Treatment preference and recruitment to pediatric RCTs: A systematic review.

BACKGROUND: Recruitment to pediatric randomised controlled trials (RCTs) can be a challenge, with ethical issues surrounding assent and consent. Pediatric RCTs frequently recruit from a smaller pool of patients making adequate recruitment difficult. One factor which influences recruitment and retention in pediatric trials is patient and parent preferences for treatment. PURPOSE: To systematically review pediatric RCTs reporting treatment preference. METHODS: Database searches included: MEDLINE, CINAHL, EMBASE, and COCHRANE.Qualitative or quantitative papers were eligible if they reported: pediatric population, (0-17 years) recruited to an RCT and reported treatment preference for all or some of the participants/parents in any clinical area. Data extraction included: Number of eligible participants consenting to randomisation arms, number of eligible patients not randomised because of treatment preference, and any further information reported on preferences (e.g., if parent preference was different from child). RESULTS: Fifty-two studies were included. The number of eligible families declining participation in an RCT because of preference for treatment varied widely (between 2 and 70%) in feasibility, conventional and preference trial designs. Some families consented to trial involvement despite having preferences for a specific treatment. Data relating to 'participant flow and recruitment' was not always reported consistently, therefore numbers who were lost to follow-up or withdrew due to preference could not be extracted. CONCLUSIONS: Families often have treatment preferences which may affect trial recruitment. Whilst children appear to hold treatment preferences, this is rarely reported. Further investigation is needed to understand the reasons for preference and the impact preference has on RCT recruitment, retention and outcome.

Autism, early psychosis, and social anxiety disorder: understanding the role of social cognition and its relationship to disability in young adults with disorders characterized by social impairments.

Impairments in social cognition are believed contribute to disability, particularly for disorders characterized by difficulties in social interaction. There has been little transdiagnostic investigation of this across social cognition domains in young adults. A total of 199 young adults diagnosed with autism spectrum disorder (ASD; N = 53), early psychosis (EP; N = 51), and social anxiety disorder (SAD; N = 64) were compared against neurotypical controls (NT; N = 31) on a battery of lower and higher-order and self-report social cognition measures. For both ASD and EP, participants showed impaired performance on all lower-order emotion recognition tasks and one higher-order social cognition test. Self-reports of empathy were reduced in all clinical groups and particularly in ASD. For SAD, despite showing no objective social cognition impairment, self-reported empathy was reduced to the same level as EP. Discriminant analysis revealed that self-reported empathy and lower-order emotion recognition tests provide best capacity to differentiate groups. Regressions predicting disability revealed depression as the strongest predictor across all disability measures. Empathy provided additional predictive value for social disability and social interaction anxiety. Overall, results support a similar social-cognitive development profile across ASD and EP. While self-reported empathy differentiated between groups, discrepancy between objective social cognition test performance and self-reported empathy in the SAD group suggests probable threat-related self-monitoring report biases that likely further influence all group outcomes. As depression and empathy were the most important predictors of disability, regardless of diagnostic group, research is required to explore targeted interventions for difficulties in these domains to reduce disability.

A qualitative study of nurses' perceptions of a behavioural strategies e-learning program to reduce interruptions during medication administration.

OBJECTIVES: We sought to evaluate the perceptions of nurses of an e-learning educational program to encourage the use of behavioural strategies-blocking, engaging, mediating, multitasking, and preventing-to reduce the negative effects of interruptions during medication administration. DESIGN: A qualitative design was used to evaluate the impact of this e-learning educational intervention on nurses' behaviour. SETTINGS: Two wards (palliative care and aged care) from two different hospitals within a large local health service within Sydney Australia, were included in the study. These wards were also involved in a cluster randomised trial to test the effectiveness of the program. PARTICIPANTS: A purposive sample participated comprising nine registered and enrolled nurses certified to conduct medication administration, who had reviewed the educational modules. METHODS: Two focus groups were conducted and these sessions were digitally recorded and transcribed verbatim. Thematic analysis identified seven themes. RESULTS: The major themes identified included: perceptions of interruptions, accessing the program, content of the program, impact, maintaining good practice and facilitators and barriers to changing behaviour. CONCLUSIONS: The use of embedded authentic images of patient interruptions and management strategies increased some nurses' perceived use of strategies to manage interruptions. Nurses varied in their perception as to whether they could change their behaviour with some describing change at the individual and ward team levels, while others described patient caseload and other health professionals as a barrier. The use of this innovative educational intervention is recommended for staff orientation, student nurses, medical officers and allied health staff. Further research is required in how this e-learning program can be used in combination with other effective interventions to reduce interruptions.

