Dose–response approaches for nuclear receptor-mediated modes of action for liver carcinogenicity: Results of a workshop

A public workshop, organized by a Steering Committee of scientists from government, industry, universities and research organizations, was held at the National Institute of Environmental Health Sciences (NIEHS) in September, 2010. The workshop explored the dose–response implications of toxicant modes of action (MOA) mediated by nuclear receptors. The dominant paradigm in human health risk assessment has been linear extrapolation without a threshold for cancer, and estimation of sub-threshold doses for non-cancer and (in appropriate cases) cancer endpoints. However, recent publications question the application of dose–response modeling approaches with a threshold. The growing body of molecular toxicology information and computational toxicology tools has allowed for exploration of the presence or absence of sub-threshold doses for a number of receptor-mediated MOAs. The workshop explored the development of dose–response approaches for nuclear receptor-mediated liver cancer, within a MOA Human Relevance Framework (HRF). Case studies addressed activation of the AHR, the CAR and the PPARα. This article describes the workshop process, key issues discussed and conclusions. The value of an interactive workshop approach to apply current MOA/HRF frameworks was demonstrated. The results may help direct research on the MOA and dose–response of receptor-based toxicity, since there are commonalities for many receptors in the basic pathways involved for late steps in the MOA, and similar data gaps in early steps. Three additional papers in this series describe the results and conclusions for each case-study receptor regarding its MOA, relevance of the MOA to humans and the resulting dose–response implications.     

Micropapillary bladder cancer: Current treatment patterns and review of the literature

ObjectivesNo guidelines exist for the management of micropapillary bladder cancer (MPBC) and most reports of this variant of urothelial carcinoma are case series comprising small numbers of patients. We sought to determine current practice patterns for MPBC using a survey sent to the Society of Urologic Oncology (SUO) and to present those results in the setting of a comprehensive review of the existing literature.Materials and methodsA survey developed by the Translational Science Working Group of the Bladder Cancer Advocacy Network–sponsored Think Tank meeting was distributed to members of the SUO. The results from 118 respondents were analyzed and presented with a literature review.ResultsMost survey respondents were urologists, with 80% considering bladder cancer their primary area of interest. Although 78% of the respondents reported a dedicated genitourinary pathologist at their institution, there were discrepant opinions on how a pathologic diagnosis of MPBC is determined as well as variability on the proportion of MPBC that is clinically significant. Among them, 78% treat MPBC differently than conventional urothelial carcinoma, with 81% reporting that they would treat cT1 MPBC with upfront radical cystectomy. However, the respondents had split opinions regarding the sensitivity of MPBC to cisplatin-based chemotherapy, which affected utilization of neoadjuvant chemotherapy in muscle-invasive disease.ConclusionsThe management of MPBC is diverse among members of the SUO. Although most favors early cystectomy for cT1 MPBC, there is no consensus on the use of neoadjuvant chemotherapy for muscle-invasive MPBC.     

Percutaneous single- and double-balloon aortic valvotomy in adolescents and young adults with congenital aortic stenosis

Percutaneous balloon aortic valvotomy was attempted in six consecutiveadolescents and young adults, (meanage 18 ± 5 years),with severe congenital aortic valvular stenosis. Peak systolicaortic valve gradient measurement and aortography was performedbefore and immediately after valvotomy, and a 1–6 monthsfollow-up. The single-balloon technique was used in two patientsand the double-balloon technique in four patients. After balloonvalvotomy the mean peak systolic aortic valve gradient (PSG)decreased from 122 ± 53 to 43 ± 20 mmHg (P >001). The haemodynamic improvement persisted at follow-up (PSG= 47 ±31 mmHg), except in one patient who had previouslyundergone aortic surgical valvotomy. One balloon valvotomy wasunsuccessful, presumably because of the selection of an inappropriatelysmall balloon. Two patients with critical aortic stenosis (PSG>165mmHg), who exhibited a thick aortic valve on echocardiographywith a relatively small aortic root and annulus, had a dramaticreduction in PSG. However, the degree of aortic regurgitationincreased significantly in both cases. The theoretical haemodynamicadvantage of the double versus the single balloon techniqueswas confirmed in one patient. We have demonstrated that percutaneousballoon aortic valvotomy using either the single- or double-balloontechnique is feasible in young adults with severe congenitalaortic stenosis. Further studies are required both to defineappropriate patients and the selection of balloon diameter andlength.     

Factors Affecting Job Satisfaction and Their Correlation with Educational Standards among Dental Assistants

A disparity exists in the educational qualifications of dental assistants working in various public and private institutions in Riyadh, Saudi Arabia. The aim of this study was to assess the influence of professional and personal characteristics on job satisfaction among dental assistants. A cross-sectional survey was performed among dental assistants using a 24-item self-administered questionnaire. Multinomial logistic regression was used to assess the relationship between overall job satisfaction and other variables. The overall response rate was 72.1%. Factor analysis suggested that five underlying factors were related to job satisfaction. The mean score for overall job satisfaction was 3.86 (satisfied) out of 5. Among the work environment factors, the highest mean score, 4.26 (satisfied), was obtained for quality of service, and the lowest mean score, 2.78 (neutral), was obtained for the perception of income. The income and general prospects of the profession was significantly associated with overall job satisfaction. This study suggests that for dental assistants, professional and personal life, quality of service, perception of income and prestige and self-respect are important factors for job satisfaction. Despite differences in professional formation standards, in general, the study participants were considerably satisfied with their jobs.     

