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Stereotactic radiosurgery (SRS) has proven itself as an effective tool in the treatment of intracranial lesions. Image-guided high dose single fraction treatments have the potential to deliver ablative doses to tumours; however, treatment times can be long. Flattening filter free (FFF) beams are available on most modern linacs and offer a higher dose rate compared to conventional flattened beams which should reduce treatment times. This study aimed to compare 6 MV FFF and 10 MV FFF to a 6 MV flattened beam for single fraction dynamic conformal arc SRS for a Varian Truebeam linac.
Materials and methods:
In total, 21 individual clinical treatment plans for 21 brain metastases treated with 6 MV were retrospectively replanned using both 6 MV FFF and 10 MV FFF. Plan quality and efficiency metrics were evaluated by analysing dose coverage, dose conformity, dose gradients, dose to normal brain, beam-on-time (BOT), treatment time and monitor units.
FFF resulted in a significant reduction in median BOT for both 6 MV FFF (57·9%; p < 0·001) and 10 MV FFF (76·3%; p < 0·001) which led to reductions in treatment times of 16·8 and 21·5% respectively. However, 6 MV FFF showed superior normal brain dose sparing (p < 0·001) and dose gradient (p < 0·001) compared to 10 MV FFF. No differences were observed for conformity.
6 MV FFF offers a significant reduction in average treatment time compared to 6 MV (3·7 minutes; p = 0·002) while maintaining plan quality.
Sensing of nutrients by chemosensory cells in the gastrointestinal tract plays a key role in transmitting food-related signals, linking information about the composition of ingested foods to digestive processes. In recent years, a number of G protein-coupled receptors (GPCR) responsive to a range of nutrients have been identified. Many are localised to intestinal enteroendocrine (chemosensory) cells, promoting hormonal and neuronal signalling locally, centrally and to the periphery. The field of gut sensory systems is relatively new and still evolving. Despite huge interest in these nutrient-sensing GPCR, both as sensors for nutritional status and targets for preventing the development of metabolic diseases, major challenges remain to be resolved. However, the gut expressed sweet taste receptor, resident in L-enteroendocrine cells and responsive to dietary sweetener additives, has already been successfully explored and utilised as a therapeutic target, treating weaning-related disorders in young animals. In addition to sensing nutrients, many GPCR are targets for drugs used in clinical practice. As such these receptors, in particular those expressed in L-cells, are currently being assessed as potential new pathways for treating diabetes and obesity. Furthermore, growing recognition of gut chemosensing of microbial-produced SCFA acids has led further attention to the association between nutrition and development of chronic disorders focusing on the relationship between nutrients, gut microbiota and health. The central importance of gut nutrient sensing in the control of gastrointestinal physiology, health promotion and gut–brain communication offers promise that further therapeutic successes and nutritional recommendations will arise from research in this area.
To compare Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopy (1H-MRS) between people with Alzheimer's disease (AD) and mild cognitive impairment (MCI).
AD is characterised by cognitive impairment. 10-15% of people with MCI progress to dementia each year. The hippocampus is involved in memory functioning and is one of the brain regions first affected by AD. MRI based hippocampal volumetric measurement enables accurate quantification of atrophy. In addition, 1H-MRS can be used to measure concentrations of brain metabolites including myoinositol (mI) and N-acetylaspartate (NAA). NAA is a proxy measure of neuronal density.
Subjects with AD (n=46), MCI (n=28) and controls (n=39) were scanned using a 1.5 Tesla MR system. Manual tracing of hippocampal volumes was undertaken using Measure software. 1H-MRS voxels of interest were defined in the left and right hippocampi. A point-resolved spectroscopy pulse sequence produced spectra from each voxel and clearly resolved NAA and mI peaks. Statistical analysis was undertaken using SPSS15.
Hippocampal volumes were significantly reduced between AD and controls (p=0.003) and between AD and MCI (p=0.001). Compared to controls, individuals with AD and MCI had a significant reduction in [NAA]. MCI showed a non-significant increase in [mI]. A positive relationship was found between hippocampal volume and [NAA] and between hippocampal volume and [mI] for MCI.
AD is associated with decreased viable neuronal density/function (as measured by NAA) and a reduction in hippocampal volume associated with impaired cognitive functioning. The elevated [mI] in MCI may be a “tipping point” into dementia.
To compare Magnetic Resonance Imaging (MRI) findings in Alzheimer's dementia (AD) in the general population with Down's syndrome dementia.
Background review: AD is characterised by cognitive dysfunction interfering with activities of daily living. Mild cognitive impairment (MCI) is an intermediate state between normal aging and dementia. People with Down's syndrome have an increased risk of developing AD. AD pathology initially appears in the entorhinal cortex, followed by the hippocampus and later in the temporal lobes. These areas are critical for memory functioning.
Volumetric analysis was performed on MRI brain scans using Measure software. Manual tracing was undertaken for the hippocampus, temporal lobes and lateral ventricles as well as the total brain volume of the cerebral hemispheres and cerebellum. Brain volumes were normalised as a percentage of traced intracranial volumes. Freesurfer software was used to obtain entorhinal cortical thickness measures. Statistical analysis was undertaken using SPSS15.