Belief-bias reasoning in non-clinical delusion-prone individuals.

BACKGROUND AND OBJECTIVES: It has been proposed that people with delusions have difficulty inhibiting beliefs (i.e., "doxastic inhibition") so as to reason about them as if they might not be true. We used a continuity approach to test this proposal in non-clinical adults scoring high and low in psychometrically assessed delusion-proneness. High delusion-prone individuals were expected to show greater difficulty than low delusion-prone individuals on "conflict" items of a "belief-bias" reasoning task (i.e. when required to reason logically about statements that conflicted with reality), but not on "non-conflict" items. METHODS: Twenty high delusion-prone and twenty low delusion-prone participants (according to the Peters et al. Delusions Inventory) completed a belief-bias reasoning task and tests of IQ, working memory and general inhibition (Excluded Letter Fluency, Stroop and Hayling Sentence Completion). RESULTS: High delusion-prone individuals showed greater difficulty than low delusion-prone individuals on the Stroop and Excluded Letter Fluency tests of inhibition, but no greater difficulty on the conflict versus non-conflict items of the belief-bias task. They did, however, make significantly more errors overall on the belief-bias task, despite controlling for IQ, working memory and general inhibitory control. LIMITATIONS: The study had a relatively small sample size and used non-clinical participants to test a theory of cognitive processing in individuals with clinically diagnosed delusions. CONCLUSIONS: Results failed to support a role for doxastic inhibitory failure in non-clinical delusion-prone individuals. These individuals did, however, show difficulty with conditional reasoning about statements that may or may not conflict with reality, independent of any general cognitive or inhibitory deficits.

Belief-bias reasoning in non-clinical delusion-prone individuals.

BACKGROUND AND OBJECTIVES: It has been proposed that people with delusions have difficulty inhibiting beliefs (i.e., "doxastic inhibition") so as to reason about them as if they might not be true. We used a continuity approach to test this proposal in non-clinical adults scoring high and low in psychometrically assessed delusion-proneness. High delusion-prone individuals were expected to show greater difficulty than low delusion-prone individuals on "conflict" items of a "belief-bias" reasoning task (i.e. when required to reason logically about statements that conflicted with reality), but not on "non-conflict" items. METHODS: Twenty high delusion-prone and twenty low delusion-prone participants (according to the Peters et al. Delusions Inventory) completed a belief-bias reasoning task and tests of IQ, working memory and general inhibition (Excluded Letter Fluency, Stroop and Hayling Sentence Completion). RESULTS: High delusion-prone individuals showed greater difficulty than low delusion-prone individuals on the Stroop and Excluded Letter Fluency tests of inhibition, but no greater difficulty on the conflict versus non-conflict items of the belief-bias task. They did, however, make significantly more errors overall on the belief-bias task, despite controlling for IQ, working memory and general inhibitory control. LIMITATIONS: The study had a relatively small sample size and used non-clinical participants to test a theory of cognitive processing in individuals with clinically diagnosed delusions. CONCLUSIONS: Results failed to support a role for doxastic inhibitory failure in non-clinical delusion-prone individuals. These individuals did, however, show difficulty with conditional reasoning about statements that may or may not conflict with reality, independent of any general cognitive or inhibitory deficits.

Efficacy and safety of initial combination treatment with sitagliptin and pioglitazone--a factorial study.

AIM: To evaluate the efficacy and safety of initial combination therapy of sitagliptin 100 mg/day coadministered with all marketed doses of pioglitazone in patients with type 2 diabetes. METHODS: Patients with A1c ≥7.5 and ≤11.0% were randomized among seven arms that received, once daily, 100 mg sitagliptin alone; 15, 30 or 45 mg pioglitazone alone, or 100 mg sitagliptin plus 15, 30 or 45 mg pioglitazone for 54 weeks. The primary endpoint was change from baseline in A1c at week 24. Protocol-specified analyses compared combination therapies with monotherapies at respective dose-strengths and combination of sitagliptin plus pioglitazone 30 mg with pioglitazone 45 mg monotherapy. Post-hoc analyses compared sitagliptin plus pioglitazone 15 mg with pioglitazone monotherapy at the two higher doses. RESULTS: Initial combination therapy with sitagliptin and pioglitazone provided significantly greater reductions in A1c (0.4-0.7% differences) and other glycaemic endpoints than either monotherapy at the same doses. Combining sitagliptin with low-dose pioglitazone generally produced greater glycaemic improvements than higher doses of pioglitazone monotherapy (0.3-0.4% differences in A1c). Combination therapy was generally well tolerated; adverse events (AEs) of hypoglycaemia were reported with similar incidence (7.8-11.1%) in all treatment groups over the 54 weeks of study; oedema was reported in 0.5% of patients in the sitagliptin monotherapy group and 2.7-5.3% among pioglitazone-treated groups. Significant weight gain was observed in all combination-treated groups compared with the sitagliptin monotherapy group. CONCLUSIONS: Initial combination therapy with sitagliptin and pioglitazone provided better glycaemic control than either monotherapy and was generally well tolerated.

