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Serum samples from 150 NS1-negative (Platelia ELISA) patients presumptively diagnosed with dengue were analyzed by the TaqMan probed real-time reverse transcription PCR (TaqMan qRT-PCR) method. The qRT-PCR positive samples were tested for serotype by semi-nested RT-PCR and a qualitative immunochromatographic assay for IgG and IgM. Molecular detection methods showed 33 (22%) positive samples out of 150 NS1-antigen negative samples. Of these, 72% were collected up to day 2 after the onset of symptoms, when diagnostic sensitivity of NS1-antigen test assays is significantly enhanced. Most of the cases were not characterized as secondary infection. Twenty-eight samples were successfully serotyped, 75% of which for DENV-4, 14% for DENV-2, 7% for DENV-3 and 4% for DENV-1. These findings reaffirm the hyperendemic situation of the state of Roraima and suggest a lower sensitivity of the NS1 test, mainly when DENV-4 is the predominant serotype. Health care providers should therefore be aware of samples tested negative by NS1 antigen assays, especially when clinical symptoms and other laboratory data results show evidence of dengue infection.
PMCID: PMC4172119  PMID: 25229228
Dengue; Serotypes; Diagnosis; NS1 antigen; qRT-PCR
2.  Hemagglutinin Stalk-Based Universal Vaccine Constructs Protect against Group 2 Influenza A Viruses 
Journal of Virology  2013;87(19):10435-10446.
Current influenza virus vaccines contain H1N1 (phylogenetic group 1 hemagglutinin), H3N2 (phylogenetic group 2 hemagglutinin), and influenza B virus components. These vaccines induce good protection against closely matched strains by predominantly eliciting antibodies against the membrane distal globular head domain of their respective viral hemagglutinins. This domain, however, undergoes rapid antigenic drift, allowing the virus to escape neutralizing antibody responses. The membrane proximal stalk domain of the hemagglutinin is much more conserved compared to the head domain. In recent years, a growing collection of antibodies that neutralize a broad range of influenza virus strains and subtypes by binding to this domain has been isolated. Here, we demonstrate that a vaccination strategy based on the stalk domain of the H3 hemagglutinin (group 2) induces in mice broadly neutralizing anti-stalk antibodies that are highly cross-reactive to heterologous H3, H10, H14, H15, and H7 (derived from the novel Chinese H7N9 virus) hemagglutinins. Furthermore, we demonstrate that these antibodies confer broad protection against influenza viruses expressing various group 2 hemagglutinins, including an H7 subtype. Through passive transfer experiments, we show that the protection is mediated mainly by neutralizing antibodies against the stalk domain. Our data suggest that, in mice, a vaccine strategy based on the hemagglutinin stalk domain can protect against viruses expressing divergent group 2 hemagglutinins.
PMCID: PMC3807421  PMID: 23903831
3.  Neurobiological Abnormalities in the First Few Years of Life in Individuals Later Diagnosed with Autism Spectrum Disorder: A Review of Recent Data 
Behavioural Neurology  2014;2014:210780.
Background. Despite the widely-held understanding that the biological changes that lead to autism usually occur during prenatal life, there has been relatively little research into the functional development of the brain during early infancy in individuals later diagnosed with autism spectrum disorder (ASD). Objective. This review explores the studies over the last three years which have investigated differences in various brain regions in individuals with ASD or who later go on to receive a diagnosis of ASD. Methods. We used PRISMA guidelines and selected published articles reporting any neurological abnormalities in very early childhood in individuals with or later diagnosed with ASD. Results. Various brain regions are discussed including the amygdala, cerebellum, frontal cortex, and lateralised abnormalities of the temporal cortex during language processing. This review discusses studies investigating head circumference, electrophysiological markers, and interhemispheric synchronisation. All of the recent findings from the beginning of 2009 across these different aspects of defining neurological abnormalities are discussed in light of earlier findings. Conclusions. The studies across these different areas reveal the existence of atypicalities in the first year of life, well before ASD is reliably diagnosed. Cross-disciplinary approaches are essential to elucidate the pathophysiological sequence of events that lead to ASD.
PMCID: PMC4006615  PMID: 24825948
4.  Bacteremia as a Cause of Fever in Ambulatory, HIV-Infected Mozambican Adults: Results and Policy Implications from a Prospective Observational Study 
PLoS ONE  2013;8(12):e83591.
