novel macrophage populations within tendon and skeletal muscle and underlying the mesothelial/serosal/capsular surfaces of every major organ. The CSF1R-FRed mouse provides a novel reporter with exquisite specificity for cells of the MPS.Item Open Access A kinase-dead Csf1r mutation associated with adult-onset leukoencephalopathy has a dominant inhibitory impact on CSF1R signalling(Company of Biologists, 2022) Stables, J.; Green, E.K.; Sehgal, A.; Patkar, O.L.; Keshvari, S.; Taylor, I.; Ashcroft, M.E.; Grabert, K.; Wollscheid-Lengeling, E.; Szymkowiak, S.; McColl, B.W.; Adamson, A.; Humphreys, N.E.; Mueller, W.; Starobova, H.; Vetter, I.; Shabestari, S.K.; Blurton-Jones, M.M.; Summers, K.M.; Irvine, K.M.; et al.Amino acid substitutions in the kinase domain of the human CSF1R gene are associated with autosomal dominant adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP). To model the human disease, we created a disease-associated mutation (pGlu631Lys; E631K) in the mouse Csf1r locus. Homozygous mutation (Csf1rE631K/E631K) phenocopied the Csf1r knockout, with prenatal mortality or severe postnatal growth retardation and hydrocephalus. Heterozygous mutation delayed the postnatal expansion of tissue macrophage populations in most organs. Bone marrow cells from Csf1rE631K/+mice were resistant to CSF1 stimulation in vitro, and Csf1rE631K/+ mice were unresponsive to administration of a CSF1-Fc fusion protein, which expanded tissue macrophage populations in controls. In the brain, microglial cell numbers and dendritic arborisation were reduced in Csf1rE631K/+ mice, as in patients with ALSP. The microglial phenotype is the opposite of microgliosis observed in Csf1r+/− mice. However, we found no evidence of brain pathology or impacts on motor function in aged Csf1rE631K/+ mice. We conclude that heterozygous disease-associated CSF1R mutations compromise CSF1R signalling. We speculate that leukoencephalopathy associated with dominant human CSF1R mutations requires an environmental trigger and/or epistatic interaction with common neurodegenerative disease-associated alleles.Item Open Access Cognitive impairment, fatigue and depression in multiple sclerosis: Is there a difference between benign and non-benign MS?(Elsevier BV, 2023) Bogaardt, H.; Golan, D.; Barrera, M.A.; Attrill, S.; Kaczmarek, O.; Zarif, M.; Bumstead, B.; Buhse, M.; Wilken, J.; Doniger, G.M.; Hancock, L.M.; Penner, I.-K.; Halper, J.; Morrow, S.A.; Covey, T.J.; Gudesblatt, M.Introduction: Multiple Sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system (CNS). The severity of disability in people with MS (PwMS) is generally measured with the Expanded Disability Status Scale (EDSS). A variant of MS known as ‘benign MS’ (BMS) has been defined as an EDSS score of 3 or lower, combined with a disease duration of 10 years or longer; however, there is disagreement in the field about whether BMS really exists. Given that the EDSS does not capture cognitive issues, communication dysfunction, fatigue, depression, or anxiety properly, its ability to accurately represent disability in all PwMS, including BMS, remains questionable. Methods: In this study, 141 persons with BMS (PwBMS) were included, consisting of 115 females (82%) and 26 males (18%) with a mean age of 50.8 (±8.68). A computerized test battery (NeuroTrax®) was used to assess cognition, covering seven cognitive domains (memory, executive function, visual-spatial processing, verbal function, attention, information processing, and motor skills). Fatigue was measured using the Fatigue Severity Scale (FSS). The Beck Depression Inventory (BDI) was used to assess symptoms of depression. Cognitive impairment was defined for this study as when someone has a score lower than 85 in at least two subdomains of the cognitive test battery. Rates of impairment were compared to 158 persons with non-benign MS (PwNBMS; with a disease duration of 10 years and longer and an EDSS score higher than 3) and 487 PwMS with a disease duration of fewer than 10 years. Results: Cognitive impairment was found in 38% of PwBMS and in 66% of PwNBMS (p<0.001). In PwBMS, the lowest rate of impairment was found in the verbal function domain (18%) and the highest rate of impairment in the domain of information processing (32%). Fatigue and depression were found in 78% and 55% of all PwBMS, with no difference in these rates between PwBMS and PwNBMS (p = 0.787 and p = 0.316 resp.) Conclusion: Cognitive impairment, fatigue and depression are common among people with an EDSS-based definition of benign MS. These aspects should be incorporated into a new and better definition of truly benign MSItem Metadata only Documentation of