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1.  Chronic cat-allergen exposure induces a TH2 cell-dependent IgG4 response related to low-sensitization 
In human subjects, allergen-tolerance has been observed after high dose allergen exposure or after completed allergen immunotherapy, which is related to the accumulation of anti-inflammatory IgG4. However, the specific T cell response that leads to the induction of IgG4 during chronic allergen exposure remains poorly understood.
To evaluate the relationship between cat allergen-specific T cell frequency, cat allergen-specific IgE and IgG4 titers and clinical status in cat allergic adults with and without cat ownership and the cellular mechanism by which IgG4 is produced.
Fel d 1, Fel d 4, Fel d 7 and Fel d 8- specific T cell responses were characterized by CD154 expression after antigen stimulation.
In allergic subjects without cat ownership, the frequency of cat allergen (Fel d 1 and Fel d 4) specific TH2 cells (sTH2 cells) correlates with IgE level and is linked to asthma. Paradoxically, we observed that cat allergic subjects with chronic cat exposure maintain high frequency of sTH2 cells, which correlates with IgG4 level and low-sensitization. B cells from allergic, but not from non-allergic subjects, are able to produce IgG4 after cognate interactions with sTH2 clones, and Fel d 1 peptide or the Fel d 1 recombinant protein.
These experiments suggest that 1) allergen-experienced B cells with capacity to produce IgG4 are present in allergic subjects; and 2) cat-allergen exposure induces an IgG4 response in a TH2 cell-dependent manner. Thus, IgG4 accumulation could be mediated by chronic activation of the TH2 response, which in turn drives desensitization.
PMCID: PMC4679456  PMID: 26371841
Cat allergy; Fel d 1; Fel d 4; TH2 cells; allergen tolerance; asthma; class II tetramer; CD154; IgG4; allergen exposure
2.  Exploiting members of the BAHD acyltransferase family to synthesize multiple hydroxycinnamate and benzoate conjugates in yeast 
BAHD acyltransferases, named after the first four biochemically characterized enzymes of the group, are plant-specific enzymes that catalyze the transfer of coenzyme A-activated donors onto various acceptor molecules. They are responsible for the synthesis in plants of a myriad of secondary metabolites, some of which are beneficial for humans either as therapeutics or as specialty chemicals such as flavors and fragrances. The production of pharmaceutical, nutraceutical and commodity chemicals using engineered microbes is an alternative, green route to energy-intensive chemical syntheses that consume petroleum-based precursors. However, identification of appropriate enzymes and validation of their functional expression in heterologous hosts is a prerequisite for the design and implementation of metabolic pathways in microbes for the synthesis of such target chemicals.
For the synthesis of valuable metabolites in the yeast Saccharomyces cerevisiae, we selected BAHD acyltransferases based on their preferred donor and acceptor substrates. In particular, BAHDs that use hydroxycinnamoyl-CoAs and/or benzoyl-CoA as donors were targeted because a large number of molecules beneficial to humans belong to this family of hydroxycinnamate and benzoate conjugates. The selected BAHD coding sequences were synthesized and cloned individually on a vector containing the Arabidopsis gene At4CL5, which encodes a promiscuous 4-coumarate:CoA ligase active on hydroxycinnamates and benzoates. The various S. cerevisiae strains obtained for co-expression of At4CL5 with the different BAHDs effectively produced a wide array of valuable hydroxycinnamate and benzoate conjugates upon addition of adequate combinations of donors and acceptor molecules. In particular, we report here for the first time the production in yeast of rosmarinic acid and its derivatives, quinate hydroxycinnamate esters such as chlorogenic acid, and glycerol hydroxycinnamate esters. Similarly, we achieved for the first time the microbial production of polyamine hydroxycinnamate amides; monolignol, malate and fatty alcohol hydroxycinnamate esters; tropane alkaloids; and benzoate/caffeate alcohol esters. In some instances, the additional expression of Flavobacterium johnsoniae tyrosine ammonia-lyase (FjTAL) allowed the synthesis of p-coumarate conjugates and eliminated the need to supplement the culture media with 4-hydroxycinnamate.
We demonstrate in this study the effectiveness of expressing members of the plant BAHD acyltransferase family in yeast for the synthesis of numerous valuable hydroxycinnamate and benzoate conjugates.
Electronic supplementary material
The online version of this article (doi:10.1186/s12934-016-0593-5) contains supplementary material, which is available to authorized users.
PMCID: PMC5117604  PMID: 27871334
Yeast; BAHD; Antioxidant; Therapeutics; Flavors and fragrances; CAPE
3.  The impact of economic downturns and budget cuts on homelessness claim rates across 323 local authorities in England, 2004–12 
It is unclear why rates of homelessness claims in England have risen since 2010. We used variations in rates across local authorities to test the impact of economic downturns and budget cuts.