Fever is typically treated empirically in rural Mozambique. We examined the distribution and antimicrobial susceptibility patterns of bacterial pathogens isolated from blood-culture specimens, and clinical characteristics of ambulatory HIV-infected febrile patients with and without bacteremia. This analysis was nested within a larger prospective observational study to evaluate the performance of new Mozambican guidelines for fever and anemia in HIV-infected adults (clinical trial registration NCT01681914,; the guidelines were designed to be used by non-physician clinicians who attended ambulatory HIV-infected patients in very resource-constrained peripheral health units. In 2012 (April-September), we recruited 258 HIV-infected adults with documented fever or history of recent fever in three sites within Zambézia Province, Mozambique. Although febrile patients were routinely tested for malaria, blood culture capacity was unavailable in Zambézia prior to study initiation. We confirmed bacteremia in 39 (15.1%) of 258 patients. The predominant organisms were non-typhoid Salmonella, nearly all resistant to multiple first-line antibiotics (ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole). Features most associated with bacteremia included higher temperature, lower CD4+ T-lymphocyte count, lower hemoglobin, and headache. Introduction of blood cultures allowed us to: 1) confirm bacteremia in a substantial proportion of patients; 2) tailor specific antimicrobial therapy for confirmed bacteremia based on known susceptibilities; 3) make informed choices of presumptive antibiotics for patients with suspected bacteremia; and 4) construct a preliminary clinical profile to help clinicians determine who would most likely benefit from presumptive bacteremia treatment. Our findings demonstrate that in resource-limited settings, there is urgent need to expand local microbiologic capacity to better identify and treat cases of bacteremia in HIV-infected and other patients, and to support surveillance. Data on the prevalence and susceptibility patterns of important pathogens can guide national formulary and prescribing practices.
PMCID: PMC3875454  PMID: 24386229
5.  Visual Fields at Follow-up in the Ischemic Optic Neuropathy Decompression Trial 
Ophthalmology  2008;115(10):1809-1817.
To evaluate change from baseline to 12 months follow-up in study and nonstudy (fellow) eye visual fields from the Ischemic Optic Neuropathy Decompression Trial (IONDT).
Randomized controlled trial and observational study.
The IONDT enrolled patients ≥50 years with acute nonarteritic ischemic optic neuropathy (NAION). Randomized patients (n = 258) had visual acuity ≤20/64; nonrandomized patients (n = 160) had visual acuity >20/64 or refused randomization.
Optic nerve decompression surgery (n = 127) or careful follow-up (n = 131).
Main Outcome Measures
We measured visual fields at baseline and at 6 and 12 months follow-up. Using a computerized system, we classified visual field defects by pattern, location, and severity. We examined changes over time by treatment group, age, baseline comorbidities, and change in visual acuity. In fellow (nonstudy) eyes, we assessed change by whether NAION was present at baseline and also incidence of NAION by whether a visual field defect was present at baseline.
We analyzed 245 study eye visual field pairs (179 and 66, randomized and nonrandomized, respectively) for change from baseline to 12 months. We observed significant changes in defect distribution within the central field (P = 0.02) for randomized eyes. Superior and inferior altitudinal defects were less severe at follow-up in both randomized and nonrandomized eyes. We observed an association between change in central field severity and change in visual acuity from baseline (P<0.001 at 6 months; P = 0.01 at 12 months; Kendall’s tau-b), but no association between visual field change and treatment group, age, or baseline comorbidities. Superior and inferior visual field defects present at baseline in nonstudy eyes improved at follow-up. Fellow (nonstudy) eyes with normal fields did not have an increased risk of developing NAION compared with eyes with ≥1 defects.
Visual fields of NAION patients enrolled in the IONDT were relatively stable from baseline to follow-up. A visual field defect in the nonstudy eye at baseline was not associated with development of NAION during follow-up compared with eyes with normal fields.
PMCID: PMC3789533  PMID: 18486224
6.  Revisiting the ultra-high dose rate effect: implications for charged particle radiotherapy using protons and light ions 
The British Journal of Radiology  2012;85(1018):e933-e939.
To reinvestigate ultra-high dose rate radiation (UHDRR) radiobiology and consider potential implications for hadrontherapy.
A literature search of cellular UHDRR exposures was performed. Standard oxygen diffusion equations were used to estimate the time taken to replace UHDRR-related oxygen depletion. Dose rates from conventional and novel methods of hadrontherapy accelerators were considered, including spot scanning beam delivery, which intensifies dose rate.
