Showing papers by "The Hertz Corporation published in 2016"

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk

Abstract: To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.

A SNP-based consensus genetic map for synteny-based trait targeting in faba bean (Vicia faba L.)

Abstract: Summary Faba bean (Vicia faba L.) is a globally important nitrogen-fixing legume, which is widely grown in a diverse range of environments. In this work, we mine and validate a set of 845 SNPs from the aligned transcriptomes of two contrasting inbred lines. Each V. faba SNP is assigned by BLAST analysis to a single Medicago orthologue. This set of syntenically anchored polymorphisms were then validated as individual KASP assays, classified according to their informativeness and performance on a panel of 37 inbred lines, and the best performing 757 markers used to genotype six mapping populations. The six resulting linkage maps were merged into a single consensus map on which 687 SNPs were placed on six linkage groups, each presumed to correspond to one of the six V. faba chromosomes. This sequence-based consensus map was used to explore synteny with the most closely related crop species, lentil and the most closely related fully sequenced genome, Medicago. Large tracts of uninterrupted colinearity were found between faba bean and Medicago, making it relatively straightforward to predict gene content and order in mapped genetic interval. As a demonstration of this, we mapped a flower colour gene to a 2-cM interval of Vf chromosome 2 which was highly colinear with Mt3. The obvious candidate gene from 78 gene models in the collinear Medicago chromosome segment was the previously characterized MtWD40-1 gene controlling anthocyanin production in Medicago and resequencing of the Vf orthologue showed a putative causative deletion of the entire 5′ end of the gene.

An overview of the main pathways of metabolic resistance in insects

Abstract: Insecticides have played and still fulfil a very important role in sustainable production of food, animal feed and also as protection against disease vectors. They act to suppress insect populations and, as a consequence of their use, insecticide resistance has evolved. An overview of insecticide resistance mechanisms in insects is given, focusing on the metabolic systems involved in xenobiotic metabolism in the class Insecta. Several enzyme families (e.g., esterases, mixed function oxidases, glutathione S-transferases) are involved in insecticide detoxification, sequestration and excretion and have differing relative importance within the various taxonomic groups. A brief discussion of their impact on control strategies is given.

Inherited erythromelalgia due to mutations in SCN9A: natural history, clinical phenotype and somatosensory profile.

Abstract: Inherited erythromelalgia, the first human pain syndrome linked to voltage-gated sodium channels, is widely regarded as a genetic model of human pain. Because inherited erythromelalgia was linked to gain-of-function changes of sodium channel Nav1.7 only a decade ago, the literature has mainly consisted of reports of genetic and/or clinical characterization of individual patients. This paper describes the pattern of pain, natural history, somatosensory profile, psychosocial status and olfactory testing of 13 subjects with primary inherited erythromelalgia with mutations of SCN9A , the gene encoding Nav1.7. Subjects were clinically profiled using questionnaires, quantitative sensory testing and olfaction testing during the in-clinic phase of the study. In addition, a detailed pain phenotype for each subject was obtained over a 3-month period at home using diaries, enabling subjects to self-report pain attacks, potential triggers, duration and severity of pain. All subjects reported pain and heat in the extremities (usually feet and/or hands), with pain attacks triggered by heat or exercise and relieved mainly by non-pharmacological manoeuvres such as cooling. A large proportion of pain attacks (355/1099; 32%) did not involve a specific trigger. There was considerable variability in the number, duration and severity of pain attacks between subjects, even those carrying the same mutation within a family, and within individuals over the 12–13 week observation period. Most subjects (11/13) had pain between attacks. For these subjects, mean pain severity between pain attacks was usually lower than that during an attack. Olfaction testing using the Sniffin’T test did not demonstrate hyperosmia. One subject had evidence of orthostatic hypotension. Overall, there was a statistically significant correlation between total Hospital Anxiety and Depression Scale scores ( P = 0.005) and pain between attacks and for Hospital Anxiety and Depression Scale Depression scores and pain between attacks ( P = 0.001). Hospital Anxiety and Depression Scale scores for five subjects were below the threshold for mild anxiety or depression and none of the 13 subjects were severely anxious and/or depressed. Quantitative sensory testing revealed significantly increased detection thresholds for cold and warm stimuli at affected, compared to unaffected sites. By contrast, significantly decreased cold and heat pain thresholds were found at unaffected sites. Sensory profiles varied considerably between affected and unaffected sites, suggesting the existence of small fibre neuropathy in symptomatic sites. This in-depth clinical characterization of a well-defined inherited erythromelalgia population indicates the importance of characterizing the pain phenotype in individuals before undertaking clinical trials, given the inherent variability of pain both between and within inherited erythromelalgia subjects, even those within a family who carry the same mutation. * Abbreviations : HADS : Hospital Anxiety and Depression Scale IEM : inherited erythromelalgia NRS : Numerical Rating Scale PCS : Pain Catastrophizing Questionnaire QST : quantitative sensory testing