Using cross-area fixed effects models of data from 323 UK local authorities between 2004 and 2012, we evaluated associations of changes in statutory homelessness rates with economic activity (Gross Value Added per capita), unemployment, and local and central government expenditure.
Each 10% fall in economic activity was associated with an increase of 0.45 homelessness claims per 1000 households (95% CI: 0.10–0.80). Increasing rates of homelessness were also strongly linked with government reductions in welfare spending. Disaggregating types of welfare expenditure, we found that strongest associations with reduced homelessness claims were spending on social care, housing services, discretionary housing payments and income support for older persons.
Recession and austerity measures are associated with significant increases in rates of homelessness assistance. These findings likely understate the full burden of homelessness as they only capture those who seek aid. Future research is needed to investigate what is happening to vulnerable groups who may not obtain assistance, including those with mental health problems and rough sleepers.
PMCID: PMC5072163  PMID: 26364320
austerity; homelessness; recession
4.  Jug r 2-reactive CD4+ T-cells have a dominant immune role in walnut allergy 
Allergic reactions to walnut can be life threatening. While IgE epitopes of walnut have been studied, CD4+ T-cell specific epitopes for walnut remain uncharacterized. Particularly, the relationship of both phenotype and frequency of walnut specific T-cells to the disease have not been examined.
We sought to provide a thorough phenotypic analysis for walnut reactive T-cells in allergic and non-allergic subjects. Particularly, the relationship of phenotypes and frequencies of walnut specific T-cells with the disease.
CD154 up-regulation assay was used to examine CD4+ T-cell reactivity towards walnut allergens.Jug r 1, Jug r 2 and Jug r 3. Tetramer-Guided epitope mapping approach was utilized to identify HLA-restricted CD4+ T-cells epitopes in Jug r 2. Direct ex vivo staining with peptide-major histocompatibility complex class II (pMHC-II) tetramers enabled the comparison of frequency and phenotype of Jug r 2-specific CD4+ T-cells between allergic and non-allergic subjects. Jug r 2-specific T-cell-clones were also generated and mRNA transcription factor levels were assessed by RT qPCR. Intracellular cytokine staining (ICS) assays were performed for further phenotypical analyses.
Jug r 2 was identified as the major allergen that elicited CD4+ T-cell responses. Multiple Jug r 2 T-cell epitopes were identified. The majority of these T-cells in allergic subjects have a CCR4+ TCM (central memory) phenotype. A subset of these T-cells express CCR4+CCR6+ irrespectively of the asthmatic status of the allergic subjects. ICS confirmed these TH2, TH2/TH17 and TH17-like heterogenic profiles. Jug r 2-specific T-cell-clones from allergic subjects mainly expressed GATA3; nonetheless, a portion of T-cell clones expressed either GATA3 and RORC, or RORC, confirming the presence of TH2, TH2/TH17 and TH17 cells.
Jug r 2 specific responses dominate walnut T-cell responses in subjects with walnut allergy. Jug r 2 central memory CD4+ cells and terminal effector T-cells were detected in peripheral blood with the central memory phenotype as the most prevalent phenotype. In addition to conventional TH2-cells, TH2/TH17 and TH17 cells were also detected in non-asthmatic and asthmatic subjects with walnut allergy. Understanding this T-cell heterogeneity may render better understanding of the disease manifestation.
PMCID: PMC4568181  PMID: 25772597
Food allergy; walnut; Jug r 2; T-cells; MHC class II tetramers; epitopes
5.  Personalised Hip Therapy: development of a non-operative protocol to treat femoroacetabular impingement syndrome in the FASHIoN randomised controlled trial 
British Journal of Sports Medicine  2016;50(19):1217-1223.
Femoroacetabular impingement (FAI) syndrome is increasingly recognised as a cause of hip pain. As part of the design of a randomised controlled trial (RCT) of arthroscopic surgery for FAI syndrome, we developed a protocol for non-operative care and evaluated its feasibility.
In phase one, we developed a protocol for non-operative care for FAI in the UK National Health Service (NHS), through a process of systematic review and consensus gathering. In phase two, the protocol was tested in an internal pilot RCT for protocol adherence and adverse events.
The final protocol, called Personalised Hip Therapy (PHT), consists of four core components led by physiotherapists: detailed patient assessment, education and advice, help with pain relief and an exercise-based programme that is individualised, supervised and progressed over time. PHT is delivered over 12–26 weeks in 6–10 physiotherapist-patient contacts, supplemented by a home exercise programme. In the pilot RCT, 42 patients were recruited and 21 randomised to PHT. Review of treatment case report forms, completed by physiotherapists, showed that 13 patients (62%) received treatment that had closely followed the PHT protocol. 13 patients reported some muscle soreness at 6 weeks, but there were no serious adverse events.
