Organisational and neuromodulatory underpinnings of structural-functional connectivity decoupling in patients with Parkinson's disease

Parkinson's dementia is characterised by changes in perception and thought, and preceded by visual dysfunction, making this a useful surrogate for dementia risk. Structural and functional connectivity changes are seen in humans with Parkinson's disease, but the organisational principles are not known. We used resting-state fMRI and diffusion-weighted imaging to examine changes in structural-functional connectivity coupling in patients with Parkinson's disease, and those at risk of dementia. We identified two organisational gradients to structural-functional connectivity decoupling: anterior-to-posterior and unimodal-to-transmodal, with stronger structural-functional connectivity coupling in anterior, unimodal areas and weakened towards posterior, transmodal regions. Next, we related spatial patterns of decoupling to expression of neurotransmitter receptors. We found that dopaminergic and serotonergic transmission relates to decoupling in Parkinson's overall, but instead, serotonergic, cholinergic and noradrenergic transmission relates to decoupling in patients with visual dysfunction. Our findings provide a framework to explain the specific disorders of consciousness in Parkinson's dementia, and the neurotransmitter systems that underlie these

Exercise-based rehabilitation for heart failure (review)

Meta-AnalysisReviewThis is the final version of the article. Available from the Cochrane Collaboration via the DOI in this record.BACKGROUND: Previous systematic reviews and meta-analyses consistently show the positive effect of exercise-based rehabilitation for heart failure (HF) on exercise capacity; however, the direction and magnitude of effects on health-related quality of life, mortality and hospital admissions in HF remain less certain. This is an update of a Cochrane systematic review previously published in 2010. OBJECTIVES: To determine the effectiveness of exercise-based rehabilitation on the mortality, hospitalisation admissions, morbidity and health-related quality of life for people with HF. Review inclusion criteria were extended to consider not only HF due to reduced ejection fraction (HFREF or 'systolic HF') but also HF due to preserved ejection fraction (HFPEF or 'diastolic HF'). SEARCH METHODS: We updated searches from the previous Cochrane review. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue1, 2013) from January 2008 to January 2013. We also searched MEDLINE (Ovid), EMBASE (Ovid), CINAHL (EBSCO) and PsycINFO (Ovid) (January 2008 to January 2013). We handsearched Web of Science, bibliographies of systematic reviews and trial registers (Controlled-trials.com and Clinicaltrials.gov). SELECTION CRITERIA: Randomised controlled trials of exercise-based interventions with six months' follow-up or longer compared with a no exercise control that could include usual medical care. The study population comprised adults over 18 years and were broadened to include individuals with HFPEF in addition to HFREF. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references and rejected those that were clearly ineligible. We obtained full-text papers of potentially relevant trials. One review author independently extracted data from the included trials and assessed their risk of bias; a second review author checked data. MAIN RESULTS: We included 33 trials with 4740 people with HF predominantly with HFREF and New York Heart Association classes II and III. This latest update identified a further 14 trials. The overall risk of bias of included trials was moderate. There was no difference in pooled mortality between exercise-based rehabilitation versus no exercise control in trials with up to one-year follow-up (25 trials, 1871 participants: risk ratio (RR) 0.93; 95% confidence interval (CI) 0.69 to 1.27, fixed-effect analysis). However, there was trend towards a reduction in mortality with exercise in trials with more than one year of follow-up (6 trials, 2845 participants: RR 0.88; 95% CI 0.75 to 1.02, fixed-effect analysis). Compared with control, exercise training reduced the rate of overall (15 trials, 1328 participants: RR 0.75; 95% CI 0.62 to 0.92, fixed-effect analysis) and HF specific hospitalisation (12 trials, 1036 participants: RR 0.61; 95% CI 0.46 to 0.80, fixed-effect analysis). Exercise also resulted in a clinically important improvement superior in the Minnesota Living with Heart Failure questionnaire (13 trials, 1270 participants: mean difference: -5.8 points; 95% CI -9.2 to -2.4, random-effects analysis) - a disease specific health-related quality of life measure. However, levels of statistical heterogeneity across studies in this outcome were substantial. Univariate meta-regression analysis showed that these benefits were independent of the participant's age, gender, degree of left ventricular dysfunction, type of cardiac rehabilitation (exercise only vs. comprehensive rehabilitation), mean dose of exercise intervention, length of follow-up, overall risk of bias and trial publication date. Within these included studies, a small body of evidence supported exercise-based rehabilitation for HFPEF (three trials, undefined participant number) and when exclusively delivered in a home-based setting (5 trials, 521 participants). One study reported an additional mean healthcare cost in the training group compared with control of USD3227/person. Two studies indicated exercise-based rehabilitation to be a potentially cost-effective use of resources in terms of gain in quality-adjusted life years (QALYs) and life-years saved. AUTHORS' CONCLUSIONS: This updated Cochrane review supports the conclusions of the previous version of this review that, compared with no exercise control, exercise-based rehabilitation does not increase or decrease the risk of all-cause mortality in the short term (up to 12-months' follow-up) but reduces the risk of hospital admissions and confers important improvements in health-related quality of life. This update provides further evidence that exercise training may reduce mortality in the longer term and that the benefits of exercise training on appear to be consistent across participant characteristics including age, gender and HF severity. Further randomised controlled trials are needed to confirm the small body of evidence seen in this review for the benefit of exercise in HFPEF and when exercise rehabilitation is exclusively delivered in a home-based setting

