The combined diabetes and renal control trial (C-DIRECT) - a feasibility randomised controlled trial to evaluate outcomes in multi-morbid patients with diabetes and on dialysis using a mixed methods approach

Background: This cluster randomised controlled trial set out to investigate the feasibility and acceptability of the “Combined Diabetes and Renal Control Trial” (C-DIRECT) intervention, a nurse-led intervention based on motivational interviewing and self-management in patients with coexisting end stage renal diseases and diabetes mellitus (DM ESRD). Its efficacy to improve glycaemic control, as well as psychosocial and self-care outcomes were also evaluated as secondary outcomes. Methods: An assessor-blinded, clustered randomised-controlled trial was conducted with 44 haemodialysis patients with DM ESRD and ≥ 8% glycated haemoglobin (HbA1c), in dialysis centres across Singapore. Patients were randomised according to dialysis shifts. 20 patients were assigned to intervention and 24 were in usual care. The C-DIRECT intervention consisted of three weekly chair-side sessions delivered by diabetes specialist nurses. Data on recruitment, randomisation, and retention, and secondary outcomes such as clinical endpoints, emotional distress, adherence, and self-management skills measures were obtained at baseline and at 12 weeks follow-up. A qualitative evaluation using interviews was conducted at the end of the trial. Results: Of the 44 recruited at baseline, 42 patients were evaluated at follow-up. One patient died, and one discontinued the study due to deteriorating health. Recruitment, retention, and acceptability rates of C-DIRECT were generally satisfactory HbA1c levels decreased in both groups, but C-DIRECT had more participants with HbA1c < 8% at follow up compared to usual care. Significant improvements in role limitations due to physical health were noted for C-DIRECT whereas levels remained stable in usual care. No statistically significant differences between groups were observed for other clinical markers and other patient-reported outcomes. There were no adverse effects. Conclusions: The trial demonstrated satisfactory feasibility. A brief intervention delivered on bedside as part of routine dialysis care showed some benefits in glycaemic control and on QOL domain compared with usual care, although no effect was observed in other secondary outcomes. Further research is needed to design and assess interventions to promote diabetes self-management in socially vulnerable patients

Designing a physical activity parenting course : parental views on recruitment, content and delivery

Background Many children do not engage in sufficient levels of physical activity (PA) and spend too much time screen-viewing (SV). High levels of SV (e.g. watching TV, playing video games and surfing the internet) and low levels of PA have been associated with adverse health outcomes. Parenting courses may hold promise as an intervention medium to change children’s PA and SV. The current study was formative work conducted to design a new parenting programme to increase children’s PA and reduce their SV. Specifically, we focussed on interest in a course, desired content and delivery style, barriers and facilitators to participation and opinions on control group provision. Methods In-depth telephone interviews were conducted with thirty two parents (29 female) of 6–8 year olds. Data were analysed thematically. An anonymous online survey was also completed by 750 parents of 6–8 year old children and descriptive statistics calculated. Results Interview participants were interested in a parenting course because they wanted general parenting advice and ideas to help their children be physically active. Parents indicated that they would benefit from knowing how to quantify their child’s PA and SV levels. Parents wanted practical ideas of alternatives to SV. Most parents would be unable to attend unless childcare was provided. Schools were perceived to be a trusted source of information about parenting courses and the optimal recruitment location. In terms of delivery style, the majority of parents stated they would prefer a group-based approach that provided opportunities for peer learning and support with professional input. Survey participants reported the timing of classes and the provision of childcare were essential factors that would affect participation. In terms of designing an intervention, the most preferred control group option was the opportunity to attend the same course at a later date. Conclusions Parents are interested in PA/SV parenting courses but the provision of child care is essential for attendance. Recruitment is likely to be facilitated via trusted sources. Parents want practical advice on how to overcome barriers and suggest advice is provided in a mutually supportive group experience with expert input

Spitting Performance Parameters and Their Biomechanical Implications in the Spitting Spider, Scytodes thoracica

Spitting spiders Scytodes spp. subdue prey by entangling them at a distance with a mixture of silk, glue, and venom. Using high-speed videography and differential interference contrast microscopy, the performance parameters involved in spit ejection by Scytodes thoracica (Araneae, Scytodidae) were measured. These will ultimately need to be explained in biomechanical and fluid dynamic terms. It was found that the ejection of “spit” from the opening of the venom duct (near the proximal end of the fang) was orderly. It resulted in a pattern that scanned along a lateral-medial axis (due to fang oscillations) while traversing from ventral to dorsal (due to cheliceral elevation). Each lateral-to-medial sweep of a fang produced silk-borne beads of glue that were not present during each subsequent medial-to-lateral sweep. The ejection of “spit” was very rapid. A full scan (5–57 fang cycles, one upsweep of a chelicera) typically occupied less than 30 ms and involved fang oscillations at 278–1781 Hz. Ejection velocities were measured as high as 28.8 m/s. The “spit” was contractile. During the 0.2 s following ejection, silk shortened by 40–60% and the product of a full scan by both of the chelicerae could exert an aggregate contractile force of 0.1 – 0.3 mN. Based on these parameters, hypotheses are described concerning the biomechanical and fluid dynamic processes that could enable this kind of material ejection

