Optic radiation structure and anatomy in the normally developing brain determined using diffusion MRI and tractography

The optic radiation (OR) is a component of the visual system known to be myelin mature very early in life. Diffusion tensor imaging (DTI) and its unique ability to reconstruct the OR in vivo were used to study structural maturation through analysis of DTI metrics in a cohort of 90 children aged 5–18 years. As the OR is at risk of damage during epilepsy surgery, we measured its position relative to characteristic anatomical landmarks. Anatomical distances, DTI metrics and volume of the OR were investigated for age, gender and hemisphere effects. We observed changes in DTI metrics with age comparable to known trajectories in other white matter tracts. Left lateralization of DTI metrics was observed that showed a gender effect in lateralization. Sexual dimorphism of DTI metrics in the right hemisphere was also found. With respect to OR dimensions, volume was shown to be right lateralised and sexual dimorphism demonstrated for the extent of the left OR. The anatomical results presented for the OR have potentially important applications for neurosurgical planning

‘Potentially inappropriate or specifically appropriate?’ Qualitative evaluation of general practitioners views on prescribing, polypharmacy and potentially inappropriate prescribing in older people

BACKGROUND: Potentially inappropriate prescribing (PIP) is common in older people in primary care, as evidenced by a significant body of quantitative research. However, relatively few qualitative studies have investigated the phenomenon of PIP and its underlying processes from the perspective of general practitioners (GPs). The aim of this paper is to explore qualitatively, GP perspectives regarding prescribing and PIP in older primary care patients. METHOD: Semi-structured qualitative interviews were conducted with GPs participating in a randomised controlled trial (RCT) of an intervention to decrease PIP in older patients (≥70 years) in Ireland. Interviews were conducted with GP participants (both intervention and control) from the OPTI-SCRIPT cluster RCT as part of the trial process evaluation between January and July 2013. Interviews were conducted by one interviewer and audio recorded. Interviews were transcribed verbatim and a thematic analysis was conducted. RESULTS: Seventeen semi-structured interviews were conducted (13 male; 4 female). Three main, inter-related themes emerged (complex prescribing environment, paternalistic doctor-patient relationship, and relevance of PIP concept). Patient complexity (e.g. polypharmacy, multimorbidity), as well as prescriber complexity (e.g. multiple prescribers, poor communication, restricted autonomy) were all identified as factors contributing to a complex prescribing environment where PIP could occur, as was a paternalistic-doctor patient relationship. The concept of PIP was perceived to be of variable usefulness to GPs and the criteria to measure it may be at odds with the complex processes of prescribing for this patient population. CONCLUSIONS: Several inter-related factors contributing to the occurrence of PIP were identified, some of which may be amenable to intervention. Improvement strategies focused on improved management of polypharmacy and multimorbidity, and communication across primary and secondary care could result in substantial improvements in PIP. TRIAL REGISTRATION: Current controlled trials ISRCTN4169400

A process evaluation of a cluster randomised trial to reduce potentially inappropriate prescribing in older people in primary care (OPTI-SCRIPT study)

BACKGROUND: The OPTI-SCRIPT cluster randomised controlled trial (RCT) found that a three-phase multifaceted intervention including academic detailing with a pharmacist, GP-led medicines reviews, supported by web-based pharmaceutical treatment algorithms, and tailored patient information leaflets, was effective in reducing potentially inappropriate prescribing (PIP) in Irish primary care. We report a process evaluation exploring the implementation of the intervention, the experiences of those participating in the study and lessons for future implementation. METHODS: The OPTI-SCRIPT trial included 21 GP practices and 196 patients. The process evaluation used mixed methods. Quantitative data were collected from all GP practices and semi-structured interviews were conducted with GPs from intervention and control groups, and a purposive sample of patients from the intervention group. All interviews were transcribed verbatim and analysed using a thematic analysis. RESULTS: Despite receiving a standardised academic detailing session, intervention delivery varied among GP practices. Just over 70 % of practices completed medicines review as recommended with the patient present. Only single-handed practices conducted reviews without patients present, highlighting the influence of practice characteristics and resources on variation. Medications were more likely to be completely stopped or switched to another more appropriate medication when reviews were conducted with patients present. The patient information leaflets were not used by any of the intervention practices. Both GP (32 %) and patient (40 %) recruitment rates were modest. For those who did participate, overall, the experience was positively viewed, with GPs and patients referring to the value of medication reviews to improve prescribing and reduce unnecessary medications. Lack of time in busy GP practices and remuneration were identified as organisational barriers to future implementation. CONCLUSIONS: The OPTI-SCRIPT intervention was positively viewed by both GPs and patients, both of whom valued the study’s objectives. Patient information leaflets were not a successful component of the intervention. Academic detailing and medication reviews are important components in changing PIP, and having patients present during the review process seems to be a more effective approach for decreasing PIP. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007. Registered on 21 March 2012

Beliefs about prescribed medication among older patients with polypharmacy: a mixed methods study in primary care