PHT provides a structure for the non-operative care of FAI and offers guidance to clinicians and researchers in an evolving area with limited evidence. PHT was deliverable within the National Health Service, is safe, and now forms the comparator to arthroscopic surgery in the UK FASHIoN trial (ISRCTN64081839).
Trial registration number
ISRCTN 09754699.
PMCID: PMC5036255  PMID: 27629405
Hip; Exercise rehabilitation; Physiotherapy; Orthopaedics
6.  Long-term adverse effects after curative radiotherapy and radical prostatectomy: population-based nationwide register study 
Scandinavian Journal of Urology  2016;50(5):338-345.
Objective: The aim of this study was to assess the risk of serious adverse effects after radiotherapy (RT) with curative intention and radical prostatectomy (RP).
Materials and methods: Men who were diagnosed with prostate cancer between 1997 and 2012 and underwent curative treatment were selected from the Prostate Cancer data Base Sweden. For each included man, five prostate cancer-free controls, matched for birth year and county of residency, were randomly selected. In total, 12,534 men underwent RT, 24,886 underwent RP and 186,624 were controls. Adverse effects were defined according to surgical and diagnostic codes in the National Patient Registry. The relative risk (RR) of adverse effects up to 12 years after treatment was compared to controls and the risk was subsequently compared between RT and RP in multivariable analyses.
Results: Men with intermediate- and localized high-risk cancer who underwent curative treatment had an increased risk of adverse effects during the full study period compared to controls: the RR of undergoing a procedures after RT was 2.64 [95% confidence interval (CI) 2.56–2.73] and after RP 2.05 (95% CI 2.00–2.10). The risk remained elevated 10–12 years after treatment. For all risk categories of prostate cancer, the risk of surgical procedures for urinary incontinence was higher after RP (RR 23.64, 95% CI 11.71–47.74), whereas risk of other procedures on the lower urinary tract and gastrointestinal tract or abdominal wall was higher after RT (RR 1.67, 95% CI 1.44–1.94, and RR 1.86, 95% CI 1.70–2.02, respectively).
Conclusion: The risk of serious adverse effects after curative treatment for prostate cancer remained significantly elevated up to 12 years after treatment.
PMCID: PMC5020330  PMID: 27333148
Adverse effects; prostate cancer; radical prostatectomy; radiotherapy
7.  Poverty and child health in the UK: using evidence for action 
Archives of Disease in Childhood  2016;101(8):759-766.
There are currently high levels of child poverty in the UK, and for the first time in almost two decades child poverty has started to rise in absolute terms. Child poverty is associated with a wide range of health-damaging impacts, negative educational outcomes and adverse long-term social and psychological outcomes. The poor health associated with child poverty limits children's potential and development, leading to poor health and life chances in adulthood. This article outlines some key definitions with regard to child poverty, reviews the links between child poverty and a range of health, developmental, behavioural and social outcomes for children, describes gaps in the evidence base and provides an overview of current policies relevant to child poverty in the UK. Finally, the article outlines how child health professionals can take action by (1) supporting policies to reduce child poverty, (2) providing services that reduce the health consequences of child poverty and (3) measuring and understanding the problem and assessing the impact of action.
PMCID: PMC4975805  PMID: 26857824
Children's Rights; Child poverty; Health inequalities; Child health professionals
8.  Exploring the impact of early life factors on inequalities in risk of overweight in UK children: findings from the UK Millennium Cohort Study 
Archives of Disease in Childhood  2016;101(8):724-730.
Overweight and obesity in childhood are socially patterned, with higher prevalence in more disadvantaged populations, but it is unclear to what extent early life factors attenuate the social inequalities found in childhood overweight/obesity.
We estimated relative risks (RRs) for being overweight (combining with obesity) at age 11 in 11 764 children from the UK Millennium Cohort Study (MCS) according to socio-economic circumstances (SEC). Early life risk factors were explored to assess if they attenuated associations between SECs and overweight.
28.84% of children were overweight at 11 years. Children of mothers with no academic qualifications were more likely to be overweight (RR 1.72, 95% CI 1.48 to 2.01) compared to children of mothers with degrees and higher degrees. Controlling for prenatal, perinatal, and early life characteristics (particularly maternal pre-pregnancy overweight and maternal smoking during pregnancy) reduced the RR for overweight to 1.44, 95% CI 1.23 to 1.69 in the group with the lowest academic qualifications compared to the highest.
