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This review describes the scientific basis of a research and breeding pathway designed to boost genetic gains in wheat under drought and heat stress., Despite being the world’s most widely grown crop, research investments in wheat (Triticum aestivum and Triticum durum) fall behind those in other staple crops. Current yield gains will not meet 2050 needs, and climate stresses compound this challenge. However, there is good evidence that heat and drought resilience can be boosted through translating promising ideas into novel breeding technologies using powerful new tools in genetics and remote sensing, for example. Such technologies can also be applied to identify climate resilience traits from among the vast and largely untapped reserve of wheat genetic resources in collections worldwide. This review describes multi-pronged research opportunities at the focus of the Heat and Drought Wheat Improvement Consortium (coordinated by CIMMYT), which together create a pipeline to boost heat and drought resilience, specifically: improving crop design targets using big data approaches; developing phenomic tools for field-based screening and research; applying genomic technologies to elucidate the bases of climate resilience traits; and applying these outputs in developing next-generation breeding methods. The global impact of these outputs will be validated through the International Wheat Improvement Network, a global germplasm development and testing system that contributes key productivity traits to approximately half of the global wheat-growing area.

Genetic variation in wheat is needed to address global food security challenges, particularly as climates change. Crop wild relatives are unique reservoirs of useful alleles for crop improvement and are important components of genebank collections. We analyzed how the derivatives of ‘goat grass’ (Aegilops tauschii) have been used to widen the genetic base for wheat breeding and surveyed wheat breeders to elicit adoption estimates. Synthetic hexaploid wheat (SHW) is derived by crossing goat grass with durum wheat, serving as a bridge to transfer desirable traits into modern varieties of bread wheat. Our data show that wheat scientists used 629 unique accessions from 15 countries for pre-breeding, producing 1577 primary SHWs. These derivatives represented 21% of the germplasm distributed by the genebank of the International Maize and Wheat Improvement Center between 2000 and 2018. Over the period, more than 10,000 samples of SHW were sent to 110 institutions in 40 countries, with rising numbers of synthetic hexaploid-derived lines (SHDL) included in international nurseries. Lines were screened for major diseases of wheat. At least 86 varieties have been selected from SHDL and released in 20 countries. Survey estimates indicate the highest scale of adoption in southwest China and India, with 34% and 7% of reported wheat area, respectively. These varieties demonstrate resistance to pests and pathogens, high yield potential, good quality attributes, and suitability for biofortified wheat.

The history of CGIAR and the development and implementation of the International Treaty on Plant Genetic Resources for Food and Agriculture (“Plant Treaty”) are closely intertwined. In accordance with the agreements that 11 CGIAR centers signed with the Plant Treaty’s Governing Body under Article 15 of the treaty, >730,000 accessions of crop, tree, and forage germplasm conserved in CGIAR genebanks are made available under the terms and conditions of the multilateral system of access and benefit sharing, and the CGIAR centers have transferred almost 4 million samples of plant genetic resources under the system. Many activities of CGIAR centers and their genebanks (e.g., crop enhancement, improved agronomic methods, seed system strengthening, and capacity building) are influenced by, and promote, the Plant Treaty’s objectives. The continued existence and optimal functioning of the Plant Treaty’s multilateral system of access and benefit sharing is critically important to CGIAR in the pursuit of its mission. However, the multilateral system has encountered some challenges since the Plant Treaty came into force. The successful conclusion of the ongoing process for enhancing the functioning of the multilateral system could increase monetary benefit sharing and incentives for exchanging more germplasm. In the meantime, increased efforts are necessary to promote nonmonetary benefit sharing through partnerships, technology transfer, information exchange, and capacity building. These efforts should be integrated into countries’ and organizations’ work to implement the Plant Treaty’s provisions on conservation and sustainable use of plant genetic resources, and farmers’ rights.

Surgery has a rich history, and in order to understand the various training pathways for aspiring surgeons one must have an appreciation of the evolution of surgery. This manuscript aims to deliver a brief review of the history of surgery, and explore the historical moments that have shaped the training pathway of surgeons in the United Kingdom (UK), and in doing so disseminate the latest information about surgical training in the UK. doi: https://doi.org/10.12669/pjms.37.5.4628 How to cite this:Payne T, Toms JD, Zaidi A, Thrumurthy SG. The history of surgery and surgical training in the UK. Pak J Med Sci. 2021;37(5):1532-1535. doi: https://doi.org/10.12669/pjms.37.5.4628 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Wheat grain yield (GY) improvement using genomic tools is important for achieving yield breakthroughs. To dissect the genetic architecture of wheat GY potential and stress-resilience, we have designed this large-scale genome-wide association study using 100 datasets, comprising 105,000 GY observations from 55,568 wheat lines evaluated between 2003 and 2019 by the International Maize and Wheat Improvement Center and national partners. We report 801 GY-associated genotyping-by-sequencing markers significant in more than one dataset and the highest number of them were on chromosomes 2A, 6B, 6A, 5B, 1B and 7B. We then used the linkage disequilibrium (LD) between the consistently significant markers to designate 214 GY-associated LD-blocks and observed that 84.5% of the 58 GY-associated LD-blocks in severe-drought, 100% of the 48 GY-associated LD-blocks in early-heat and 85.9% of the 71 GY-associated LD-blocks in late-heat, overlapped with the GY-associated LD-blocks in the irrigated-bed planting environment, substantiating that simultaneous improvement for GY potential and stress-resilience is feasible. Furthermore, we generated the GY-associated marker profiles and analyzed the GY favorable allele frequencies for a large panel of 73,142 wheat lines, resulting in 44.5 million datapoints. Overall, the extensive resources presented in this study provide great opportunities to accelerate breeding for high-yielding and stress-resilient wheat varieties.

