Repeated sleep-quality assessment and use of sleep-promoting interventions in ICU.

To describe sleep quality using repeated subjective assessment and the ongoing use of sleep-promoting interventions in intensive care. It is well known that the critically ill experience sleep disruption while receiving treatment in the intensive care unit. Both the measurement and promotion of sleep is challenging in the complex environment of intensive care unit. Repeated subjective assessment of patients' sleep in the intensive care unit and use of sleep-promoting interventions has not been widely reported. An observational study was conducted in a 58-bed adult intensive care unit. Sleep quality was assessed using the Richards-Campbell Sleep Questionnaire (RCSQ) each morning. intensive care unit audit sleep-promoting intervention data were compared to data obtained prior to the implementation of a sleep guideline. Patients answered open-ended questions about the facilitators and deterrents of their sleep in intensive care unit. The sample (n = 50) was predominately male (76%) with a mean age: 62.6±16.9 years. Sleep quality was assessed on 2 days or more for 21 patients. The majority of patients (98%) received sleep-promoting interventions. Sleep quality had not improved significantly since the guideline was first implemented. The mean Richards-Campbell Sleep Questionnaire score was 47.9±24.1 mm. The main sleep deterrents were discomfort and noise. Frequently cited facilitators were nothing (i.e. nothing helped) and analgesia. The Richards-Campbell Sleep Questionnaire was used on repeated occasions, and sleep-promoting interventions were used extensively. There was no evidence of improvement in sleep quality since the implementation of a sleep guideline. The use of the Richards-Campbell Sleep Questionnaire for the subjective self-assessment of sleep quality in intensive care unit patients and the implementation of simple-promoting interventions by intensive care unit clinicians is both feasible and may be the most practical way to assess sleep in the intensive care unit context

A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours

BACKGROUND: Poly adenosine diphosphate (ADP)-ribose polymerase (PARP) is essential in cellular processing of DNA damage via the base excision repair pathway (BER). The PARP inhibition can be directly cytotoxic to tumour cells and augments the anti-tumour effects of DNA-damaging agents. This study evaluated the optimally tolerated dose of olaparib (4-(3--4-fluorophenyl) methyl-1(2H)-one; AZD2281, KU0059436), a potent PARP inhibitor, with dacarbazine and assessed safety, toxicity, clinical pharmacokinetics and efficacy of combination treatment. PATIENTS AND METHODS: Patients with advanced cancer received olaparib (20-200 mg PO) on days 1-7 with dacarbazine (600-800 mg m(-2) IV) on day 1 (cycle 2, day 2) of a 21-day cycle. An expansion cohort of chemonaive melanoma patients was treated at an optimally tolerated dose. The BER enzyme, methylpurine-DNA glycosylase and its substrate 7-methylguanine were quantified in peripheral blood mononuclear cells. RESULTS: The optimal combination to proceed to phase II was defined as 100 mg bd olaparib with 600 mg m(-2) dacarbazine. Dose-limiting toxicities were neutropaenia and thrombocytopaenia. There were two partial responses, both in patients with melanoma. CONCLUSION: This study defined a tolerable dose of olaparib in combination with dacarbazine, but there were no responses in chemonaive melanoma patients, demonstrating no clinical advantage over single-agent dacarbazine at these doses

Human Monocytes Undergo Excessive Apoptosis following Temozolomide Activating the ATM/ATR Pathway While Dendritic Cells and Macrophages Are Resistant

