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1.  Phenotype Standardization for Statin-Induced Myotoxicity 
Statins are widely used lipid-lowering drugs that are effective in reducing cardiovascular disease risk. Although they are generally well tolerated, they can cause muscle toxicity, which can lead to severe rhabdomyolysis. Research in this area has been hampered to some extent by the lack of standardized nomenclature and phenotypic definitions. We have used numerical and descriptive classifications and developed an algorithm to define statin-related myotoxicity phenotypes, including myalgia, myopathy, rhabdomyolysis, and necrotizing autoimmune myopathy.
doi:10.1038/clpt.2014.121
PMCID: PMC4172546  PMID: 24897241
2.  Phenotype Standardization of Angioedema in the Head and Neck Region Caused by Agents Acting on the Angiotensin System 
Angioedema is a potentially life-threatening adverse reaction to angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. To study the genetic etiology of this rare adverse event, international consortia and multicenter recruitment of patients are needed. To reduce patient heterogeneity, we have standardized the phenotype. In brief, it comprises swelling in the head and neck region that first occurs during treatment. It should not coincide with urticaria or have another likely cause such as hereditary angioedema.
doi:10.1038/clpt.2014.138
PMCID: PMC4172548  PMID: 24960520
3.  Reasons for non-uptake and subsequent participation in the NHS Bowel Cancer Screening Programme: a qualitative study 
British Journal of Cancer  2014;110(7):1705-1711.
Background:
Screening for bowel cancer using the guaiac faecal occult blood test offered by the NHS Bowel Cancer Screening Programme (BCSP) is taken up by 54% of the eligible population. Uptake ranges from 35% in the most to 61% in the least deprived areas. This study explores reasons for non-uptake of bowel cancer screening, and examines reasons for subsequent uptake among participants who had initially not taken part in screening.
Methods:
Focus groups with a socio-economically diverse sample of participants were used to explore participants' experience of invitation to and non-uptake of bowel cancer screening.
Results:
Participants described sampling faeces and storing faecal samples as broaching a cultural taboo, and causing shame. Completion of the test kit within the home rather than a formal health setting was considered unsettling and reduced perceived importance. Not knowing screening results was reported to be preferable to the implications of a positive screening result. Feeling well was associated with low perceived relevance of screening. Talking about bowel cancer screening with family and peers emerged as the key to subsequent participation in screening.
Conclusions:
Initiatives to normalise discussion about bowel cancer screening, to link the BCSP to general practice, and to simplify the test itself may lead to increased uptake across all social groups.
doi:10.1038/bjc.2014.125
PMCID: PMC3974074  PMID: 24619071
bowel cancer; bowel cancer screening; colorectal cancer screening; guaiac faecal occult blood test (gFOBt); non-uptake; socio-economic circumstances; qualitative
4.  Enzyme activity demonstrates multiple pathways of innate immunity in Indo-Pacific anthozoans 
Coral reefs are threatened by increasing levels of coral disease and the functional loss of obligate algal symbionts (bleaching). Levels of immunity relate directly to susceptibility to these threats; however, our understanding of fundamental aspects of coral immunology is lacking. We show that three melanin-synthesis pathway components (mono-phenoloxidase, ortho-diphenoloxidase (tyrosinase-type pathway) and para-diphenoloxidase (laccase-type pathway)) are present in both their active (phenoloxidase, PO) and inactive (prophenoloxidase, PPO) forms across a diverse range of 22 species of healthy Indo-Pacific anthozoans. We also demonstrate transglutaminase activity of the coagulation cascade for, to our knowledge, the first time in a coral. Melanin-synthesis enzyme activities varied among taxa, although they were generally lowest in the coral family Acroporidae and highest in the Poritidae and Oculinidae. Inactive tyrosinase-type activity (PPO) and active laccase-type activity (PO) correlate with taxonomic patterns in disease resistance, whereas the converse pattern in activity levels correlates with bleaching resistance. Overall, we demonstrate the presence of several melanin-synthesis pathways in Indo-Pacific corals, co-regulation among some pathway components, and highlight their potential roles in coral health.
doi:10.1098/rspb.2011.2487
PMCID: PMC3415895  PMID: 22810430
coral; phenoloxidase; melanin; coagulation; disease; bleaching
6.  Complementary and Alternative Medicine Use among Cancer Survivors: a Population-Based Study 
Introduction
The use of complementary and alternative medicine (CAM) among cancer survivors is high, yet less is known about reasons behind such use or the communication of CAM with conventional medical providers.