Subjects with AD (n=46), MCI (n=28) and controls (n=39) were compared with Down's syndrome demented subjects (DS+, n=20), non-demented subjects with Down's syndrome (DS-, n=45) and age-matched controls (n=43). Hippocampi, entorhinal cortex and temporal lobes were significantly reduced in AD and DS+ compared to controls. Lateral ventricles were significantly increased in AD and DS+ compared to controls. MCI and DS- produced findings between those of dementia and controls.
Critical memory regions atrophy in dementia corresponding to decreased cognitive functioning. DS+ morphology is comparable to AD in the general population but the atrophy is less pronounced.
To obtainconsensus from non-consultant hospital doctors and consultants indeveloping a eLearning module for teaching non-consultant hospital doctorsabout delirium
1) A questionnaire to assess knowledge regarding deliriumwas administered to Medical NCHDs and toPsychiatry NCHDs. A 50 minute teaching session was provided to the PsychiatryNCHDs, which included an existing e-learning module for undergraduateson delirium developed in University College Dublin(UCD). Followingthis feedback was obtained regarding the module and what changes would berequired for it to meet the training needs of non consultant hospital doctors.
2) In the first step of the DELPHIprocess, feedback from medical consultants was obtained in relation to thethemes and topics to be included in the delirium e-learning module.
•In the first iteration of the DELPHI process, both NCHDs and Consultants identified relevant learning outcomes for an eLearning module on delirium for postgraduate medical trainees.
The next iteration of the DELPHI process will refine the themespreviously identified in order to achieve consensus among the NCHD andconsultant groups surveyed. This will be the basis for the design of aneLearning module about delirium.
Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders.
We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia.
Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50.
Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.
The Mental Health Act 2001 has introduced significant changes to the process of admission to hospital for individuals affected by mental health disorders. This study aimed to determine whether a newly designed smartphone application could result in an improvement in service users’ knowledge of their rights compared with the paper booklet.
This was a randomized study conducted in an outpatient and day-hospital in North Dublin. Participants were randomized to receive the information booklet as either a smartphone application or in the paper form. A questionnaire which was scored from 0 to 10 was devised and was completed at baseline and at 1-week follow-up.
A total of 42 individuals completed the baseline and follow-up questionnaire and of these, 53.7% were female and the mean age was 38.2 years (s.d.±13.5). A total of 34.1% had a diagnosis of a psychotic disorder, 29.3% had a depressive disorder and 22% had bipolar-affective disorder. The mean score before the intervention in the total group was 3.5 (s.d.±2.2) and this increased to 5.8 (s.d.±2.2) at follow-up. Participants randomized to the smartphone application improving by a mean of 2.5 (s.d.±2.5), while those randomized to the booklet improving by a mean of 2.3 (s.d.±2.6), which was not statistically significant.
Both forms of the information booklet showed improvement in service users’ knowledge of their legal rights. It is possible that each individual will have preference for either a paper form or a smartphone form and this study suggests that both forms should be offered to each individual service user.
In the United States alone, ∼14,000 children are hospitalised annually with acute heart failure. The science and art of caring for these patients continues to evolve. The International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was held on February 4 and 5, 2015. The 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute was funded through the Andrews/Daicoff Cardiovascular Program Endowment, a philanthropic collaboration between All Children’s Hospital and the Morsani College of Medicine at the University of South Florida (USF). Sponsored by All Children’s Hospital Andrews/Daicoff Cardiovascular Program, the International Pediatric Heart Failure Summit assembled leaders in clinical and scientific disciplines related to paediatric heart failure and created a multi-disciplinary “think-tank”. The purpose of this manuscript is to summarise the lessons from the 2015 International Pediatric Heart Failure Summit of Johns Hopkins All Children’s Heart Institute, to describe the “state of the art” of the treatment of paediatric cardiac failure, and to discuss future directions for research in the domain of paediatric cardiac failure.
Multiple salmonellosis outbreaks have been linked to contaminated tomatoes. We investigated a multistate outbreak of Salmonella Typhimurium infections among 190 cases. For hypothesis generation, review of patients' food histories from four restaurant-associated clusters in four states revealed that large tomatoes were the only common food consumed by patients. Two case-control studies were conducted to identify food exposures associated with infections. In a study conducted in nine states illness was significantly associated with eating raw, large, round tomatoes in a restaurant [matched odds ratio (mOR) 3·1, 95% confidence interval (CI) 1·3–7·3]. In a Minnesota study, illness was associated with tomatoes eaten at a restaurant (OR 6·3, mid-P 95% CI 1·05–50·4, P=0·046). State, local and federal regulatory officials traced the source of tomatoes to Ohio tomato fields, a growing area not previously identified in past tomato-associated outbreaks. Because tomatoes are commonly eaten raw, prevention of tomato contamination should include interventions on the farm, during packing, and at restaurants.