The international collections of plant genetic resources for food and agriculture (PGRFA) hosted by 11 CGIAR Centers are important components of the United Nations Food and Agriculture Organization&rsquo, s global system of conservation and use of PGRFA. They also play an important supportive role in realizing Target 2.5 of the Sustainable Development Goals. This paper analyzes CGIAR genebanks&rsquo, trends in acquiring and distributing PGRFA over the last 35 years, with a particular focus on the last decade. The paper highlights a number of factors influencing the Centers&rsquo, acquisition of new PGRFA to include in the international collections, including increased capacity to analyze gaps in those collections and precisely target new collecting missions, availability of financial resources, and the state of international and national access and benefit-sharing laws and phytosanitary regulations. Factors contributing to Centers&rsquo, distributions of PGRFA included the extent of accession-level information, users&rsquo, capacity to identify the materials they want, and policies. The genebanks&rsquo, rates of both acquisition and distribution increased over the last decade. The paper ends on a cautionary note concerning the potential of unresolved tensions regarding access and benefit sharing and digital genomic sequence information to undermine international cooperation to conserve and use PGRFA.

Extragonadal non-gestational choriocarcinoma is a rare but well-described phenomenon occurring in patients with midline germ cell tumors. Choriocarcinoma (ChC) is an aggressive neoplasm usually developing in women as a rare complication of pregnancy. In male patients ChC occurs in the testes, usually as a component of mixed germ cell tumors. Very few patients develop extragonadal choriocarcinoma with the tumor occurring in midline locations, such as the mediastinum, retroperitoneum, and central nervous system (mostly pineal gland). Non-midline choriocarcinoma can occur in the lung, gastrointestinal tract, and breast, sometimes blended with another primary malignancy. A midline choriocarcinoma manifesting as a head and neck malignancy is exceptional. During an evaluation of multiple enlarged cervical lymph nodes suspected to be lymphoma in a 72-year-old man, a core biopsy was taken from one of the left neck lymph nodes which histologically showed a necrotic malignancy with strong diffuse pancytokeratin staining. After an initial interpretation of metastatic carcinoma, further samples were taken from both tonsils and from a right level 5 neck lymph node. Histologically, all samples contained the same tumor, showing profound pleomorphism and multinucleated syncytial-type giant cells. A panel of immunohistochemistry studies were performed, including β-human chorionic gonadotropin, with positive findings leading to a diagnosis of extragonadal non-gestational choriocarcinoma.

IntroductionThere are no disease-modifying treatments for Parkinson’s disease (PD). We undertook the first drug screen in PD patient tissue and idntified ursodeoxycholic acid (UDCA) as a promising mitochondrial rescue agent. The aims of this trial are to determine safety and tolerability of UDCA in PD at 30 mg/kg, confirm the target engagement of UDCA, apply a novel motion sensor-based approach to quantify disease progression objectively, and estimate the mean effect size and its variance on the change in motor severity.Methods and analysisThis is a phase II, two-centre, double-blind, randomised, placebo-controlled trial of UDCA at a dose of 30 mg/kg in 30 participants with early PD. Treatment duration is 48 weeks, followed by an 8-week washout phase. Randomisation is 2:1, drug to placebo. Assessments are performed at baseline, week 12, 24, 36, 48 and 56. The primary outcome is safety and tolerability. Secondary outcomes will compare the change between baseline and week 48 using the following three approaches: the Movement Disorders Society Unified Parkinson’s Disease Rating Scale Part 3 in the practically defined ‘OFF’ medication state; confirmation of target engagement, applying 31Phosphorus MR Spectroscopy to assess the levels of ATP and relevant metabolites in the brain; and objective quantification of motor impairment, using a validated, motion sensor-based approach. The primary outcome will be reported using descriptive statistics and comparisons between treatment groups. For each secondary outcome, the change from baseline will be summarised within treatment groups using summary statistics and appropriate statistical tests assessing for significant differences. All outcomes will use an intention-to-treat analysis population.Ethics and disseminationThis trial has been approved by the East of England – Cambridgeshire and Hertfordshire Research Ethics committee. Results will be disseminated in peer-reviewed journals, presentations at scientific meetings and to patients in a lay-summary format.Trial registration numberNCT03840005.

Mechanistic disease stratification will be crucial to develop a precision medicine approach for future disease modifying therapy in sporadic Parkinson’s disease (sPD). Mitochondrial and lysosomal dysfunction are key mechanisms in the pathogenesis of sPD and therefore promising targets for therapeutic intervention. We investigated mitochondrial and lysosomal function in skin fibroblasts of 100 sPD patients and 50 age-matched controls. A combination of cellular assays, RNA-seq based pathway analysis and genotyping was applied. Distinct subgroups with mitochondrial (mito-sPD) or lysosomal (lyso-sPD) dysfunction were identified. Mitochondrial dysfunction correlated with reduction in complex I and IV protein levels. RNA-seq based pathway analysis revealed marked activation of the lysosomal pathway with enrichment for lysosomal disease gene variants in lyso-sPD. Conversion of fibroblasts to induced neuronal progenitor cells and subsequent differentiation into tyrosine hydroxylase positive neurons confirmed and further enhanced both mitochondrial and lysosomal abnormalities. Treatment with ursodeoxycholic acid improved mitochondrial membrane potential and intracellular ATP levels even in sPD patient fibroblast lines with comparatively mild mitochondrial dysfunction. The results of our study suggest that in-depth phenotyping and focussed assessment of putative neuroprotective compounds in peripheral tissue are a promising approach towards disease stratification and precision medicine in sPD.

