Developmental toxicity study of sodium molybdate dihydrate administered in the diet to Sprague Dawley rats

AbstractMolybdenum is an essential nutrient for humans and animals and is a constituent of several important oxidase enzymes. It is normally absorbed from the diet and to a lesser extent from drinking water and the typical human intake is around 2μg/kg bodyweight per day. No developmental toxicity studies to contemporary standards have been published and regulatory decisions have been based primarily on older studies where the nature of the test material, or the actual dose levels consumed is uncertain.In the current study the developmental toxicity of sodium molybdate dihydrate as a representative of a broad class of soluble molybdenum(VI) compounds, was given in the diet to Sprague Dawley rats in accordance with OECD Test Guideline 414. Dose levels of 0, 3, 10, 20 and 40mgMo/kgbw/day were administered from GD6 to GD20. No adverse effects were observed at any dose level on the dams, or on embryofetal survival, fetal bodyweight, or development, with no increase in malformations or variations. Significant increases in serum and tissue copper levels were observed but no toxicity related to these was observed. The NOAEL observed in this study was 40mgMo/kgbw/day, the highest dose tested

Exploring the impact of a decision support intervention on vascular access decisions in chronic hemodialysis patients: study protocol

<p>Abstract</p> <p>Background</p> <p>In patients with Stage 5 Chronic Kidney Disease who require renal replacement therapy a major decision concerns modality choice. However, many patients defer the decision about modality choice or they have an urgent or emergent need of RRT, which results in them starting hemodialysis with a Central Venous Catheter. Thereafter, efforts to help patients make more timely decisions about access choices utilizing education and resource allocation strategies met with limited success resulting in a high prevalent CVC use in Canada. Providing decision support tailored to meet patients' decision making needs may improve this situation. The Registered Nurses Association of Ontario has developed a clinical practice guideline to guide decision support for adults living with Chronic Kidney Disease <it>(Decision Support for Adults with Chronic Kidney Disease</it>.) The purpose of this study is to determine the impact of implementing selected recommendations this guideline on priority provincial targets for hemodialysis access in patients with Stage 5 CKD who currently use Central Venous Catheters for vascular access.</p> <p>Methods/Design</p> <p>A non-experimental intervention study with repeated measures will be conducted at St. Michaels Hospital in Toronto, Canada. Decisional conflict about dialysis access choice will be measured using the validated SURE tool, an instrument used to identify decisional conflict. Thereafter a tailored decision support intervention will be implemented. Decisional conflict will be re-measured and compared with baseline scores. Patients and staff will be interviewed to gain an understanding of how useful this intervention was for them and whether it would be feasible to implement more widely. Quantitative data will be analyzed using descriptive and inferential statistics. Statistical significance of difference between means over time for aggregated SURE scores (pre/post) will be assessed using a paired t-test. Qualitative analysis with content coding and identification of themes will be conducted for the focus group and patient interview data.</p> <p>Discussion</p> <p>Coupling the SURE tool with a decision support system structured so that a positive test result triggers providers to help patients through the decision-making process and/or refer patients to appropriate resources could benefit patients and ensure they have the opportunity to make informed HD access choices.</p

Using interpretative phenomenological analysis to inform physiotherapy practice: An introduction with reference to the lived experience of cerebellar ataxia

The attached file is a pre-published version of the full and final paper which can be found at the link below.This article has been made available through the Brunel Open Access Publishing Fund.Qualitative research methods that focus on the lived experience of people with health conditions are relatively underutilised in physiotherapy research. This article aims to introduce interpretative phenomenological analysis (IPA), a research methodology oriented toward exploring and understanding the experience of a particular phenomenon (e.g., living with spinal cord injury or chronic pain, or being the carer of someone with a particular health condition). Researchers using IPA try to find out how people make sense of their experiences and the meanings they attach to them. The findings from IPA research are highly nuanced and offer a fine grained understanding that can be used to contextualise existing quantitative research, to inform understanding of novel or underresearched topics or, in their own right, to provoke a reappraisal of what is considered known about a specified phenomenon. We advocate IPA as a useful and accessible approach to qualitative research that can be used in the clinical setting to inform physiotherapy practice and the development of services from the perspective of individuals with particular health conditions.This article is available through the Brunel Open Access Publishing Fund

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

Increased risk of type I errors in cluster randomised trials with small or medium numbers of clusters: a review, reanalysis,and simulation study