Immunodeficiency is a severe therapy-limiting side effect of anticancer chemotherapy resulting from sensitivity of immunocompetent cells to DNA damaging agents. A central role in the immune system is played by monocytes that differentiate into macrophages and dendritic cells (DCs). In this study we compared human monocytes isolated from peripheral blood and cytokine matured macrophages and DCs derived from them and assessed the mechanism of toxicity of the DNA methylating anticancer drug temozolomide (TMZ) in these cell populations. We observed that monocytes, but not DCs and macrophages, were highly sensitive to the killing effect of TMZ. Studies on DNA damage and repair revealed that the initial DNA incision was efficient in monocytes while the re-ligation step of base excision repair (BER) can not be accomplished, resulting in an accumulation of DNA single-strand breaks (SSBs). Furthermore, monocytes accumulated DNA double-strand breaks (DSBs) following TMZ treatment, while DCs and macrophages were able to repair DSBs. Monocytes lack the DNA repair proteins XRCC1, ligase IIIα and PARP-1 whose expression is restored during differentiation into macrophages and DCs following treatment with GM-CSF and GM-CSF plus IL-4, respectively. These proteins play a key role both in BER and DSB repair by B-NHEJ, which explains the accumulation of DNA breaks in monocytes following TMZ treatment. Although TMZ provoked an upregulation of XRCC1 and ligase IIIα, BER was not enhanced likely because PARP-1 was not upregulated. Accordingly, inhibition of PARP-1 did not sensitize monocytes, but monocyte-derived DCs in which strong PARP activation was observed. TMZ induced in monocytes the DNA damage response pathways ATM-Chk2 and ATR-Chk1 resulting in p53 activation. Finally, upon activation of the Fas-receptor and the mitochondrial pathway apoptosis was executed in a caspase-dependent manner. The downregulation of DNA repair in monocytes, resulting in their selective killing by TMZ, might impact on the immune response during cancer chemotherapy

A study protocol of a randomised controlled trial to investigate if a community based strength training programme improves work task performance in young adults with Down syndrome

<p>Abstract</p> <p>Background</p> <p>Muscle strength is important for young people with Down syndrome as they make the transition to adulthood, because their workplace activities typically emphasise physical rather than cognitive skills. Muscle strength is reduced up to 50% in people with Down syndrome compared to their peers without disability. Progressive resistance training improves muscle strength and endurance in people with Down syndrome. However, there is no evidence on whether it has an effect on work task performance or physical activity levels. The aim of this study is to investigate if a student-led community-based progressive resistance training programme can improve these outcomes in adolescents and young adults with Down syndrome.</p> <p>Methods</p> <p>A randomised controlled trial will compare progressive resistance training with a control group undertaking a social programme. Seventy adolescents and young adults with Down syndrome aged 14-22 years and mild to moderate intellectual disability will be randomly allocated to the intervention or control group using a concealed method. The intervention group will complete a 10-week, twice a week, student-led progressive resistance training programme at a local community gymnasium. The student mentors will be undergraduate physiotherapy students. The control group will complete an arts/social programme with a student mentor once a week for 90 minutes also for 10 weeks to control for the social aspect of the intervention. Work task performance (box stacking, pail carry), muscle strength (1 repetition maximum for chest and leg press) and physical activity (frequency, duration, intensity over 7-days) will be assessed at baseline (Week 0), following the intervention (Week 11), and at 3 months post intervention (Week 24) by an assessor blind to group allocation. Data will be analysed using ANCOVA with baseline measures as covariates.</p> <p>Discussion</p> <p>This paper outlines the study protocol for a randomised controlled trial on the effects of progressive resistance training on work task performance and physical activity for adolescents and young adults with Down syndrome. The intervention addresses the impairment of muscle weakness which may improve work task performance and help to increase physical activity levels.</p> <p>Clinical trial registration number</p> <p>Australian New Zealand Clinical Trials Registry ACTRN12609000938202</p

DOGS: Reaction-Driven de novo Design of Bioactive Compounds

We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated ‘in silico’ assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to known bioactive reference ligands in terms of structural and pharmacophoric features. We implemented a deterministic compound construction procedure that explicitly considers compound synthesizability, based on a compilation of 25'144 readily available synthetic building blocks and 58 established reaction principles. This enables the software to suggest a synthesis route for each designed compound. Two prospective case studies are presented together with details on the algorithm and its implementation. De novo designed ligand candidates for the human histamine H4 receptor and γ-secretase were synthesized as suggested by the software. The computational approach proved to be suitable for scaffold-hopping from known ligands to novel chemotypes, and for generating bioactive molecules with drug-like properties