We observed a clear social gradient in overweight 11-year-old children using a representative UK sample. Moreover, we identified specific early life risk factors, including maternal smoking during pregnancy and maternal pre-pregnancy overweight, that partially account for the social inequalities found in childhood overweight. Policies to support mothers to maintain a healthy weight, breastfeed and abstain from smoking during pregnancy are important to improve maternal and child health outcomes, and our study provides some evidence that they may also help to address the continuing rise in inequalities in childhood overweight.
PMCID: PMC4975808  PMID: 27162002
Child health; Obesity; Health inequalities; Socioeconomic circumstances; Smoking
9.  Risk of Localized and Advanced Prostate Cancer Among Immigrants Versus Native-Born Swedish Men: A nation-wide, population-based study 
Cancer causes & control : CCC  2012;24(2):383-390.
Prostate cancer (PCa) incidence and prognosis vary geographically. We examined possible differences in PCa risk by clinical risk category between native-born and immigrant populations in Sweden. Our hypothesis was that lower PSA-testing uptake among foreign-born men would result in lower rates of localized disease, and similar or higher risk of metastatic disease.
Using the Prostate Cancer database Sweden (PCBaSe), we identified 117,328 men with PCa diagnosed from 1991–2008, of which 8,332 were foreign-born. For each case, 5 cancer-free matched controls were randomly selected from the population register. Conditional logistic regression was used to compare low-risk, intermediate-risk, high-risk, regionally metastatic, and distant metastatic PCa based upon region of origin.
Across all risk categories, immigrants had significantly lower PCa risk than native-born Swedish men, except North Americans and Northern Europeans. The lowest PCa risk was observed in men from the Middle East, Southern Europe and Asia. Multivariable adjustment for socioeconomic factors and comorbidities did not materially change risk estimates. Older age at immigration and more recent arrival in Sweden were associated with lower PCa risk. Non-native men were less likely to be diagnosed with PCa through PSA-testing during a health check-up.
The risk for all stages of PCa was lower among first-generation immigrants to Sweden compared to native-born men. Older age at immigration and more recent immigration were associated with particularly low risks. Patterns of PSA testing appeared to only partly explain the differences in PCa risk, since immigrant men also had a lower risk of metastatic disease.
PMCID: PMC4968041  PMID: 23266834
prostate cancer; immigrants; risk; prognosis; geography
10.  Population Structure, Abundance and Movement of Whale Sharks in the Arabian Gulf and the Gulf of Oman 
PLoS ONE  2016;11(6):e0158593.
Data on the occurrence of whale sharks, Rhincodon typus, in the Arabian Gulf and Gulf of Oman were collected by dedicated boat surveys and via a public-sightings scheme during the period from 2011 to 2014. A total of 422 individual whale sharks were photo-identified from the Arabian Gulf and the northern Gulf of Oman during that period. The majority of sharks (81%, n = 341) were encountered at the Al Shaheen area of Qatar, 90 km off the coast, with the Musandam region of Oman a secondary area of interest. At Al Shaheen, there were significantly more male sharks (n = 171) than females (n = 78; X2 = 17.52, P < 0.05). Mean estimated total length (TL) for sharks was 6.90 m ± 1.24 (median = 7 m; n = 296). Males (7.25 m ± 1.34; median = 8 m, n = 171) were larger than females (6.44 m ±1.09; median = 7 m, n = 78; Mann-Whitney U test, p < 0.01). Of the male sharks assessed for maturity 63% were mature (n = 81), with 50% attaining maturity by 7.29 m and 100% by 9.00 m. Two female sharks of >9 m individuals were visually assessed as pregnant. Connectivity among sharks sighted in Qatari, Omani and UAE waters was confirmed by individual spot pattern matches. A total of 13 identified sharks were re-sighted at locations other than that at which they were first sighted, including movements into and out of the Arabian Gulf through the Strait of Hormuz. Maximum likelihood techniques were used to model an estimated combined population for the Arabian Gulf and Gulf of Oman of 2837 sharks ± 1243.91 S.E. (95% C.I. 1720–6295). The Al Shaheen aggregation is thus the first site described as being dominated by mature males while the free-swimming pregnant females are the first reported from the Indian Ocean.
PMCID: PMC4928964  PMID: 27362839
11.  The Roles of MDs and RNs as Initiators and Recipients of Interruptions in Workflow 
Previous research studies have focused on the recipients of interruptions because of the negative impact interruptions have on task performance. It is equally important to understand the initiators of interruptions to help design strategies to lessen the number of interruptions and the possible negatives consequences. The purpose of this study was to examine MDs and RNs as initiators and recipients of interruptions.
This was an instrumental case study using the shadowing method. A convenience sample of five attending trauma MDs and eight RNs were observed during the 0700–1500 and 1500–2100 shifts in the trauma section of a level one trauma center.