chemotherapy administration by nursing staff in inpatient and outpatient oncology/hematology settings: a best practice implementation project(Wolters Kluwer, 2015) Turner, A.; Stephenson, M.Background: Documentation of chemotherapy administration by nursing staff is undertaken in a written and electronic form at the Canberra Hospital and has been identified as requiring improvement in both inpatient and outpatient settings. Safe prescribing, dispensing, administration and documentation are essential to patient safety, outcomes and quality of care, and to staff safety. Due to the limited available research and evidence on this topic, recommended safety standards for the safe administration of chemotherapy formed the framework for audit criteria and documentation requirements. Objectives: The aim of this evidence implementation project was to improve documentation of chemotherapy administration by nursing staff in inpatient and outpatient oncology/hematology units, thereby improving patient care and safety, as well as meeting the legal and educational responsibilities of the nursing staff. Methods: This evidence implementation project used the JBI Practical Application of Clinical Evidence System and Getting Research into Practice audit and feedback tool. A baseline audit was conducted to assess current practice and identify areas requiring improvement, followed by reflection on results and design, and implementation of strategies for documentation improvement. Lastly, a follow-up audit was conducted to assess compliance and practice improvement. Results: The baseline audit results highlighted areas of good current practice, areas requiring improvement and barriers to data collection and practice improvement. Strategies based on raising awareness of best practice guidelines, education and useful tools were developed and implemented. It was evident that the electronic documentation prompts used in the outpatient setting, compared to paper-based documentation in the inpatient setting, contributed to better compliance to documentation guidelines. The follow-up audit demonstrated improved practices across both the inpatient and outpatient settings. Conclusions: The aim of improving documentation after chemotherapy administration was achieved, yet there is still room for further improvement. Education will continue through training courses, communication at meetings and utilization of the tools developed. Future auditing is planned to ensure sustainability.Item Open Access Cytolytic DNA vaccine encoding lytic perforin augments the maturation of- and antigen presentation by- dendritic cells in a time-dependent manner(Nature Publishing Group, 2017) Wijesundara, D.; Yu, W.; Quah, B.; Eldi, P.; Hayball, J.; Diener, K.; Voskoboinik, I.; Gowans, E.; Grubor-Bauk, B.The use of cost-effective vaccines capable of inducing robust CD8+ T cell immunity will contribute significantly towards the elimination of persistent viral infections and cancers worldwide. We have previously reported that a cytolytic DNA vaccine encoding an immunogen and a truncated mouse perforin (PRF) protein significantly augments anti-viral T cell (including CD8+ T cell) immunity. Thus, the current study investigated whether this vaccine enhances activation of dendritic cells (DCs) resulting in greater priming of CD8+ T cell immunity. In vitro data showed that transfection of HEK293T cells with the cytolytic DNA resulted in the release of lactate dehydrogenase, indicative of necrotic/lytic cell death. In vitro exposure of this lytic cell debris to purified DCs from naïve C57BL/6 mice resulted in maturation of DCs as determined by up-regulation of CD80/CD86. Using activation/proliferation of adoptively transferred OT-I CD8+ T cells to measure antigen presentation by DCs in vivo, it was determined that cytolytic DNA immunisation resulted in a time-dependent increase in the proliferation of OT-I CD8+ T cells compared to canonical DNA immunisation. Overall, the data suggest that the cytolytic DNA vaccine increases the activity of DCs which has important implications for the design of DNA vaccines to improve their translational prospects.Item Open Access Genome-wide physical activity interactions in adiposity ― A meta-analysis of 200,452 adults(Public Library of Science, 2017) Graff, M.; Scott, R.; Justice, A.; Young, K.; Feitosa, M.; Barata, L.; Winkler, T.; Chu, A.; Mahajan, A.; Hadley, D.; Xue, L.; Workalemahu, T.; Heard-Costa, N.; den Hoed, M.; Ahluwalia, T.; Qi, Q.; Ngwa, J.; Renström, F.; Quaye, L.; Eicher, J.; et al.; Edwards, T.Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by ~30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.Item Metadata only The association of host and genetic melanoma risk factors with Breslow thickness in the Western Australian Melanoma Health Study(Wiley, 2014) Cadby, G.; Ward, S.; Cole, J.; Moses, E.; Millward, M.; Palmer, L.BACKGROUND: Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness; however, the role of genetic loci has been little investigated to date. OBJECTIVES: To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. METHODS: Participants were 800 individuals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA sample. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. RESULTS: Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. CONCLUSIONS: Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding.Item Metadata only Quality control and conduct of genome-wide association meta-analyses(Nature Publishing Group, 2014) Winkler, T.W.; Day, F.R.; Croteau-Chonka, D.C.; Wood, A.R.; Locke, A.E.; Maegi, R.; Ferreira, T.; Fall, T.; Graff, M.; Justice, A.E.; Luan, J.; Gustafsson, S.; Randall, J.C.; Vedantam, S.; Workalemahu, T.; Kilpelainen, T.O.; Scherag, A.; Esko, T.; Kutalik, Z.; Heid, I.M.; et al.Rigorous organization and quality control (QC) are necessary to facilitate successful genome-wide association meta-analyses (GWAMAs) of statistics aggregated across multiple genome-wide association studies. This protocol provides guidelines for (i) organizational aspects of GWAMAs, and for (ii) QC at the study file level, the meta-level across studies and the meta-analysis output level. Real-world examples highlight issues experienced and solutions developed by the GIANT Consortium that has conducted meta-analyses including data from 125 studies comprising more than 330,000 individuals. We provide a general protocol for conducting GWAMAs and carrying out QC to minimize errors and to guarantee maximum use of the data. We also include details for the use of a powerful and flexible software package called EasyQC. Precise timings will be greatly influenced by consortium size. For consortia of comparable size to the GIANT Consortium, this protocol takes a minimum of about 10 months to complete.Item Open Access Gastrointestinal perforation in metastatic colorectal cancer patients with peritoneal metastases receiving bevacizumab(Baishideng Publishing Group, 2015) Roohullah, A.; Wong, H.; Sjoquist, K.; Gibbs, P.; Field, K.; Tran, B.; Shapiro, J.; Mckendrick, J.; Yip, D.; Nott, L.; Gebski, V.; Ng, W.; Chua, W.; Price, T.; Tebbutt, N.; Chantrill, L.Aim: To investigate the safety and efficacy of adding bevacizumab to first-line chemotherapy in metastatic colorectal cancer patients with peritoneal disease. Methods: We compared rates of gastrointestinal perforation in patients with metastatic colorectal cancer and peritoneal disease receiving first-line chemotherapy with and without bevacizumab in three distinct cohorts: (1) the AGITG MAX trial (Phase III randomised clinical trial comparing capecitabine vs capecitabine and bevacizumab vs capecitabine, bevacizumab and mitomycinC); (2) the prospective Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry (any first-line regimen ± bevacizumab); and (3) two cancer centres in New South Wales, Australia [Macarthur Cancer Therapy Centre and Liverpool Cancer Therapy Centre (NSWCC) from January 2005 to Decenber 2012, (any first-line regimen ± bevacizumab). For the AGITG MAX trial capecitabine was compared to the other two arms (capecitabine/bevacizumab and capecitabine/bevacizumab/mitomycinC). In the AGITG MAX trial and the TRACC registry rates of gastrointestinal perforation were also collected in patients who did not have peritoneal metastases. Secondary endpoints included progression-free survival, chemotherapy duration, and overall survival. Time-to-event outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: Eighty-four MAX, 179 TRACC and 69 NSWCC patients had peritoneal disease. There were no gastrointestinal perforations recorded in either the MAX subgroup or the NSWCC cohorts. Of the patients without peritoneal disease in the MAX trial, 4/300 (1.3%) in the bevacizumab arms had gastrointestinal perforations compared to 1/123 (0.8%) in the capecitabine alone arm. In the TRACC registry 3/126 (2.4%) patients who had received bevacizumab had a gastrointestinal perforation compared to 1/53 (1.9%) in the chemotherapy alone arm. In a further analysis of patients without peritoneal metastases in the TRACC registry, the rate of gastrointestinal perforations was 9/369 (2.4%) in the chemotherapy/bevacizumab group and 5/177 (2.8%) in the chemotherapy alone group. The addition of bevacizumab to chemotherapy was associated with improved progression-free survival in all three cohorts: MAX 6.9 m vs 4.9 m, HR = 0.64 (95%CI: 0.42-1.02); P = 0.063; TRACC 9.1 m vs 5.5 m, HR = 0.61 (95%CI: 0.37-0.86); P = 0.009; NSWCC 8.7 m vs 6.8 m, HR = 0.75 (95%CI: 0.43-1.32); P = 0.32. Chemotherapy duration was similar across the groups. Conclusion: Patients with peritoneal disease do not appear to have an increased risk of gastrointestinal perforations when receiving first-line therapy with bevacizumab compared to systemic therapy alone.Item Open Access Patient safety's missing link: using clinical expertise to recognize, respond to and reduce risks at a population level(Oxford University Press, 2016) Hibbert, P.; Healey, F.; Lamont, T.; Marela, W.; Warner, B.; Runciman, W.Introduction: Although incident reporting systems are widespread in health care as a strategy to reduce harm to patients, the focus has been on reporting incidents rather than responding to them. Systems containing large numbers of incidents are uniquely placed to raise awareness of, and then characterize and respond to infrequent, but significant risks. The aim of this paper is to outline a framework for the surveillance of such risks, their systematic analysis, and for the development and dissemination of population-based preventive and corrective strategies using clinical and human factors expertise. Requirements for a population-level response: The framework outlines four system requirements: to report incidents; to aggregate them; to support and conduct a risk surveillance, review and response process; and to disseminate recommendations. Personnel requirements include a non-hierarchical multidisciplinary team comprising clinicians and subject-matter and human factors experts to provide interpretation and high-level judgement from a range of perspectives. The risk surveillance, review and response process includes searching of large incident and other databases for how and why things have gone wrong, narrative analysis by clinical experts, consultation with the health care sector, and development and pilot testing of corrective strategies. Criteria for deciding which incidents require a population-level response are outlined. Discussion: The incremental cost of a population-based response function is modest compared with the 'reporting' element. Combining clinical and human factors expertise and a systematic approach underpins the creation of credible risk identification processes and the development of preventive and corrective strategies.Item Metadata only Physical inactivity is associated with moderate-severe obstructive sleep apnea(American Academy of Sleep Medicine, 2015) Simpson, L.; McArdle, N.; Eastwood, P.; Ward, K.; Cooper, M.; Wilson, A.; Hillman, D.; Palmer, L.; Mukherjee, S.Study Objectives: To investigate whether low levels of physical activity were associated with an increased occurrence of obstructive sleep apnea (OSA), OSA-related symptoms, and cardiometabolic risk. Methods: A case-control study design was used. OSA cases were patients referred to a sleep clinic for suspected OSA (n = 2,340). Controls comprised participants from the Busselton community (n = 1,931). Exercise and occupational activity were derived from questionnaire data. Associations were modelled using logistic and linear regression and adjusted for confounders. Results: In comparison with moderate exercise, the high, low, and nil exercise groups had an odds ratio (OR) for moderate-severe OSA of 0.6 (95% CI 0.5–0.8), 1.6 (95% CI 1.2–2.0), and 2.7 (95% CI 1.9–3.7), respectively. Relative to men in heavy activity occupations, men in medium, light and sedentary occupations had an OR for moderate-severe OSA of 1.7 (95% CI 1.1–2.5), 2.1 (95% CI 1.4–3.2), and 1.8 (95% CI 1.2–2.8), respectively. Relative to women in medium activity occupations, women in light and sedentary occupations had an OR for moderate-severe OSA of 4.2 (95% CI 2.6–7.2) and 3.5 (2.0–6.0). OSA patients who adequately exercised had lower: levels of doctor-diagnosed depression (p = 0.047); symptoms of fatigue (p < 0.0001); systolic (p = 0.015) and diastolic blood pressure (p = 0.015); and C-reactive protein (CRP) (p = 0.003). Conclusions: Low levels of physical activity were associated with moderate-severe OSA. Exercise in individuals with OSA is associated with lower levels of depression, fatigue, blood pressure and CRP.Item Metadata only Depressive symptoms before and after treatment of obstructive sleep apnea in men and women(American Academy of Sleep Medicine, 2015) Edwards, C.; Mukherjee, S.; Simpson, L.; Palmer, L.; Almeida, O.; Hillman, D.Study Objectives: To determine prevalence of depressive symptoms in obstructive sleep apnea (OSA) and the impact of OSA treatment on depression