Twinkle-Associated Mitochondrial DNA Depletion.

BACKGROUND: Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy. METHODS: We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed. RESULTS: Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years. CONCLUSIONS: In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered

Drivers of overall satisfaction with primary care: Evidence from the English General Practice Patient Survey

This is the final version. Available from Wiley via the DOI in this record.Background/objectives: To determine which aspects of primary care matter most to patients, we aim to identify those aspects of patient experience that show the strongest relationship with overall satisfaction and examine the extent to which these relationships vary by socio-demographic and health characteristics. Design/setting: Data from the 2009/10 English General Practice Patient Survey including 2 169 718 respondents registered with 8362 primary care practices. Measures/analyses: Linear mixed-effects regression models (fixed effects adjusting for age, gender, ethnicity, deprivation, self-reported health, self-reported mental health condition and random practice effect) predicting overall satisfaction from six items covering four domains of care: access, helpfulness of receptionists, doctor communication and nurse communication. Additional models using interactions tested whether associations between patient experience and satisfaction varied by socio-demographic group. Results: Doctor communication showed the strongest relationship with overall satisfaction (standardized coefficient 0.48, 95% CI = 0.48, 0.48), followed by the helpfulness of reception staff (standardized coefficient 0.22, 95% CI = 0.22, 0.22). Among six measures of patient experience, obtaining appointments in advance showed the weakest relationship with overall satisfaction (standardized coefficient 0.06, 95% CI = 0.05, 0.06). Interactions showed statistically significant but small variation in the importance of drivers across different patient groups. Conclusions: For all patient groups, communication with the doctor is the most important driver of overall satisfaction with primary care in England, along with the helpfulness of receptionists. In contrast, and despite being a policy priority for government, measures of access, including the ability to obtain appointments, were poorly related to overall satisfaction.UK Department of HealthNational Institute for Health Research (NIHR

Idiosyncratic responding during movie-watching predicted by age differences in attentional control.

Much is known about how age affects the brain during tightly controlled, though largely contrived, experiments, but do these effects extrapolate to everyday life? Naturalistic stimuli, such as movies, closely mimic the real world and provide a window onto the brain's ability to respond in a timely and measured fashion to complex, everyday events. Young adults respond to these stimuli in a highly synchronized fashion, but it remains to be seen how age affects neural responsiveness during naturalistic viewing. To this end, we scanned a large (N = 218), population-based sample from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) during movie-watching. Intersubject synchronization declined with age, such that older adults' response to the movie was more idiosyncratic. This decreased synchrony related to cognitive measures sensitive to attentional control. Our findings suggest that neural responsivity changes with age, which likely has important implications for real-world event comprehension and memory.This work and the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) are supported by the Biotechnology and Biological Sciences Research Council (grant number BB/H008217/1).This is the final version of the article. It first appeared from Elsevier via http://dx.doi.org/10.1016/j.neurobiolaging.2015.07.02

Age-related delay in visual and auditory evoked responses is mediated by white- and grey-matter differences

Slowing is a common feature of ageing, yet a direct relationship between neural slowing and brain atrophy is yet to be established in healthy humans. We combine magnetoencephalo-graphic (MEG) measures of neural processing speed with magnetic resonance imaging (MRI) measures of white and grey matter in a large population-derived cohort to investigate the relationship between age-related structural differences and visual evoked field (VEF) and auditory evoked field (AEF) delay across two different tasks. Here we use a novel technique to show that VEFs exhibit a constant delay, whereas AEFs exhibit delay that accumulates over time. White-matter (WM) microstructure in the optic radiation partially mediates visual delay, suggesting increased transmission time, whereas grey matter (GM) in auditory cortex partially mediates auditory delay, suggesting less efficient local processing. Our results demonstrate that age has dissociable effects on neural processing speed, and that these effects relate to different types of brain atrophy.Peer reviewe

Effect of dose and duration of reduction in dietary sodium on blood pressure levels: systematic review and meta-analysis of randomised trials.