Is food allergen analysis flawed? Health and supply chain risks and a proposed framework to address urgent analytical needs

Abstract: Food allergy is an increasing problem for those affected, their families or carers, the food industry and for regulators. The food supply chain is highly vulnerable to fraud involving food allergens, risking fatalities and severe reputational damage to the food industry. Many facets are being pursued to ameliorate the difficulties including better food labelling and the concept of thresholds of elicitation of allergy symptoms as risk management tools. These efforts depend to a high degree on the ability reliably to detect and quantify food allergens; yet all current analytical approaches exhibit severe deficiencies that jeopardise accurate results being produced particularly in terms of the risks of false positive and false negative reporting. If we fail to realise the promise of current risk assessment and risk management of food allergens through lack of the ability to measure food allergens reproducibly and with traceability to an international unit of measurement, the analytical community will have failed a significant societal challenge. Three distinct but interrelated areas of analytical work are urgently needed to address the substantial gaps identified: (a) a coordinated international programme for the production of properly characterised clinically relevant reference materials and calibrants for food allergen analysis; (b) an international programme to widen the scope of proteomics and genomics bioinformatics for the genera containing the major allergens to address problems in ELISA, MS and DNA methods; (c) the initiation of a coordinated international programme leading to reference methods for allergen proteins that provide results traceable to the SI. This article describes in more detail food allergy, the risks of inapplicable or flawed allergen analyses with examples and a proposed framework, including clinically relevant incurred allergen concentrations, to address the currently unmet and urgently required analytical requirements. Support for the above recommendations from food authorities, business organisations and National Measurement Institutes is important; however transparent international coordination is essential. Thus our recommendations are primarily addressed to the European Commission, the Health and Food Safety Directorate, DG Sante. A global multidisciplinary consortium is required to provide a curated suite of data including genomic and proteomic data on key allergenic food sources, made publically available on line.

The INNs and outs of antibody nonproprietary names.

Abstract: An important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a -mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies.

Implementation of antimicrobial stewardship interventions recommended by national toolkits in primary and secondary healthcare sectors in England: TARGET and Start Smart Then Focus

Abstract: Objectives: To assess and compare the implementation of antimicrobial stewardship (AMS) interventions recommended within the national AMS toolkits, TARGET and Start Smart Then Focus, in English primary and secondary healthcare settings in 2014, to determine the prevalence of cross-sector engagement to drive AMS interventions and to propose next steps to improve implementation of AMS. / Methods: Electronic surveys were circulated to all 211 Clinical Commissioning Groups (CCGs; primary sector) and to 146 (out of the 159) Acute Trusts (secondary sector) in England. Response rates were 39% and 68% for the primary and secondary sectors respectively. / Results: The majority of CCGs and Acute Trusts reported reviewing national AMS toolkits formally or informally (60% and 86% respectively). However, only 13% of CCGs and 46% of Acute NHS Trusts had developed an action plan for the implementation of these toolkits. Only 5% of CCGs had antimicrobial pharmacists in post; however the role of specialist antimicrobial pharmacists continued to remain embedded within Acute Trusts with 83% of responding Trusts having an antimicrobial pharmacist at a senior grade. / Conclusions: Review of national AMS toolkits in primary and secondary care is high; however implementation of the toolkits, through the development of action plans to deliver AMS interventions, requires improvement. For the first time, we report the extent of cross-sector and multidisciplinary collaboration to deliver AMS interventions in both primary and secondary care sectors in England. Results highlight that further qualitative and quantitative work is required to explore mutual benefits and promote best practice. Antimicrobial pharmacists remain leaders for implementing AMS interventions across both primary and secondary healthcare sectors.