The literature findings were that, for X-ray and electron dose rates of around 109 Gy s–1, 5–10 Gy depletes cellular oxygen, significantly changing the radiosensitivity of cells already in low oxygen tension (around 3 mmHg or 0.4 kPa). The time taken to reverse the oxygen depletion of such cells is estimated to be over 20–30 s at distances of over 100 μm from a tumour blood vessel. In this time window, tumours have a higher hypoxic fraction (capable of reducing tumour control), so the next application of radiation within the same fraction should be at a time that exceeds these estimates in the case of scanned beams or with ultra-fast laser-generated particles.
This study has potential implications for particle therapy, including laser-generated particles, where dose rate is greatly increased. Conventional accelerators probably do not achieve the critical UHDRR conditions. However, specific UHDRR oxygen depletion experiments using proton and ion beams are indicated.
PMCID: PMC3474025  PMID: 22496068
7.  Dilemmas concerning dose distribution and the influence of relative biological effect in proton beam therapy of medulloblastoma 
The British Journal of Radiology  2012;85(1018):e912-e918.
To improve medulloblastoma proton therapy. Although considered ideal for proton therapy, there are potential disadvantages. Expected benefits include reduced radiation-induced cancer and circulatory complications, while avoiding small brain volumes of dose in-homogeneity when compared with conventional X-rays. Several aspects of proton therapy might contribute to reduced tumour control due to (a) the use of more homogenous dose levels which can result in under-dosage, (b) differences in relative biological effectiveness (RBE) between that prescription RBE of 1.1 and the RBE of brain and spinal cord (likely to exceed 1.1) and in medulloblastoma cells (where RBE is likely to be below 1.1). Such changes, although speculative for RBE, might result in potential underdosage of tumour cells and a higher bio-effect in brain tissue.
Dose distributions for X-ray and proton treatment are compared, with allocation of likely RBE values for fast growing medullolastoma cells and stable central nervous system tissue.
These physical and radiobiological factors are shown to combine to give a higher risk of tumour recurrence with further risks on tumour control when dose reduction schedules used for X-ray therapy are replicated for proton therapy for “low-risk” patients.
The dose distributions and prescribed doses of proton therapy, taking into account RBE, in children and adults with medulloblastoma, need to be reconsidered.
PMCID: PMC3474038  PMID: 22553304
8.  Barriers and incentives to the production of bioethanol from cereal straw: A farm business perspective 
Energy Policy  2013;59(100):161-171.
The EU renewable energy directive stipulates a requirement for 10% of transport fuels to be derived from renewable sources by 2020. Second generation biofuels offer potential to contribute towards this target with cereal straw representing a potentially large feedstock source. From an on-farm survey of 240 arable farmers, timeliness of crop establishment and benefits of nutrient retention from straw incorporation were cited as reasons for straw incorporation. However, two-thirds (one-third) of farmers would supply wheat (barley) straw for bioenergy. The most popular contract length and continuous length of straw supply was either 1 or 3 years. Contracts stipulating a fixed area of straw supply for a fixed price were the most frequently cited preferences, with £50 t−1 the most frequently cited minimum contract price that farmers would find acceptable. Arable farmers in England would be willing to sell 2.52 Mt of cereal straw for bioenergy purposes nationally and 1.65 Mt in the main cereal growing areas of Eastern England. Cereal straw would be diverted from current markets or on-farm uses and from straw currently incorporated into soil. Policy interventions may be required to incentivise farmers to engage in this market, but food and fuel policies must increasingly be integrated to meet societal goals.
•English arable farmer survey to determine potential supply for straw based biofuel.•Two-thirds of farmers would supply wheat straw for bioenergy.•Farmers willing to sell 1.65 Mt of cereal straw from the main cereal producing regions.•Farmer preference for a fixed area of straw supply for a contracted fixed price.•£50 t−1 the most frequently cited minimum contract price farmers find acceptable.
PMCID: PMC4048105  PMID: 24926116
Cereal straw; Bioenergy; Second generation biofuels
9.  The Cyclin D1 (CCND1) A870G polymorphism predicts clinical outcome to lapatinib and capecitabine in HER2-positive metastatic breast cancer 
Annals of Oncology  2011;23(6):1455-1464.
Lapatinib plus capecitabine emerged as an efficacious therapy in metastatic breast cancer (mBC). We aimed to identify germline single-nucleotide polymorphisms (SNPs) in genes involved in capecitabine catabolism and human epidermal receptor signaling that were associated with clinical outcome to assist in selecting patients likely to benefit from this combination.