Bone loss in the oestrogen-depleted rat is not exacerbated by sitagliptin, either alone or in combination with a thiazolidinedione.

Antihyperglycaemic therapy on bone was evaluated in the ovariectomized (OVX), non-diabetic adult rat. Animals were treated daily for 12 weeks with various doses of sitagliptin, pioglitazone, rosiglitazone, combinations of sitagliptin with pioglitazone or vehicle alone. Sitagliptin target engagement was confirmed by assessing inhibition of plasma dipeptidyl peptidase-4 (DPP-4) and oral glucose tolerance. Parameters related to bone health were evaluated in femur and vertebrae by dual-energy X-ray absorptiometry and histomorphometry. Bone mineral density (BMD) generally did not differ significantly between OVX-sitagliptin-treated animals and OVX-vehicle controls. In lumbar vertebrae, however, there was significantly less BMD loss with increasing sitagliptin dose. Thiazolidinedione (TZD) treatment generally resulted in lower BMD; OVX-TZD-treated (but not OVX-sitagliptin-treated) animals also had lessened cortical thickness in central femur and profoundly greater bone marrow adiposity in lumbar vertebrae. These findings support prior findings with TZDs and suggest a neutral or beneficial impact of DPP-4 inhibition on bone health.

Evaluating an intensive ward-based writing coach programme to improve nursing documentation: lessons learned.

AIM: This study aimed to develop a ward-based writing coach programme to improve the quality of patient information in nursing documentation. BACKGROUND: Omissions in the patient information make nursing notes an unreliable source for care planning. Strategies to improve the quality of nursing documentation have been unsuccessful. An education programme, with one-to-one coaching in the clinical environment, was tested. METHOD: A concurrent mixed methods approach including a pre-post test intervention and control design for the quantitative component combined with a qualitative approach using a focus group (eight nurses) was used. Healthcare records for 87 patients (intervention) (46 pre and 41 post) and 88 patients (control) (51 pre and 37 post) were reviewed using the Nursing and Midwifery Content Audit Tool for quality nursing documentation. Sixteen nurses from two intervention wards participated in an introductory workshop with 2 weeks of coaching. No intervention was given to the control ward. RESULTS: No significant differences were found between the wards across the 14 criteria representing quality documentation; most criteria were present in 75% or more of the records. Improvements were demonstrated in both the intervention and comparison units. Themes identified from the focus groups included the impact these changes had on nurses and patients, perceived difficulties with nursing documentation, medicolegal aspects and the attributes of an effective writing coach. CONCLUSION: Writing coaching is a supportive approach to improving nursing documentation. Also, regular auditing prompts nurses to improve nursing documentation. Further research using larger sample sizes can further confirm or refute these findings.

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.

AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. CONCLUSIONS/INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.

Genome sequence of the emerging pathogen Helicobacter canadensis.

We determined the genome sequence of the type strain of Helicobacter canadensis, an emerging human pathogen with diverse animal reservoirs. Potential virulence determinants carried by the genome include systems for N-linked glycosylation and capsular export. A protein-based phylogenetic analysis places H. canadensis close to Wolinella succinogenes.

The phenomenology of inner speech: comparison of schizophrenia patients with auditory verbal hallucinations and healthy controls.

BACKGROUND: Despite the popularity of inner-speech theories of auditory verbal hallucinations (AVHs), little is known about the phenomenological qualities of inner speech in patients with schizophrenia who experience AVHs (Sz-AVHs), or how this compares to inner speech in the non-voice-hearing general population. METHOD: We asked Sz-AVHs (n=29) and a non-voice-hearing general population sample (n=42) a series of questions about their experiences of hearing voices, if present, and their inner speech. RESULTS: The inner speech reported by patients and controls was found to be almost identical in all respects. Furthermore, phenomenological qualities of AVHs (e.g. second- or third-person voices) did not relate to corresponding qualities in inner speech. CONCLUSIONS: No discernable differences were found between the inner speech reported by Sz-AVHs and healthy controls. Implications for inner-speech theories of AVHs are discussed.

