Study recruitment factors in advanced cancer: the Prognosis in Palliative care Study II (PiPS2) - a multicentre, prospective, observational cohort project.

OBJECTIVES: The Prognosis in Palliative care Study II (PiPS2) was a large multicentre observational study validating prognostic tools in patients with advanced cancer. Many palliative care studies fail to reach their recruitment target. To inform future studies, PiPS2 rigorously monitored and identified any potential recruitment barriers. METHODS: Key recruitment stages (ie, whether patients were eligible for the study, approached by the researchers and whether consent was obtained for enrolment) were monitored via comprehensive screening logs at participating sites (inpatient hospices, hospitals and community palliative care teams). The reasons for patients' ineligibility, inaccessibility or decision not to consent were documented. RESULTS: 17 014 patients were screened across 27 participating sites over a 20-month recruitment period. Of those, 4642 (27%) were ineligible for participation in the study primarily due to non-cancer diagnoses. Of 12 372 eligible patients, 9073 (73%) were not approached, the most common reason being a clinical decision not to do so. Other reasons included patients' death or discharge before they were approached by the researchers. Of the 3299 approached patients, 1458 (44%) declined participation mainly because of feeling too unwell, experiencing severe distress or having other competing priorities. 11% (n=1841/17 014) of patients screened were enrolled in the study, representing 15% (n=1841/12 372) of eligible patients. Different recruitment patterns were observed across inpatient hospice, hospital and community palliative care teams. CONCLUSIONS: The main barrier to recruitment was 'accessing' potentially eligible patients. Monitoring key recruitment stages may help to identify barriers and facilitators to enrolment and allow results to be put into better context. TRIAL REGISTRATION NUMBER: ISRCTN13688211.

The effect of training intensity on implicit learning rates in schizophrenia.

Cognitive impairments in learning and memory are core symptoms of schizophrenia, associated with reduced self-reported quality of life. The most effective treatment of cognitive impairments is drill and practice cognitive training. Still, to date no study has investigated the effect of varying the frequency of training on cognitive outcomes. Here we utilized a verbal memory based language learning task, tapping into implicit cognitive processes, to investigate the role of training intensity on learning rates in individuals with schizophrenia. Data from 47 participants across two studies was utilized, one with a daily training regimen over 5 days and the other with a more intensive schedule of 5 sessions delivered over 2 days. The primary outcome measure was the change in implicit learning performance across five sessions, quantified with the Matthews Correlation Coefficient (MCC). Participants in the daily training group showed improved performance compared to the intensive group only at session 4. This is the first study to show that implicit learning rates are influenced by training intensity, with daily sessions outperforming a more intensive regimen; a period of consolidation overnight may be necessary to optimize cognitive training for individuals with schizophrenia.

Barriers to recruitment when conducting a commissioned randomised controlled trial of medication versus psychological therapy for generalised anxiety disorder: some lessons learned.

BACKGROUND: Poor recruitment is the most common reason for premature discontinuation of randomised controlled trials (RCTs). An RCT of medication versus psychological therapy for generalised anxiety disorder (GAD) was discontinued prematurely by the UK National Institute of Health Research funders because of recruitment failure. In order to inform future research studies, this article explores the reasons for poor recruitment and aspects which could have been improved. METHODS: The trial recruited participants via psychological well-being practitioners (PWPs) employed within local Improving Assess to Psychological Therapies (IAPT) services at four sites in England. For this study, we initially examined the recruitment data to identify reasons why potential participants were reluctant to participate in the trial. We then investigated reasons the PWPs did not identify more potential participants. Finally, we performed retrospective analyses of a computerised clinical records system used by the IAPT services in this study. These analyses aimed to establish the number of potential participants who had not been approached about the trial as well as whether there were additional factors affecting the numbers of people who might be eligible to take part. Data were obtained for all patients assessed during the period from the date on which recruitment commenced until the closure of the trial. RESULTS: Three quarters of those patients identified as possibly suitable for the trial declined to take part; the great majority did so because they did not want to be randomly assigned to receive medication. Our retrospective database analyses showed that only around 12% of potentially eligible patients for the trial were identified by the PWPs at the pilot sites. The results also indicated that only 5% of those noted at entry to the IAPT services to have a score of at least 10 on the GAD-7 questionnaire (a self-completed questionnaire with high sensitivity and specificity for GAD) would have been eligible for the trial. CONCLUSIONS: Our findings suggest that poor recruitment to RCTs can be significantly affected by participants' treatment preferences and by factors influencing the recruiting clinicians. It may also be important not to include too many restrictions on inclusion criteria for pragmatic trials aiming for generalisable results. TRIAL REGISTRATION: ISCRTN14845583 . Registration date: 5 February 2015.