scores. Methods: Consecutive new patients referred for investigation of suspected OSA were approached. Consenting patients completed a patient health questionnaire (PHQ-9) for depressive symptoms when attending for laboratory polysomnography. Those with moderate/severe (apneahypopnea index [AHI] ≥ 15 events/h) and/or symptomatic mild OSA (AHI 5–14.99 events/h) were offered continuous positive airway pressure (CPAP) therapy. PHQ-9 was repeated after 3 months of CPAP with compliance recorded. Of a maximum PHQ-9 score of 27, a cut point ≥ 10 (PHQ-9 ≥ 10) was used to indicate presence of clinically signifi cant depressive symptoms. Results: A total of 426 participants (243 males) were recruited. Mean ± standard deviation body mass index (BMI) was 32.1 ± 7.1 kg/m2 and AHI 33.6 ± 28.9 events/h. PHQ-9 was 10.5 ± 6.1 and independently related to AHI (p < 0.001) and BMI (p < 0.001). In those without OSA, PHQ-9 ≥ 10 was more common in women, but no gender difference was evident with OSA. Of 293 patients offered CPAP, 228 were compliant (mean nightly use > 5 h) over 3 months of therapy. In them, with therapy, AHI decreased from 46.7 ± 27.4 to 6.5 ± 1.6 events/h, PHQ-9 from 11.3 ± 6.1 to 3.7 ± 2.9 and PHQ-9 ≥ 10 from 74.6% to 3.9% (p < 0.001 in each case). Magnitude of change in PHQ-9 was similar in men and women. Antidepressant use was constant throughout. Conclusions: Depressive symptoms are common in OSA and related to its severity. They improve markedly with CPAP, implying a relationship to untreated OSA.Item Metadata only Intermittent and daily therapy for tuberculosis in children(EMAP Publishing, 2014) Stern, C.J.There is insufficient evidence to support one drug treatment regimen for children with tuberculosis over any other. Research is therefore needed to identify effective medication regimens In this article… > Results of a Cochrane review that compared treatment regimens for children with tuberculosis > Implications for research and practiceItem Metadata only Constructing a search strategy and searching for evidence: a guide to the literature search for a systematic review(Lippincott Williams & Wilkins, 2014) Aromataris, E.; Riitano, D.This article is the third in a new series on the systematic review from the Joanna Briggs Institute, an international collaborative supporting evidence-based practice in nursing, medicine, and allied health fields. The purpose of the series is to show nurses how to conduct a systematic review-one step at a time. This article details the major considerations surrounding search strategies and presents an example of a search using the PubMed platform (pubmed.gov).Item Metadata only New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk(Nature Publishing Group, 2010) Dupuis, J.; Palmer, L.Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.Item Metadata only Genome-wide association study of body mass index in 23 000 individuals with and without asthma(Blackwell Science, 2013) Melen, E.; Palmer, L.BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10−7 for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms (SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m2 (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1B SNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.Item Metadata only Lipidomic profiling before and after Roux-en-Y gastric bypass in obese patients with diabetes(Macmillan, 2014) Graessler, J.; Bornstein, T.; Goel, D.; Bhalla, V.; Lohmann, T.; Wolf, T.; Koch, M.; Qin, Y.; Licinio, J.; Wong, M.; Chavakis, T.; Xu, A.; Shevchenko, A.; Schuhmann, K.; Schwarz, P.; Schulte, K.; Patel, A.; Bornstein, S.Bariatric surgery is a well-established approach to improve metabolic disease in morbidly obese patients with high cardiovascular risk. The post-operative normalization of lipid metabolism has a central role in the prevention of future cardiovascular events. The aim of the present study therefore was to characterize changes of plasma lipidomic patterns, consisting of 229 lipid species of 13 lipid classes, 3 months after Roux-en-Y gastric bypass (RYGB) in morbidly obese patients with and without diabetes. RYGB resulted in a 15–32% decrease of body mass index, which was associated with a significant reduction of total cholesterol (TC, −28.3%; P=0.02), LDL-cholesterol (LDL-C, −26.8%; P=0.03) and triglycerides (TGs, −63.0%; P=0.05) measured by routine clinical chemistry. HDL-cholesterol remained unchanged. The effect of RYGB on the plasma lipidomic profile was characterized by significant decreases of 87 lipid species from triacylglycerides (TAGs), cholesterol esters (CholEs), lysophosphatidylcholines (LPCs), phosphatidylcholines (PCs), phosphatidylethanolamine