Background: Polypharmacy (≥5 medications) is common in older patients and is associated with adverse outcomes. Patients’ beliefs about medication can influence their expectations for medication, adherence, and willingness to deprescribe. Few studies have examined beliefs about prescribed medication among older patients with polypharmacy in primary care.Aim: To explore medication-related beliefs in older patients with polypharmacy and factors that might influence beliefs.Design and setting: A mixed methods study utilising data from a randomised controlled trial aiming to decrease potentially inappropriate prescribing in older patients (≥70 years) in Ireland.Method: Beliefs were assessed quantitatively and qualitatively. Participants completed the Beliefs about Medicines Questionnaire by indicating their degree of agreement with individual statements about medicines on a 5-point Likert scale. Semi-structured qualitative interviews were conducted with a purposive sample of participants. Interviews were transcribed verbatim and a thematic analysis conducted. Quantitative and qualitative data were analysed separately and triangulated during the interpretation stage.Results: In total, 196 patients were included (mean age 76.7 years, SD 4.9, 54% male), with a mean of 9.5 (SD 4.1) medications per patient. The majority (96.3%) believed strongly in the necessity of their medication, while 33.9% reported strong concerns. Qualitative data confirmed these coexisting positive and negative attitudes to medications and suggested the importance of patients’ trust in GPs in establishing positive beliefs and potential willingness to deprescribe.Conclusion: Participants reported strong beliefs in medications with coexisting positive and negative attitudes. The doctor–patient relationship may have influenced beliefs and attitudes towards medicines, highlighting the importance of strong doctor–patient relationships, which need to be considered in the context of deprescribin

Sustained effectiveness of a multifaceted intervention to reduce potentially inappropriate prescribing in older patients in primary care (OPTI-SCRIPT study)

BACKGROUND: Potentially inappropriate prescribing (PIP) is common in older people in primary care and can result in increased morbidity, adverse drug events and hospitalisations. We previously demonstrated the success of a multifaceted intervention in decreasing PIP in primary care in a cluster randomised controlled trial (RCT). OBJECTIVE: We sought to determine whether the improvement in PIP in the short term was sustained at 1-year follow-up. METHODS: A cluster RCT was conducted with 21 GP practices and 196 patients (aged ≥70) with PIP in Irish primary care. Intervention participants received a complex multifaceted intervention incorporating academic detailing, medicine review with web-based pharmaceutical treatment algorithms that provide recommended alternative treatment options, and tailored patient information leaflets. Control practices delivered usual care and received simple, patient-level PIP feedback. Primary outcomes were the proportion of patients with PIP and the mean number of potentially inappropriate prescriptions at 1-year follow-up. Intention-to-treat analysis using random effects regression was used. RESULTS: All 21 GP practices and 186 (95 %) patients were followed up. We found that at 1-year follow-up, the significant reduction in the odds of PIP exposure achieved during the intervention was sustained after its discontinuation (adjusted OR 0.28, 95 % CI 0.11 to 0.76, P = 0.01). Intervention participants had significantly lower odds of having a potentially inappropriate proton pump inhibitor compared to controls (adjusted OR 0.40, 95 % CI 0.17 to 0.94, P = 0.04). CONCLUSION: The significant reduction in the odds of PIP achieved during the intervention was sustained after its discontinuation. These results indicate that improvements in prescribing quality can be maintained over time. TRIAL REGISTRATION: Current controlled trials ISRCTN41694007

‘Potentially inappropriate or specifically appropriate?’ Qualitative evaluation of general practitioners views on prescribing, polypharmacy and potentially inappropriate prescribing in older people

Background: Potentially inappropriate prescribing (PIP) is common in older people in primary care, as evidenced by a significant body of quantitative research. However, relatively few qualitative studies have investigated the phenomenon of PIP and its underlying processes from the perspective of general practitioners (GPs). The aim of this paper is to explore qualitatively, GP perspectives regarding prescribing and PIP in older primary care patients. Method: Semi-structured qualitative interviews were conducted with GPs participating in a randomised controlled trial (RCT) of an intervention to decrease PIP in older patients (≥70 years) in Ireland. Interviews were conducted with GP participants (both intervention and control) from the OPTI-SCRIPT cluster RCT as part of the trial process evaluation between January and July 2013. Interviews were conducted by one interviewer and audio recorded. Interviews were transcribed verbatim and a thematic analysis was conducted. Results: Seventeen semi-structured interviews were conducted (13 male; 4 female). Three main, inter-related themes emerged (complex prescribing environment, paternalistic doctor-patient relationship, and relevance of PIP concept). Patient complexity (e.g. polypharmacy, multimorbidity), as well as prescriber complexity (e.g. multiple prescribers, poor communication, restricted autonomy) were all identified as factors contributing to a complex prescribing environment where PIP could occur, as was a paternalistic-doctor patient relationship. The concept of PIP was perceived to be of variable usefulness to GPs and the criteria to measure it may be at odds with the complex processes of prescribing for this patient population. Conclusions: Several inter-related factors contributing to the occurrence of PIP were identified, some of which may be amenable to intervention. Improvement strategies focused on improved management of polypharmacy and multimorbidity, and communication across primary and secondary care could result in substantial improvements in PIP. Trial registration: Current controlled trials ISRCTN4169400