OBJECTIVE: To examine the dose-response relation between reduction in dietary sodium and blood pressure change and to explore the impact of intervention duration. DESIGN: Systematic review and meta-analysis following PRISMA guidelines. DATA SOURCES: Ovid MEDLINE(R), EMBASE, and Cochrane Central Register of Controlled Trials (Wiley) and reference lists of relevant articles up to 21 January 2019. INCLUSION CRITERIA: Randomised trials comparing different levels of sodium intake undertaken among adult populations with estimates of intake made using 24 hour urinary sodium excretion. DATA EXTRACTION AND ANALYSIS: Two of three reviewers screened the records independently for eligibility. One reviewer extracted all data and the other two reviewed the data for accuracy. Reviewers performed random effects meta-analyses, subgroup analyses, and meta-regression. RESULTS: 133 studies with 12 197 participants were included. The mean reductions (reduced sodium v usual sodium) of 24 hour urinary sodium, systolic blood pressure (SBP), and diastolic blood pressure (DBP) were 130 mmol (95% confidence interval 115 to 145, P<0.001), 4.26 mm Hg (3.62 to 4.89, P<0.001), and 2.07 mm Hg (1.67 to 2.48, P<0.001), respectively. Each 50 mmol reduction in 24 hour sodium excretion was associated with a 1.10 mm Hg (0.66 to 1.54; P<0.001) reduction in SBP and a 0.33 mm Hg (0.04 to 0.63; P=0.03) reduction in DBP. Reductions in blood pressure were observed in diverse population subsets examined, including hypertensive and non-hypertensive individuals. For the same reduction in 24 hour urinary sodium there was greater SBP reduction in older people, non-white populations, and those with higher baseline SBP levels. In trials of less than 15 days' duration, each 50 mmol reduction in 24 hour urinary sodium excretion was associated with a 1.05 mm Hg (0.40 to 1.70; P=0.002) SBP fall, less than half the effect observed in studies of longer duration (2.13 mm Hg; 0.85 to 3.40; P=0.002). Otherwise, there was no association between trial duration and SBP reduction. CONCLUSIONS: The magnitude of blood pressure lowering achieved with sodium reduction showed a dose-response relation and was greater for older populations, non-white populations, and those with higher blood pressure. Short term studies underestimate the effect of sodium reduction on blood pressure. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019140812

Optimisation of complex health interventions prior to a randomised controlled trial: a scoping review of strategies used.

Background Many complex intervention trials fail to show an intervention effect. Although this may be due to genuine ineffectiveness, it may also be the result of sub-optimal intervention design, implementation failure or a combination of these. Given current financial constraints and the pressure to reduce waste and increase value in health services research, pre-trial strategies are needed to reduce the likelihood of design or implementation failure and to maximise the intervention’s potential for effectiveness. In this scoping review, we aimed to identify and synthesise the available evidence relating to the strategies and methods used to ‘optimise’ complex interventions at the pre-trial stage. Methods We searched MEDLINE, CINAHL, AMED, PsycINFO and ProQuest Nursing & Allied Health Source for papers published between January 2000 and March 2015. We included intervention development and optimisation studies that explored potential intervention weaknesses and limitations before moving to a definitive randomised controlled trial (RCT). Two reviewers independently applied selection criteria and systematically extracted information relating to the following: study characteristics; intervention under development; framework used to guide the development process; areas of focus of the optimisation process, methods used and outcomes of the optimisation process. Data were tabulated and summarised in a narrative format. Results We screened 3968 titles and 231 abstracts for eligibility. Eighty-nine full-text papers were retrieved; 27 studies met our selection criteria. Optimisation strategies were used for a range of reasons: to explore the feasibility and acceptability of the intervention to patients and healthcare professionals; to estimate the effectiveness and cost-effectiveness of different combinations of intervention components; and to identify potential barriers to implementation. Methods varied widely across studies, from interviews and focus groups to economic modelling and probability analysis. Conclusions The review identifies a range of optimisation strategies currently used. Although a preliminary classification of these strategies can be proposed, a series of questions remain as to which methods to use for different interventions and how to determine when the intervention is ready or ‘optimised enough’ to be tested in a RCT. Future research should explore potential answers to the questions raised, to guide researchers in the development and evaluation of more effective interventions

Tools to overcome potential barriers to chlamydia screening in general practice: Qualitative evaluation of the implementation of a complex intervention