A phase II trial of imatinib (ST1571) in patients with c-kit expressing relapsed small-cell lung cancer: a CALGB and NCCTG study.

BACKGROUND: The aim of the present study was to evaluate the clinical activity of imatinib mesylate in patients with recurrent and refractory c-kit-expressing small-cell lung cancer. PATIENTS AND METHODS: Patients with c-kit-expressing SCLC (> or =1+ by immunohistochemistry) were enrolled in two groups. Arm A included patients with disease progression <3 months and arm B included patients with disease progression > or =3 months after previous treatment. Imatinib was administered at a dose of 400 mg b.i.d. continuously, with a cycle length of 28 days. A single stage Simon design with a planned interim analysis was used to evaluate the 16-week progression free rate in each arm. RESULTS: A total of 29 evaluable patients were entered into the study (seven in arm A, median age 68; 22 in arm B, median age 64.5). Median number of treatment cycles was one in both arms. Grade 3+ non-hematologic adverse events were seen in 15 (52%) patients, with nausea, vomiting, dyspnea, fatigue, anorexia and dehydration each occurring in at least 10% of patients. Median survival was 3.9 and 5.3 months and median time to progression was 1 and 1.1 months for arms A and B, respectively. Enrollment to arm A was temporarily suspended prior to reaching interim analysis due to striking early disease progression (29%), early deaths (29%) and patient refusal (42%). No objective responses and no confirmed stable disease > or =6 weeks were seen in either arm. Accrual was permanently terminated to both arms as only one patient was progression-free at 16 weeks. CONCLUSION: Imatinib failed to demonstrate any clinical activity in spite of patient selection for c-kit-expressing SCLC. Our results strengthen the collective evidence that prediction of efficacy of novel therapeutic agents based on target expression, rather than pathway activation (for example, through activating mutations), may not be a valid paradigm for drug development.

Disturbed communication in schizophrenia: the role of poor pragmatics and poor mind-reading.

BACKGROUND: Disturbed speech in schizophrenia may reflect pragmatic deficits of expressive language. Pragmatic comprehension deficits also occur in schizophrenia. This study investigated whether poor 'mind-reading' (i.e. a general difficulty with inferring and monitoring other people's thoughts) causes pragmatic language impairments of both expression and comprehension in patients with schizophrenia. METHOD: Mind-reading (or theory of mind) was tested in patients with schizophrenia and in healthy controls using a false-belief picture-sequencing task. Pragmatic comprehension skills were assessed using a test of non-literal speech interpretation. Clinical ratings of formal thought disorder (FTD) indexed the expressive language deficits of patients. To control for possible contributory effects of executive dysfunction, inhibitory control was tested using capture picture-sequences and executive-planning was tested using the Tower of London task. RESULTS: False-belief picture-sequencing, understanding of irony and understanding of metaphors were all selectively impaired in the patients. Poor mind-reading (indexed by high error rate in sequencing false-belief stories) was associated with poor understanding of irony, but was unrelated to poor understanding of metaphors. Whereas poor appreciation of irony and poor mind-reading were associated with high ratings of positive formal thought disorder, high ratings of negative formal thought disorder were associated with poor understanding of metaphors and executive dysfunction. CONCLUSIONS: Whereas poor mind-reading may contribute to positive aspects of formal thought disorder and impaired appreciation of irony in patients with schizophrenia; negative features of formal thought disorder and poor understanding of metaphors appear better explained by abnormal semantics. Overall, the findings of this study support the view that the functional basis of formal thought disorder in schizophrenia is not unitary.

Synaptically driven spikes and long-term potentiation in neocortical layer 2/3.