Background: Cluster randomised trials (CRTs) are commonly analysed using mixed-effects models or generalised estimating equations (GEEs). However, these analyses do not always perform well with the small number of clusters typical of most CRTs. They can lead to increased risk of a type I error (finding a statistically significant treatment effect when it does not exist) if appropriate corrections are not used. Methods: We conducted a small simulation study to evaluate the impact of using small-sample corrections for mixed-effects models or GEEs in CRTs with a small number of clusters. We then reanalysed data from TRIGGER, a CRT with six clusters, to determine the effect of using an inappropriate analysis method in practice. Finally, we reviewed 100 CRTs previously identified by a search on PubMed in order to assess whether trials were using appropriate methods of analysis. Trials were classified as at risk of an increased type I error rate if they did not report using an analysis method which accounted for clustering, or if they had fewer than 40 clusters and performed an individual-level analysis without reporting the use of an appropriate small-sample correction. Results: Our simulation study found that using mixed-effects models or GEEs without an appropriate correction led to inflated type I error rates, even for as many as 70 clusters. Conversely, using small-sample corrections provided correct type I error rates across all scenarios. Reanalysis of the TRIGGER trial found that inappropriate methods of analysis gave much smaller P values (P ≤ 0.01) than appropriate methods (P = 0.04–0.15). In our review, of the 99 trials that reported the number of clusters, 64 (65 %) were at risk of an increased type I error rate; 14 trials did not report using an analysis method which accounted for clustering, and 50 trials with fewer than 40 clusters performed an individual-level analysis without reporting the use of an appropriate correction. Conclusions: CRTs with a small or medium number of clusters are at risk of an inflated type I error rate unless appropriate analysis methods are used. Investigators should consider using small-sample corrections with mixed-effects models or GEEs to ensure valid results. Abbreviations: CRT, Cluster randomised trial; CI, Confidence interval; GEE, Generalised estimating equations; TRIGGER, Trial in Gastrointestinal Transfusio

Trust as a daily defense against collective disease threats

Although the isolated threat of disease often motivates people to avoid others, people need the help and cooperation of others to protect themselves against pandemic disease threats. Therefore, the fear of contracting a highly contagious virus like COVID-19 should motivate people to believe that they can in fact count on the help and cooperation of others for protection. Trusting in others provides the basis to anticipate their cooperation. Therefore, we expected a greater daily threat of contracting COVID-19 to motivate people to trust more in others, providing needed assurance that others would keep them safe from harm. We obtained 4 daily diary samples involving 2794 participants who provided in excess of 18,000 daily observations within the first three months of the COVID-19 pandemic. Each day, we tracked (1) disease threat, captured daily by personal concerns about COVID-19 and infection totals in the nearest most populous city, and (2) trust in others, captured daily by expressions of trust in intimates, collective caregivers (e.g., President, Congress), and strangers. Participants in two samples completed 2-month follow-ups. Integrative analyses of the daily diaries revealed that people trusted more in intimates and collective caregivers on days they had greater (vs. less) reason to be concerned about COVID-19. Further integrative analyses of the follow-up data revealed that participants who were initially more likely to trust in others on days when COVID-19 cases in nearby communities spread more rapidly later reported greater confidence that others would keep them safe from harm. That is, they evidenced greater physical, interpersonal, and collective security in social connection than participants who were initially less likely to defensively trust in others on such occasions. The present findings suggest that ecological threats may dynamically motivate people to trust others more than they otherwise would, providing optimism that collectively-faced crises may motivate social cooperation when it is most needed

Immunochip analysis identifies multiple susceptibility loci for systemic sclerosis

In this study, 1,833 systemic sclerosis (SSc) cases and 3,466 controls were genotyped with the Immunochip array. Classical alleles, amino acid residues, and SNPs across the human leukocyte antigen (HLA) region were imputed and tested. These analyses resulted in a model composed of six polymorphic amino acid positions and seven SNPs that explained the observed significant associations in the region. In addition, a replication step comprising 4,017 SSc cases and 5,935 controls was carried out for several selected non-HLA variants, reaching a total of 5,850 cases and 9,401 controls of European ancestry. Following this strategy, we identified and validated three SSc risk loci, including DNASE1L3 at 3p14, the SCHIP1-IL12A locus at 3q25, and ATG5 at 6q21, as well as a suggested association of the TREH-DDX6 locus at 11q23. The associations of several previously reported SSc risk loci were validated and further refined, and the observed peak of association in PXK was related to DNASE1L3. Our study has increased the number of known genetic associations with SSc, provided further insight into the pleiotropic effects of shared autoimmune risk factors, and highlighted the power of dense mapping for detecting previously overlooked susceptibility loci

