Assessment of the In Vivo Toxicity of Gold Nanoparticles

The environmental impact of nanoparticles is evident; however, their toxicity due to their nanosize is rarely discussed. Gold nanoparticles (GNPs) may serve as a promising model to address the size-dependent biological response to nanoparticles because they show good biocompatibility and their size can be controlled with great precision during their chemical synthesis. Naked GNPs ranging from 3 to 100 nm were injected intraperitoneally into BALB/C mice at a dose of 8 mg/kg/week. GNPs of 3, 5, 50, and 100 nm did not show harmful effects; however, GNPs ranging from 8 to 37 nm induced severe sickness in mice. Mice injected with GNPs in this range showed fatigue, loss of appetite, change of fur color, and weight loss. Starting from day 14, mice in this group exhibited a camel-like back and crooked spine. The majority of mice in these groups died within 21 days. Injection of 5 and 3 nm GNPs, however, did not induce sickness or lethality in mice. Pathological examination of the major organs of the mice in the diseased groups indicated an increase of Kupffer cells in the liver, loss of structural integrity in the lungs, and diffusion of white pulp in the spleen. The pathological abnormality was associated with the presence of gold particles at the diseased sites, which were verified by ex vivo Coherent anti-Stoke Raman scattering microscopy. Modifying the surface of the GNPs by incorporating immunogenic peptides ameliorated their toxicity. This reduction in the toxicity is associated with an increase in the ability to induce antibody response. The toxicity of GNPs may be a fundamental determinant of the environmental toxicity of nanoparticles

A hybrid BAC physical map of potato: a framework for sequencing a heterozygous genome

<p>Abstract</p> <p>Background</p> <p>Potato is the world's third most important food crop, yet cultivar improvement and genomic research in general remain difficult because of the heterozygous and tetraploid nature of its genome. The development of physical map resources that can facilitate genomic analyses in potato has so far been very limited. Here we present the methods of construction and the general statistics of the first two genome-wide BAC physical maps of potato, which were made from the heterozygous diploid clone RH89-039-16 (RH).</p> <p>Results</p> <p>First, a gel electrophoresis-based physical map was made by AFLP fingerprinting of 64478 BAC clones, which were aligned into 4150 contigs with an estimated total length of 1361 Mb. Screening of BAC pools, followed by the KeyMaps <it>in silico </it>anchoring procedure, identified 1725 AFLP markers in the physical map, and 1252 BAC contigs were anchored the ultradense potato genetic map. A second, sequence-tag-based physical map was constructed from 65919 whole genome profiling (WGP) BAC fingerprints and these were aligned into 3601 BAC contigs spanning 1396 Mb. The 39733 BAC clones that overlap between both physical maps provided anchors to 1127 contigs in the WGP physical map, and reduced the number of contigs to around 2800 in each map separately. Both physical maps were 1.64 times longer than the 850 Mb potato genome. Genome heterozygosity and incomplete merging of BAC contigs are two factors that can explain this map inflation. The contig information of both physical maps was united in a single table that describes hybrid potato physical map.</p> <p>Conclusions</p> <p>The AFLP physical map has already been used by the Potato Genome Sequencing Consortium for sequencing 10% of the heterozygous genome of clone RH on a BAC-by-BAC basis. By layering a new WGP physical map on top of the AFLP physical map, a genetically anchored genome-wide framework of 322434 sequence tags has been created. This reference framework can be used for anchoring and ordering of genomic sequences of clone RH (and other potato genotypes), and opens the possibility to finish sequencing of the RH genome in a more efficient way via high throughput next generation approaches.</p

The Number of Patients and Events Required to Limit the Risk of Overestimation of Intervention Effects in Meta-Analysis—A Simulation Study

BACKGROUND: Meta-analyses including a limited number of patients and events are prone to yield overestimated intervention effect estimates. While many assume bias is the cause of overestimation, theoretical considerations suggest that random error may be an equal or more frequent cause. The independent impact of random error on meta-analyzed intervention effects has not previously been explored. It has been suggested that surpassing the optimal information size (i.e., the required meta-analysis sample size) provides sufficient protection against overestimation due to random error, but this claim has not yet been validated. METHODS: We simulated a comprehensive array of meta-analysis scenarios where no intervention effect existed (i.e., relative risk reduction (RRR) = 0%) or where a small but possibly unimportant effect existed (RRR = 10%). We constructed different scenarios by varying the control group risk, the degree of heterogeneity, and the distribution of trial sample sizes. For each scenario, we calculated the probability of observing overestimates of RRR>20% and RRR>30% for each cumulative 500 patients and 50 events. We calculated the cumulative number of patients and events required to reduce the probability of overestimation of intervention effect to 10%, 5%, and 1%. We calculated the optimal information size for each of the simulated scenarios and explored whether meta-analyses that surpassed their optimal information size had sufficient protection against overestimation of intervention effects due to random error. RESULTS: The risk of overestimation of intervention effects was usually high when the number of patients and events was small and this risk decreased exponentially over time as the number of patients and events increased. The number of patients and events required to limit the risk of overestimation depended considerably on the underlying simulation settings. Surpassing the optimal information size generally provided sufficient protection against overestimation. CONCLUSIONS: Random errors are a frequent cause of overestimation of intervention effects in meta-analyses. Surpassing the optimal information size will provide sufficient protection against overestimation

An audit and feedback intervention for reducing antibiotic prescribing in general dental practice:the RAPiD Cluster Randomised Controlled Trial

Acknowledgments: We thank the TRiaDS Research Methodology Group, including Irene Black, Debbie Bonetti, Heather Cassie, Martin Eccles, Sandra Eldridge, Jill J. Francis, Jeremy M. Grimshaw, Lorna Macpherson, Lorna McKee, Susan Michie, Nigel Pitts, Derek Richards, Douglas Stirling, Colin Tilley, Carole Torgerson, Shaun Treweek, Luke Vale, and Alan Walker for their guidance and contribution to the design and development of the study. We also thank Maria Prior for overseeing the running of the study, drafting of the published protocol, and her contribution to the design and analysis of the process evaluation. Thanks are also extended to Jill Farnham, Jenny Eades, Sarah Blackburn, and Lorna Barnsley for providing invaluable administrative support for this study. The views expressed in this article are those of the authors and may not reflect those of the funder. Funding: This study was conducted as part of the TRiaDS programme of implementation research which is funded by NHS Education for Scotland (NES). The Health Services Research Unit which is funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorates supported the study. The funder had no influence over the design, conduct, analysis and write up of the study. Data Availability: Researchers can request to access the data from the Information Services Division of NHS National Services Scotland http://www.isdscotland.org/. Some restrictions may apply for the protection of privacy and appropriate usage of the data.Peer reviewedPublisher PD

Acupuncture for persistent allergic rhinitis: a multi-centre, randomised, controlled trial protocol

<p>Abstract</p> <p>Background</p> <p>Allergic rhinitis is one of the most common health complaints worldwide. Complementary and alternative medical approaches have been employed to relieve allergic rhinitis symptoms and to avoid the side effects of conventional medication. Acupuncture has been widely used to treat patients with allergic rhinitis, but the available evidence of its effectiveness is insufficient. Our objective is to evaluate the effectiveness of acupuncture in patients in Korea and China with persistent allergic rhinitis compared to sham acupuncture treatment or waitlist control.</p> <p>Methods</p> <p>This study consists of a multi-centre (two centres in Korea and two centres in China), randomised, controlled trial with three parallel arms (active acupuncture, sham acupuncture, and waitlist group). The active acupuncture and sham acupuncture groups will receive real or sham acupuncture treatment, respectively, three times per week for a total of 12 sessions over four weeks. Post-treatment follow-up will be performed a month later to complement these 12 acupuncture sessions. Participants in the waitlist group will not receive real or sham acupuncture treatments during this period but will only be required to keep recording their symptoms in a daily diary. After four weeks, the same treatment given to the active acupuncture group will be provided to the waitlist group.</p> <p>Discussion</p> <p>This trial will provide evidence for the effectiveness of acupuncture as a treatment for persistent allergic rhinitis. The primary outcome between groups is a change in the self-reported total nasal symptom score (i.e., nasal obstruction, rhinorrhea, sneezing, and itching) from baseline at the fourth week. Secondary outcome measures include the Rhinitis Quality of Life Questionnaire score and total non-nasal symptom score (i.e., headache, itching, pain, eye-dropping). The quantity of conventional relief medication used during the follow-up period is another secondary outcome measure.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN90807007</p

COgnitive behavioural therapy vs standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): a multicentre randomised controlled trial protocol