Recently, variation upon a well-established hippocampal model has given rise to a new paradigm in which the strength of synaptic inputs to neocortical layer 2/3 is estimated in vitro by recording synaptically driven extracellular potentials elicited there by electrical stimulation applied to underlying layer 4. The analysis of these potentials is commonly based upon an assumption that postsynaptic spiking has played no significant role in their generation. Here, we have tested this assumption by quantifying in rats (using data obtained by cell-attached recording) the rate at which unit spikes are elicited in layer 2/3 under commonly used conditions of stimulation and recording. We found that spike responses were regularly elicited at the same latencies as field potential peaks and the rising phases of intracellularly recorded synaptic currents, and the incidence of such spiking (the fractional rate of cells spiking versus cells sampled) was sufficient to give this higher-order activity a major role in determining response amplitudes. We then analyzed layer 2/3 waveform characteristics before and after inducing long-term potentiation (LTP) by theta-burst stimulation (TBS) and found that the induction of LTP succeeded only when the initial response included a strong spike component. We further observed that LTP expression was always accompanied by a pronounced enhancement of such components. Our data suggest that, unlike in hippocampal CA1, LTP elicited by TBS in this neocortical paradigm depends upon modification of synaptically driven spike activity, through either enhanced synchronization of unitary responses, the recruitment of additional responding units, or both. This potentiation of the spike response could arise (as previously proposed) through an increase in the efficacy of synapses mediating projection from layer 4 to 2/3, but other mechanisms may also contribute, such as modification of short-range recurrent connections within layer 2/3, which are likely to play an important role in defining local-network cell ensembles.

Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces.

To examine the in vivo function of presenilin-1 (PS1), we selectively deleted the PS1 gene in excitatory neurons of the adult mouse forebrain. These conditional knockout mice were viable and grew normally, but they exhibited a pronounced deficiency in enrichment-induced neurogenesis in the dentate gyrus. This reduction in neurogenesis did not result in appreciable learning deficits, indicating that addition of new neurons is not required for memory formation. However, our postlearning enrichment experiments lead us to postulate that adult dentate neurogenesis may play a role in the periodic clearance of outdated hippocampal memory traces after cortical memory consolidation, thereby ensuring that the hippocampus is continuously available to process new memories. A chronic, abnormal clearance process in the hippocampus may conceivably lead to memory disorders in the mammalian brain.

Visual perspective-taking and schizotypy: evidence for a simulation-based account of mentalizing in normal adults.

Modular theory-of-mind accounts attribute poor mentalizing to disruption of a cognitive module dedicated to computing higher-order representations of primary representations (metarepresentations). Since metarepresentational capacity is needed to mentalize about other people's beliefs but is not needed to judge visual perspectives (which can be done by mentally rotating primary representations of seen objects), this view predicts that visual perspective-taking will be intact in individuals with selective mentalizing impairments. Counter to that prediction, this study found evidence of disturbed visual perspective-taking in normal adults who score higher on the personality variable of schizotypy and who are known to be relatively poor mentalizers (despite intact ability to inhibit salient inappropriate information in order to reason consequentially on the basis of hypothetical states, other than mental states). Whereas high-schizotypal adults and low-schizotypal adults did not differ in their ability to judge item questions (asking the relative location of array features), high-schizotypal adults performed more poorly than low-schizotypal adults in judging appearance questions (asking how an array would appear from another perspective) under viewer-rotation instructions (asking subjects to imagine moving themselves relative to a fixed array) and performed better than low-schizotypal adults in judging appearance questions under array-rotation instructions (asking subjects to imagine rotating an array relative to their own fixed viewer position). Based on these and other findings we conclude that poor mentalizing in normal adults is better understood as an impairment of perspective-taking (visual and/or cognitive) and introduce the concept of allocentric simulation to explain the functional basis of this perspective-taking impairment.

A chimeric activator of transcription that uses two DNA-binding domains to make simultaneous contact with pairs of recognition sites.

Many well-known transcriptional regulatory proteins are composed of at least two independently folding domains and, typically, only one of these is a DNA-binding domain. However, some transcriptional regulators have been described that have more than one DNA-binding domain. Regulators with a single DNA-binding domain often bind co-operatively to the DNA in homotypic or heterotypic combinations, and two or more DNA-binding domains of a single regulatory protein can also bind co-operatively to suitably positioned recognition sequences. Here, we examine the behaviour of a chimeric activator of transcription with two different DNA-binding domains, that of the bacteriophage lambda cI protein and that of the Escherichia coli cyclic AMP receptor protein. We show that these two DNA-binding moieties, when present in the same molecule, can bind co-operatively to a pair of cognate recognition sites located upstream of a test promoter, thereby permitting the chimera to function as a particularly strong activator of transcription from this promoter. Our results show how such a bivalent DNA-binding protein can be used to regulate transcription differentially from promoters that bear either one or both recognition sites.