Object storage, handling, and retrieving system and method

Abstract: A storage system may comprise a frame 14 containing stacks of containers 10, and a plurality of load handling devices (30, fig 4) above the frame rails 14, independently moveable to access different container stacks. Containers 10, e.g. frequently used containers, may be temporarily stored in a sequencing portion 160 (140 of fig 5; 12/170 of fig 8a; fig 9a; 360 of fig 11) and conveyed to workstation 120 in a predetermined order, irrespective of the order in which they reached a drop off point in the sequencing portion 160. Sequencing portion 160 may have moving means (e.g. a conveyor) to move a container (10, fig 4) to an output port of the sequencing portion 160 under the control of a computer utility, when required. The frame grid 14 may have two sets of rails, each set in a perpendicular direction to the other. The load handling devices (30, fig 4) may have two sets of wheels, each wheel set for engaging respective each set of rails 14.

Prediction of high naevus count in a healthy U.K. population to estimate melanoma risk.

Abstract: Summary Background Despite recent discoveries of germline and somatic mutations in melanoma, naevus count remains the most important risk factor for melanoma. Counting naevi on the whole body is time consuming. In order to identify patients at risk for melanoma, many studies have used naevus count on selected body sites as a proxy for total body naevus count (TBNC). Objectives The main aim of this study was to assess the predictive value of naevus count on 17 different body sites in estimating TBNC in a large cohort of healthy U.K. Caucasian female subjects. Once the site with the best predictive value for TBNC was determined, a second aim was to estimate the cut-off values of naevus counts at this anatomical site that best predict the presence of 50 or 100 naevi, respectively. Methods The most predictive body site for TBNC was assessed in a cohort of healthy female twins. This finding was replicated on a control group from a U.K. case–control study and a prediction model was performed afterwards. The area under the receiver operating characteristics curve was used to evaluate the best cut-off for the prediction of having a TBNC of more than 50 or 100. Results There were 3694 female twins included. The TBNC showed a steady decline after the age of 30 years (P < 0·001). The most predictive sites for TBNC were the arms and legs: the adjusted correlation coefficients were 0·50 and 0·51 (P < 0·001) for the right and left arm, respectively, and 0·49 and 0·48 for the right and left legs, respectively (P < 0·001). The arm remained the most predictive site for TBNC when replicated in a control population including both sexes. In the twin study, women with more than 11 naevi on the right arm were approximately nine times more likely to have more than 100 naevi (odds ratio = 9·38, 95% confidence interval 6·71–13·11). Conclusions The ability to estimate TBNC quickly by counting naevi on one arm could be a very useful tool in assessing melanoma risk in primary care.

Evidence of improved fluid management in patients receiving haemodialysis following a self-affirmation theory-based intervention: A randomised controlled trial.

Abstract: Objective: Haemodialysis patients are at risk of serious health complications; yet, treatment non-adherence remains high. Warnings about health risks associated with non-adherence may trigger defensive reactions. We studied whether an intervention based on self-affirmation theory reduced resistance to health-risk information and improved fluid treatment adherence.Design: In a cluster randomised controlled trial, 91 patients either self-affirmed or completed a matched control task before reading about the health-risks associated with inadequate fluid control.Outcome measures: Patients’ perceptions of the health-risk information, intention and self-efficacy to control fluid were assessed immediately after presentation of health-risk information. Interdialytic weight gain (IDWG), excess fluid removed during haemodialysis, is a clinical measure of fluid treatment adherence. IDWG data were collected up to 12 months post-intervention.Results: Self-affirmed patients had significantly reduced IDWG levels over 12 ...