Correction to: The prognosis in palliative care study II (PiPS2): study protocol for a multi-centre, prospective, observational, cohort study.

After publication, the authors noticed some minor errors in "Nested qualitative sub-study" section, first paragraph of the section, page 7 of the published article.

The Prognosis in Palliative care Study II (PiPS2): study protocol for a multi-centre, prospective, observational, cohort study.

BACKGROUND: More accurate methods of prognostication are likely to lead to improvements in the quality of care of patients approaching the ends of their lives. The Prognosis in Palliative care Scales (PiPS) are prognostic models of survival. The scores are calculated using simple clinical data and observations. There are two separate PiPS models; PiPS-A for patients without blood test results and PiPS-B for patients with blood test results. Both models predict whether a patient is likely to live for "days", "weeks" or "months" and have been shown to perform as well as clinicians' estimates of survival. PiPS-B has also been found to be significantly better than doctors' estimates of survival. We report here a protocol for the validation of PiPS and for the evaluation of the accuracy of other prognostic tools in a new, larger cohort of patients with advanced cancer. METHODS: This is a national, multi-centre, prospective, observational cohort study, aiming to recruit 1778 patients via palliative care services across England and Wales. Eligible patients have advanced, incurable cancer and have recently been referred to palliative care services. Patients with or without capacity are included in the study. The primary outcome is the accuracy of PiPS predictions and the difference in accuracy between these predictions and the clinicians' estimates of survival; with PiPS-B being the main model of interest. The secondary outcomes include the accuracy of predictions by the Palliative Prognostic Index (PPI), Palliative Performance Scale (PPS), Palliative Prognostic score (PaP) and the Feliu Prognostic Nomogram (FPN) compared with actual patient survival and clinicians' estimates of survival. A nested qualitative sub-study using face-to-face interviews with patients, carers and clinicians is also being undertaken to assess the acceptability of the prognostic models and to identify barriers and facilitators to clinical use. DISCUSSION: The study closed to recruitment at the end of April 2018 having exceeded the required sample size of 1778 patients. The qualitative sub-study is nearing completion. This demonstrates the feasibility of recruiting large numbers of participants to a prospective palliative care study. TRIAL REGISTRATION: ISRCTN13688211 (registration date: 28/06/2016).

Modafinil combined with cognitive training: pharmacological augmentation of cognitive training in schizophrenia.

Several efforts to develop pharmacological treatments with a beneficial effect on cognition in schizophrenia are underway, while cognitive remediation has shown modest effects on cognitive performance. Our goal was to test if pharmacological augmentation of cognitive training would result in enhancement of training-induced learning. We chose modafinil as the pharmacological augmenting agent, as it is known to have beneficial effects on learning and cognition. 49 participants with chronic schizophrenia were enroled in a double-blind, placebo-controlled study across two sites and were randomised to either modafinil (200mg/day) or placebo. All participants engaged in a cognitive training program for 10 consecutive weekdays. The primary outcome measure was the performance on the trained tasks and secondary outcome measures included MATRICS cognitive battery, proxy measures of everyday functioning and symptom measures. 84% of the participants completed all study visits. Both groups showed significant improvement in the performance of the trained tasks suggesting potential for further learning. Modafinil did not induce differential enhancement on the performance of the trained tasks or any differential enhancement of the neuropsychological and functional measures compared to placebo. Modafinil showed no significant effects on symptom severity. Our study demonstrated that combining pharmacological compounds with cognitive training is acceptable to patients and can be implemented in large double-blind randomised controlled trials. The lack of differential enhancement of training-induced learning raises questions, such as choice and optimal dose of drug, cognitive domains to be trained, type of cognitive training, intervention duration and chronicity of illness that require systematic investigation in future studies.