Resettlement experiences and resilience in refugee youth in Perth, Western Australia

Background: In Australia, the two major pathways of refugee entry are the United Nations High Commissioner for Refugees resettlement programme and irregular maritime arrivals (IMAs) seeking asylum. The Australian Government’s policies towards IMAs since July 2013 are controversial, uncompromising and consistently harsh, with asylum seekers held in detention centres for prolonged periods. Refugees and asylum seekers have distinct and unique stressors that make resettlement difficult. Methods: This exploratory study examines resettlement experiences for refugee youth in Western Australia using the psychosocial conceptual framework and qualitative methods. Focus group discussions and key informant interviews were undertaken with verbatim transcripts analysed using thematic analysis to identify themes. Results: Themes documented that language and its impact, and experience with education, health, and social activities, support structures provided to youth and supporting future aspirations as critical to successful resettlement. This exploratory study contributes to developing a broader understanding of the resettlement experiences of refugee youth, drawing on their current and past experiences, cultural differences and mechanisms for coping. Conclusion: Fluency in English language, especially spoken, was a facilitator of successful resettlement. Our results align with previous studies documenting that support programs are vital for successful resettlement. Although faced with immense difficulties refugee youth are resilient, want to succeed and have aspirations for the future. Strategies and recommendations suggested by refugee youth themselves could be used for developing interventions to assist successful resettlement

Pursuing Safety in Social Connection Regulates the Risk-Regulation, Social-Safety and Behavioral-Immune Systems

A new goal-systems model is proposed to help explain when individuals will protect themselves against the risks inherent to social connection. This model assumes that people satisfy the goal to feel included in safe social connections—connections where they are valued and protected rather than at risk of being harmed—by devaluing rejecting friends, trusting in expectancy–consistent relationships, and avoiding infectious strangers. In the hypothesized goal system, frustrating the fundamental goal to feel safe in social connection sensitizes regulatory systems that afford safety from the risk of being interpersonally rejected (i.e., the risk-regulation system), existentially uncertain (i.e., the social-safety system), or physically infected (i.e., the behavioral-immune system). Conversely, fulfilling the fundamental goal to feel safe in social connection desensitizes these self-protective systems. A 3-week experimental daily diary study (N = 555) tested the model hypotheses. We intervened to fulfill the goal to feel safe in social connection by repeatedly conditioning experimental participants to associate their romantic partners with highly positive, approachable words and images. We then tracked how vigilantly experimental versus control participants protected themselves when they encountered social rejection, unexpected behavior, or contagious illness in everyday life. Multilevel analyses revealed that the intervention lessoned self-protective defenses against each of these risks for participants who ordinarily felt most vulnerable to them. The findings provide the first evidence that the fundamental goal to feel safe in social connection can co-opt the risk-regulation, social-safety, and behavioral-immune systems as independent means for its pursuit

Improving access for community health and sub-acute outpatient services: protocol for a stepped wedge cluster randomised controlled trial

BACKGROUND: Waiting lists for treatment are common in outpatient and community services, Existing methods for managing access and triage to these services can lead to inequities in service delivery, inefficiencies and divert resources from frontline care. Evidence from two controlled studies indicates that an alternative to the traditional &quot;waitlist and triage&quot; model known as STAT (Specific Timely Appointments for Triage) may be successful in reducing waiting times without adversely affecting other aspects of patient care. This trial aims to test whether the model is cost effective in reducing waiting time across multiple services, and to measure the impact on service provision, health-related quality of life and patient satisfaction. METHODS/DESIGN: A stepped wedge cluster randomised controlled trial has been designed to evaluate the impact of the STAT model in 8 community health and outpatient services. The primary outcome will be waiting time from referral to first appointment. Secondary outcomes will be nature and quantity of service received (collected from all patients attending the service during the study period and health-related quality of life (AQOL-8D), patient satisfaction, health care utilisation and cost data (collected from a subgroup of patients at initial assessment and after 12&nbsp;weeks). Data will be analysed with a multiple multi-level random-effects regression model that allows for cluster effects. An economic evaluation will be undertaken alongside the clinical trial. DISCUSSION: This paper outlines the study protocol for a fully powered prospective stepped wedge cluster randomised controlled trial (SWCRCT) to establish whether the STAT model of access and triage can reduce waiting times applied across multiple settings, without increasing health service costs or adversely impacting on other aspects of patient care. If successful, it will provide evidence for the effectiveness of a practical model of access that can substantially reduce waiting time for outpatient and community services with subsequent benefits for both efficiency of health systems and patient care.<br /