Introduction PDAC is increasing in incidence and has the worst survival of any malignancy. Lifestyle choices to reduce risk, based on robust evidence, are required. There are plausible biological mechanisms for how a moderate intake of alcohol (UK recommendations of ≤14 units/week) could prevent PDAC. These are alcohol: mitigating against pathological effects of KRAS genetic mutations, decreasing excess mitogenic insulin secretion, and the effects of antioxidants in alcoholic drinks. These mechanisms must be supported by robust epidemiological data to infer causality. The aim of this work is to systematically review prospective cohort studies, selected according to predefined criteria, to assess if a moderate alcohol consumption is inversely associated with PDAC risk. Cohort studies minimise biases inherent in other observational methodologies. Methods Medline, PubMed and EMBASE electronic databases were searched for prospective cohort studies investigating a moderate alcohol consumption and PDAC up to January 2019. The inclusion criteria were: >100 PDAC cases, definition of moderate consumption within UK guidelines, clear description of the comparator group, reporting effect sizes as risk/hazard ratios (RR/HR) and adjustment for covariates including: age, sex, smoking, body mass index and diabetes mellitus. Pooled effect sizes were calculated using an inverse variance random-effects model. Results Four prospective cohort studies meeting inclusion criteria were identified (9,090 PDAC cases, 57.5% female, mean age at diagnosis was 61.1 years). The cohorts were in the Netherlands, UK, pan-European and the US. The pooled effect size showed no association between a moderate alcohol consumption and PDAC risk (HR = 0.97, 95% CI; 0.91–1.03, I2 for heterogeneity 0.0%). There was no evidence of publication bias (Egger’s p = 0.404). Three cohorts investigated moderate intake of different beverages, reporting no association with either: wine (HR = 0.95, 95% CI; 0.83–1.09, I2 = 0.0%) beer (HR = 0.96, 95% CI; 0.79–1.17, I2 = 0.0%) or liquor (HR = 1.18, 95% CI, 0.89–1.57, I2 = 71.7%). There was no biological gradient within the moderate range. Conclusions The plausible biological mechanisms for a protective effect of alcohol are not supported by the epidemiological work. Drinking alcohol moderately cannot be recommended to decrease PDAC risk in the general population. Further research in a large prospective cohort which investigates risk in specific groups such as smokers and according to body mass index is required to see if alcohol may be beneficial in high risk groups for PDAC.

This study examines genomic prediction within 8416 Mexican landrace accessions and 2403 Iranian landrace accessions stored in gene banks. The Mexican and Iranian collections were evaluated in separate field trials, including an optimum environment for several traits, and in two separate environments (drought, D and heat, H) for the highly heritable traits, days to heading (DTH), and days to maturity (DTM). Analyses accounting and not accounting for population structure were performed. Genomic prediction models include genotype × environment interaction (G × E). Two alternative prediction strategies were studied: (1) random cross-validation of the data in 20% training (TRN) and 80% testing (TST) (TRN20-TST80) sets, and (2) two types of core sets, “diversity” and “prediction”, including 10% and 20%, respectively, of the total collections. Accounting for population structure decreased prediction accuracy by 15–20% as compared to prediction accuracy obtained when not accounting for population structure. Accounting for population structure gave prediction accuracies for traits evaluated in one environment for TRN20-TST80 that ranged from 0.407 to 0.677 for Mexican landraces, and from 0.166 to 0.662 for Iranian landraces. Prediction accuracy of the 20% diversity core set was similar to accuracies obtained for TRN20-TST80, ranging from 0.412 to 0.654 for Mexican landraces, and from 0.182 to 0.647 for Iranian landraces. The predictive core set gave similar prediction accuracy as the diversity core set for Mexican collections, but slightly lower for Iranian collections. Prediction accuracy when incorporating G × E for DTH and DTM for Mexican landraces for TRN20-TST80 was around 0.60, which is greater than without the G × E term. For Iranian landraces, accuracies were 0.55 for the G × E model with TRN20-TST80. Results show promising prediction accuracies for potential use in germplasm enhancement and rapid introgression of exotic germplasm into elite materials.

To address the expanding costs of providing a reliable facility infrastructure, eliminating single points of failure, and achieving tier 3 or 4 status in a data center, alternative approaches must be considered. This article will discuss an integration of facility infrastructure and information technology (IT) communications within different tier classes of data centers to provide a significant cost-saving solution for the development of data centers while still maintaining operational readiness.

There is strong evidence of a key role for mitochondrial dysfunction in both sporadic and all forms of familial Parkinson's disease (PD). However, none of the clinical trials carried out with putative mitochondrial rescue agents has been successful. Firm establishment of a wet biomarker or a reliable readout from imaging studies detecting mitochondrial dysfunction and reflecting disease progression is also awaited. We will provide an overview of our current knowledge about mitochondrial dysfunction in PD and related drug screens. We will also summarize previously undertaken mitochondrial wet biomarker studies and relevant imaging studies with particular focus on 31P-MRI Spectroscopy. We will conclude with an overview of clinical trials which tested putative mitochondrial rescue agents in PD patients. Parkinson's disease is a common, relentlessly progressive neurodegenerative disorder. The pathological hallmark is loss of dopaminergic neurons in the substantia nigra. The resulting motor presentation includes rest tremor, bradykinesia and rigidity but the importance of non-motor symptoms such as cognitive impairment and depression is increasingly recognized, too. Currently available dopaminergic treatment often only addresses the motor impairment partially. This review will summarize our current knowledge about mitochondrial dysfunction as a key target for disease-modifying treatment for PD. We will also provide an update on mitochondrial readouts in PD patients, namely imaging and putative mitochondrial biomarkers, which may become highly relevant in the context of future drug trials. This article is protected by copyright. All rights reserved.

Synthetic impact surrogates are widely used in the sporting goods industry in the evaluation of personal protective equipment. Existing surrogates, exemplified by those used in safety standards, have many shortcomings, primarily relating to their mass, stiffness, geometries and levels of constraint which limit their biofidelity and subsequent usefulness in personal protective equipment evaluations. In sports, absence from competition is a primary severity measure for injuries; consequently, blunt trauma injuries, such as contusions and lacerations, become pertinent and serious concerns. It is important, therefore, that synthetic surrogates provide an adequate description of these soft tissues to effectively evaluate injury risk. A novel, multi-material human thigh surrogate has been presented with consideration to the tissue structures, geometries and simulant materials used. This study presents the detailed development stages undertaken to fabricate a multi-material synthetic soft tissue surrogate with skin, subcutaneous adipose and muscle tissue components. The resultant surrogate demonstrates the successful use of sequential moulding techniques to construct a full-scale anatomical human impact surrogate which can be used in personal protective equipment testing.