Exercise-based rehabilitation for heart failure: systematic review and meta-analysis

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.OBJECTIVE: To update the Cochrane systematic review of exercise-based cardiac rehabilitation (CR) for heart failure. METHODS: A systematic review and meta-analysis of randomised controlled trials was undertaken. MEDLINE, EMBASE and the Cochrane Library were searched up to January 2013. Trials with 6 or more months of follow-up were included if they assessed the effects of exercise interventions alone or as a component of comprehensive CR programme compared with no exercise control. RESULTS: 33 trials were included with 4740 participants predominantly with a reduced ejection fraction (<40%) and New York Heart Association class II and III. Compared with controls, while there was no difference in pooled all-cause mortality between exercise CR with follow-up to 1 year (risk ratio (RR) 0.93; 95% CI 0.69 to 1.27, p=0.67), there was a trend towards a reduction in trials with follow-up beyond 1 year (RR 0.88; 0.75 to 1.02, 0.09). Exercise CR reduced the risk of overall (RR 0.75; 0.62 to 0.92, 0.005) and heart failure-specific hospitalisation (RR 0.61; 0.46 to 0.80, 0.0004) and resulted in a clinically important improvement in the Minnesota Living with Heart Failure questionnaire (mean difference: -5.8 points, -9.2 to -2.4, 0.0007). Univariate meta-regression analysis showed that these benefits were independent of the type and dose of exercise CR, and trial duration of follow- up, quality or publication date. CONCLUSIONS: This updated Cochrane review shows that improvements in hospitalisation and health-related quality of life with exercise-based CR appear to be consistent across patients regardless of CR programme characteristics and may reduce mortality in the longer term. An individual participant data meta-analysis is needed to provide confirmatory evidence of the importance of patient subgroup and programme level characteristics (eg, exercise dose) on outcome.This publication presents independent research funded by the National Institute for Health Research (NIHR) under its Programme Grants for Applied Research Programme (Grant Reference Number RP-PG-1210-12004)

Occupational choice, number of entrepreneurs and output: theory and empirical evidence with Spanish data

This paper extends the (Lucas, Bell J Econ 9:508–523,1978) model of occupational choices by individuals with different skills, beyond the simple options of self-employment or wage-employment, by including a second choice for the self-employed. That is, an option to hire employees and so become self-employed with employees (SEWEs), or to be self-employed without employees (SEWNEs). We solve for the market equilibrium and examine the sensitivity of relative sizes of occupational groups, and of the level of productivity, to changes in the exogenous parameters. The results show that the positive (negative) association between number of SEWEs (SEWNEs) and productivity, observed in the Spanish data, can be explained, under certain conditions, as the result of cross-region and time differences in average skills. These findings point to the importance of distinguishing between SEWEs and SEWNEs in drawing valid conclusions concerning any link between entrepreneurship and economic development

Carbon sequestration in the deep Atlantic enhanced by Saharan dust

sinking rates of particulate organicmatter. Here we present a two-year time series of sediment trap observations of particulate organic carbon flux to 3,000m depth, measured directly in two locations: the dust-rich central North Atlantic gyre and the dust-poor South Atlantic gyre. We find that carbon fluxes are twice as high and a higher proportion of primary production is exported to depth in the dust-rich North Atlantic gyre. Low stable nitrogen isotope ratios suggest that high fluxes result from the stimulation of nitrogen fixation and productivity following the deposition of dust-borne nutrients. Sediment traps in the northern gyre also collected intact colonies of nitrogen-fixing Trichodesmium species. Whereas ballast in Enhanced atmospheric input of dust-borne nutrients and minerals to the remote surface ocean can potentially increase carbon uptake and sequestration at depth. Nutrients can enhance primary productivity, and mineral particles act as ballast, increasing the southern gyre is predominantly biogenic, dust-derived mineral particles constitute the dominant ballast element during the enhanced carbon fluxes in the northern gyre. We conclude that dust deposition increases carbon sequestration in the North Atlantic gyre through the fertilization of the nitrogen-fixing community in surface waters and mineral ballasting of sinking particles

Can neuroimaging predict dementia in Parkinson’s disease?