Patients and methods:
DNA was extracted from 240 of 399 patients enrolled in EGF100151 clinical trial (NCT00078572; and SNPs were successfully evaluated in 234 patients. The associations between SNPs and clinical outcome were analyzed using Fisher’s exact test, Kaplan–Meier curves, log-rank tests, likelihood ratio test within logistic or Cox regression model, as appropriate.
There were significant interactions between CCND1 A870G and clinical outcome. Patients carrying the A-allele were more likely to benefit from lapatinib plus capecitabine versus capecitabine when compared with patients harboring G/G (P = 0.022, 0.024 and 0.04, respectively). In patients with the A-allele, the response rate (RR) was significantly higher with lapatinib plus capecitabine (35%) compared with capecitabine (11%; P = 0.001) but not between treatments in patients with G/G (RR = 24% and 32%, respectively; P = 0.85). Time to tumor progression (TTP) was longer in patients with the A-allele treated with lapatinib plus capecitabine compared with capecitabine (median TTP = 7.9 and 3.4 months; P < 0.001), but not in patients with G/G (median TTP = 6.1 and 6.6 months; P = 0.92).
Our findings suggest that CCND1A870G may be useful in predicting clinical outcome in HER2-positive mBC patients treated with lapatinib plus capecitabine.
PMCID: PMC3360546  PMID: 21989330
capecitabine; cyclin D1; lapatinib; metastatic breast cancer; polymorphisms
10.  Parent–infant vocalisations at 12 months predict psychopathology at 7 years 
► Reduced caregiver vocalisations were associated with development of disruptive behaviour disorders. ► Higher infant vocalisations were associated with disruptive behaviour disorders. ► Study into parental vocalisation behaviours early in life may be clinically important.
This study investigated the utility of adult and infant vocalisation in the prediction of child psychopathology. Families were sampled from the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort. Vocalisation patterns were obtained from 180 videos (60 cases and 120 randomly selected sex-matched controls) of parent–infant interactions when infants were one year old. Cases were infants who had been subsequently diagnosed aged seven years, with at least one psychiatric diagnostic categorisation using the Development and Wellbeing Assessment. Psychopathologies included in the case group were disruptive behaviour disorders, oppositional-conduct disorders, Attention Deficit Hyperactivity Disorder, pervasive development disorder, and emotional disorders. Associations between infant and parent vocalisations and later psychiatric diagnoses were investigated. Low frequencies of maternal vocalisation predicted later development of infant psychopathology. A reduction of five vocalisations per minute predicted a 44% (95%CI: 11–94%; p-value = 0.006) increase in the odds of an infant being a case. No association was observed between infant vocalisations and overall case status. In sum, altered vocalisation frequency in mother–infant interactions at one year is a potential risk marker for later diagnosis of a range of child psychopathologies.
PMCID: PMC4046631  PMID: 23291516
Avon Longitudinal Study of Parents and Children (ALSPAC); Autism; Attention Deficit Hyperactivity Disorder (ADHD); Disruptive behaviour disorders; Vocalisation patterns
11.  Intracranial phosphaturic mesenchymal tumor, mixed connective tissue variant presenting without oncogenic osteomalacia 
Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT) is a rare tumor typically occurring in soft tissues and bone, causing oncogenic (tumor-induced) osteomalacia (TIO) through secretion of the phosphaturic hormone, fibroblast growth factor-23 (FGF-23). Rare tumors identical to PMTMCT occur without known TIO. Intracranial localization of PMTMCT is extremely rare, with only two cases reported in the literature. We present a very unusual case of a patient with an intracranial PMTMCT that presented with neurologic changes without osteomalacia.
Case Description:
A 67-year-old woman presented with progressive incontinence, apathy, and abulia after having undergone a total knee replacement 1 month earlier. Imaging disclosed a large left frontal anterior fossa mass. She underwent uncomplicated surgical resection of this tumor. Surprisingly, histopathology suggested PMTMCT. Reverse transcription polymerase chain reaction (RT-PCR) assay demonstrating FGF-23 expression in the tumor confirmed the diagnosis. Serum FGF-23 levels postoperatively were normal and she had no clinical or laboratory evidence of osteomalacia or phosphaturia.
This report should serve to alert clinicians to the possibility that PMTMCT can be included in the differential diagnosis of intracranial masses even in the absence of tumor-induced osteomalacia.
PMCID: PMC3551505  PMID: 23372968
Intracranial; neoplasm; neuropathology; oncogenic osteomalacia
12.  Accelerator science in medical physics 
The British Journal of Radiology  2011;84(Spec Iss 1):S004-S010.