Enhanced near band-edge (NBE) emission was observed from composite structures fabricated from a PVA coated ZnO (PVA-ZnO) nanoparticle thin film embedded with multi-walled carbon nanotubes (MWCNTs). The enhancement is attributed to the resonant coupling between the bandgap transition of the semiconductor and the surface plasmon (SP) of MWCNTs. Moreover, the PVA-ZnO/MWCNTs/PVA-ZnO composite structures show faster transient response, which is due to the carrier transportation process in the composite structure. Reductions are observed for both photocurrent to dark current ratio and intensity of photoresponsivity, demonstrating a tradeoff between the time transient response and the detectivity.
Epithelial cells lining the inner surface of the intestinal epithelium are in direct contact with a lumenal environment that varies dramatically with diet. It has long been suggested that the intestinal epithelium can sense the nutrient composition of lumenal contents. It is only recently that the nature of intestinal nutrient-sensing molecules and underlying mechanisms have been elucidated. There are a number of nutrient sensors expressed on the luminal membrane of endocrine cells that are activated by various dietary nutrients. We showed that the intestinal glucose sensor, T1R2+T1R3 and the G-protein, gustducin are expressed in endocrine cells. Eliminating sweet transduction in mice in vivo by deletion of either gustducin or T1R3 prevented dietary monosaccharide- and artificial sweetener-induced up-regulation of the Na+/glucose cotransporter, SGLT1 observed in wild-type mice. Transgenic mice, lacking gustducin or T1R3 had deficiencies in secretion of glucagon-like peptide 1 (GLP-1) and, glucose-dependent insulinotrophic peptide (GIP). Furthermore, they had an abnormal insulin profile and prolonged elevation of postprandial blood glucose in response to orally ingested carbohydrates. GIP and GLP-1 increase insulin secretion, while glucagon-like peptide 2 (GLP-2) modulates intestinal growth, blood flow and expression of SGLT1. The receptor for GLP-2 resides in enteric neurons and not in any surface epithelial cells, suggesting the involvement of the enteric nervous system in SGLT1 up-regulation. The accessibility of the glucose sensor and the important role that it plays in regulation of intestinal glucose absorption and glucose homeostasis makes it an attractive nutritional and therapeutic target for manipulation.
In an intensive livestock production, a shorter suckling period allows more piglets to be born. However, this practice leads to a number of disorders including nutrient malabsorption, resulting in diarrhoea, malnutrition and dehydration. A number of strategies have been proposed to overcome weaning problems. Artificial sweeteners, routinely included in piglets' diet, were thought to enhance feed palatability. However, it is shown in rodent models that when included in the diet, they enhance the expression of Na+/glucose co-transporter (SGLT1) and the capacity of the gut to absorb glucose. Here, we show that supplementation of piglets' feed with a combination of artificial sweeteners saccharin and neohesperidin dihydrochalcone enhances the expression of SGLT1 and intestinal glucose transport function. Artificial sweeteners are known to act on the intestinal sweet taste receptor T1R2/T1R3 and its partner G-protein, gustducin, to activate pathways leading to SGLT1 up-regulation. Here, we demonstrate that T1R2, T1R3 and gustducin are expressed together in the enteroendocrine cells of piglet intestine. Furthermore, gut hormones secreted by the endocrine cells in response to dietary carbohydrates, glucagon-like peptides (GLP)-1, GLP-2 and glucose-dependent insulinotrophic peptide (GIP), are co-expressed with type 1 G-protein-coupled receptors (T1R) and gustducin, indicating that L- and K-enteroendocrine cells express these taste elements. In a fewer endocrine cells, T1R are also co-expressed with serotonin. Lactisole, an inhibitor of human T1R3, had no inhibitory effect on sweetener-induced SGLT1 up-regulation in piglet intestine. A better understanding of the mechanism(s) involved in sweetener up-regulation of SGLT1 will allow the identification of nutritional targets with implications for the prevention of weaning-related malabsorption.
Diets rich in fruits and vegetables are associated with lower risk of cancer which may be conferred in part by the antioxidant properties of these foods. However, antioxidant supplementation or increased consumption of antioxidant-rich foods has been reported to have inconsistent effects on DNA damage. The present work (the DART study) investigated the extent of inter-individual variation in DNA damage, the capacity for base excision repair (BER) and the responses of both variables to supplementation with an antioxidant supplement for 6 weeks. There was a wide inter-individual variation in endogenous lymphocyte DNA strand breaks (8-fold variation), in damage after a challenge with H2O2 (16-fold variation) and in DNA repair (41-fold variation) measured using the comet assay. When stratified into tertiles according to the pre-supplementation level of endogenous DNA damage, there was a statistically significant decrease in DNA damage after supplementation in the tertile with the highest pre-supplementation level of damage. There was no effect of supplementation on BER. Endogenous DNA damage level before supplementation was significantly different (P = 0·037) between the three genotypes for the Val16Ala single nucleotide polymorphism in manganese superoxide dismutase (rs4880) with individuals homozygous/wild type showing less damage than those carrying the alanine variant.