Background: Chlamydia trachomatis remains a significant public health problem. We used a complex intervention, with general practice staff, consisting of practice based workshops, posters, computer prompts and testing feedback and feedback to increase routine chlamydia screening tests in under 25 year olds in South West England. We aimed to evaluate how intervention components were received by staff and to understand what determined their implementation into ongoing practice. Methods: We used face-to-face and telephone individual interviews with 29 general practice staff analysed thematically within a Normalisation Process Theory Framework which explores: 1. Coherence (if participants understand the purpose of the intervention); 2. Cognitive participation (engagement with and implementation of the intervention); 3. Collective action (work actually undertaken that drives the intervention forwards); 4. Reflexive monitoring (assessment of the impact of the intervention). Results: Our results showed coherence as all staff including receptionists understood the purpose of the training was to make them aware of the value of chlamydia screening tests and how to increase this in their general practice. The training was described by nearly all staff as being of high quality and responsible for creating a shared understanding between staff of how to undertake routine chlamydia screening. Cognitive participation in many general practice staff teams was demonstrated through their engagement by meeting after the training to discuss implementation, which confirmed the role of each staff member and the use of materials. However several participants still felt unable to discuss chlamydia in many consultations or described sexual health as low priority among colleagues. National targets were considered so high for some general practice staff that they didn’t engage with the screening intervention. Collective action work undertaken to drive the intervention included use of computer prompts which helped staff remember to make the offer, testing rate feedback and having a designated lead. Ensuring patients collected samples when still in the general practice was not attained in most general practices. Reflexive monitoring showed positive feedback from patients and other staff about the value of screening, and feedback about the general practices testing rates helped sustain activity. Conclusions: A complex intervention including interactive workshops, materials to help implementation and feedback can help chlamydia screening testing increase in general practices

Multiple determinants of lifespan memory differences

Memory problems are among the most common complaints as people grow older. Using structural equation modeling of commensurate scores of anterograde memory from a large (N = 315), population-derived sample (www.cam-can.org), we provide evidence for three memory factors that are supported by distinct brain regions and show differential sensitivity to age. Associative memory and item memory are dramatically affected by age, even after adjusting for education level and fluid intelligence, whereas visual priming is not. Associative memory and item memory are differentially affected by emotional valence, and the age-related decline in associative memory is faster for negative than for positive or neutral stimuli. Gray-matter volume in the hippocampus, parahippocampus and fusiform cortex, and a white-matter index for the fornix, uncinate fasciculus and inferior longitudinal fasciculus, show differential contributions to the three memory factors. Together, these data demonstrate the extent to which differential ageing of the brain leads to differential patterns of memory loss.The Cambridge Centre for Ageing and Neuroscience (Cam-CAN) research was supported by the Biotechnology and Biological Sciences Research Council (BB/H008217/1); R.N.H., S.E. and T.E. are additionally supported by the UK Medical Research Council (MC_A060_5PR10). RAK is supported by the Wellcome Trust (grant number 107392/Z/15/Z and the UK Medical Research Council (MC-A060-5PR61). We are grateful to the Cam-CAN respondents and their primary care teams in Cambridge for their participation in this study. We also thank colleagues at the MRC Cognition and Brain Sciences Unit MEG and MRI facilities for their assistance

Physical Activity Predicts Population-Level Age-Related Differences in Frontal White Matter.

Physical activity has positive effects on brain health and cognitive function throughout the life span. Thus far, few studies have examined the effects of physical activity on white matter microstructure and psychomotor speed within the same, population-based sample (critical if conclusions are to extend to the wider population). Here, using diffusion tensor imaging and a simple reaction time task within a relatively large population-derived sample (N = 399; 18-87 years) from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN), we demonstrate that physical activity mediates the effect of age on white matter integrity, measured with fractional anisotropy. Higher self-reported daily physical activity was associated with greater preservation of white matter in several frontal tracts, including the genu of corpus callosum, uncinate fasciculus, external capsule, and anterior limb of the internal capsule. We also show that the age-related slowing is mediated by white matter integrity in the genu. Our findings contribute to a growing body of work, suggesting that a physically active lifestyle may protect against age-related structural disconnection and slowing