The use of cyclotrons and synchrotrons to accelerate charged particles in hospital settings for the purpose of cancer therapy is increasing. Consequently, there is a growing demand from medical physicists, radiographers, physicians and oncologists for articles that explain the basic physical concepts of these technologies. There are unique advantages and disadvantages to all methods of acceleration. Several promising alternative methods of accelerating particles also have to be considered since they will become increasingly available with time; however, there are still many technical problems with these that require solving. This article serves as an introduction to this complex area of physics, and will be of benefit to those engaged in cancer therapy, or who intend to acquire such technologies in the future.
PMCID: PMC3473892  PMID: 22374548
14.  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?
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.
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.
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
15.  GRP78 promoter polymorphism rs391957 as potential predictor for clinical outcome in gastric and colorectal cancer patients 
Annals of Oncology  2011;22(11):2431-2439.
Background: Recently, the analysis of gastric and colorectal tumor specimens determined that 78-kiloDalton glucose-regulated protein (GRP78), an endoplasmic reticulum chaperone, up-regulation serves as an efficient mechanism protecting cells against apoptosis and can confer drug resistance. We tested whether functional polymorphisms within the GRP78 gene are related to clinical outcome in gastric and colorectal cancer (CRC) patients.
Patients and methods: Blood samples of 234 stage II/III CRC patients at the University of Southern California (USC) and formalin-fixed paraffin-embedded tissues of 137 patients with localized gastric adenocarcinoma (GA) at USC and Memorial Sloan-Kettering Cancer Centers were obtained. GRP78 polymorphisms analyzed on germline DNA were correlated with clinical outcome using univariate and multivariate analyses.
Results: GA patients with the combined GRP78 rs391957 C/T and T/T genotype were at higher risk for tumor recurrence and death [hazard ratio (HR) 2.61; P < 0.001 and HR 3.17; P < 0.001, respectively], than those with C/C. These findings were subsequently tested in a CRC cohort where patients with the homozygous T/T genotype were at highest risk for tumor recurrence (HR 2.61; P = 0.015). The results remained significant after adjusting for clinicopathologic determinants.
Conclusion: These data provide the first evidence that the GRP78 rs391957 polymorphism can predict clinical outcome in localized GA and locally advanced CRC patients.
PMCID: PMC3200220  PMID: 21382870
colorectal cancer; gastric cancer; GRP78; outcome; polymorphism
16.  Ochronosis in a murine model of alkaptonuria is synonymous to that in the human condition 
Osteoarthritis and Cartilage  2012;20(8):880-886.
Alkaptonuria (AKU) is a rare genetic disease which results in severe early onset osteoarthropathy. It has recently been shown that the subchondral interface is of key significance in disease pathogenesis. Human surgical tissues are often beyond this initial stage and there is no published murine model of pathogenesis, to study the natural history of the disease. The murine genotype exists but it has been reported not to demonstrate ochronotic osteoarthropathy consistent with the human disease. Recent anecdotal evidence of macroscopic renal ochronosis in a mouse model of tyrosinaemia led us to perform histological analysis of tissues of these mice that are known to be affected in human AKU.
The homogentisate 1,2-dioxygenase Hgd+/−Fah−/− mouse can model either hereditary tyrosinaemia type I (HT1) or AKU depending on selection conditions. Mice having undergone Hgd reversion were sacrificed at various time points, and their tissues taken for histological analysis. Sections were stained with haematoxylin eosin (H&E) and Schmorl’s reagent.
Early time point observations at 8 months showed no sign of macroscopic ochronosis of tissues. Macroscopic examination at 13 months revealed ochronosis of the kidneys. Microscopic analysis of the kidneys revealed large pigmented nodules displaying distinct ochre colouration. Close microscopic examination of the distal femur and proximal fibula at the subchondral junctions revealed the presence of numerous pigmented chondrocytes.
Here we present the first data showing ochronosis of tissues in a murine model of AKU. These preliminary histological observations provide a stimulus for further studies into the natural history of the disease to provide a greater understanding of this class of arthropathy.
PMCID: PMC3406176  PMID: 22542924
Alkaptonuria; Mouse model; Arthropathy; Arthritis; Ochronosis
17.  Farm systems assessment of bioenergy feedstock production: Integrating bio-economic models and life cycle analysis approaches 
Agricultural Systems  2012;109:53-64.
► A modelling framework for managing energy and emissions trade-offs in agriculture. ► Combination of bio-economic process modelling and life cycle assessment. ► Captures financial, energy and emissions trade-offs and cereal straw use. ► The gross margin-energy trade-off is £36 GJ−1. ► All cereal straw is baled for sale when gross margin or net energy is maximised.