Methods
Cross-sectional, multivariate logistic regression models were developed to evaluate the similarities and differences between cancer survivors and non-cancer controls in the 2007 National Health Interview Survey with 23,393 participants, including 1,471 cancer survivors.
Results
Among cancer survivors, 66.5% reported ever using CAM and 43.3% having used CAM in the past year. When compared with the general population, cancer survivors used CAM more often for general disease prevention, immune enhancement, and for pain (Adjusted Odds Ratio [AOR] 1.27, 95% Confidence Interval [CI] 1.10-1.48; AOR 1.32, 95% CI 1.05-1.62; AOR 1.42, 95% CI 1.05-1.92, respectively). Cancer survivors were more likely to use CAM because of recommendations from their provider (AOR 1.54, 95% CI 1.26-1.88) and were more likely to disclose their CAM use to their provider (AOR 1.45, 95% CI 1.22-1.72).
Discussions/Conclusions
When compared to the general population, cancer survivors were more likely to use CAM and communicate this use with providers, indicating a growing integration of CAM in conventional medical care.
Implications for Cancer Survivors
Cancer survivors are more likely than the general population to communicate CAM use with providers, suggesting greater integration of CAM use in conventional care. However, the majority of CAM use is still not being communicated to providers, indicating an important area for improvement in patient-centered care.
doi:10.1007/s11764-010-0153-7
PMCID: PMC3564962  PMID: 20924711
Complementary Therapies; Clinical Oncology; Communication
7.  Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes 
Albrechtsen, A. | Grarup, N. | Li, Y. | Sparsø, T. | Tian, G. | Cao, H. | Jiang, T. | Kim, S. Y. | Korneliussen, T. | Li, Q. | Nie, C. | Wu, R. | Skotte, L. | Morris, A. P. | Ladenvall, C. | Cauchi, S. | Stančáková, A. | Andersen, G. | Astrup, A. | Banasik, K. | Bennett, A. J. | Bolund, L. | Charpentier, G. | Chen, Y. | Dekker, J. M. | Doney, A. S. F. | Dorkhan, M. | Forsen, T. | Frayling, T. M. | Groves, C. J. | Gui, Y. | Hallmans, G. | Hattersley, A. T. | He, K. | Hitman, G. A. | Holmkvist, J. | Huang, S. | Jiang, H. | Jin, X. | Justesen, J. M. | Kristiansen, K. | Kuusisto, J. | Lajer, M. | Lantieri, O. | Li, W. | Liang, H. | Liao, Q. | Liu, X. | Ma, T. | Ma, X. | Manijak, M. P. | Marre, M. | Mokrosiński, J. | Morris, A. D. | Mu, B. | Nielsen, A. A. | Nijpels, G. | Nilsson, P. | Palmer, C. N. A. | Rayner, N. W. | Renström, F. | Ribel-Madsen, R. | Robertson, N. | Rolandsson, O. | Rossing, P. | Schwartz, T. W. | Slagboom, P. E. | Sterner, M. | Tang, M. | Tarnow, L. | Tuomi, T. | van’t Riet, E. | van Leeuwen, N. | Varga, T. V. | Vestmar, M. A. | Walker, M. | Wang, B. | Wang, Y. | Wu, H. | Xi, F. | Yengo, L. | Yu, C. | Zhang, X. | Zhang, J. | Zhang, Q. | Zhang, W. | Zheng, H. | Zhou, Y. | Altshuler, D. | ‘t Hart, L. M. | Franks, P. W. | Balkau, B. | Froguel, P. | McCarthy, M. I. | Laakso, M. | Groop, L. | Christensen, C. | Brandslund, I. | Lauritzen, T. | Witte, D. R. | Linneberg, A. | Jørgensen, T. | Hansen, T. | Wang, J. | Nielsen, R. | Pedersen, O.
Diabetologia  2012;56(2):298-310.
Aims/hypothesis
Human complex metabolic traits are in part regulated by genetic determinants. Here we applied exome sequencing to identify novel associations of coding polymorphisms at minor allele frequencies (MAFs) >1% with common metabolic phenotypes.
Methods
The study comprised three stages. We performed medium-depth (8×) whole exome sequencing in 1,000 cases with type 2 diabetes, BMI >27.5 kg/m2 and hypertension and in 1,000 controls (stage 1). We selected 16,192 polymorphisms nominally associated (p < 0.05) with case–control status, from four selected annotation categories or from loci reported to associate with metabolic traits. These variants were genotyped in 15,989 Danes to search for association with 12 metabolic phenotypes (stage 2). In stage 3, polymorphisms showing potential associations were genotyped in a further 63,896 Europeans.