Genotypes produced from plant breeding programs for annual crops are evaluated in multiyear, multilocation field trials where a large number of genotypes grown in a few locations in the first year are progressively reduced by selection and tested in a greater number of locations in successive years. Provided fixed resources are specified, the efficiencies of testing strategies differing in the number of locations and replications used and in the number of genotypes tested in successive years can be evaluated by three statistics (genetic repeatability, acceptance probability, and potential gain) calculated from five variance components applicable to the field trials. The five variance components required are deployed genetic variance, genotype-by-year, genotype-by-location, and genotype-by-year-by-location interaction variances and the residual (error) variance. Strictly, known variance components are required, but the statistics and their standard errors can be calculated using robust estimates of the variance components obtained from a combined analysis over years of a large set of historical data from field trials that are connected by shared genotypes across years, as genotype-by-year and genotype-by-year-by-location variance components are estimable. Single-year analyses are unsuitable, as no estimate of the interactions with year are available, and such analyses produce biased estimates of genetic variance and genotype-by-location interaction variance. These procedures are illustrated using an example from the CIMMYT international wheat breeding program to evaluate 2-yr testing strategies for CIMMYT’s Elite Spring Wheat Yield Trials that has been distributed and evaluated internationally since 1979.

Impact injuries are commonplace in sport and often lead to performance detriment and debilitation. Personal Protective Equipment (PPE) is prescribed as a mandatory requirement in most sports where these impacts are likely to occur, though the methods of governance and evaluation criteria often do not accurately represent sports specific injury scenarios. One of the key shortcomings of such safety test standards is the human surrogate to which the PPE is affixed; this typically embodies unrepresentative geometries, masses, stiffness and levels of constraint when compared to humans. A key aspect of any human surrogate element is the simulant material used. Most previous sports specific surrogates tend to use off-the-shelf silicone blends to represent all the soft tissue structures within the human limb segment or organ; this approach potentially neglects important human response phenomena caused by the different tissue structures. This study presents an investigation into the use of bespoke additive cure Polydimethysiloxane (PDMS) silicone blends to match the reported mechanical properties of human relaxed and contracted skeletal muscle tissues. The silicone simulants have been tested in uniaxial compression through a range of strain rates and fit with a range of constitutive hyperelastic models (Mooney Rivlin, Ogden and Neo Hookean) and a viscoelastic Prony series.

To accelerate genetic gains in breeding, physiological trait (PT) characterization of candidate parents can help make more strategic crosses, increasing the probability of accumulating favorable alleles compared to crossing relatively uncharacterized lines. In this study, crosses were designed to complement “source” with “sink” traits, where at least one parent was selected for favorable expression of biomass and/or radiation use efficiency—source—and the other for sink-related traits like harvest-index, kernel weight and grains per spike. Female parents were selected from among genetic resources—including landraces and products of wide-crossing (i.e. synthetic wheat)—that had been evaluated in Mexico at high yield potential or under heat stress, while elite lines were used as males. Progeny of crosses were advanced to the F4 generation within Mexico, and F4-derived F5 and F6 generations were yield tested to populate four international nurseries, targeted to high yield environments (2nd and 3rd WYCYT) for yield potential, and heat stressed environments (2nd and 4th SATYN) for climate resilience, respectively. Each nursery was grown as multi-location yield trials. Genetic gains were achieved in both temperate and hot environments, with most new PT-derived lines expressing superior yield and biomass compared to local checks at almost all international sites. Furthermore, the tendency across all four nurseries indicated either the superiority of the best new PT lines compared with the CIMMYT elite checks, or the superiority of all new PT lines as a group compared with all checks, and in some cases, both. Results support—in a realistic breeding context—the hypothesis that yield and radiation use efficiency can be increased by improving source:sink balance, and validate the feasibility of incorporating exotic germplasm into mainstream breeding efforts to accelerate genetic gains for yield potential and climate resilience.

Climate change is expected to impact global food supply and food security by affecting growing conditions for agricultural production. Process-based dynamic growth models are important tools to estimate crop yields based on minimum inputs of climate, soil, crop management, and crop cultivar parameters. Using region-specific cultivar parameters is critical when applying crop models at a global scale because cultivars vary in response to climate conditions, soils, and crop management. In this study, parameters were developed for modern cultivars representing all 17 CIMMYT wheat Mega Environments (MEs) using field experimental data and genetic cultivar relationships for the CROPSIM-CERES model in DSSAT v 4.5 (Decision-Support System for Agrotechnology Transfer). Cultivar performance was tested with independent CIMMYT breeding trial field experiments across several locations. Then crop simulations were carried out at 0.5 × 0.5 ° pixels for global wheat-growing areas, using cultivars representing MEs, soil information, region-specific crop management, and initial soil conditions. Aggregated simulated wheat yields and production were compared to reported country yields and production from Food and Agriculture Organization (FAO) statistics, resulting in a Root Mean Square Error (RMSE) of 1.3 t/ha for yield and 2.2 M t/country for country production. Some of the simulated errors are relatively large at country level because of uncertainties in pixel information for climate, soil, and crop management input and partly because of crop model uncertainties. In addition, FAO yield statistics have uncertainties because of incomplete farm reports or poor estimates. Nevertheless, this new cultivar-specific, partially-validated global baseline simulation enables new studies on issues of food security, agricultural technology, and breeding advancement impacts combined with climate change at a global scale.

What exactly is a video game? How do we as gamers experience its liminal bounds? Moreover, how do we as scholars delimit those experiential parameters for the purposes of study? These are, of cours...