Climate change and energy security concerns have driven the development of policies that encourage bioenergy production. Meeting EU targets for the consumption of transport fuels from bioenergy by 2020 will require a large increase in the production of bioenergy feedstock. Initially an increase in ‘first generation’ biofuels was observed, however ‘food competition’ concerns have generated interest in second generation biofuels (SGBs). These SGBs can be produced from co-products (e.g. cereal straw) or energy crops (e.g. miscanthus), with the former largely negating food competition concerns. In order to assess the sustainability of feedstock supply for SGBs, the financial, environmental and energy costs and benefits of the farm system must be quantified. Previous research has captured financial costs and benefits through linear programming (LP) approaches, whilst environmental and energy metrics have been largely been undertaken within life cycle analysis (LCA) frameworks. Assessing aspects of the financial, environmental and energy sustainability of supplying co-product second generation biofuel (CPSGB) feedstocks at the farm level requires a framework that permits the trade-offs between these objectives to be quantified and understood. The development of a modelling framework for Managing Energy and Emissions Trade-Offs in Agriculture (MEETA Model) that combines bio-economic process modelling and LCA is presented together with input data parameters obtained from literature and industry sources. The MEETA model quantifies arable farm inputs and outputs in terms of financial, energy and emissions results. The model explicitly captures fertiliser: crop-yield relationships, plus the incorporation of straw or removal for sale, with associated nutrient impacts of incorporation/removal on the following crop in the rotation. Key results of crop-mix, machinery use, greenhouse gas (GHG) emissions per kg of crop product and energy use per hectare are in line with previous research and industry survey findings. Results show that the gross margin – energy trade-off is £36 GJ−1, representing the gross margin forgone by maximising net farm energy cf. maximising farm gross margin. The gross margin–GHG emission trade-off is £0.15 kg−1 CO2 eq, representing the gross margin forgone per kg of CO2 eq reduced when GHG emissions are minimised cf. maximising farm gross margin. The energy–GHG emission trade-off is 0.03 GJ kg−1 CO2 eq quantifying the reduction in net energy from the farm system per kg of CO2 eq reduced when minimising GHG emissions cf. maximising net farm energy. When both farm gross margin and net farm energy are maximised all the cereal straw is baled for sale. Sensitivity analysis of the model in relation to different prices of cereal straw shows that it becomes financially optimal to incorporate wheat straw at price of £11 t−1 for this co-product. Local market conditions for straw and farmer attitudes towards incorporation or sale of straw will impact on the straw price at which farmers will supply this potential bioenergy feedstock and represent important areas for future research.
PMCID: PMC4268688  PMID: 25540473
Bioenergy; Cereal straw; Greenhouse gas emissions; Modelling; Farm systems
18.  Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: KORA S4/F4 study and Framingham Offspring Study 
Diabetologia  2011;54(5):1019-1024.
Lower adiponectin levels are associated with higher risk of incident type 2 diabetes (T2D). Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident T2D differs in insulin resistant (IR) vs sensitive (IS) individuals.
We studied two prospective cohorts: the Framingham Offspring (n=2023) and KORA S4/F4 Studies (n=887). Insulin resistance was estimated by homeostasis model assessment (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident T2D overall and in IR vs IS individuals (defined by ≥ vs <75th percentile of HOMA-IR).
At baseline, Framigham’s participants were 60±9 years old and 56% were women; KORA’s participants were 63±5 years old and 49% were women. T2D incidence was 5.4% over 6.5 years (n=109) in Framingham and 10.5% over 8 years (n=93) in KORA. Lower adiponectin levels were associated with T2D incidence in both cohorts. In IR individuals, lower adiponectin levels were associated with higher risk of T2D incidence (OR=1.60 [95%CI: 1.10–2.31] per SD decrease in Framingham; p=0.01, and OR= 2.34 [95%CI: 1.16–4.73] in KORA; P=0.02); while this was not observed in IS individuals (OR=1.10 [95%CI: 0.73–1.67] in Framingham; p=0.64, and OR=1.34 [95%CI: 0.88–2.03] in KORA; P=0.18).
We conclude that lower adiponectin levels are associated with higher risk of T2D in IR but not in IS individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.