Results
Exome sequencing identified 70,182 polymorphisms with MAF >1%. In stage 2 we identified 51 potential associations with one or more of eight metabolic phenotypes covered by 45 unique polymorphisms. In meta-analyses of stage 2 and stage 3 results, we demonstrated robust associations for coding polymorphisms in CD300LG (fasting HDL-cholesterol: MAF 3.5%, p = 8.5 × 10−14), COBLL1 (type 2 diabetes: MAF 12.5%, OR 0.88, p = 1.2 × 10−11) and MACF1 (type 2 diabetes: MAF 23.4%, OR 1.10, p = 8.2 × 10−10).
Conclusions/interpretation
We applied exome sequencing as a basis for finding genetic determinants of metabolic traits and show the existence of low-frequency and common coding polymorphisms with impact on common metabolic traits. Based on our study, coding polymorphisms with MAF above 1% do not seem to have particularly high effect sizes on the measured metabolic traits.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2756-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-012-2756-1
PMCID: PMC3536959  PMID: 23160641
Exome sequencing; Genetic epidemiology; Genetics; Lipids; Next-generation sequencing; Obesity; Type 2 diabetes
8.  Is leaf dry matter content a better predictor of soil fertility than specific leaf area? 
Annals of Botany  2011;108(7):1337-1345.
Background and Aims
Specific leaf area (SLA), a key element of the ‘worldwide leaf economics spectrum’, is the preferred ‘soft’ plant trait for assessing soil fertility. SLA is a function of leaf dry matter content (LDMC) and leaf thickness (LT). The first, LDMC, defines leaf construction costs and can be used instead of SLA. However, LT identifies shade at its lowest extreme and succulence at its highest, and is not related to soil fertility. Why then is SLA more frequently used as a predictor of soil fertility than LDMC?
Methods
SLA, LDMC and LT were measured and leaf density (LD) estimated for almost 2000 species, and the capacity of LD to predict LDMC was examined, as was the relative contribution of LDMC and LT to the expression of SLA. Subsequently, the relationships between SLA, LDMC and LT with respect to soil fertility and shade were described.
Key Results
Although LD is strongly related to LDMC, and LDMC and LT each contribute equally to the expression of SLA, the exact relationships differ between ecological groupings. LDMC predicts leaf nitrogen content and soil fertility but, because LT primarily varies with light intensity, SLA increases in response to both increased shade and increased fertility.
Conclusions
Gradients of soil fertility are frequently also gradients of biomass accumulation with reduced irradiance lower in the canopy. Therefore, SLA, which includes both fertility and shade components, may often discriminate better between communities or treatments than LDMC. However, LDMC should always be the preferred trait for assessing gradients of soil fertility uncoupled from shade. Nevertheless, because leaves multitask, individual leaf traits do not necessarily exhibit exact functional equivalence between species. In consequence, rather than using a single stand-alone predictor, multivariate analyses using several leaf traits is recommended.
doi:10.1093/aob/mcr225
PMCID: PMC3197453  PMID: 21948627
Ellenberg numbers; functional traits; leaf density; leaf nitrogen; leaf size; leaf thickness; relative growth rate (RGR); shade tolerance; variation in trait expression
9.  Towards an integrated network of coral immune mechanisms 
Reef-building corals form bio-diverse marine ecosystems of high societal and economic value, but are in significant decline globally due, in part, to rapid climatic changes. As immunity is a predictor of coral disease and thermal stress susceptibility, a comprehensive understanding of this new field will likely provide a mechanistic explanation for ecological-scale trends in reef declines. Recently, several strides within coral immunology document defence mechanisms that are consistent with those of both invertebrates and vertebrates, and which span the recognition, signalling and effector response phases of innate immunity. However, many of these studies remain discrete and unincorporated into the wider fields of invertebrate immunology or coral biology. To encourage the rapid development of coral immunology, we comprehensively synthesize the current understanding of the field in the context of general invertebrate immunology, and highlight fundamental gaps in our knowledge. We propose a framework for future research that we hope will stimulate directional studies in this emerging field and lead to the elucidation of an integrated network of coral immune mechanisms. Once established, we are optimistic that coral immunology can be effectively applied to pertinent ecological questions, improve current prediction tools and aid conservation efforts.
doi:10.1098/rspb.2012.1477
PMCID: PMC3441085  PMID: 22896649
invertebrate immunity; coral immunology; melanin; coagulation; TOLL-like receptors; immune cells
10.  A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts 
Diabetologia  2012;55(7):1971-1977.