Despite significant advances in materials and manufacturing techniques applied to sports protective equipment in recent years, sports injuries due to impact, contusions in particular, continue to occur. In this paper, a test methodology aimed at collecting data from laboratory-simulated human-on-human impacts in Basketball is presented. The study was executed in three stages with data being collected from: i) human on instrumented bag; ii) impactor on instrumented bag and iii) impactor on instrumented human impacts. In all cases, high-speed video and/or kinematic motion data capture systems were used to obtain parameters such as inbound/outbound velocities, contact durations while resistive ink technology pressure sensing films were used to estimate parameters such as pressure distributions, peak pressures, contact areas, impact forces. Elite-level athletes were used in all human trials to ensure that impact techniques and levels representative of the elite game were obtained and that tolerance to impacts was similarly representative. Two common strikes were simulated: knee on thigh and elbow on rib/torso. Five participants were used to collect the human-on-bag data while 12 participants were used to collect the impactor-on-human data. Between three and five impacts per scenario were performed to enable noise averaging and, importantly, likely injurycausing outlier capture. © 2014 Published by Elsevier Ltd.

BackgroundThere is strong evidence of mitochondrial dysfunction in both familial and sporadic Parkinson’s disease (PD). A biomarker reliably identifying mitochondrial dysfunction would be particularly important for future stratified/personalized medicine trials in Parkinson’s disease. A previous comparison of serum biomarkers in mitochondrial disease established that serum growth differentiation factor 15 (GDF-15) outperforms fibroblast growth factor-21 (FGF-21) and distinguishes patients with mitochondrial diseases from those without them.ObjectiveTo systematically assess GDF-15, FGF-21 and mitochondrial DNA copy number (mtDNA) levels in the serum of patients with sporadic PD and controls to determine their utility as a suitable mitochondrial biomarker panel for PD.Methods120 patients with PD and 102 age-matched controls were recruited from a single centre. GDF-15, FGF-21 and mtDNA copy number were quantified using previously established assays.ResultsFGF-21 concentrations did not significantly differ between groups. GDF-15 serum levels were significantly raised in late onset PD compared to controls and early onset PD. There was no difference in mtDNA between groups. None of the biomarkers tested showed a significant association with disease following multivariate logistic regression analysis.ConclusionSerum FGF-21, GDF-15 and blood mtDNA could not accurately differentiate between PD and controls when assessed as candidate biomarkers.

Human surrogates are representations of living human structures employed to replicate "real-life" injurious scenarios in artificial environments. They are used primarily to evaluate personal protective equipment (PPE) or integrated safety systems (e.g., seat belts) in a wide range of industry sectors (e.g., automotive, military, security service, and sports equipment). Surrogates are commonly considered in five major categories relative to their form and functionality: human volunteers, postmortem human surrogates, animal surrogates, anthropomorphic test devices, and computational models. Each surrogate has its relative merits. Surrogates have been extensively employed in scenarios concerning "life-threatening" impacts (e.g., penetrating bullets or automotive accidents). However, more frequently occurring nonlethal injuries (e.g., fractures, tears, lacerations, contusions) often result in full or partial debilitation in contexts where optimal human performance is crucial (e.g., military, sports). Detailed study of these injuries requires human surrogates with superior biofidelity to those currently available if PPE designs are to improve. The opportunities afforded by new technologies, materials, instrumentation, and processing capabilities should be exploited to develop a new generation of more sophisticated human surrogates. This paper presents a review of the current state of the art in human surrogate construction, highlighting weaknesses and opportunities, to promote research into improved surrogates for PPE development.

In arena blast testing, a common and economical practice employed is to distribute several targets radially around a central charge. However, if these targets are positioned too proximally, reflections and diffractions of blast waves off neighbouring cubicles can affect the nature of expected blast loading. Computational fluid dynamics software has been used through an extensive series of simulations to identify the levels of interference in incident pressure–time histories with and without an obstructing target present. The data were post-processed to identify the Cartesian co-ordinates in which different levels of interference in peak incident overpressure and incident positive phase impulse were achieved. The results indicated that in all cases, there was a greater interference in peak incident overpressure than incident positive phase impulse values directly proximal to the target but, at greater separations, significant differences in incident positive phase impulse existed where peak incident overpressure had returned to free-field equivalent magnitudes. When compared with the established ‘rules of thumb’ for cubicle placement, for targets at different stand-off ranges, an angle of 45° to the rear cubicle still holds some practical relevance, although it is too acute to cover all interference effects. For targets positioned at the same stand-off range, a separation distance of two cubicle widths is generally too conservative and, in many cases, more cubicles can be positioned around the charge. A bespoke recommendation table has been presented for targets at stand-off ranges between 15 and 50 m to allow users to identify the minimum distance from a target at which obstructed-field peak incident overpressure and incident positive phase impulse values differ negligibly from free-field equivalents.

Climate change and slow yield gains pose a major threat to global wheat production. Underutilized genetic resources including landraces and wild relatives are key elements for developing high-yielding and climate-resilient wheat varieties. Landraces introduced into Mexico from Europe, also known as Creole wheats, are adapted to a wide range of climatic regimes and represent a unique genetic resource. Eight thousand four hundred and sixteen wheat landraces representing all dimensions of Mexico were characterized through genotyping-by-sequencing technology. Results revealed sub-groups adapted to specific environments of Mexico. Broadly, accessions from north and south of Mexico showed considerable genetic differentiation. However, a large percentage of landrace accessions were genetically very close, although belonged to different regions most likely due to the recent (nearly five centuries before) introduction of wheat in Mexico. Some of the groups adapted to extreme environments and accumulated high number of rare alleles. Core reference sets were assembled simultaneously using multiple variables, capturing 89% of the rare alleles present in the complete set. Genetic information about Mexican wheat landraces and core reference set can be effectively utilized in next generation wheat varietal improvement.