PMCID: PMC3223124  PMID: 21336532
19.  Dural prostate metastasis resembling a chronic subdural haematoma 
Subdural hematoma (SDH) is a common neurosurgical pathology, characteristically recognised on plain CT and can be treated with simple and effective surgical intervention. In contrast, dural metastatic adenocarcinoma of the prostate with SDH and malignant extension into the subdural membranes is extremely rare. We describe the case of a 62-year old Caucasian male, provide a brief review of the literature, and explore the potential role of neoangiogenesis and disseminated intravascular coagulopathy in SDH development.
PMCID: PMC3649540  PMID: 24960135
20.  A multi-centre randomised phase III trial of Dexamethasone vs Dexamethasone and diethylstilbestrol in castration-resistant prostate cancer: immediate vs deferred Diethylstilbestrol 
British Journal of Cancer  2011;104(4):620-628.
The role of further hormone therapy in castration-resistant prostate cancer (CRPC) remains unclear. We performed a multi-centre randomised phase III study comparing the use of Dexamethasone, Aspirin, and immediate addition of Diethylstilbestrol (DAiS) vs Dexamethasone, Aspirin, and deferred (until disease progression) addition of Diethylstilbestrol (DAdS).
From 2001 to 2008, 270 men with chemotherapy-naive CRPC were randomly assigned, in a 1 : 1 ratio, to receive either DAiS or DAdS. They were stratified for performance status, presence of bone metastases, and previous normalisation of prostate-specific antigen (PSA) to androgen deprivation. The study end points were the proportion of patients achieving a 50% PSA response, progression-free survival (PFS), overall survival, and quality of life. Intention-to-treat analysis was carried out. The effect of treatment was studied first by Kaplan–Meier curves and log-rank test, and finally through multivariable stratified Cox's proportional hazards model adjusting for the effects of possible baseline prognostic factors. Quality of life was analysed using multivariate analysis of variance.
At study entry, the median age was 76 years (inter-quartile range: 70–80 years), the median PSA was 79 ng ml−1, and 76% of the cohort had metastatic disease. The response rates for DAiS (68%) and DAdS (64%) were not significantly different (P=0.49). Similar to the response rate, neither the PFS (median=8.1 months for both arms) nor the overall survival (19.4 vs 18.8 months) differed significantly between the DAiS and DAdS groups (P>0.20). However, the response rate for the DAiS (68%) was significantly higher than the response rate of DA (before adding Diethylstilbestrol) (50%) (P=0.002). Similarly, the median time to progression for DAiS (8.6 months) was significantly longer than that of DA (4.5 months) (P<0.001). Multivariable analysis showed that patients with previous haemoglobin ⩾11 g dl−1 decreased the risk of death significantly (hazard ratio: 0.44, 95% CI: 0.25–0.77). Patients treated with previous anti-androgens alone had more than 5 times more risk of death compared with patients treated with gonadorelin analogues throughout their castration-sensitive phase. Treatment sequencing did not affect the quality of life but pre-treatment performance status did. The incidence of veno–thromboembolic events was 22% (n=28) in DAiS and 11% (n=14) in the DA arm (P=0.02). Painful gynaecomastia occurred in only 1% on DA, whereas in 40% on DAiS (P=0.001).
Dexamethasone and immediate Diethylstilbestrol resulted in neither higher PSA response rate nor higher PFS compared with Dexamethasone with deferred Diethylstilbestrol. There was no suggestion of significantly improved overall survival or quality of life. Given the significantly higher toxicity of Diethylstilbestrol, deferring Diethylstilbestrol until failure of Dexamethasone is the preferred strategy when using these agents in CRPC.
PMCID: PMC3049603  PMID: 21285990
CRPC; Dexamethasone; Diethylstilbestrol; treatment sequencing
21.  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.
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.
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.
PMCID: PMC2850795  PMID: 20375204
Stomatal size; genome size; seed size; life history; photosynthesis; allometry; ecology; evolution; SLA; leaf structure; CAM; C4
22.  Clinical presentation and initial management of Black men and White men with prostate cancer in the United Kingdom: the PROCESS cohort study 
British Journal of Cancer  2009;102(2):249-254.
In the United States, Black men have a higher risk of prostate cancer and worse survival than do White men, but it is unclear whether this is because of differences in diagnosis and management. We re-examined these differences in the United Kingdom, where health care is free and unlikely to vary by socioeconomic status.
This study is a population-based retrospective cohort study of men diagnosed with prostate cancer with data on ethnicity, prognostic factors, and clinical care. A Delphi panel considered the appropriateness of investigations and treatments received.