GPCR-Bench: A Benchmarking Set and Practitioners’ Guide for G Protein-Coupled Receptor Docking

Abstract: Virtual screening is routinely used to discover new ligands and in particular new ligand chemotypes for G protein-coupled receptors (GPCRs). To prepare for a virtual screen, we often tailor a docking protocol that will enable us to select the best candidates for further screening. To aid this, we created GPCR-Bench, a publically available docking benchmarking set in the spirit of the DUD and DUD-E reference data sets for validation studies, containing 25 nonredundant high-resolution GPCR costructures with an accompanying set of diverse ligands and computational decoy molecules for each target. Benchmarking sets are often used to compare docking protocols; however, it is important to evaluate docking methods not by “retrospective” hit rates but by the actual likelihood that they will produce novel prospective hits. Therefore, docking protocols must not only rank active molecules highly but also produce good poses that a chemist will select for purchase and screening. Currently, no simple objective machine-...

What Is New in Melanoma Genetics and Treatment

Abstract: New therapies for advanced melanoma have led to major advances, which, for the first time, showed improved survival for patients with this very challenging neoplasm. These new treatments are based on gene-targeted therapies or stimulation of immune responses. However, these treatments are not without challenges in terms of resistance and toxicity. Physicians should be aware of these side effects as prompt treatment may save lives. Melanoma genetics is also unravelling new genetic risk factors involving telomere genes as well as new gene pathways at the somatic level which may soon become therapeutic targets. It is also shedding new light onto the pathology of this tumour with links to neural diseases and longevity.

Identification of Ligand Binding Hot Spots of the Histamine H1 Receptor following Structure-Based Fragment Optimization.

Abstract: Developments in G protein-coupled receptor (GPCR) structural biology provide insights into GPCR-ligand binding. Compound 1 (4-(2-benzylphenoxy)piperidine) with high ligand efficiency for the histamine H1 receptor (H1R) was used to design derivatives to investigate the roles of (i) the amine-binding region, (ii) the upper and lower aromatic region, and (iii) binding site solvation. SAR analysis showed that the amine-binding region serves as the primary binding hot spot, preferably binding small tertiary amines. In silico prediction of water network energetics and mutagenesis studies indicated that the displacement of a water molecule from the amine-binding region is most likely responsible for the increased affinity of the N-methylated analog of 1. Deconstruction of 1 showed that the lower aromatic region serves as a secondary binding hot spot. This study demonstrates that an X-ray structure in combination with tool compounds, assessment of water energetics, and mutagenesis studies enables SAR exploration ...

Clinical outcomes from The BodyMind Approach™ in the treatment of patients with medically unexplained symptoms in primary health care in England: Practice-based evidence

Abstract: This is the accepted manuscript version of the following article: Helen Payne and Susan D. M. Brooks, ‘Clinical outcomes from The BodyMind Approach™ in the treatment of patients with medically unexplained symptoms in primary health care in England: Practice-based evidence’, The Arts in Psychotherapy, Vol 47: 55-65, February 2016, doi: http://dx.doi.org/10.1016/j.aip.2015.12.001. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/.

Management of adults with diabetes on the haemodialysis unit: summary of new guidance from the Joint British Diabetes Societies (JBDS) and the Renal Association

Abstract: Diabetic nephropathy remains the principal cause of end-stage renal failure (ESRF) in the UK, as elsewhere in the developed world, and its prevalence is set to increase. People with diabetes and ESRF on maintenance haemodialysis are a highly vulnerable group, often with complex comorbidities, who are at high risk of adverse cardiovascular outcomes, which is the leading cause of mortality in this population. The management of people with diabetes receiving maintenance haemodialysis is shared between diabetes and renal specialist teams and the primary care team, with input from additional healthcare professionals providing foot care, dietary support and other aspects of multidisciplinary care. In this setting, one specialty may assume that key aspects of care are being provided elsewhere, which can lead to important components of care being overlooked. People with diabetes and ESRF require improved delivery of care to overcome organisational difficulties and barriers to communication between healthcare teams. No comprehensive guidance on the management of this population has previously been produced. These national guidelines, the first in this area, bring together in one document the disparate needs of the diabetes patient on maintenance haemodialysis. The guideline is based on the best available evidence, or on expert opinion where there is no clear evidence to inform practice. We aim to provide clear advice to clinicians caring for this vulnerable population and to encourage and improve education for clinicians and patients to promote patient empowerment and self-management.