Aims/hypothesis
In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations.
Methods
Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA1c reduction and treatment success, defined as the ability to reach the treatment target of an HbA1c ≤7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed.
Results
In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10−6, respectively).
Conclusions/interpretation
A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2537-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
doi:10.1007/s00125-012-2537-x
PMCID: PMC3369131  PMID: 22453232
Genetics of type 2 diabetes; Human; Meta-analysis; Metformin; Oral pharmacological agents
11.  Effects of daily treatment with citicoline: A double-blind, placebo-controlled study in cocaine-dependent volunteers 
Journal of addiction medicine  2011;5(1):57-64.
Many pharmacotherapies for treating cocaine dependence are aimed at reducing drug effects, alleviating craving, and/or preventing relapse. We demonstrated previously that citicoline, a compound used to repair neuronal damage in stroke and brain injury, is safe in cocaine-abusing volunteers.
Objectives
This study assessed the effectiveness of an eight-week citicoline treatment period and four-week follow-up in cocaine-dependent individuals.
Methods
Twenty-nine healthy non-treatment-seeking cocaine-dependent male and female volunteers were randomized in this double-blind, placebo-controlled study, eighteen of whom completed the treatment period of the study. Participants took citicoline (500 mg b.i.d) or matched placebo each day, and recorded measures of craving and drug use. Participants visited the laboratory twice a week for urine screens, as well as to attend weekly group therapy sessions.
Results
Citicoline had no effect on cocaine craving or total use.
Conclusions
While the current preliminary results from this small trial suggest that citicoline is not an effective treatment for heavy cocaine users, further investigation of citicoline’s efficacy as a treatment for substance dependence in other settings may be warranted.
doi:10.1097/ADM.0b013e3181d80c93
PMCID: PMC3140015  PMID: 21769048
Citicoline; Cocaine; Alcohol; Marihuana; Pharmacotherapy
12.  Diet and Caries-Associated Bacteria in Severe Early Childhood Caries 
Journal of dental research  2010;89(11):1224-1229.
Frequent consumption of cariogenic foods and bacterial infection are risk factors for early childhood caries (ECC). This study hypothesized that a short diet survey focused on frequency of foods, categorized by putative cariogenicity, would differentiate severe ECC (S-ECC) from caries-free children. Childrens’ diet was obtained by survey and plaque bacteria detected by PCR from 72 S-ECC and 38 caries-free children. S-ECC children had higher scores for between-meal juice (p<0.01), solid-retentive foods (p<0.001), eating frequency (p <0.005), and estimated food cariogenicity (p<0.0001) than caries-free children. S-ECC children with lesion recurrence ate fewer putative caries-protective foods than children without new lesions. S. mutans (p<0.005), S. sobrinus (p<0.005) and bifidobacteria (p<0.0001) were associated with S-ECC, and S. mutans with S. sobrinus was associated with lesion recurrence (p<0.05). S. mutans positive children had higher food cariogenicity scores. Food frequency, putative cariogenicity, and S. mutans were associated with S-ECC individually, and in combination.
doi:10.1177/0022034510376543
PMCID: PMC2954266  PMID: 20858780
Childhood Caries; Food Frequency; Cariogenicity; S. mutans; Bifidobacteria
13.  Diet and Caries-associated Bacteria in Severe Early Childhood Caries 
Journal of Dental Research  2010;89(11):1224-1229.
Frequent consumption of cariogenic foods and bacterial infection are risk factors for early childhood caries (ECC). This study hypothesized that a short diet survey focused on frequency of foods, categorized by putative cariogenicity, would differentiate severe ECC (S-ECC) from caries-free children. Children’s diets were obtained by survey and plaque bacteria detected by PCR from 72 S-ECC and 38 caries-free children. S-ECC children had higher scores for between-meal juice (p < 0.01), solid-retentive foods (p < 0.001), eating frequency (p < 0.005), and estimated food cariogenicity (p < 0.0001) than caries-free children. S-ECC children with lesion recurrence ate fewer putative caries-protective foods than children without new lesions. Streptococcus mutans (p < 0.005), Streptococcus sobrinus (p < 0.005), and Bifidobacteria (p < 0.0001) were associated with S-ECC, and S. mutans with S. sobrinus was associated with lesion recurrence (p < 0.05). S. mutans-positive children had higher food cariogenicity scores. Food frequency, putative cariogenicity, and S. mutans were associated with S-ECC individually and in combination.
doi:10.1177/0022034510376543
PMCID: PMC2954266  PMID: 20858780
childhood caries; food frequency; cariogenicity; S. mutans; Bifidobacteria
14.  A role for coding functional variants in HNF4A in Type 2 Diabetes susceptibility 
Diabetologia  2010;54(1):111-119.