The anti-vaccination movement and resistance to allergen-immunotherapy: a guide for clinical allergists

Despite over a century of clinical use and a well-documented record of efficacy and safety, a growing minority in society questions the validity of vaccination and fear that this common public health intervention is the root-cause of severe health problems. This article questions whether growing public anti-vaccine sentiments might have the potential to spill-over into other therapies distinct from vaccination, namely allergen-immunotherapy. Allergen-immunotherapy shares certain medical vernacular with vaccination (e.g., allergy shots, allergy vaccines), and thus may become "guilty by association" due to these similarities. Indeed, this article demonstrates that anti-vaccine websites have begun unduly discrediting this allergy treatment regimen. Following an explanation of the anti-vaccine movement, the article aims to provide guidance on how clinicians can respond to patient fears towards allergen-immunotherapy in the clinical setting. This guide focuses on the provision of reliable information to patients in order to dispel misconceived associations between vaccination and allergen-immunotherapy, and the discussion of the risks and benefits of both therapies in order to assist patients in making autonomous decisions about their choice of allergy treatment

Phylostratigraphic tracking of cancer genes suggests a link to the emergence of multicellularity in metazoa

Background: Phylostratigraphy is a method used to correlate the evolutionary origin of founder genes (that is, functional founder protein domains) of gene families with particular macroevolutionary transitions. It is based on a model of genome evolution that suggests that the origin of complex phenotypic innovations will be accompanied by the emergence of such founder genes, the descendants of which can still be traced in extant organisms. The origin of multicellularity can be considered to be a macroevolutionary transition, for which new gene functions would have been required. Cancer should be tightly connected to multicellular life since it can be viewed as a malfunction of interaction between cells in a multicellular organism. A phylostratigraphic tracking of the origin of cancer genes should, therefore, also provide insights into the origin of multicellularity. Results: We find two strong peaks of the emergence of cancer related protein domains, one at the time of the origin of the first cell and the other around the time of the evolution of the multicellular metazoan organisms. These peaks correlate with two major classes of cancer genes, the 'caretakers', which are involved in general functions that support genome stability and the 'gatekeepers', which are involved in cellular signalling and growth processes. Interestingly, this phylogenetic succession mirrors the ontogenetic succession of tumour progression, where mutations in caretakers are thought to precede mutations in gatekeepers. Conclusions: A link between multicellularity and formation of cancer has often been predicted. However, this has not so far been explicitly tested. Although we find that a significant number of protein domains involved in cancer predate the origin of multicellularity, the second peak of cancer protein domain emergence is, indeed, connected to a phylogenetic level where multicellular animals have emerged. The fact that we can find a strong and consistent signal for this second peak in the phylostratigraphic map implies that a complex multi-level selection process has driven the transition to multicellularity

Clinician and Parent Perspectives on Parent and Family Contextual Factors that Impact Community Mental Health Services for Children with Behavior Problems

The present study employed qualitative methods to examine multiple stakeholder perspectives regarding the role of parent and family contextual factors on community child mental health treatment for children with behavior problems. Findings suggest agreement between clinicians and parents on the number, types and importance of parent and family factors in children’s mental health services; however, stakeholders differed in reports of which factors were most salient. Specifically, clinicians endorsed most factors as being equally salient, while parents described a few salient factors, with parental stress and inadequate social support being the most frequently discussed. These qualitative data further elucidate the context of community services and have implications for evidence-based practice implementation and improving community care

Variations in the NBN/NBS1 gene and the risk of breast cancer in non-BRCA1/2 French Canadian families with high risk of breast cancer

