Patient and public involvement in a study of multimedia clinical trial information for children, young people and families

There is increasing recognition of the need to involve the public in health research, but accounts of how best to achieve this are scarce. This article describes public involvement in the TRials Engagement in Children and Adolescents (TRECA) study, which is developing and evaluating multimedia information resources to inform children, young people and their familes about clinical trials. A dedicated group of young people with long-term health conditions and their parents met regularly throughout the study; further involvement was sought when specific input was required. Review of formal impact records and informal discussions highlighted how public involvement can positively influence research practice and the people involved. By detailing the methods of involvement used, this work also provides guidance for successfully implementing public involvement in research, and highlights challenges that should be considered in future research projects

Defining the tipping point. A complex cellular life/death balance in corals in response to stress

Apoptotic cell death has been implicated in coral bleaching but the molecules involved and the mechanisms by which apoptosis is regulated are only now being identified. In contrast the mechanisms underlying apoptosis in higher animals are relatively well understood. To better understand the response of corals to thermal stress, the expression of coral homologs of six key regulators of apoptosis was studied in Acropora aspera under conditions simulating those of a mass bleaching event. Significant changes in expression were detected between the daily minimum and maximum temperatures. Maximum daily temperatures from as low as 3°C below the bleaching threshold resulted in significant changes in both pro- and anti-apoptotic gene expression. The results suggest that the control of apoptosis is highly complex in this eukaryote-eukaryote endosymbiosis and that apoptotic cell death cascades potentially play key roles tipping the cellular life/death balance during environmental stress prior to the onset of coral bleaching

PRISM protocol: A randomised phase II trial of nivolumab in combination with alternatively scheduled ipilimumab in first-line treatment of patients with advanced or metastatic renal cell carcinoma

Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established

Regulation of Apoptotic Mediators Reveals Dynamic Responses to Thermal Stress in the Reef Building Coral Acropora millepora

Background: Mass coral bleaching is increasing in scale and frequency across the world's coral reefs and is being driven primarily by increased levels of thermal stress arising from global warming. In order to understand the impacts of projected climate change upon corals reefs, it is important to elucidate the underlying cellular mechanisms that operate during coral bleaching and subsequent mortality. In this respect, increased apoptotic cell death activity is an important cellular process that is associated with the breakdown of the mutualistic symbiosis between the cnidarian host and their dinoflagellate symbionts

Quality of the parent-child interaction in young children with type 1 diabetes mellitus: study protocol

<p>Abstract</p> <p>Background</p> <p>In young children with type 1 diabetes mellitus (T1DM) parents have full responsibility for the diabetes-management of their child (e.g. blood glucose monitoring, and administering insulin). Behavioral tasks in childhood, such as developing autonomy, and oppositional behavior (e.g. refusing food) may interfere with the diabetes-management to achieve an optimal blood glucose control. Furthermore, higher blood glucose levels are related to more behavioral problems. So parents might need to negotiate with their child on the diabetes-management to avoid this direct negative effect. This interference, the negotiations, and the parent's responsibility for diabetes may negatively affect the quality of parent-child interaction. Nevertheless, there is little knowledge about the quality of interaction between parents and young children with T1DM, and the possible impact this may have on glycemic control and psychosocial functioning of the child. While widely used global parent-child interaction observational methods are available, there is a need for an observational tool specifically tailored to the interaction patterns of parents and children with T1DM. The main aim of this study is to construct a disease-specific observational method to assess diabetes-specific parent-child interaction. Additional aim is to explore whether the quality of parent-child interactions is associated with the glycemic control, and psychosocial functioning (resilience, behavioral problems, and quality of life).</p> <p>Methods/Design</p> <p>First, we will examine which situations are most suitable for observing diabetes-specific interactions. Then, these situations will be video-taped in a pilot study (N = 15). Observed behaviors are described into rating scales, with each scale describing characteristics of parent-child interactional behaviors. Next, we apply the observational tool on a larger scale for further evaluation of the instrument (N = 120). The parents are asked twice (with two years in between) to fill out questionnaires about psychosocial functioning of their child with T1DM. Furthermore, glycemic control (HbA_1c) will be obtained from their medical records.</p> <p>Discussion</p> <p>A disease-specific observational tool will enable the detailed assessment of the quality of diabetes-specific parent-child interactions. The availability of such a tool will facilitate future (intervention) studies that will yield more knowledge about impact of parent-child interactions on psychosocial functioning, and glycemic control of children with T1DM.</p