Aims/hypothesis
Rare mutations in the gene (HNF4A) encoding the transcription factor HNF-4A account for ~5% of cases of maturity-onset diabetes of the young (MODY) and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%, T130I, MAF ~3.0%), known to influence downstream HNF-4A target gene expression, are of interest but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis.
Methods
We genotyped both variants in at least 5745 cases and 14756 population controls from the UK and Denmark. We also undertook an expanded association-analysis including previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14279 cases and 26835 controls.
Results
We found no association between V255M and type 2 diabetes in either the initial (p=0.28) or expanded analysis (p=0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [1.08-1.28]; p=1.5×10−4), which was strengthened in the meta-analysis (OR 1.20 [1.10-1.30]; p=2.1×10−5).
Conclusions/interpretation
Our data are consistent with T130I as a low frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low frequency variants.
doi:10.1007/s00125-010-1916-4
PMCID: PMC3119815  PMID: 20878384
Type 2 Diabetes; HNF4A; Low frequency variants; T130I; V255M
15.  Stomatal vs. genome size in angiosperms: the somatic tail wagging the genomic dog? 
Annals of Botany  2010;105(4):573-584.
Background and Aims
Genome size is a function, and the product, of cell volume. As such it is contingent on ecological circumstance. The nature of ‘this ecological circumstance’ is, however, hotly debated. Here, we investigate for angiosperms whether stomatal size may be this ‘missing link’: the primary determinant of genome size. Stomata are crucial for photosynthesis and their size affects functional efficiency.
Methods
Stomatal and leaf characteristics were measured for 1442 species from Argentina, Iran, Spain and the UK and, using PCA, some emergent ecological and taxonomic patterns identified. Subsequently, an assessment of the relationship between genome-size values obtained from the Plant DNA C-values database and measurements of stomatal size was carried out.
Key Results
Stomatal size is an ecologically important attribute. It varies with life-history (woody species < herbaceous species < vernal geophytes) and contributes to ecologically and physiologically important axes of leaf specialization. Moreover, it is positively correlated with genome size across a wide range of major taxa.
Conclusions
Stomatal size predicts genome size within angiosperms. Correlation is not, however, proof of causality and here our interpretation is hampered by unexpected deficiencies in the scientific literature. Firstly, there are discrepancies between our own observations and established ideas about the ecological significance of stomatal size; very large stomata, theoretically facilitating photosynthesis in deep shade, were, in this study (and in other studies), primarily associated with vernal geophytes of unshaded habitats. Secondly, the lower size limit at which stomata can function efficiently, and the ecological circumstances under which these minute stomata might occur, have not been satisfactorally resolved. Thus, our hypothesis, that the optimization of stomatal size for functional efficiency is a major ecological determinant of genome size, remains unproven.
doi:10.1093/aob/mcq011
PMCID: PMC2850795  PMID: 20375204
Stomatal size; genome size; seed size; life history; photosynthesis; allometry; ecology; evolution; SLA; leaf structure; CAM; C4
16.  A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma 
British Journal of Cancer  2009;100(8):1245-1249.
Lomeguatrib, an O6-methylguanine-DNA methyltransferase inactivator, was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40 mg, b.i.d. for 10 or 14 days and temozolomide 75–100 mg m−2 on days 1–5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. A total of 32 patients were recruited to the study. Lomeguatrib for 10 days with temozolomide 75 mg m−2 was established as the optimal extended lomeguatrib dosing schedule, with haematological toxicity being dose limiting. There were two partial responses to treatment giving an overall response rate of 6.25%. Extending lomeguatrib administration beyond that of temozolomide requires a reduced dose of the latter agent. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma.
doi:10.1038/sj.bjc.6605016
PMCID: PMC2676549  PMID: 19367282
O6-methylguanine-DNA methyltransferase; lomeguatrib; temozolomide; melanoma
17.  Genetic association analysis of LARS2 with type 2 diabetes 
Diabetologia  2009;53(1):103-110.
Aims/hypothesis
LARS2 has been previously identified as a potential type 2 diabetes susceptibility gene through the low-frequency H324Q (rs71645922) variant (minor allele frequency [MAF] 3.0%). However, this association did not achieve genome-wide levels of significance. The aim of this study was to establish the true contribution of this variant and common variants in LARS2 (MAF > 5%) to type 2 diabetes risk.