Seventy hours of observations were recorded. Initiator and recipient of an interruption emerged as major roles during categorization of the notes. Medical doctors and RNs were found to be the recipient of an interruption more frequently than the initiator. Findings from this study indicate that MDs and RNs initiate interruptions most often through face-to-face interactions and use of the telephone.
A role-based taxonomy of interruptions was derived from the recorded notes. Strategies to successfully manage interruptions must consider both the role of initiator as well as the recipient when an interruption occurs. It is suggested that the role-based taxonomy presented in this paper be used to classify interruptions in future studies.
PMCID: PMC4892847  PMID: 18996736
Interruption; workflow; emergency medicine; taxonomy
12.  Comparing the harmful effects of nontuberculous mycobacteria and Gram negative bacteria on lung function in patients with cystic fibrosis☆ 
Journal of Cystic Fibrosis  2016;15(3):380-385.
To better understand the relative effects of infection with nontuberculous mycobacteria and Gram negative bacteria on lung function decline in cystic fibrosis, we assessed the impact of each infection in a Danish setting.
Longitudinal registry study of 432 patients with cystic fibrosis contributing 53,771 lung function measures between 1974 and 2014. We used a mixed effects model with longitudinally structured correlation, while adjusting for clinically important covariates.
Infections with a significant impact on rate of decline in %FEV1 were Mycobacterium abscessus complex with − 2.22% points per year (95% CI − 3.21 to − 1.23), Burkholderia cepacia complex − 1.95% (95% CI − 2.51 to − 1.39), Achromobacterxylosoxidans − 1.55% (95% CI − 2.21 to − 0.90), and Pseudomonas aeruginosa − 0.95% (95% CI − 1.24 to − 0.66). Clearing M. abscessus complex was associated with a change to a slower decline, similar in magnitude to the pre-infection slope.
In a national population we have demonstrated the impact on lung function of each chronic CF pathogen. M. abscessus complex was associated with the worst impact on lung function. Eradication of M. abscessus complex may significantly improve lung function.
Graphical abstract
Effect on lung function of chronic infection from onset to end stage lung disease in Danish cystic fibrosis patients.
PMCID: PMC4893021  PMID: 26482717
ATS, American Thoracic Society; CF, cystic fibrosis; CFRD, cystic fibrosis related diabetes; CI, confidence interval; %FEV1, forced expiratory volume in 1 s expressed as % of predicted; IDSA, Infectious Disease Society of America; MABSC, Mycobacterium abscessus complex; MAC, Mycobacterium avium complex; NTM, nontuberculous mycobacteria.; Lung function; Abscessus; NTM; Gram negative; CF
13.  The Canadian Systemic Sclerosis Oral Health Study II: the relationship between oral and global health-related quality of life in systemic sclerosis 
Rheumatology (Oxford, England)  2014;54(4):692-696.
Objective. Both oral and global health-related quality of life (HRQoL) are markedly impaired in SSc. In this study we aimed to determine the degree of association between oral HRQoL and global HRQoL in SSc.
Methods. Subjects were recruited from the Canadian Scleroderma Research Group registry. Global HRQoL was measured using the Medical Outcomes Trust 36-item Short Form Health Survey (SF-36) and oral HRQoL with the Oral Health Impact Profile (OHIP). The Medsger Disease Severity Score was used to determine organ involvement. Multivariate regression models determined the independent association of the OHIP with the SF-36 after adjusting for confounders.
Results. This study included 156 SSc subjects. The majority (90%) were women, with a mean age of 56 years, mean disease duration 13.8 years (s.d. 8.5) and 29% of the subjects had dcSSc. Mean total OHIP score was 40.8 (s.d. 32.4). Mean SF-36 mental component summary (MCS) score was 49.7 (s.d. 11.1) and physical component summary (PCS) score was 37.0 (s.d. 10.7). In adjusted analyses, the total OHIP score was significantly associated with the SF-36 MCS and PCS, accounting for 9.7% and 5.6% of their respective variances. Measures of disease severity were not related to OHIP score.
Conclusion. Oral HRQoL in SSc is independently associated with global HRQoL. Oral HRQoL, however, is not related to physician-assessed disease severity. This suggests that physicians may be disregarding issues related to oral health. HRQoL is an additional dimension of HRQoL not captured by generic instruments such as the SF-36.
PMCID: PMC4372678  PMID: 25288781
systemic scleroderma; oral health; oral pathology; oral hygiene; quality of life; questionnaires
14.  Social inequalities in wheezing in children: findings from the UK Millennium Cohort Study 
The European Respiratory Journal  2015;47(3):818-828.