Improving organizational capacity to address health literacy in public health: a rapid realist review

Objectives

Despite the growing significance of health literacy to public health, relatively little is known about how organizational capacity may be improved for planning, implementing and sustaining health literacy interventions. This study aimed to connect decision makers in a public health agency with evidence of how organizational capacity may be improved for delivering health literacy services.

Study design

A rapid realist review of published and grey literature was conducted by a partnership between the Public Health Agency of Canada (PHAC) and the InSource Research Group.

Methods

Realist review methodology attempts to understand what works for whom under what circumstances, and is characterized by its focus on strategies/interventions, contexts, mechanisms and their relationship to outcome. This review was completed in collaboration with a reference panel (comprised of a broad range of PHAC representatives) and an expert panel. Literature searching was conducted using three databases supplemented with bibliographic hand searches and articles recommended by panels. Data were extracted on key variables related to definitions, strategies/interventions associated with increased organizational capacity, contextual factors associated with success (and failure), mechanisms activated as a result of different strategies and contexts, key outcomes, and evidence cited.

Results

Strategies found to be associated with improved organizational capacity for delivering health literacy services may be classified into three domains: (1) government action; (2) organizational/practitioner action; and (3) partnership action. Government action includes developing policies to reinforce social norms; setting standards for education; conducting research; and measuring health literacy levels. Organizational/practitioner action relates to appropriate models of leadership (both high-level government engagement and distributed leadership). Innovative partnership action includes collaborations with media outlets, those producing electronic materials, community organizations and school-based programs. Contextual factors for success include positive leadership models, interorganizational relationships, and a culture committed to experimentation and learning. Potential mechanisms activated by strategies and contextual factors include increased visibility and recognition of health literacy efforts, enthusiasm and momentum for health literacy activities, reduced cognitive dissonance between vision and action, a sense of ownership for health literacy data, and creation of a common language and understanding.

Conclusions

Government initiated interventions and policies are powerful strategies by which organizational capacity to improve health literacy may be affected. Using the foundations created by the government policy environment, organizations may improve the impact of health literacy interventions through supported distributed leadership.     

Predictors of remission and relapse in idiopathic nephrotic syndrome: a prospective cohort study

Background

Although most children with idiopathic nephrotic syndrome will respond to corticosteroid therapy, 80–90 % suffer one or more relapses.

Methods

Using Cox proportional hazard models, we analyzed predictors of remission and relapse in 1-year follow-up data on children aged below 15 years with new-onset nephrotic syndrome.

Results

Of 129 children, 107 achieved remission with corticosteroid therapy and 86 subsequently relapsed. Boys achieved remission more often than girls (adjusted hazard ratio [AHR] 1.52, 95 % confidence interval (CI) 1.02–2.3). Boys relapsed significantly more frequently than girls (AHR 1.77, 95 % CI 1.11–2.83) and were more likely to have frequently relapsing disease (AHR 3.3, 95 % CI 1.18–9.23). The risk of first relapse increased with the number of days to first remission (AHR 1.02, 95 % CI 1.01–1.04). The risk for a frequently relapsing course increased with a shorter time from remission to first relapse (AHR 0.92, 95 % CI 0.87–0.97).

Conclusions

In idiopathic nephrotic syndrome, boys are more likely to respond initially, more likely to relapse, and to be classified as having frequently relapsing nephrotic syndrome. A decrease in time from remission to first relapse predicts for a frequently relapsing course.     

Father involvement with three-to-four-year olds at home: giving fathers a chance

This study examined fathers' perceptions regarding their home-based activities (HBA) and the influence of fathers' demographic characteristics on their perceptions and practices at home. A total of 396 fathers completed a survey questionnaire describing their demographic information, perceptions and their practices regarding their involvement in HBA. Results indicated that fathers have moderate level of practice concerning their HBA, yet they have low perception of their actual practice at HBA. In addition, there was a statistical significance in HBA due to fathers' age, educational level and specialisation which had an influence on their perceptions as well. Recommendations and implications of future research were discussed.     

A new methodology for studying multiple-site-type catalysts for the copolymerization of olefins

A novel methodology is presented for studying the nature of multiple-site-type catalysts used for the synthesis of olefin copolymers. Experimental results of copolymer composition (short-chain branching) versus molecular weight are obtained by analyzing high-temperature gel-permeation chromatography fractions with Fourier-transform infrared spectroscopy. The molecular weight distribution obtained by gel-permeation chromatography is deconvoluted to determine the number of different site types on the catalyst. The average copolymer composition of chains made on each site type is then determined from copolymer composition versus molecular weight data. It is also shown how to extend this methodology to determine the comonomer reactivity ratios per site type.