Regulation of Apoptotic Pathways by Stylophora pistillata (Anthozoa, Pocilloporidae) to Survive Thermal Stress and Bleaching

Elevated seawater temperatures are associated with coral bleaching events and related mortality. Nevertheless, some coral species are able to survive bleaching and recover. The apoptotic responses associated to this ability were studied over 3 years in the coral Stylophora pistillata from the Gulf of Eilat subjected to long term thermal stress. These include caspase activity and the expression profiles of the S. pistillata caspase and Bcl-2 genes (StyCasp and StyBcl-2-like) cloned in this study. In corals exposed to thermal stress (32 or 34°C), caspase activity and the expression levels of the StyBcl-2-like gene increased over time (6–48 h) and declined to basal levels within 72 h of thermal stress. Distinct transcript levels were obtained for the StyCasp gene, with stimulated expression from 6 to 48 h of 34°C thermal stress, coinciding with the onset of bleaching. Increased cell death was detected in situ only between 6 to 48 h of stress and was limited to the gastroderm. The bleached corals survived up to one month at 32°C, and recovered back symbionts when placed at 24°C. These results point to a two-stage response in corals that withstand thermal stress: (i) the onset of apoptosis, accompanied by rapid activation of anti-oxidant/anti-apoptotic mediators that block the progression of apoptosis to other cells and (ii) acclimatization of the coral to the chronic thermal stress alongside the completion of symbiosis breakdown. Accordingly, the coral's ability to rapidly curb apoptosis appears to be the most important trait affecting the coral's thermotolerance and survival

Analysis of obstetric complications and uterine connective tissue in tenascin-X-deficient humans and mice

Tenascin-X (TNX) is a large, multi-domain, extracellular matrix glycoprotein. Complete deficiency of TNX in humans leads to a recessive form of Ehlers-Danlos syndrome (EDS), and TNX haploinsufficiency is a cause of hypermobility type EDS. EDS patients appear to have a higher risk of several complications during pregnancy, such as pelvic instability, premature rupture of membranes, and postpartum hemorrhage. Here, we present a study of genitourinary and obstetric complications in TNX-deficient women of reproductive age. We have found complications, such as uterus prolapses, that are in agreement with previous findings in other EDS types. In TNX knockout (KO) mice, we have observed mild pregnancy-related abnormalities. Morphological and immunohistological analysis of uterine tissues has not revealed obvious quantitative or spatial differences between TNX KO and wildtype mice with respect to collagen types I, III, V, and XII or elastic fibers. We conclude that TNX-deficient women are at risk of obstetric complications, but that TNX KO mice show only a mild phenotype. Furthermore, we show that TNX is involved in the stability of elastic fibers rather than in their initial deposition

Who Benefits Most from a University Degree?: A Cross-National Comparison of Selection and Wage Returns in the US, UK, and Germany

Recent research on economic returns to higher education in the United States suggests that those with the highest wage returns to a college degree are least likely to obtain one. We extend the study of heterogeneous returns to tertiary education across multiple institutional contexts, investigating how the relationship between wage returns and the propensity to complete a degree varies by the level of expansion, differentiation, and cost of higher education. Drawing on panel data and matching techniques, we compare findings from the US with selection into degree completion in Germany and the UK. Contrary to previous studies, we find little evidence for population level heterogeneity in economic returns to higher education