Wheezing in childhood is socially patterned, but it is unclear what factors explain the social differences.
Regression analysis of the UK Millennium Cohort Study, based on 11 141 singleton children who participated at ages 9 months and 3, 5 and 7 years. Relative risk ratios (RRR) for early and persistent/relapsing wheeze were estimated using multinomial regression, according to measures of socioeconomic circumstances. Maternal, antenatal and early-life characteristics were assessed as potential mediators.
Children of mothers with no educational qualifications were more likely to have both wheeze types, compared to children of mothers with degree-level qualifications (RRR 1.53, 95% CI 1.26–1.86 for early wheeze; 1.32 95% CI 1.04–1.67 for persistent/relapsing wheeze). Controlling for maternal age, smoking during pregnancy and breastfeeding removed the elevated risk of wheezing. Male sex, maternal age, body mass index, atopy, smoking during pregnancy, preterm birth, breastfeeding, exposure to other children and furry pets were independently associated with wheezing, but the pattern of association varied between wheezing types.
In this representative UK cohort, adjustment for maternal smoking during pregnancy and breastfeeding removed the socioeconomic inequalities in common wheezing phenotypes. Policies to reduce the social gradient in these risk factors may reduce inequalities in wheezing and asthma.
Increased wheeze in disadvantaged children removed by adjusting for smoking in pregnancy and lower breastfeeding rate
PMCID: PMC4771620  PMID: 26677938
15.  Association between baseline serum glucose, triglycerides and total cholesterol, and prostate cancer risk categories 
Cancer Medicine  2016;5(6):1307-1318.
Lifestyle‐related risk factors such as hyperglycemia and dyslipidemia have been associated with several cancers. However, studies exploring their link with prostate cancer (PCa) clinicopathological characteristics are sparse and inconclusive. Here, we investigated the associations between serum metabolic markers and PCa clinicopathological characteristics. The study comprised 14,294 men from the Swedish Apolipoprotein MOrtality RISk (AMORIS) cohort who were diagnosed with PCa between 1996 and 2011. Univariate and multivariable logistic regression were used to investigate the relation between glucose, triglycerides and total cholesterol and PCa risk categories, PSA, Gleason score, and T‐stage. Mean age at time of PCa diagnosis was 69 years. Men with glucose levels >6.9 mmol/L tend to have PSA<4 μg/L, while those with glucose levels of 5.6–6.9 mmol/L had a greater odds of PSA>20 μg/L compared to PSA 4.0–9.9 μg/L. Hypertriglyceridemia was also positively associated with PSA>20 μg/L. Hyperglycemic men had a greater odds of intermediate‐ and high‐grade PCa and advanced stage or metastatic PCa. Similarly, hypertriglyceridemia was positively associated with high‐grade PCa. There was also a trend toward an increased odds of intermediate risk localized PCa and advanced stage PCa among men with hypertriglyceridemia. Total cholesterol did not have any statistically significant association with any of the outcomes studied. Our findings suggest that high serum levels of glucose and triglycerides may influence PCa aggressiveness and severity. Further investigation on the role of markers of glucose and lipid metabolism in influencing PCa aggressiveness and severity is needed as this may help define important targets for intervention.
PMCID: PMC4924389  PMID: 26923095
Glucose; prostate cancer; total cholesterol; triglycerides
16.  Experimental evidence for drought induced alternative stable states of soil moisture 
Scientific Reports  2016;6:20018.
Ecosystems may exhibit alternative stable states (ASS) in response to environmental change. Modelling and observational data broadly support the theory of ASS, however evidence from manipulation experiments supporting this theory is limited. Here, we provide long-term manipulation and observation data supporting the existence of drought induced alternative stable soil moisture states (irreversible soil wetting) in upland Atlantic heath, dominated by Calluna vulgaris (L.) Hull. Manipulated repeated moderate summer drought, and intense natural summer drought both lowered resilience resulting in shifts in soil moisture dynamics. The repeated moderate summer drought decreased winter soil moisture retention by ~10%. However, intense summer drought, superimposed on the experiment, that began in 2003 and peaked in 2005 caused an unexpected erosion of resilience and a shift to an ASS; both for the experimental drought manipulation and control plots, impairing the soil from rewetting in winter. Measurements outside plots, with vegetation removal, showed no evidence of moisture shifts. Further independent evidence supports our findings from historical soil moisture monitoring at a long-term upland hydrological observatory. The results herald the need for a new paradigm regarding our understanding of soil structure, hydraulics and climate interaction.
PMCID: PMC4726285  PMID: 26804897
17.  Accelerated soil carbon turnover under tree plantations limits soil carbon storage 
Scientific Reports  2016;6:19693.