ethers (PEOs), phosphatidylinositols (PIs) and ceramides (Cers). The total of plasma lipid components exhibited a substantial decline of 32.6% and 66 lipid species showed a decrease by over 50%. A direct correlation with HbA1C values could be demonstrated for 24 individual lipid species (10 TAG, three CholE, two LPC, one lysophosphatidylcholine ethers (LPCO) (LPC ether), one PC, two phosphatidylcholine ethers (PCO) and five Cer). Notably, two lipid species (TAG 58:5 and PEO 40:5) were inversely correlated with HbA1C. LPCO, as single whole lipid class, was directly related to HbA1C. These data indicate that RYGB-induced modulation of lipidomic profiles provides important information about post-operative metabolic adaptations and might substantially contribute to improvements of glycemic control. These striking changes in the human plasma lipidome may explain acute, weight independent and long-term effects of RYGB on the cardiovascular system, mental status and immune regulation.Item Metadata only The effectiveness of GLP-1 analogues compared to DPP-4 inhibitors for beta cell function and diabetes related complications among adults with type 2 diabetes: a systematic review protocol(Joanna Briggs Institute and The University of Adelaide, 2014) Bellman, S.; Aromataris, E.Review question/objective: What is the effectiveness of GLP-1 analogues compared to DPP-4 inhibitors for beta cell function and diabetes related complications among adults with type 2 diabetes?Item Metadata only The effectiveness of Ayurvedic oil based nasal instillation (Nasya) medicines for the treatment of facial paralysis (Ardita): a systematic review protocol(Joanna Briggs Institute, 2013) Vivera, M.J.; Streak Gomersall, J.C.; Lisy, K.Review question/objective The objective of this review is to establish the effectiveness of oil based nasal instillation medicines in the treatment of Ardita (facial paralysis). The question that will be asked in the review is: Which of the commonly used Ayurvedic nasal instillation medicated oils is the most effective for treating Ardita either solely or in combination with other Ayurvedic medical interventions? Inclusion criteria Types of participants Adults (18-70 years of age) with Ardita (chronic or acute) are the participants to be included in this review. More specifically, the review will consider for inclusion studies that have examined the effectiveness of Naysa for treating acute or chronic Ardita in adults. An inclusive approach will be adopted with respect to geographical location of the participants with patients located in any country, and both rural and urban areas to be considered. Participants of any socio-economic status, both sexes and all ethnic origins will be considered. Studies whose participants have been pregnant women, adults older than 70 years and patients with allergic rhinitis, fever, intracranial tumour/haemorrhage and bilateral facial palsy will be excluded from the review. The reason for the lower age limit of 18 is because oil based Nasya is not usually administered to children, according to the ancient textual source Astanga Hridaya Sootra Sthanna. Types of intervention(s) and comparator(s) The review will include for consideration all quantitative studies conducted worldwide that have examined the effectiveness of nasal instillation of Ayurvedic oil-based herbal medicine. All studies that quantified the effectiveness of Nasya either administered by a therapist or by self administration in treating facial paralysis will be considered for inclusion. All dosages and frequencies of Nasya use will be considered and if possible how effectiveness varies with dosage and frequency of use will be detailed in the analysis. All studies in which the comparator was conventional medical management or placebo will be considered for inclusion. However, studies of Ayurvedic Nasya medicine in conjunction with conventional medicine, if any, will be excluded. As the objective is not only to shed light on the effectiveness of Nasya for treating facial paralysis, but also the effectiveness of one kind of Nasya medicine compared to another, all studies that have compared the effectiveness of one Nasya instillation medicine compared to another will be considered. Types of Outcomes The review will consider both Ayurvedic and Conventional medicine outcome assessment criterion as described in the research papers. With respect to the conventional medicine this will include, but not be limited to facial function as measured by the House-Brackmann grading of facial function measure. With respect to the Ayurvedic medicine approach this will include but not limited to Ayurvedic diagnostic scoring.