A HER2 selective theranostic agent for surgical resection guidance and photodynamic therapy

Abstract: In many cancers early intervention involves surgical resection of small localised tumour masses. Inadequate resection leads to recurrence whereas overzealous treatment can lead to organ damage. This work describes production of a HER2 targeting antibody Fab fragment dual conjugated to achieve both real time near-infrared fluorescent imaging and photodynamic therapy. The use of fluorescence emission from a NIR-dye could be used to guide resection of tumour bulk, for example during endoscopic diagnosis for oesophago-gastric adenocarcinoma, this would then be followed by activation of the photodynamic therapeutic agent to destroy untreated localised areas of cancer infiltration and tumour infiltrated lymph nodes. This theranostic agent was prepared from the Fab fragment of trastuzumab initially by functional disulfide re-bridging and site-specific click reaction of a NIR-dye. This was followed by further reaction with a novel pre-activated form of the photosensitiser chlorin e6 with the exposed fragments’ lysine residues. Specific binding of the theranostic agent was observed in vitro with a HER2 positive cell line and cellular near-infrared fluorescence was observed with flow cytometry. Specific photo-activity of the conjugates when exposed to laser light was observed with HER2 positive but not HER2 negative cell lines in vitro, this selectivity was not seen with the unconjugated drug. This theranostic agent demonstrates that two different photo-active functions can be coupled to the same antibody fragment with little interference to their independent activities.

Storage systems and methods

Abstract: A storage system comprising a framework 14 made up of uprights 16 supporting a grid network of horizontal rails or tracks 18, 20, a plurality of storage containers 10 arranged in stacks 12 within the framework and at least one load handling device 30 disposed on the grid and movable laterally above the stacks on the rails to lift one or more containers, or parts thereof, from a stack, wherein the framework comprises service means for providing services to the storage system enabling interaction, control and monitoring thereof from within the framework. The services may include power supply, power control, heating, cooling, lighting, sensing and data logging and transfer. Accordingly, the service means may include electric cables, magnetic or radiofrequency induction, lights (60, fig. 5b), water or gas pipes (19, fig. 5b), sprinklers, fire or smoke detectors, cameras (CCD) etc. Each container may bear an identification label detectable by suitable sensors e.g. barcode readers. The containers may also have a reservoir acting as a fluid sink. A method of condition monitoring a storage system by providing sensor and data logging means, as well as means to communicate the data to a central data logging and monitoring device is also claimed.

Screening of Cognitive Impairment in Schizophrenia: Reliability, Sensitivity, and Specificity of the Repeatable Battery for the Assessment of Neuropsychological Status in a Spanish Sample

Abstract: Background. In recent years, a number of studies focusing on the evaluation of neuropsychological deficits in individuals with schizophrenia have shown deficits that include several cognitive functions. Attention deficits as well as memory or executive function deficits are common in this kind of disorder together with sustained attention problems, working memory deficiencies, and problem-solving difficulties, among many others. Currently, the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) is gaining special importance in the evaluation of the cognitive deficits associated with schizophrenia. Method. In this article, we describe an RBANS screening in a sample of 88 Spanish patients diagnosed with schizophrenia. We also aimed to check the battery’s reliability, sensitivity, and specificity in the studied sample. We performed a comparative study with 88 healthy participants. Results. The results showed a reliability index value of α = .795 and an item value of α = .762. For total...

‘Acceptability’ of a new oral suspension formulation of mercaptopurine in children with acute lymphoblastic leukaemia

Abstract: AimThe aim of this questionnaire-based survey was to determine the ‘acceptability’ of Xaluprine®, a new oral liquid formulation of mercaptopurine, when administered chronically to children during the maintenance treatment phase of acute lymphoblastic leukaemia.Patients and methodsThis was a single centre survey of children (aged 3 to 16 years) and their parents at a routine follow-up visit during the maintenance phase of acute lymphoblastic leukaemica treatment. The questionnaire probed for their views on overall acceptability such as taste, smell, incidences of vomiting, ease and willingness to take Xaluprine® on a daily basis, and utilised a 5-point facial hedonic scale (1 = bad, 5 = good) as well as open/closed questions.ResultsTwenty-two children were recruited; 17 (77%) scored taste between 3 and 5 (‘okay’ to ‘good’) and 20 (91%) scored smell between 3 and 5. Only four children (18%) reported an aftertaste. Of the five children (23%) who scored taste as 1 or 2 (‘bad’), three found taking all oral med...