The replacement of native forests by tree plantations is increasingly common globally, especially in tropical and subtropical areas. Improving our understanding of the long-term effects of this replacement on soil organic carbon (SOC) remains paramount for effectively managing ecosystems to mitigate anthropogenic carbon emissions. Meta-analyses imply that native forest replacement usually reduces SOC stocks and may switch the forest from a net sink to a net source of atmospheric carbon. Using a long-term chronosequence during which areas of subtropical native forest were replaced by Chinese fir, we show by direct measurement that plantations have significantly accelerated SOC turnover compared with native forest, an effect that has persisted for almost a century. The immediate stimulation of SOC decomposition was caused by warmer soil before the closure of the plantation’s canopy. Long-term reductions in SOC mean residence times were coupled to litter inputs. Faster SOC decomposition was associated with lower soil microbial carbon use efficiency, which was due to smaller litter inputs and reduced nutrient availabilities. Our results indicate a previously unelucidated control on long-term SOC dynamics in native forests and demonstrate a potential constraint on climate mitigation when such forests are replaced by plantations.
PMCID: PMC4726314  PMID: 26805949
18.  Relationship between socioeconomic status and gastrointestinal infections in developed countries: a systematic review protocol 
Systematic Reviews  2016;5:13.
The association between low socioeconomic status (SES) and poor health is well documented in the existing literature. Nonetheless, evidence on the relationship between SES and gastrointestinal (GI) infections is limited, and the mechanisms underlying this relationship are not well understood with published studies pointing to conflicting results. This review aims to identify studies that investigate the relationship between SES and GI infections in developed countries, in order to assess the direction of the association and explore possible explanations for any differences in the risk, incidence or prevalence of GI infections across socioeconomic groups.
Three systematic methods will be used to identify relevant literature: electronic database, reference list and grey literature searching. The databases MEDLINE, Scopus and Web of Science Core Collection will be searched using a broad range of search terms. Screening of the results will be performed by two reviewers using pre-defined inclusion and exclusion criteria. The reference lists of included studies will be searched, and Google will be used to identify grey literature. Observational studies reporting quantitative results on the prevalence or incidence of any symptomatic GI infections by SES, in a representative population sample from a member country of the Organisation for Economic Co-operation and Development (OECD), will be included. Data will be extracted using a standardised form. Study quality will be assessed using the Liverpool University Quality Assessment Tools (LQAT). A narrative synthesis will be performed including tabulation of studies for comparison.
This systematic review will consolidate the existing knowledge on the relationship between SES and GI infections. The results will help to identify gaps in the literature and will therefore provide an evidence base for future empirical studies to deepen the understanding of the relationship, including effective study design and appropriate data analysis methods. Ultimately, gaining insight into this relationship will help to inform policies to reduce any health inequalities identified.
Systematic review registration
PROSPERO CRD42015027231
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0187-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4721014  PMID: 26791956
Socioeconomic factors; Income; Social class; Employment; Education; Gastrointestinal infection; Diarrhoea; Gastroenteritis; Foodborne diseases
19.  Genetic susceptibility loci of idiopathic interstitial pneumonia do not represent risk for systemic sclerosis: a case control study in Caucasian patients 
Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc.
A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc.
We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (β = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (β = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (β = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort.
Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-0923-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4719560  PMID: 26792595
Idiopathic interstitial pneumonia (IIP); SSc-ILD; Genetic susceptibility
20.  Ulster's Fulton Physicians 
The Ulster Medical Journal  2016;85(1):29-32.
PMCID: PMC4847847  PMID: 27158163
21.  Yes, We Have an Inflation of Reviews: But of the Wrong Kind! 
PMCID: PMC4844604  PMID: 27200000
scientific writing; review articles; catalog reviews; critical reviews; open debates
22.  Arginine kinase Pen m 2 as an important shrimp allergen recognized by TH2 cells 
PMCID: PMC4349443  PMID: 25224098
Shrimp allergy; Pen m 1; Pen m 2; Tropomyosin; Arginine Kinase; TH2 cells; Class II tetramers
23.  How to model temporal changes in comorbidity for cancer patients using prospective cohort data 
The presence of comorbid conditions is strongly related to survival and also affects treatment choices in cancer patients. This comorbidity is often quantified by the Charlson Comorbidity Index (CCI) using specific weights (1, 2, 3, or 6) for different comorbidities. It has been shown that the CCI increases at different times and with different sizes, so that traditional time to event analysis is not adequate to assess these temporal changes. Here, we present a method to model temporal changes in CCI in cancer patients using data from PCBaSe Sweden, a nation-wide population-based prospective cohort of men diagnosed with prostate cancer. Our proposed model is based on the assumption that a change in comorbidity, as quantified by the CCI, is an irreversible one-way process, i.e., CCI accumulates over time and cannot decrease.