PurposeIn the UK, Japanese knotweed is an invasive, non‐native plant that has the potential to cause significant damage to buildings, foundations and development sites if left to establish. The plant's bamboo‐like stems can push their way through tarmac and expose weaknesses or cracks in concrete. The purpose of this paper is to investigate the current problems caused by Japanese knotweed within the UK and to ascertain the extent to which the knotweed legislation provides clear enough guidelines and measures, and, if not, how this could be addressed.Design/methodology/approachA literature review and interviews have investigated the current and future eradication and control techniques available for Japanese knotweed. The primary and secondary research conducted has incorporated the views and opinions of experienced Japanese knotweed experts. Case studies of sites infested with knotweed have also been carried out.FindingsThe study has identified and recommended that both public and professional awareness of Japanese knotweed still needs to be increased, throughout the UK. A detailed identification card has therefore been produced as part of this study, in order to show the different growth stages of the invasive plant, throughout the year. The study has demonstrated that an eradication technique must be carefully chosen and tailored to suit each infested site after a full site survey. The semi‐structured interviews have established that the current legislation, guidance notes and also the “Knotweed Code of Practice” produced by the Environmental Agency, provide adequate guidance on controlling Japanese knotweed. The research highlighted that knotweed spreading from neighbouring properties was a potential problem, but in practice, neighbours usually reach mutual agreement to avoid high legal costs.Originality/valueJapanese knotweed is an increasing problem in the UK and this research will increase the awareness of those instructed to inspect property or development sites where infestation may have occurred. Professionals within the construction industry including surveyors, estate agents, developers and project managers will all find this paper of benefit.

Disease incidence and severity was studied for winter wheat variety Bezostaya 1 and susceptible checks based on data from international nurseries from 1969 to 2010 and from 51 countries across major winter wheat production regions totalling 1,047 reports. The frequency of leaf rust and stripe rust occurrence was stable over time with marked increases in severity in 2001–2010 especially in Europe and Central and West Asia. Substantial global reductions in stem rust occurrence were recorded and attributed primarily to use of resistance genes although the recent emergence of race Ug99 makes wheat more vulnerable. The occurrence of powdery mildew remained globally stable over time. It was the most important foliar disease in Western and Southern Europe, where the frequency was very high for all time periods coupled with slight increases in severity during 2001–2010. The durable resistance of variety Bezostaya 1 to all four diseases was demonstrated in the study using comparisons of disease severities of Bezostaya 1 and the most susceptible entries. The Lr34/Yr18/Pm38 pleiotrophic set possessed by Bezostaya 1 is currently an important target for selection because it is now amenable to molecular selection. Increased use of genes like Lr34 combined with strategies to minimize cultivation of extremely susceptible varieties will contribute to long term maintenance of low and non-damaging disease levels. The durable disease resistance of Bezostaya 1, combined with its adaptability and good end-use quality, was a significant reason for its huge impact in agriculture over the last 50 years.

Purpose The aim of this study was to assess the distribution of CT dose index (CTDI) values reported by sites undergoing ACR CT accreditation between 2002 and 2004. Methods Weighted CTDI (CTDI w ) values were measured and reported by sites applying for ACR CT accreditation, and the percentage of scanners with values above the 2002 ACR diagnostic reference levels (DRLs) was determined. Acquisition parameters for a site's adult head, adult abdominal, and pediatric abdominal examinations were used to calculate volume CTDI (CTDI vol ), and the average and standard deviation were calculated by year. Histogram analysis was performed to determine 75th and 90th percentiles of CTDI vol . Results Between September 2002 and December 2004, 829 scanners underwent the accreditation process. Volume CTDI values (average ± SD) for 2002, 2003, 2004, and 2002 to 2004, respectively, were 66.7 ± 23.5, 58.5 ± 17.5, 55.8 ± 15.7, and 59.1 ± 18.6 mGy for adult head examinations; 18.7 ± 8.0, 19.2 ± 8.6, 17.0 ± 7.6, and 18.4 ± 8.3 for adult abdominal examinations; and 17.2 ± 9.7, 15.9 ± 8.6, 14.0 ± 7.0, and 15.5 ± 8.4 for pediatric abdominal examinations. For 2004 data, 23.8%, 2.3%, and 6.9% of sites reported doses above the 2002 CTDI w reference levels, compared with 49.6%, 4.7%, and 15% for 2002 data for adult head, adult abdominal, and pediatric abdominal examinations, respectively. Seventy-fifth percentiles of CTDI vol were 76.8 mGy (adult head, 2002 only), 22.2 mGy (adult abdominal), and 20.0 mGy (pediatric abdominal). Conclusions From 2002 to 2004, average CTDI vol values decreased by 10.9, 1.7, and 3.2 mGy for adult head, adult abdominal, and pediatric abdominal examinations. Effective January 1, 2008, the ACR program implemented United States-specific diagnostic reference levels of 75, 25, and 20 mGy, respectively, for the CTDI vol of routine adult head, adult abdominal, and pediatric abdominal CT scans.

The National Lung Screening Trial (NLST) is a randomized multicenter study comparing low-dose helical computed tomography (CT) with chest radiography in the screening of older current and former heavy smokers for early detection of lung cancer, which is the leading cause of cancer-related death in the United States. Five-year survival rates approach 70% with surgical resection of stage IA disease; however, more than 75% of individuals have incurable locally advanced or metastatic disease, the latter having a 5-year survival of less than 5%. It is plausible that treatment should be more effective and the likelihood of death decreased if asymptomatic lung cancer is detected through screening early enough in its preclinical phase. For these reasons, there is intense interest and intuitive appeal in lung cancer screening with low-dose CT. The use of survival as the determinant of screening effectiveness is, however, confounded by the well-described biases of lead time, length, and overdiagnosis. Despite previous attempts, no test has been shown to reduce lung cancer mortality, an endpoint that circumvents screening biases and provides a definitive measure of benefit when assessed in a randomized controlled trial that enables comparison of mortality rates between screened individuals and a control group that does not undergo the screening intervention of interest. The NLST is such a trial. The rationale for and design of the NLST are presented.