Methods
We combined genome-wide association data (n = 10,128) from the DIAGRAM consortium with independent data derived from a tagging single nucleotide polymorphism (SNP) approach in Dutch individuals (n = 999) and took forward two SNPs of interest to replication in up to 11,163 Dutch participants (rs17637703 and rs952621). In addition, because inspection of genome-wide association study data identified a cluster of low-frequency variants with evidence of type 2 diabetes association, we attempted replication of rs9825041 (a proxy for this group) and the previously identified H324Q variant in up to 35,715 participants of European descent.
Results
No association between the common SNPs in LARS2 and type 2 diabetes was found. Our replication studies for the two low-frequency variants, rs9825041 and H324Q, failed to confirm an association with type 2 diabetes in Dutch, Scandinavian and UK samples (OR 1.03 [95% CI 0.95–1.12], p = 0.45, n = 31,962 and OR 0.99 [0.90–1.08], p = 0.78, n = 35,715 respectively).
Conclusions/interpretation
In this study, the largest study examining the role of sequence variants in LARS2 in type 2 diabetes susceptibility, we found no evidence to support previous data indicating a role in type 2 diabetes susceptibility.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-009-1557-7) contains supplementary material, which is available to authorised users.
doi:10.1007/s00125-009-1557-7
PMCID: PMC2789927  PMID: 19847392
Genetics; LARS2; Mitochondria; SNP; Type 2 diabetes
18.  Gene variants influencing measures of inflammation or predisposing to autoimmune and inflammatory diseases are not associated with the risk of type 2 diabetes 
Diabetologia  2008;51(12):2205-2213.
Aims/hypothesis
There are strong associations between measures of inflammation and type 2 diabetes, but the causal directions of these associations are not known. We tested the hypothesis that common gene variants known to alter circulating levels of inflammatory proteins, or known to alter autoimmune-related disease risk, influence type 2 diabetes risk.
Methods
We selected 46 variants: (1) eight variants known to alter circulating levels of inflammatory proteins, including those in the IL18, IL1RN, IL6R, MIF, PAI1 (also known as SERPINE1) and CRP genes; and (2) 38 variants known to predispose to autoimmune diseases, including type 1 diabetes. We tested the associations of these variants with type 2 diabetes using a meta-analysis of 4,107 cases and 5,187 controls from the Wellcome Trust Case Control Consortium, the Diabetes Genetics Initiative, and the Finland-United States Investigation of NIDDM studies. We followed up associated variants (p<0.01) in a further set of 3,125 cases and 3,596 controls from the UK.
Results
We found no evidence that inflammatory or autoimmune disease variants are associated with type 2 diabetes (at p≤0.01). The OR observed between the variant altering IL-18 levels, rs2250417, and type 2 diabetes (OR 1.00 [95% CI 0.99-1.03]), is much lower than that expected given (1) the effect of the variant on IL-18 levels (0.28 SDs per allele); and (2) estimates, based on other studies, of the correlation between IL-18 levels and type 2 diabetes risk (approximate OR 1.15 [95% CI 1.09-1.21] per 0.28 SD increase in IL-18 levels).
Conclusions/interpretation
Our study provided no evidence that variants known to alter measures of inflammation, autoimmune or inflammatory disease risk, including type 1 diabetes, alter type 2 diabetes risk.
doi:10.1007/s00125-008-1160-3
PMCID: PMC2662689  PMID: 18853133
Autoimmune disease; Genes; Genetic epidemiology; Inflammation; Mendelian randomisation; SNP; Type 2 diabetes
19.  Arginine‐16 β2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol 
Thorax  2006;61(11):940-944.
Background
The homozygous presence of the arginine‐16 variant of the β2 adrenoceptor gene ADRB2 reverses the benefits from the regular use of short acting β2 agonists in asthmatic adults compared with the homozygous glycine‐16 genotype. We studied the effect of this polymorphic variation on asthma exacerbations in children and young adults and its relation to long acting β2 agonists.
Methods
A cross‐sectional survey was undertaken using electronic records, direct interviews, and genotype determination of position 16 and 27 of the ADRB2 gene in DNA from mouthwash samples of 546 children and young asthmatics attending paediatric and young adult asthma clinics in Tayside, Scotland during 2004–5. The primary outcome measure was asthma exacerbations over the previous 6 months.