Functional neuroanatomy of executive function after neonatal brain injury in adults who were born very preterm.

Individuals who were born very preterm (VPT; <33 gestational weeks) are at risk of experiencing deficits in tasks involving executive function in childhood and beyond. In addition, the type and severity of neonatal brain injury associated with very preterm birth may exert differential effects on executive functioning by altering its neuroanatomical substrates. Here we addressed this question by investigating with functional magnetic resonance imaging (fMRI) the haemodynamic response during executive-type processing using a phonological verbal fluency and a working memory task in VPT-born young adults who had experienced differing degrees of neonatal brain injury. 12 VPT individuals with a history of periventricular haemorrhage and ventricular dilatation (PVH+VD), 17 VPT individuals with a history of uncomplicated periventricular haemorrhage (UPVH), 13 VPT individuals with no history of neonatal brain injury and 17 controls received an MRI scan whilst completing a verbal fluency task with two cognitive loads ('easy' and 'hard' letters). Two groups of VPT individuals (PVH+VD; n = 10, UPVH; n = 8) performed an n-back task with three cognitive loads (1-, 2-, 3-back). Results demonstrated that VPT individuals displayed hyperactivation in frontal, temporal, and parietal cortices and in caudate nucleus, insula and thalamus compared to controls, as demands of the verbal fluency task increased, regardless of type of neonatal brain injury. On the other hand, during the n-back task and as working memory load increased, the PVH+VD group showed less engagement of the frontal cortex than the UPVH group. In conclusion, this study suggests that the functional neuroanatomy of different executive-type processes is altered following VPT birth and that neural activation associated with specific aspects of executive function (i.e., working memory) may be particularly sensitive to the extent of neonatal brain injury.

Neonatal brain injury and neuroanatomy of memory processing following very preterm birth in adulthood: an fMRI study.

Altered functional neuroanatomy of high-order cognitive processing has been described in very preterm individuals (born before 33 weeks of gestation; VPT) compared to controls in childhood and adolescence. However, VPT birth may be accompanied by different types of adverse neonatal events and associated brain injury, the severity of which may have differential effects on brain development and subsequent neurodevelopmental outcome. We conducted a functional magnetic resonance imaging (fMRI) study to investigate how differing degrees of neonatal brain injury, detected by neonatal ultrasounds, affect the functional neuroanatomy of memory processing in VPT young adults. We used a verbal paired associates learning task, consisting of four encoding, four cued-recall and four baseline condition blocks. To further investigate whether differences in neural activation between the groups were modulated by structural brain changes, structural MRI data were also collected. We studied 12 VPT young adults with a history of periventricular haemorrhage with associated ventricular dilatation, 17 VPT individuals with a history of uncomplicated periventricular haemorrhage, 12 individuals with normal ultrasonographic findings, and 17 controls. Results of a linear trend analysis demonstrated that during completion of the paired associates learning task right frontal and right parietal brain activation decreased as the severity of neonatal brain injury increased. There were no statistically significant between-group differences in on-line task performance and participants' intelligence quotient (IQ) at assessment. This pattern of differential activation across the groups was observed particularly in the right middle frontal gyrus during encoding and in the right posterior cingulate gyrus during recall. Structural MRI data analysis revealed that grey matter volume in the right superior temporal gyrus, right cerebellum, left middle temporal gyrus, right globus pallidus and right medial frontal gyrus decreased with increasing severity of neonatal brain injury. However, the significant between-group functional neuroanatomical differences were not directly attributable to the detected structural regional differences.