The high rainfall mega-environment [mega environment 2 (ME2)], characterized by more than 500 mm rainfall during wheat season, is one of the 12 mega-environments on which the global wheat breeding program of the International Maize and Wheat Improvement Center (CIMMYT) has been assembling and distributing high rainfall wheat yield trials (HRWYT) since 1992. In this study, our objectives were to evaluate the adaptation and performance of entries included in the 1st through the 12th HRWYT (1992-2004), identify best lines as parents for crossing and recommend for direct release by the National Agricultural Research Systems (NARS), and test the association among sites and determine yield progress in HRWYTs. Combined ANOVA across locations for grain yield showed highly significant difference among genotypes and genotype x environment interactions (p < 0.001) for each of the HRWYTs. At regional level, wide range of yield variability was observed in Africa (0.69-9.614 t ha ―1 ) followed by Asia (0.389-6.93 t ha ―1 ) with the highest mean yields in Europe (4.392 t ha ―1 ). Two widely grown mega-cultivars have been developed from Attila cross: entry number 4 (CM85836-4Y-0M-0Y-8M-0Y) from 1stHRWYT, which is released as PBW343 in India, and entry number 48 from 4thHRWYT (CM85836-50Y-0M-0Y-3M-0Y), which is released in Ethiopia, Tunisia, Iran, Pakistan, and Sudan with local names of Kubsa, Utique96, Chamran, MH97, and Imam, respectively. There is a significant positive association between plant height and grain yield in rain-fed environments whereas the association between heading dates and yield is location specific indicating the importance of selecting broad range of materials for heading date at the main station in Mexico. Correlation analysis shows that the sites giving the best prediction of global performance are Marcos Juarez (Argentina), Pergamino (Argentina), Izmir (Turkey), Bethlehem (South Africa), Sakha (Egypt), and Tassaout (Morocco). In each year, it was possible to find a line out yielding the local check in at least 52% of the sites. However, at the trial level, lines were beating the local checks more frequently in the first trials than in the last trials. Regular assessment of the current and future HRWYTs in terms of adaptation, resistance, diversity, and quality will be of paramount importance in improving the breeding process.

The Acute neurology unit (ANU), located at the Royal Hallamshire Hospital, Sheffield is a regional centre for a population of approximately 1.5 million. We are unusual, as our neurologists manage both hyperacute stroke and hyperacute neurology. HASU is located within our ANU. We had 4026 neurology ward admissions, 3265 emergency cases and 761 elective cases last year. We receive acute admissions from Trust A and E, direct admissions from general practitioners and urgent transfers from DGHs.We provide 24 hour stroke thrombolysis and a weekday working hours thrombectomy service. Overnight thrombolysis is supervised through a regional ‘Telemedicine’ system. A 2 week survey in July 2017 showed that only 59% patients, who were referred with suspected stroke, had stroke/TIA. Neurological conditions, such as migraine, seizure, syncope, acute vestibulopathy, Bell’s palsy and medically unexplained symptoms were common ‘stroke mimics’. 46% of patients with ‘stroke mimic’ were discharged on the day of admission. Average length of stay was 3 days. A separate survey of acute neurology referrals showed that 58% of patients did not require admission and were managed through an ambulatory care pathway. Patient satisfaction regarding their rapid assessment and diagnosis was high. Co-location of ANU and HASU allows rapid and effective management of ‘stroke mimics’.

The International Adaptation Trial (IAT) is a special purpose nursery designed to investigate the genotype-by-environment interactions and worldwide adaptation for grain yield of Australian and CIMMYT spring bread wheat (Triticum aestivum L.) and durum wheat (T. turgidum L. var. durum). The IAT contains lines representing Australian and CIMMYT wheat breeding programs and was distributed to 91 countries between 2000 and 2004. Yield data of 41 reference lines from 106 trials were analysed. A multiplicative mixed model accounted for trial variance heterogeneity and inter-trial correlations characteristic of multi-environment trials. A factor analytic model explained 48% of the genetic variance for the reference lines. Pedigree information was then incorporated to partition the genetic line effects into additive and non-additive components. This model explained 67 and 56% of the additive by environment and non-additive by environment genetic variances, respectively. Australian and CIMMYT germplasm showed good adaptation to their respective target production environments. In general, Australian lines performed well in south and west Australia, South America, southern Africa, Iran and high latitude European and Canadian locations. CIMMYT lines performed well at CIMMYT's key yield testing location in Mexico (CIANO), north-eastern Australia, the Indo-Gangetic plains, West Asia North Africa and locations in Europe and Canada. Maturity explained some of the global adaptation patterns. In general, southern Australian germplasm were later maturing than CIMMYT material. While CIANO continues to provide adapted lines to northern Australia, selecting for yield among later maturing CIMMYT material in CIANO may identify lines adapted to southern and western Australian environments.

Identifying and mobilizing useful genetic variation from germplasm banks to breeding programs is an important strategy for sustaining crop genetic improvement. The molecular diversity of 1,423 spring bread wheat accessions representing major global production environments was investigated using high quality genotyping-by-sequencing (GBS) loci, and gene-based markers for various adaptive and quality traits. Mean diversity index (DI) estimates revealed synthetic hexaploids to be genetically more diverse (DI= 0.284) than elites (DI = 0.267) and landraces (DI = 0.245). GBS markers discovered thousands of new SNP variations in the landraces which were well known to be adapted to drought (1273 novel GBS SNPs) and heat (4473 novel GBS SNPs) stress environments. This may open new avenues for pre-breeding by enriching the elite germplasm with novel alleles for drought and heat tolerance. Furthermore, new allelic variation for vernalization and glutenin genes was also identified from 47 landraces originating from Iraq, Iran, India, Afghanistan, Pakistan, Uzbekistan and Turkmenistan. The information generated in the study has been utilized to select 200 diverse gene bank accessions to harness their potential in pre-breeding and for allele mining of candidate genes for drought and heat stress tolerance, thus channeling novel variation into breeding pipelines. This research is part of CIMMYT’s ongoing ‘Seeds of Discovery’ project visioning towards the development of high yielding wheat varieties that address future challenges from climate change.