Results
There was an increased hazard of asthma exacerbations across all treatment steps of the British Thoracic Society (BTS) asthma guidelines when the homozygous genotypes Arg/Arg and Gly/Gly were compared (OR 2.05, 95% CI 1.19 to 3.53, p = 0.010), particularly in patients treated with salmeterol (OR 3.40, 95% CI 1.19 to 9.40, p = 0.022). The Glu27Gln polymorphism had no significant effect on asthma exacerbations in any treatment group.
Conclusions
The arginine‐16 genotype of ADRB2 predisposes to exacerbations in asthmatic children and young adults, particularly in those exposed to regular salmeterol. This may be explained by genotype selective salmeterol induced downregulation and impaired receptor coupling, and associated subsensitivity of the response.
doi:10.1136/thx.2006.059386
PMCID: PMC2121164  PMID: 16772309
asthma; children; polymorphism; salmeterol;  ADRB2
20.  Is breeding of farmland wading birds depressed by a combination of predator abundance and grazing? 
Biology Letters  2008;4(3):256-258.
Agri-environment schemes have been implemented across Europe to counter biodiversity loss in agricultural landscapes and halt the continual decline of farmland birds, including waders. Such schemes provide financial compensation for changes in agricultural practice, including livestock grazing regimes. Scheme uptake has been variable, partly because farmers believe that other factors, notably predation, are key to wader population declines. On the basis of wader breeding surveys across Shetland, UK, we show that predator density and livestock grazing, through reducing sward height, interact to influence territoriality and thereby are likely to affect wader breeding success. Our results appear to reflect views of both farmers and government agencies, which indicates that future agri-environment schemes would benefit from genuine stakeholder participation to maximize scheme uptake, implementation and beneficial effects on biodiversity. Our findings also imply that agri-environment schemes will reap the greatest benefits for waders through reducing stocking rate where avian predators are abundant.
doi:10.1098/rsbl.2008.0012
PMCID: PMC2610041  PMID: 18381262
agri-environment scheme; farmers; lapwing; livestock grazing; oystercatcher; predation
21.  Urban legend versus rural reality: patients' experience of attendance at accident and emergency departments in west Wales 
Emergency Medicine Journal : EMJ  2005;22(3):165-170.
Objectives: To investigate why and how patients decide to attend accident and emergency (A&E) departments, and to assess their satisfaction with the experience, in a predominantly rural west Wales population.
Methods: This was a semi-structured follow up telephone interview of patients who walked in to A&E in one of four general hospitals in west Wales and were triaged as Manchester Triage score 4 or 5. Patients were recruited by nurses during the period July–November 2002. The study sample consisted of 176 male and 145 female patients, mean (SD) age 36.6 (20.0) years. The main outcome measure was a quantitative and qualitative description of the recalled experiences of A&E attenders, the circumstances of their attendance, and their satisfaction with the experience.
Results: Of the study sample, 78% attended with injury or illnesses of recent origin, and 50% with actual or presumed musculoskeletal injury, 73% of which were sustained within 10 miles of home. Travel to hospital was by private transport for 86%, average distance 7.4 miles. The majority (90%) were registered with a local GP, but 32% felt A&E was the obvious choice, and a further 44% considered their GP inaccessible to their needs. Patients' reasons for seeking health care at A&E were similar to those described in an English urban study. Waiting times were rarely excessive; 80% left within 2 hours, and patient satisfaction was generally high. Among the 87 patients (27%) who reported a less satisfactory experience, 48 (55%) of these complained of dismissive attitudes of doctors.
Conclusions: Anecdotal accounts of abuse of A&E services and unreasonable patient expectations gain the status of "urban legends" within the medical profession. Among the predominantly settled rural population in west Wales, there is little evidence of unreasonable patient expectations, and most patients report high satisfaction levels. Patients' bad experiences most frequently arise from a dismissive attitude on the part of medical staff. These attitudes are often consequent on an A&E culture that views some patients' attendances as less appropriate than others.
doi:10.1136/emj.2003.007674
PMCID: PMC1726710  PMID: 15735261
22.  Spatial processes can determine the relationship between prey encounter rate and prey density 
Biology Letters  2005;1(2):136-138.