Dementia in Parkinson’s disease affects 50% of patients within 10 years of diagnosis but there is wide variation in severity and timing. Thus, robust neuroimaging prediction of cognitive involvement in Parkinson’s disease is important: (i) to identify at-risk individuals for clinical trials of potential new treatments; (ii) to provide reliable prognostic information for individuals and populations; and (iii) to shed light on the pathophysiological processes underpinning Parkinson’s disease dementia. To date, neuroimaging has not made major contributions to predicting cognitive involvement in Parkinson’s disease. This is perhaps unsurprising considering conventional methods rely on macroscopic measures of topographically distributed neurodegeneration, a relatively late event in Parkinson’s dementia. However, new technologies are now emerging that could provide important insights through detection of other potentially relevant processes. For example, novel MRI approaches can quantify magnetic susceptibility as a surrogate for tissue iron content, and increasingly powerful mathematical approaches can characterize the topology of brain networks at the systems level. Here, we present an up-to-date overview of the growing role of neuroimaging in predicting dementia in Parkinson’s disease. We discuss the most relevant findings to date, and consider the potential of emerging technologies to detect the earliest signs of cognitive involvement in Parkinson’s disease

How long does a shoulder replacement last? A systematic review and meta-analysis of case series and national registry reports with more than 10 years of follow-up

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordBackground: Shoulder replacement is an increasingly common treatment for end-stage degenerative shoulder conditions. Some shoulder replacements are unsuccessful and additional operations might be required. It is important for patients and clinicians to know how long shoulder replacements last and how effectively they reduce pain and improve function. This study aims to determine the longevity and long-term efficacy of shoulder replacements. Methods: In this systematic review and meta-analysis, we searched MEDLINE and Embase from their inception to Sept 24, 2019, for case series and registry data reporting 10-year or longer survival of total shoulder replacements, humeral hemiarthroplasties, and reverse total shoulder replacements of a specific brand of implant. Survival, implant, and patient-reported outcome measures data were extracted. The primary outcome was implant survival. We reviewed and analysed national joint replacement registries separately. We weighted each series by SE and calculated a pooled survival estimate at years 10, 15, and 20. For patient-reported outcome measures we pooled the standardised mean difference at 10 years. This study is registered with PROSPERO, CRD42019140221. Findings: 927 non-duplicate articles were identified by our search, nine articles (reporting ten series) were eligible for analysis of survival and six articles were eligible for analysis of patient reported outcomes. The ten series reported all-cause survival of 529 total shoulder replacements and 364 humeral hemiarthroplasties; no series for reverse total shoulder replacement met the inclusion criteria. The estimated 10-year survival for total shoulder replacement was 94·6% (95% CI 93·6–97·6) and humeral hemiarthroplasties was 90·4% (87·0–94·0). A single registry contributed 7651 total shoulder replacements, 1395 humeral hemiarthroplasties, and 7953 reverse total shoulder replacements. The pooled registry 10-year survival was 92·0% (95% CI 91·0–93·0) for total shoulder replacement, 85·5% (83·3–87·7) for humeral hemiarthroplasties, and 94·4% (93·4–95·7) for patients with osteoarthritis who had reverse total shoulder replacement and 93·6% (91·1–95·8) for patients with rotator cuff arthropathy who had reverse total shoulder replacement. Pooled 10-year patient-reported outcome measures showed a substantial improvement from baseline scores, with a standardised mean difference of 2·13 (95% CI 1·93–2·34). Interpretation: Our data show that approximately 90% of shoulder replacements last for longer than 10 years and patient-reported benefits are sustained. Our findings will be of use to surgeons and patients in the informed consent process and to health-care providers for resource planning. Funding: The National Institute for Health Research, the National Joint Registry for England, Wales, Northern Ireland, and Isle of Man, and the Royal College of Surgeons of England.National Institute for Health Research (NIHR)National Joint Registry for England, Wales, Northern Ireland, and Isle of ManRoyal College of Surgeons of Englan

Using primary care-based paper and telephone interventions to increase uptake of bowel scope screening in Yorkshire: a protocol of a randomised controlled trial

INTRODUCTION: Evidence suggests bowel scope screening (BSS) can significantly reduce an individual's risk of developing colorectal cancer (CRC). BSS for 55 year olds was therefore introduced to the English Bowel Cancer Screening Programme (BCSP) in 2013. However, the benefits are only gained from test completion and uptake is low (43%). Primary care involvement has consistently shown benefits to cancer screening uptake and so this study aims to build on this knowledge and evaluate general practitioner (GP) practice led interventions designed to increase BSS attendance. METHODS AND ANALYSIS: A three-arm randomised controlled trial will be conducted to evaluate three interventions: one intervention for prospective BSS invitees (primer letter with locally tailored leaflet sent by an individual's GP practice) and two interventions for those who do not attend their BSS appointment (a self-referral letter sent by an individual's GP practice and a patient navigation call made on behalf of an individual's GP practice). The trial will be set in Yorkshire. Individuals soon to receive their invitation to attend BSS at one of the Hull and East Yorkshire Bowel Cancer Screening centre sites, will be randomly assigned to one of three groups: control (usual care; no input from GP practice), Intervention group A (primer letter/leaflet and a self-referral letter), Intervention group B (primer letter/leaflet and a patient navigation call). Attendance data will be obtained from the BCSP database (via National Health Service (NHS) Digital) 3 months after the last intervention. Regression analysis will compare uptake, and additional clinical outcomes, across the three groups. The analysis will be multivariate and adjust for several covariates including gender and area-level deprivation. ETHICS AND DISSEMINATION: NHS ethical approval has been obtained from London-Harrow Research Ethics Committee. The results will be submitted for publication in a peer-reviewed journal and presented at conferences. TRIAL REGISTRATION NUMBER: ISRCTN16252122; Pre-results

People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames