Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis

BACKGROUND: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. METHODS AND RESULTS: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i) As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13-0.67 and 0.20,0.09-0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50-0.93 and 0.55,0.28-1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57-0.92 and 0.43,0.22-0.83). ii) Mothers interested in probiotics or research or reporting infants' adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9-13.1%) to 4.6%(-1.4-+10.5%), and OR from 0.40(0.18-0.91) to 0.56(0.26-1.21). Other findings were unchanged. CONCLUSIONS: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. TRIAL REGISTRATION: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children

The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice.

BACKGROUND: In some regions in Africa, elimination of onchocerciasis may be possible with mass drug administration, although there is concern based on several factors that onchocerciasis cannot be eliminated solely through this approach. A vaccine against Onchocerca volvulus would provide a critical tool for the ultimate elimination of this infection. Previous studies have demonstrated that immunization of mice with Ov-103 and Ov-RAL-2, when formulated with alum, induced protective immunity. It was hypothesized that the levels of protective immunity induced with the two recombinant antigens formulated with alum would be improved by formulation with other adjuvants known to enhance different types of antigen-specific immune responses. METHODOLOGY/ PRINCIPAL FINDINGS: Immunizing mice with Ov-103 and Ov-RAL-2 in conjunction with alum, Advax 2 and MF59 induced significant levels of larval killing and host protection. The immune response was biased towards Th2 with all three of the adjuvants, with IgG1 the dominant antibody. Improved larval killing and host protection was observed in mice immunized with co-administered Ov-103 and Ov-RAL-2 in conjunction with each of the three adjuvants as compared to single immunizations. Antigen-specific antibody titers were significantly increased in mice immunized concurrently with the two antigens. Based on chemokine levels, it appears that neutrophils and eosinophils participate in the protective immune response induced by Ov-103, and macrophages and neutrophils participate in immunity induced by Ov-RAL-2. CONCLUSIONS/SIGNIFICANCE: The mechanism of protective immunity induced by Ov-103 and Ov-RAL-2, with the adjuvants alum, Advax 2 and MF59, appears to be multifactorial with roles for cytokines, chemokines, antibody and specific effector cells. The vaccines developed in this study have the potential of reducing the morbidity associated with onchocerciasis in humans

Cytotoxic Interactive Effects of Dentin Bonding Components on Mouse Fibroblasts

Previous studies have shown a wide range of pulpal reactions to dentin bonding systems and a poor correlation between in vitro and in vivo toxicity of dentin bonding agents. Because dentin bonding agents are composed of multiple components which may diffuse through dentin, we hypothesized that these components may cause cytotoxicity through interactive (synergistic) effects. We investigated the cytotoxicities of four dentin bonding components-HEMA, Bis-GMA, TEGDMA, and UDMA-and interactive effects for three binary combinations of the dentin bonding components-HEMA and Bis-GMA, Bis-GMA and TEGDMA, and TEGDMA and UDMA. Cytotoxicities to Balb/c 3T3 mouse fibroblasts were measured by the MTT assay. Concentrations which caused 50% toxicity compared with controls (TC50 values) were compared, and the interactive effects were determined by evaluation of the differences between observed and expected MTT activities of the cells. The ranks of toxicity of the dentin bonding components in terms of TC50 values were as follows: Bis-GMA > UDMA > TEGDMA >>> HEMA (least toxic) after 24- and 72-hour exposures. As binary combinations, the three combinations of dentin bonding components interacted in three ways—synergism, additivism, and antagonism-which were influenced by the concentrations of both components. The longer period of exposure resulted in a significant increase in the cytotoxicity of the dentin bonding components and combinations. The findings indicate that both exposure time and the interactions between the dentin bonding components may be important parameters in determining the cytotoxicity of dentin bonding agents in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/66489/2/10.1177_00220345950740091601.pd

Genetic Selection of Low Fertile Onchocerca volvulus by Ivermectin Treatment

Onchocerca volvulus is the causative agent of onchocerciasis, or “river blindness”. Ivermectin has been used for mass treatment of onchocerciasis for up to 18 years, and recently there have been reports of poor parasitological responses to the drug and evidence of drug resistance. Drug resistance has a genetic basis. In this study, genetic changes in β-tubulin, a gene associated with ivermectin resistance in nematodes, were seen in parasites obtained from the patients exposed to repeated ivermectin treatment compared with parasites obtained from the same patients before any exposure to ivermectin. Furthermore, the extent of the genetic changes was dependent on the level of ivermectin treatment exposure. This genetic selection was associated with a lower reproductive rate in the female parasites. The data indicates that this genetic selection is for a population of O. volvulus that is more tolerant to ivermectin. This selection could have implications for the development of ivermectin resistance in O. volvulus and for the ongoing onchocerciasis control programmes. Monitoring for the possible development and spread of ivermectin resistance, as part of the control programmes, should be implemented so that any foci of resistant parasites can be treated by alternative control measures

Population‐based cohort study of outcomes following cholecystectomy for benign gallbladder diseases

Background The aim was to describe the management of benign gallbladder disease and identify characteristics associated with all‐cause 30‐day readmissions and complications in a prospective population‐based cohort. Methods Data were collected on consecutive patients undergoing cholecystectomy in acute UK and Irish hospitals between 1 March and 1 May 2014. Potential explanatory variables influencing all‐cause 30‐day readmissions and complications were analysed by means of multilevel, multivariable logistic regression modelling using a two‐level hierarchical structure with patients (level 1) nested within hospitals (level 2). Results Data were collected on 8909 patients undergoing cholecystectomy from 167 hospitals. Some 1451 cholecystectomies (16·3 per cent) were performed as an emergency, 4165 (46·8 per cent) as elective operations, and 3293 patients (37·0 per cent) had had at least one previous emergency admission, but had surgery on a delayed basis. The readmission and complication rates at 30 days were 7·1 per cent (633 of 8909) and 10·8 per cent (962 of 8909) respectively. Both readmissions and complications were independently associated with increasing ASA fitness grade, duration of surgery, and increasing numbers of emergency admissions with gallbladder disease before cholecystectomy. No identifiable hospital characteristics were linked to readmissions and complications. Conclusion Readmissions and complications following cholecystectomy are common and associated with patient and disease characteristics

Dentin Bonding: SEM Comparison of the Resin-Dentin Interface in Primary and Permanent Teeth

Previous studies have suggested minor differences between primary and permanent teeth in terms of dentin composition and morphology. Other reports indicated lower bond strengths of resin composites to dentin of primary teeth compared with dentin of permanent teeth; however, no information is available regarding differences in the micromorphology of the resin-dentin interface that may explain these lower bond strengths. Therefore, the purpose of the present study was to compare primary and permanent teeth in terms of the thickness of the hybrid layer developed with two bonding systems. Our hypothesis was that bonding differences previously reported between primary and permanent dentin would be reflected in hybrid layer differences observable in SEM analyses. Twenty human extracted and non-carious teeth were divided into 4 groups: 5 primary and 5 permanent teeth restored with All-Bond 2/Bisfil P system; and 5 primary and 5 permanent teeth restored with Scotchbond Multi-Purpose/ZlOO. The sample area available on each tooth was divided for the two dentin conditioning times (7 and 15 sec). Measurements of hybrid layer thickness were performed by means of SEM at xl3,000. The results of this study indicated that the hybrid layer produced is significantly thicker in primary than in permanent teeth (p = 0.0001), suggesting that primary tooth dentin is more reactive to acid conditioning. No difference was observed in the hybrid layers produced by the two adhesive systems (p = 0.7920). The increased thickness of the hybrid layer in primary teeth (25 to 30%) and the subsequent lack of complete penetration of adhesive resin into previously demineralized dentin may contribute to the lower bond strengths to primary dentin reported in the literature. If a narrower hybrid layer more uniformly infused with resin is the goal of dentin bonding, it is concluded that a differentiated protocol for bonding to primary dentin (with shorter time for dentin conditioning) can be used as a means to reproduce the hybrid layer thickness seen in permanent teeth.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67017/2/10.1177_00220345960750061101.pd

Taking Ecological Function Seriously: Soil Microbial Communities Can Obviate Allelopathic Effects of Released Metabolites

Allelopathy (negative, plant-plant chemical interactions) has been largely studied as an autecological process, often assuming simplistic associations between pairs of isolated species. The growth inhibition of a species in filter paper bioassay enriched with a single chemical is commonly interpreted as evidence of an allelopathic interaction, but for some of these putative examples of allelopathy, the results have not been verifiable in more natural settings with plants growing in soil.On the basis of filter paper bioassay, a recent study established allelopathic effects of m-tyrosine, a component of root exudates of Festuca rubra ssp. commutata. We re-examined the allelopathic effects of m-tyrosine to understand its dynamics in soil environment. Allelopathic potential of m-tyrosine with filter paper and soil (non-sterile or sterile) bioassays was studied using Lactuca sativa, Phalaris minor and Bambusa arundinacea as assay species. Experimental application of m-tyrosine to non-sterile and sterile soil revealed the impact of soil microbial communities in determining the soil concentration of m-tyrosine and growth responses.Here, we show that the allelopathic effects of m-tyrosine, which could be seen in sterilized soil with particular plant species were significantly diminished when non-sterile soil was used, which points to an important role for rhizosphere-specific and bulk soil microbial activity in determining the outcome of this allelopathic interaction. Our data show that the amounts of m-tyrosine required for root growth inhibition were higher than what would normally be found in F. rubra ssp. commutata rhizosphere. We hope that our study will motivate researchers to integrate the role of soil microbial communities in bioassays in allelopathic research so that its importance in plant-plant competitive interactions can be thoroughly evaluated

Evaluation of an inter-professional workshop to develop a psychosocial assessment and child-centred communication training programme for paediatricians in training

BACKGROUND: The quality of psychosocial assessment of children in consultations varies widely. One reason for this difference is the variability in effective mental health and communication training at undergraduate and post-qualification levels. In recognition of this problem, the Royal College of Paediatrics and Child Health in the United Kingdom have developed the Child in Mind Project that aims to meet this deficit in medical training. This paper describes the evaluation of a workshop that explored the experiences and expectations of health care professionals in the development of a training programme for doctors. METHODS: The one-day inter-professional workshop was attended by 63 participants who were invited to complete evaluation forms before and immediately after the workshop. RESULTS: The results showed that the workshop was partially successful in providing an opportunity for an inter-professional group to exchange ideas and influence the development of a significant project. Exploring the content and process of the proposed training programme and the opportunity for participants to share experiences of effective practice were valued. Participants identified that the current culture within many health care settings would be an obstacle to successful implementation of a training programme. Working within existing training structures will be essential. Areas for improvement in the workshop included clearer statement of goals at the outset and a more suitable environment for the numbers of participants. CONCLUSIONS: The participants made a valuable contribution to the development of the training programme identifying specific challenges. Inter-professional collaborations are likely to result in more deliverable and relevant training programmes. Continued consultation with potential users of the programme – both trainers and trainees will be essential

A composite transcriptional signature differentiates responses towards closely related herbicides in Arabidopsis thaliana and Brassica napus

In this study, genome-wide expression profiling based on Affymetrix ATH1 arrays was used to identify discriminating responses of Arabidopsis thaliana to five herbicides, which contain active ingredients targeting two different branches of amino acid biosynthesis. One herbicide contained glyphosate, which targets 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS), while the other four herbicides contain different acetolactate synthase (ALS) inhibiting compounds. In contrast to the herbicide containing glyphosate, which affected only a few transcripts, many effects of the ALS inhibiting herbicides were revealed based on transcriptional changes related to ribosome biogenesis and translation, secondary metabolism, cell wall modification and growth. The expression pattern of a set of 101 genes provided a specific, composite signature that was distinct from other major stress responses and differentiated among herbicides targeting the same enzyme (ALS) or containing the same chemical class of active ingredient (sulfonylurea). A set of homologous genes could be identified in Brassica napus that exhibited a similar expression pattern and correctly distinguished exposure to the five herbicides. Our results show the ability of a limited number of genes to classify and differentiate responses to closely related herbicides in A. thaliana and B. napus and the transferability of a complex transcriptional signature across species