Theoretical models frequently assume that the rate at which a searching predator encounters prey increases linearly with prey density. In a recent experiment using great tits searching for winter moth caterpillars, the time to find the first prey item did not decline as quickly with density as the standard theory assumes. Using a spatial simulation model, we show that prey aggregation and/or spatially correlated searching behaviour by the predator can generate a range of relationships, including results that are qualitatively similar to those found in the great tit experiment. We suggest that further experiments are required to determine whether the explanation proposed here is correct, and that theoretical work is needed to determine how this behaviour is likely to influence the ecological and evolutionary dynamics of predator–prey communities.
doi:10.1098/rsbl.2004.0293
PMCID: PMC1626232  PMID: 17148148
aggregation; foraging; searching; predation risk; spatial structure
23.  Quality improvement for patients with hip fracture: experience from a multi-site audit 
Quality & safety in health care  2002;11(3):239-245.


Problem: The first East Anglian audit of hip fracture was conducted in eight hospitals during 1992. There were significant differences between hospitals in 90-day mortality, development of pressure sores, median lengths of hospital stay, and in most other process measures. Only about half the survivors recovered their pre-fracture physical function. A marked decrease in physical function (for 31%) was associated with postoperative complications.
Design: A re-audit was conducted in 1997 as part of a process of continuing quality improvement. This was an interview and record based prospective audit of process and outcome of care with 3 month follow up. Seven hospitals with trauma orthopaedic departments took part in both audits. Results from the 1992 audit and indicator standards for re-audit were circulated to all orthopaedic consultants, care of the elderly consultants, and lead audit facilitators at each hospital.
Key measures for improvement: Processes likely to reduce postoperative complications and improve patient outcomes at 90 days.
Strategy for change: As this was a multi-site audit, the project group had no direct power to bring about changes within individual NHS hospital trusts.
Results: Significant increases were seen in pharmaceutical thromboembolic prophylaxis (from 45% to 81%) and early mobilisation (from 56% to 70%) between 1992 and 1997. There were reduced levels of pneumonia, wound infection, pressure sores, and fatal pulmonary embolism, but no change was recorded in 3 month functional outcomes or mortality.
Lessons learnt: While some hospitals had made improvements in care by 1997, others were failing to maintain their level of good practice. This highlights the need for continuous quality improvement by repeating the audit cycle in order to reach and then improve standards. Rehabilitation and long term support to improve functional outcomes are key areas for future audit and research.
doi:10.1136/qhc.11.3.239
PMCID: PMC1743638  PMID: 12486988
24.  Disseminating healthcare information: getting the message across 
Quality in Health Care : QHC  2000;9(1):58-62.
doi:10.1136/qhc.9.1.58
PMCID: PMC1743500  PMID: 10848372
25.  Fibrosis and other histological features in chronic hepatitis C virus infection: a statistical model. 
Journal of Clinical Pathology  1996;49(6):465-469.
AIMS: To study the inter-relation between hepatic fibrosis and other histological features of chronic hepatitis C virus (HCV) infection. METHODS: Liver biopsy specimens from 200 consecutive patients with chronic HCV infection were graded and staged separately for necro-inflammatory activity and for fibrosis. The interaction between fibrosis and other histological features was evaluated by univariate and multivariate analysis, followed by hierarchical log linear modelling. RESULTS: The most striking feature was the presence of portal tract inflammation in 177 (89%) of 200 samples. Lymphoid aggregates/follicles were observed either alone or as part of the general inflammatory infiltration of the portal tracts in 120 (60%) of 200 samples. Fatty change (macro- and microvesicular steatosis) was observed in 76 (38%) samples: mild to moderate in 60 (30%) and diffuse in 16 (8%). Bile duct damage was found in 30 (15%) of 200 specimens. Lobular activity was found in 154 (77%) of 200 samples and was significant in 44; piecemeal necrosis was present in 79 (40%). Thirty one (16%) patients had stage 0 liver fibrosis, 27 (14%) had stage 1, 69 (35%) had stage 2, 43 (22%) had stage 3, 16 (8%) had stage 4, and 12 (6%) had stage 5. On log linear analysis, piecemeal necrosis, lobular inflammation and steatosis were linked directly with fibrosis. Portal tract inflammation was linked directly and indirectly via piecemeal necrosis and lobular inflammation with fibrosis. The presence of lymphoid aggregates was associated with bile duct damage. CONCLUSIONS: Portal tract inflammation with lymphoid aggregates or follicles, together with fatty change, bile duct damage and/or lobular activity, are characteristic of chronic HCV infection, confirming previous reports. Piecemeal necrosis, lobular inflammation, portal inflammation, and steatosis are linked directly with fibrosis in this statistical model, suggesting a close inter-relation in the development of fibrosis/cirrhosis.
Images
PMCID: PMC500535  PMID: 8763259

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