Can, Want and Try: Parents' Viewpoints Regarding the Participation of Their Child with an Acquired Brain Injury

BACKGROUND: Acquired brain injury (ABI) is a leading cause of permanent disability, currently affecting 20,000 Australian children. Community participation is essential for childhood development and enjoyment, yet children with ABI can often experience barriers to participation. The factors which act as barriers and facilitators to community participation for children with an ABI are not well understood. AIM: To identify the viewpoints of parents of children with an ABI, regarding the barriers and facilitators most pertinent to community participation for their child. METHODS: Using Q-method, 41 parents of children with moderate/severe ABI sorted 37 statements regarding barriers and facilitators to community participation. Factor analysis identified three viewpoints. RESULTS: This study identified three distinct viewpoints, with the perceived ability to participate decreasing with a stepwise trend from parents who felt their child and family "can" participate in viewpoint one, to "want" in viewpoint two and "try" in viewpoint three. CONCLUSIONS: Findings indicated good participation outcomes for most children and families, however some families who were motivated to participate experienced significant barriers. The most significant facilitators included child motivation, supportive relationships from immediate family and friends, and supportive community attitudes. The lack of supportive relationships and attitudes was perceived as a fundamental barrier to community participation. SIGNIFICANCE: This research begins to address the paucity of information regarding those factors that impact upon the participation of children with an ABI in Australia. Findings have implications for therapists, service providers and community organisations

Using Technology and the Ecological Model of Constraints to Develop Story-Based Interventions for Children with Autism Spectrum Disorder

©, Copyright SHAPE America. The use of technology has proven to be a successful tool for enhancing the learning of children with disabilities. One example is the use of video-recorded social story movies as interventions for children with an autism spectrum disorder (ASD). Through the use of electronic devices such as iPads, iPods and tablets, social stories are brought to life in the form of a movie. Adopting a constraints approach can assist in the development of story movies. The model of constraints identifies individual, environmental and task constraints that can positively or negatively impact a child with ASD. The purpose of this article is to describe the use of technology-based story movies (social stories) as a method of delivery for story-based interventions, to provide information on how to script social stories suitable for physical education, and to explain how ecological theory and constraints can assist in the development and delivery of social stories

Factors associated with shared decision making among primary care physicians: Findings from a multicentre cross-sectional study

Contains fulltext : 190880.pdf (publisher's version ) (Open Access)BACKGROUND: Despite growing recognition that shared decision making (SDM) is central for patient-centred primary care, adoption by physicians remains limited in routine practice. OBJECTIVE: To examine the characteristics of physicians, patients and consultations associated with primary care physicians' SDM behaviours during routine care. METHODS: A multicentre cross-sectional survey study was conducted with 114 unique patient-physician dyads recruited from 17 primary care clinics in Quebec and Ontario, Canada. Physicians' SDM behaviours were assessed with the 12-item OPTION scale scored by third observers using audio-recordings of consultations. Independent variables included 21 physician, patient and consultation characteristics. We assessed factors associated with OPTION scores using multivariate linear regression models. RESULTS: On the OPTION scale, where higher scores indicated greater SDM behaviours, physicians earned an overall mean score of 25.7+/-9.8 of 100. In the final adjusted regression model, higher OPTION scores were associated with physicians' social participation (involvement in one committee beta=5.75, P=.04; involvement in two or more committees beta=7.74, P=.01), patients' status as employed (beta=6.48, P=.02), clinically significant decisional conflict in patients (beta=7.15, P=.002) and a longer duration of consultations (beta=0.23, P=.002). CONCLUSION: Physicians' social participation, patients' employment status and decisional conflict and the duration of consultations were associated with primary care physicians' SDM behaviours in routine care. These factors should be considered when designing strategies to implement SDM and promote more patient-centred care in primary care