<p>Abstract</p> <p>Background</p> <p>The Nijmegen Breakage Syndrome is a chromosomal instability disorder characterized by microcephaly, growth retardation, immunodeficiency, and increased frequency of cancers. Familial studies on relatives of these patients indicated that they also appear to be at increased risk of cancer.</p> <p>Methods</p> <p>In a candidate gene study aiming at identifying genetic determinants of breast cancer susceptibility, we undertook the full sequencing of the <it>NBN </it>gene in our cohort of 97 high-risk non-<it>BRCA1 </it>and -<it>BRCA2 </it>breast cancer families, along with 74 healthy unrelated controls, also from the French Canadian population. <it>In silico </it>programs (ESEfinder, NNSplice, Splice Site Finder and MatInspector) were used to assess the putative impact of the variants identified. The effect of the promoter variant was further studied by luciferase gene reporter assay in MCF-7, HEK293, HeLa and LNCaP cell lines.</p> <p>Results</p> <p>Twenty-four variants were identified in our case series and their frequency was further evaluated in healthy controls. The potentially deleterious p.Ile171Val variant was observed in one case only. The p.Arg215Trp variant, suggested to impair NBN binding to histone γ-H2AX, was observed in one breast cancer case and one healthy control. A promoter variant c.-242-110delAGTA displayed a significant variation in frequency between both sample sets. Luciferase reporter gene assay of the promoter construct bearing this variant did not suggest a variation of expression in the MCF-7 breast cancer cell line, but indicated a reduction of luciferase expression in both the HEK293 and LNCaP cell lines.</p> <p>Conclusion</p> <p>Our analysis of <it>NBN </it>sequence variations indicated that potential <it>NBN </it>alterations are present, albeit at a low frequency, in our cohort of high-risk breast cancer cases. Further analyses will be needed to fully ascertain the exact impact of those variants on breast cancer susceptibility, in particular for variants located in <it>NBN </it>promoter region.</p

Identification of Piwil2-Like (PL2L) Proteins that Promote Tumorigenesis

PIWIL2, a member of PIWI/AGO gene family, is expressed in the germline stem cells (GSCs) of testis for gametogenesis but not in adult somatic and stem cells. It has been implicated to play an important role in tumor development. We have previously reported that precancerous stem cells (pCSCs) constitutively express Piwil2 transcripts to promote their proliferation. Here we show that these transcripts de facto represent Piwil2-like (PL2L) proteins. We have identified several PL2L proteins including PL2L80, PL2L60, PL2L50 and PL2L40, using combined methods of Gene-Exon-Mapping Reverse Transcription Polymerase Chain Reaction (GEM RT-PCR), bioinformatics and a group of novel monoclonal antibodies. Among them, PL2L60 rather than Piwil2 and other PL2L proteins is predominantly expressed in various types of human and mouse tumor cells. It promotes tumor cell survival and proliferation in vitro through up-regulation of Stat3 and Bcl2 gene expressions, the cell cycle entry from G0/1 into S-phase, and the nuclear expression of NF-κB, which contribute to the tumorigenicity of tumor cells in vivo. Consistently, PL2L proteins rather than Piwil2 are predominantly expressed in the cytoplasm or cytoplasm and nucleus of euchromatin-enriched tumor cells in human primary and metastatic cancers, such as breast and cervical cancers. Moreover, nuclear PL2L proteins are always co-expressed with nuclear NF-κB. These results reveal that PL2L60 can coordinate with NF-κB to promote tumorigenesis and might mediate a common pathway for tumor development without tissue restriction. The identification of PL2L proteins provides a novel insight into the mechanisms of cancer development as well as a novel bridge linking cancer diagnostics and anticancer drug development

Tumor Transcriptome Sequencing Reveals Allelic Expression Imbalances Associated with Copy Number Alterations

Due to growing throughput and shrinking cost, massively parallel sequencing is rapidly becoming an attractive alternative to microarrays for the genome-wide study of gene expression and copy number alterations in primary tumors. The sequencing of transcripts (RNA-Seq) should offer several advantages over microarray-based methods, including the ability to detect somatic mutations and accurately measure allele-specific expression. To investigate these advantages we have applied a novel, strand-specific RNA-Seq method to tumors and matched normal tissue from three patients with oral squamous cell carcinomas. Additionally, to better understand the genomic determinants of the gene expression changes observed, we have sequenced the tumor and normal genomes of one of these patients. We demonstrate here that our RNA-Seq method accurately measures allelic imbalance and that measurement on the genome-wide scale yields novel insights into cancer etiology. As expected, the set of genes differentially expressed in the tumors is enriched for cell adhesion and differentiation functions, but, unexpectedly, the set of allelically imbalanced genes is also enriched for these same cancer-related functions. By comparing the transcriptomic perturbations observed in one patient to his underlying normal and tumor genomes, we find that allelic imbalance in the tumor is associated with copy number mutations and that copy number mutations are, in turn, strongly associated with changes in transcript abundance. These results support a model in which allele-specific deletions and duplications drive allele-specific changes in gene expression in the developing tumor