Background The evidence base for the effectiveness of psychological interventions for patients with dissociative non-epileptic seizures (DS) is currently extremely limited, although data from two small pilot randomised controlled trials (RCTs), including from our group, suggest that Cognitive Behavioural Therapy (CBT) may be effective in reducing DS occurrence and may improve aspects of psychological status and psychosocial functioning. Methods/Design The study is a multicentre, pragmatic parallel group RCT to evaluate the clinical and cost-effectiveness of specifically-tailored CBT plus standardised medical care (SMC) vs SMC alone in reducing DS frequency and improving psychological and health-related outcomes. In the initial screening phase, patients with DS will receive their diagnosis from a neurologist/epilepsy specialist. If patients are eligible and interested following the provision of study information and a booklet about DS, they will consent to provide demographic information and fortnightly data about their seizures, and agree to see a psychiatrist three months later. We aim to recruit ~500 patients to this screening stage. After a review three months later by a psychiatrist, those patients who have continued to have DS in the previous eight weeks and who meet further eligibility criteria will be told about the trial comparing CBT + SMC vs SMC alone. If they are interested in participating, they will be given a further booklet on DS and study information. A research worker will see them to obtain their informed consent to take part in the RCT. We aim to randomise 298 people (149 to each arm). In addition to a baseline assessment, data will be collected at 6 and 12 months post randomisation. Our primary outcome is monthly seizure frequency in the preceding month. Secondary outcomes include seizure severity, measures of seizure freedom and reduction, psychological distress and psychosocial functioning, quality of life, health service use, cost effectiveness and adverse events. We will include a nested qualitative study to evaluate participants’ views of the intervention and factors that acted as facilitators and barriers to participation. Discussion This study will be the first adequately powered evaluation of CBT for this patient group and offers the potential to provide an evidence base for treating this patient group. Trial registration Current Controlled Trials ISRCTN05681227 ClinicalTrials.gov NCT0232554

COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES): statistical and economic analysis plan for a randomised controlled trial.

BACKGROUND: Dissociative seizures (DSs), also called psychogenic non-epileptic seizures, are a distressing and disabling problem for many patients in neurological settings with high and often unnecessary economic costs. The COgnitive behavioural therapy versus standardised medical care for adults with Dissociative non-Epileptic Seizures (CODES) trial is an evaluation of a specifically tailored psychological intervention with the aims of reducing seizure frequency and severity and improving psychological well-being in adults with DS. The aim of this paper is to report in detail the quantitative and economic analysis plan for the CODES trial, as agreed by the trial steering committee. METHODS: The CODES trial is a multicentre, pragmatic, parallel group, randomised controlled trial performed to evaluate the clinical effectiveness and cost-effectiveness of 13 sessions of cognitive behavioural therapy (CBT) plus standardised medical care (SMC) compared with SMC alone for adult outpatients with DS. DISCUSSION: The objectives and design of the trial are summarised, and the aims and procedures of the planned analyses are illustrated. The proposed analysis plan addresses statistical considerations such as maintaining blinding, monitoring adherence with the protocol, describing aspects of treatment and dealing with missing data. The formal analysis approach for the primary and secondary outcomes is described, as are the descriptive statistics that will be reported. This paper provides transparency to the planned inferential analyses for the CODES trial prior to the extraction of outcome data. It also provides an update to the previously published trial protocol and guidance to those conducting similar trials. TRIAL REGISTRATION: ISRCTN registry ISRCTN05681227 (registered on 5 March 2014); ClinicalTrials.gov NCT02325544 (registered on 15 December 2014)

Sample size considerations for trials using cerebral white matter hyperintensity progression as an intermediate outcome at 1 year after mild stroke: Results of a prospective cohort study

Background: White matter hyperintensities (WMHs) are commonly seen on in brain imaging and are associated with stroke and cognitive decline. Therefore, they may provide a relevant intermediate outcome in clinical trials. WMH can be measured as a volume or visually on the Fazekas scale. We investigated predictors of WMH progression and design of efficient studies using WMH volume and Fazekas score as an intermediate outcome. Methods: We prospectively recruited 264 patients with mild ischaemic stroke and measured WMH volume, Fazekas score, age and cardiovascular risk factors at baseline and 1 year. We modelled predictors of WMH burden at 1 year and used the results in sample size calculations for hypothetical randomised controlled trials with different analysis plans and lengths of follow-up. Results: Follow-up WMH volume was predicted by baseline WMH: a 0.73-ml (95% CI 0.65-0.80, p < 0.0001) increase per 1-ml baseline volume increment, and a 2.93-ml increase (95% CI 1.76-4.10, p < 0.0001) per point on the Fazekas scale. Using a mean difference of 1 ml in WMH volume between treatment groups, 80% power and 5% alpha, adjusting for all predictors and 2-year follow-up produced the smallest sample size (n = 642). Other study designs produced samples sizes from 2054 to 21,270. Sample size calculations using Fazekas score as an outcome with the same power and alpha, as well as an OR corresponding to a 1-ml difference, were sensitive to assumptions and ranged from 2504 to 18,886. Conclusions: Baseline WMH volume and Fazekas score predicted follow-up WMH volume. Study size was smallest using volumes and longer-term follow-up, but this must be balanced against resources required to measure volumes versus Fazekas scores, bias due to dropout and scanner drift. Samples sizes based on Fazekas scores may be best estimated with simulation studies

Can an EASYcare based dementia training programme improve diagnostic assessment and management of dementia by general practitioners and primary care nurses? The design of a randomised controlled trial

Contains fulltext : 70099.pdf ( ) (Open Access)BACKGROUND: Early diagnosis of dementia benefits both patient and caregiver. Nevertheless, dementia in primary care is currently under-diagnosed. Some educational interventions developed to improve dementia diagnosis and management were successful in increasing the number of dementia diagnoses and in changing attitudes and knowledge of health care staff. However, none of these interventions focussed on collaboration between GPs and nurses in dementia care. We developed an EASYcare-based Dementia Training Program (DTP) aimed at stimulating collaboration in dementia primary care. We expect this program to increase the number of cognitive assessments and dementia diagnoses and to improve attitudes and knowledge of GPs and nurses. METHODS: The DTP is a complex educational intervention that consists of two workshops, a coaching program, access to an internet forum, and a Computerized Clinical Decision Support System on dementia diagnostics. One hundred duos of GPs and nurses will be recruited, from which 2/3 will be allocated to the intervention group and 1/3 to the control group. The effects of implementation of the DTP will be studied in a cluster-randomised controlled trial. Primary outcomes will be the number of cognitive assessments and dementia diagnoses in a period of 9 months following workshop participation. Secondary outcomes are measured on GP and nurse level: adherence to national guidelines for dementia, attitude, confidence and knowledge regarding dementia diagnosis and management; on patient level: number of emergency calls, visits and consultations and patient satisfaction; and on caregiver level: informal caregiver burden and satisfaction. Data will be collected from GPs' electronic medical records, self-registration forms and questionnaires. Statistical analysis will be performed using the MANOVA-method. Also, exploratory analyses will be performed, in order to gain insight into barriers and facilitators for implementation and the possible causal relations between the rate of success of the intervention components and the outcomes. DISCUSSION: We developed multifaceted dementia training programme. Novelties in this programme are the training in fixed collaborative duos and the inclusion of an individual coaching program. The intervention is designed according to international guidelines and educational standards. Exploratory analysis will reveal its successful elements. Selection bias and contamination may be threats to the reliability of future results of this trial. Nevertheless, the results of this trial may provide useful information for policy makers and developers of continuing medical education. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00459784

Design of a randomized controlled trial of physical training and cancer (Phys-Can) – the impact of exercise intensity on cancer related fatigue, quality of life and disease outcome

Background: Cancer-related fatigue is a common problem in persons with cancer, influencing health-related quality of life and causing a considerable challenge to society. Current evidence supports the beneficial effects of physical exercise in reducing fatigue, but the results across studies are not consistent, especially in terms of exercise intensity. It is also unclear whether use of behaviour change techniques can further increase exercise adherence and maintain physical activity behaviour. This study will investigate whether exercise intensity affects fatigue and health related quality of life in persons undergoing adjuvant cancer treatment. In addition, to examine effects of exercise intensity on mood disturbance, adherence to oncological treatment, adverse effects from treatment, activities of daily living after treatment completion and return to work, and behaviour change techniques effect on exercise adherence. We will also investigate whether exercise intensity influences inflammatory markers and cytokines, and whether gene expressions following training serve as mediators for the effects of exercise on fatigue and health related quality of life. Methods/design: Six hundred newly diagnosed persons with breast, colorectal or prostate cancer undergoing adjuvant therapy will be randomized in a 2 × 2 factorial design to following conditions; A) individually tailored low-to-moderate intensity exercise with or without behaviour change techniques or B) individually tailored high intensity exercise with or without behaviour change techniques. The training consists of both resistance and endurance exercise sessions under the guidance of trained coaches. The primary outcomes, fatigue and health related quality of life, are measured by self-reports. Secondary outcomes include fitness, mood disturbance, adherence to the cancer treatment, adverse effects, return to activities of daily living after completed treatment, return to work as well as inflammatory markers, cytokines and gene expression. Discussion: The study will contribute to our understanding of the value of exercise and exercise intensity in reducing fatigue and improving health related quality of life and, potentially, clinical outcomes. The value of behaviour change techniques in terms of adherence to and maintenance of physical exercise behaviour in persons with cancer will be evaluated