Established by the Metabolomics Society, 2014 saw the Early Members Network (EMN) celebrate its first birthday. Initially run by nine early career researchers, forming the EMN-committee, the official EMN mission was to recognize the value and importance of early career members, to ensure that their views are heard and acted upon, ultimately improving their experience of metabolomics science and the community as a whole (Putri 2014). Dedicated to all Metabolomics Society members who are within 5 years of completing their higher degrees, the EMN has started to make significant strides to achieve its vision to establish a real sense of community and engagement between early career researchers globally through leading initiative and enthusiastic appearance. Past activities of 2014

With the expanding costs of providing a reliable facility infrastructure, eliminating single points of failure and achieving Tier 3 or 4 status in the datacenter, alternate approaches must be considered. This paper will discuss and present an integration of facility infrastructure and IT communications within different Tier classes of datacenters to provide a cost savings solution for the development of datacenters while still maintaining operational readiness.

Recent developments have permitted accurate seed placement and dosimetry for interstitial brachytherapy of selected patients with localized prostate cancer. We present our experience with 76 patients divided into 2 groups. Group 1 included 45 patients with smaller, more well differentiated tumors, usually less than 2 cm. in diameter on digital rectal examination or transrectal ultrasound and a Gleason score of less than 7 who were treated with 125 iodine alone. Group 2 consisted of 31 patients with localized tumors greater than 2 cm. in diameter and/or a Gleason sum equal to or greater than 7 who were treated with low dose external beam radiation followed by 125 iodine boost 4 weeks later. Complete clinical progression-free survival, including prostate specific antigen, digital rectal examination and biopsy, was 51% for group 1 and 63.3% for group 2, with a mean followup of 26.3 months. Prostate specific antigen progression-free survival was 97.7% for group 1 and 94.7% for group 2.These results ap...

Objectives The aim of this study was to evaluate the therapeutic potential of human skeletal muscle-derived myoendothelial cells for myocardial infarct repair.Background We have recently identified and purified a novel population of myoendothelial cells from human skeletal muscle. These cells coexpress myogenic and endothelial cell markers and produce robust muscle regeneration when injected into cardiotoxin-injured skeletal muscle.Methods Myoendothelial cells were isolated from biopsies of human skeletal muscle using a fluorescence-activated cell sorter along with populations of regular myoblasts and endothelial cells. Acute myocardial infarction was induced in male immune-deficient mice, and cells were directly injected into the ischemic area. Cardiac function was assessed by echocardiography, and donor cell engraftment, angiogenesis, scar tissue, endogenous cardiomyocyte proliferation, and apoptosis were all evaluated by immunohistochemistry.Results A greater improvement in left ventricular function was observed after intramyocardial injection of myoendothelial cells when compared with that seen in hearts injected with myoblast or endothelial cells. Transplanted myoendothelial cells generated robust engraftments within the infarcted myocardium, and also stimulated angiogenesis, attenuation of scar tissue, and proliferation and survival of endogenous cardiomyocytes more effectively than transplanted myoblasts or endothelial cells.Conclusions Our findings suggest that myoendothelial cells represent a novel cell population from human skeletal muscle that may hold promise for cardiac repair. (J Am Coll Cardiol 2008; 52: 1869-80) (c) 2008 by the American College of Cardiology Foundation

Objectives We investigated whether vascular endothelial growth factor (VEGF) was associated with the angiogenic and therapeutic effects induced after transplantation of skeletal muscle-derived stem cells (MDSCs) into a myocardial infarction (MI). Background Because very few MDSCs were found to differentiate into new blood vessels when injected into the heart, the mechanism underlying the occurrence of angiogenesis after MDSC transplantation is currently unknown. In the present study, we used a gain- or loss-of-VEGF function approach with skeletal MDSCs engineered to express VEGF or soluble Flt1, a VEGF-specific antagonist, to identify the involvement of VEGF in MDSC transplantation-induced neoangiogenesis. Methods Vascular endothelial growth factor- and soluble Flt1-engineered MDSCs were injected into an acute MI. Angiogenesis and cardiac function were evaluated by immunohistochemistry and echocardiography. Results Both control and VEGF-overexpressing MDSCs induced angiogenesis, prevented adverse cardiac remodeling, and improved function compared with saline-injected hearts. However, these therapeutic effects were diminished in hearts transplanted with MDSCs expressing soluble Flt1 despite successful cell engraftment. In vitro experiments demonstrated that MDSCs increased secretion of VEGF in response to hypoxia and cyclic stretch (likely conditions in ischemic hearts), suggesting that transplanted MDSCs release VEGF in vivo. Conclusions Our findings suggest that VEGF is essential for the induction of angiogenesis and functional improvements observed after MDSC transplantation for infarct repair.

Image quality is proportional to radiation dose. Improvements in image quality come at a cost of increased radiation dose. CT scanners are more robust today than even 5 years ago. X-ray tubes are capable of producing high levels of almost continuous radiation for rapid CT volume acquisitions and angiographic studies. All parameters of modern CT scanners provide rapid subsecond, large-volume CT acquisitions. How high we go needs to be tempered by how high we should go regarding radiation dose from CT examinations. Radiologists, referring physicians, medical physicists, CT technologists, CT equipment manufacturers, and regulators need to evaluate the appropriateness of radiation dose for different CT studies.

The ACR CT accreditation program, begun in 2002, requires the submission of approximately 20 images, several completed data sheets and printouts of three Excel worksheets. The procedure manual is very detailed, yet participants unfamiliar with the program or having minimal CT experience have needed to redo aspects of their submission, or in some cases do not receive accreditation, due to mistakes made by the physicist. This review of the phantom portion of the ACR CT accreditation program supplements the ACR provided instructions with additional photos of phantom setup, region-of-interest (ROI), and image placement on the film sheets, and examples of completed portions of actual (but anonymous) submissions. Common mistakes, as well as uncommon but interesting images, are shown and explanations are given as to what could have been done to avoid the problem. Additionally, a review of CT dose measurement techniques and calculations will enable the physicist to better assist sites where typical exam doses are above the ACR reference values.