CCI was calculated based on 17 disease categories, which were defined using ICD-codes for discharge diagnoses in the National Patient Register. A state transition model in discrete time steps (i.e., four weeks) was applied to capture all changes in CCI. The transition probabilities were estimated from three modelling steps: 1) Logistic regression model for vital status, 2) Logistic regression model to define any changes in CCI, and 3) Poisson regression model to determine the size of CCI change, with an additional logistic regression model for CCI changes ≥ 6. The four models combined yielded parameter estimates to calculate changes in CCI with their confidence intervals.
These methods were applied to men with low-risk prostate cancer who received active surveillance (AS), radical prostatectomy (RP), or curative radiotherapy (RT) as primary treatment. There were large differences in CCI changes according to treatment.
Our method to model temporal changes in CCI efficiently captures changes in comorbidity over time with a small number of regression analyses to perform – which would be impossible with tradition time to event analyses. However, our approach involves a simulation step that is not yet included in standard statistical software packages. In our prostate cancer example we showed that there are large differences in development of comorbidities among men receiving different treatments for prostate cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/s12911-015-0217-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4652373  PMID: 26582418
Temporal changes; Comorbidity; Cancer; Cox proportional hazards; State transition model
24.  Development of Small-Molecule Trypanosoma brucei N-Myristoyltransferase Inhibitors: Discovery and Optimisation of a Novel Binding Mode 
Chemmedchem  2015;10(11):1821-1836.
The enzyme N-myristoyltransferase (NMT) from Trypanosoma brucei has been validated both chemically and biologically as a potential drug target for human African trypanosomiasis. We previously reported the development of some very potent compounds based around a pyrazole sulfonamide series, derived from a high-throughput screen. Herein we describe work around thiazolidinone and benzomorpholine scaffolds that were also identified in the screen. An X-ray crystal structure of the thiazolidinone hit in Leishmania major NMT showed the compound bound in the previously reported active site, utilising a novel binding mode. This provides potential for further optimisation. The benzomorpholinone was also found to bind in a similar region. Using an X-ray crystallography/structure-based design approach, the benzomorpholinone series was further optimised, increasing activity against T. brucei NMT by >1000-fold. A series of trypanocidal compounds were identified with suitable in vitro DMPK properties, including CNS exposure for further development. Further work is required to increase selectivity over the human NMT isoform and activity against T. brucei.
PMCID: PMC4648043  PMID: 26395087
human African trypanosomiasis (HAT); medicinal chemistry; N-myristoyltransferase; structure-based drug design; Trypanosoma brucei
25.  Protocol for systematic review of evidence on the determinants and influence of early glycaemic control in childhood-onset type 1 diabetes 
Systematic Reviews  2015;4:159.
Landmark studies in adult-onset type 1 diabetes (T1D) populations indicate that improved glycaemic control through use of intensive insulin therapy is strongly associated with reduced risk for the development of diabetes-related complications and mortality in later years. However, it is unclear whether these associations can be extrapolated to childhood-onset T1D, given the influence of other important biological and psychosocial determinants of glycaemic control, particularly during adolescence. The aims of the review are (1) to investigate the impact of early glycaemic control (within the first 2 years after diagnosis) on subsequent glycaemic trends and risk of complications during the life course of childhood-onset T1D and (2) to identify the predictors of early glycaemic control in children and young people (0–25 years).
The methods used in this study are systematic identification, review and mapping of quantitative (intervention and observational) and qualitative literature; assessing the effect and predictors of early glycaemic control in T1D (diagnosed ≤18 years) on risk or prevalence of later complications. An iterated search strategy, with no language or period restrictions, was applied to identify studies from six electronic databases. This will be supplemented by hand-searching (reference lists and contacting authors of studies meeting the inclusion criteria). Studies assessing glycaemic control within the first 2 years of diagnosis in children (at baseline) will be quality-assessed against predefined criteria and mapped descriptively to future health outcomes. Extracted data will be analysed and synthesised using narrative and forest plots or harvest plots for quantitative evidence and thematic analyses for qualitative studies. To get a deeper understanding of the predictors of early glycaemic control in reducing complications in childhood and adult life, we will integrate qualitative and quantitative evidence using mixed methods or parallel synthesis approach.
These linked reviews will be the first to systematically investigate the effects of early glycaemic control and integrate both the quantitative and qualitative evidence on predictors of early glycaemic control in childhood-onset T1D in reducing future diabetes complications. This will help identify and map current research and inform development of effective future interventions.
Systematic review registration
PROSPERO CRD42015024546
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-015-0146-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4643492  PMID: 26563100

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