Interventions to improve the appropriate use of polypharmacy in older people: a Cochrane systematic review

OBJECTIVE: To summarise the findings of an updated Cochrane review of interventions aimed at improving the appropriate use of polypharmacy in older people. DESIGN: Cochrane systematic review. Multiple electronic databases were searched including MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (from inception to November 2013). Hand searching of references was also performed. Randomised controlled trials (RCTs), controlled clinical trials, controlled before-and-after studies and interrupted time series analyses reporting on interventions targeting appropriate polypharmacy in older people in any healthcare setting were included if they used a validated measure of prescribing appropriateness. Evidence quality was assessed using the Cochrane risk of bias tool and GRADE (Grades of Recommendation, Assessment, Development and Evaluation). SETTING: All healthcare settings. PARTICIPANTS: Older people (≥65 years) with ≥1 long-term condition who were receiving polypharmacy (≥4 regular medicines). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcomes were the change in prevalence of appropriate polypharmacy and hospital admissions. Medication-related problems (eg, adverse drug reactions), medication adherence and quality of life were included as secondary outcomes. RESULTS: 12 studies were included: 8 RCTs, 2 cluster RCTs and 2 controlled before-and-after studies. 1 study involved computerised decision support and 11 comprised pharmaceutical care approaches across various settings. Appropriateness was measured using validated tools, including the Medication Appropriateness Index, Beers’ criteria and Screening Tool of Older Person's Prescriptions (STOPP)/ Screening Tool to Alert doctors to Right Treatment (START). The interventions demonstrated a reduction in inappropriate prescribing. Evidence of effect on hospital admissions and medication-related problems was conflicting. No differences in health-related quality of life were reported. CONCLUSIONS: The included interventions demonstrated improvements in appropriate polypharmacy based on reductions in inappropriate prescribing. However, it remains unclear if interventions resulted in clinically significant improvements (eg, in terms of hospital admissions). Future intervention studies would benefit from available guidance on intervention development, evaluation and reporting to facilitate replication in clinical practice

PIPc study: development of indicators of potentially inappropriate prescribing in children (PIPc) in primary care using a modified Delphi technique

OBJECTIVE: There is limited evidence regarding the quality of prescribing for children in primary care. Several prescribing criteria (indicators) have been developed to assess the appropriateness of prescribing in older and middle-aged adults but few are relevant to children. The objective of this study was to develop a set of prescribing indicators that can be applied to prescribing or dispensing data sets to determine the prevalence of potentially inappropriate prescribing in children (PIPc) in primary care settings. DESIGN: Two-round modified Delphi consensus method. SETTING: Irish and UK general practice. PARTICIPANTS: A project steering group consisting of academic and clinical general practitioners (GPs) and pharmacists was formed to develop a list of indicators from literature review and clinical expertise. 15 experts consisting of GPs, pharmacists and paediatricians from the Republic of Ireland and the UK formed the Delphi panel. RESULTS: 47 indicators were reviewed by the project steering group and 16 were presented to the Delphi panel. In the first round of this exercise, consensus was achieved on nine of these indicators. Of the remaining seven indicators, two were removed following review of expert panel comments and discussion of the project steering group. The second round of the Delphi process focused on the remaining five indicators, which were amended based on first round feedback. Three indicators were accepted following the second round of the Delphi process and the remaining two indicators were removed. The final list consisted of 12 indicators categorised by respiratory system (n=6), gastrointestinal system (n=2), neurological system (n=2) and dermatological system (n=2). CONCLUSIONS: The PIPc indicators are a set of prescribing criteria developed for use in children in primary care in the absence of clinical information. The utility of these criteria will be tested in further studies using prescribing databases

C9ORF72 hexanucleotide repeat exerts toxicity in a stable, inducible motor neuronal cell model, which is rescued by partial depletion of Pten.

Amyotrophic lateral sclerosis (ALS) is a devastating and incurable neurodegenerative disease, characterised by progressive failure of the neuromuscular system. A (G4C2)n repeat expansion in C9ORF72 is the most common genetic cause of ALS and frontotemporal dementia (FTD). To date, the balance of evidence indicates that the (G4C2)n repeat causes toxicity and neurodegeneration via a gain-of-toxic function mechanism; either through direct RNA toxicity or through the production of toxic aggregating dipeptide repeat proteins. Here, we have generated a stable and isogenic motor neuronal NSC34 cell model with inducible expression of a (G4C2)102 repeat, to investigate the gain-of-toxic function mechanisms. The expression of the (G4C2)102 repeat produces RNA foci and also undergoes RAN translation. In addition, the expression of the (G4C2)102 repeat shows cellular toxicity. Through comparison of transcriptomic data from the cellular model with laser-captured spinal motor neurons from C9ORF72-ALS cases, we also demonstrate that the PI3K/Akt cell survival signalling pathway is dysregulated in both systems. Furthermore, partial knockdown of Pten rescues the toxicity observed in the NSC34 (G4C2)102 cellular gain-of-toxic function model of C9ORF72-ALS. Our data indicate that PTEN may provide a potential therapeutic target to ameliorate toxic effects of the (G4C2)n repeat