At diagnosis, Black men had similar clinical stage and Gleason scores but higher age-adjusted prostate-specific antigen levels (geometric mean ratio 1.41, 95% confidence interval (95% CI): 1.15–1.73). Black men underwent more investigations and were more likely to undergo radical treatment, although this was largely explained by their younger age. Even after age adjustment, Black men were more likely to undergo a bone scan (odds ratio 1.37, 95% CI: 1.05–1.80). The Delphi analysis did not suggest differential management by ethnicity.
This UK-based study comparing Black men with White men found no evidence of differences in disease characteristics at the time of prostate cancer diagnosis, nor of under-investigation or under-treatment in Black men.
PMCID: PMC2816646  PMID: 19935788
clinical management; diagnosis; epidemiology; ethnicity; prostate cancer
23.  Airborne transmission of disease in hospitals 
Journal of the Royal Society Interface  2009;6(Suppl 6):S697-S702.
Hospital-acquired infection (HAI) is an important public health issue with unacceptable levels of morbidity and mortality, over the last 5 years. Disease can be transmitted by air (over large distances), by direct/indirect contact or a combination of both routes. While contact transmission of disease forms the majority of HAI cases, transmission through the air is harder to control, but one where the engineering sciences can play an important role in limiting the spread. This forms the focus of this themed volume.
In this paper, we describe the current hospital environment and review the contributions from microbiologists, mechanical and civil engineers, and mathematicians to this themed volume on the airborne transmission of infection in hospitals. The review also points out some of the outstanding scientific questions and possible approaches to mitigating transmission.
PMCID: PMC2843953  PMID: 19828499
droplet evaporation; dispersion; hospital-acquired infection
24.  Bis(tetra­phenyl­phospho­nium) bis­[N-(phenyl­sulfon­yl)dithio­carbimato-κ2 S,S′]platinate(II) monohydrate 
The asymmetric unit of the title compound, (C24H20P)2[Pt(C7H5NO2S3)2]·H2O, consists of two tetra­phenyl­phospho­nium cations, two half bis­[N-(phenyl­sulfon­yl)dithio­carbim­ato]platinate(II) dianions and one water mol­ecule. The anions are completed by crystallographic inversion symmetry associated with the central PtII ion. The PtII ion is doubly S,S′-chelated by two symmetry-related phenyl­sulfonyl­dithio­carbimate ligands, forming a slightly distorted square-planar configuration. Besides the electrostatic attraction between oppositely charged ions in the crystal packing, intra­molecular C—H⋯O and several inter­molecular C—H⋯O, C—H⋯N and O—H⋯O hydrogen-bonding inter­actions between the cations, anions and water mol­ecules are observed.
PMCID: PMC3007205  PMID: 21588196
25.  Interferon-inducible factor 16 is a novel modulator of glucocorticoid action 
The FASEB Journal  2010;24(6):1700-1713.
Previously, we used cDNA expression profiling to identify genes associated with glucocorticoid (Gc) sensitivity. We now identify which of these directly influence Gc action. Interferon-inducible protein 16 (IFI16), bone morphogenetic protein receptor type II (BMPRII), and regulator of G-protein signaling 14 (RGS14) increased Gc transactivation, whereas sialyltransferase 4B (SIAT4B) had a negative effect. Amyloid β (A4) precursor-protein binding, family B, member 1 (APBB1/Fe65) and neural cell expressed developmentally down-regulated 9 (NEDD9) were without effect. Only IFI16 potentiated Gc repression of NF-κB. In addition, IFI16 affected basal expression, and Gc induction of endogenous target genes. IFI16 did not affect glucocorticoid receptor (GR) expression, ligand-dependent repression of GR expression, or the ligand-dependent induction of GR phosphorylation on Ser-211 or Ser-203. Coimmunoprecipitation revealed an interaction, suggesting that IFI16 modulation of GR function is mediated by protein crosstalk. Transfection analysis with GR mutants showed that the ligand-binding domain of GR binds IFI16 and is the target domain for IFI16 regulation. Analysis of human lung sections identified colocalization of GR and IFI16, suggesting a physiologically relevant interaction. We demonstrate that IFI16 is a novel modulator of GR function and show the importance of analyzing variation in Gc sensitivity in humans, using appropriate technology, to drive discovery.—Berry, A., Matthews, L. Jangani, M., Plumb, J., Farrow, S., Buchan, N., Wilson, P. A., Singh, D., Ray, D., W., Donn, R. P. Interferon-inducible factor 16 is a novel modulator of glucocorticoid action.
PMCID: PMC3000051  PMID: 20086048
IFI16; steroid sensitivity; nuclear receptor; inflammation

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